Receptor interacting protein 1 inhibitors, their preparation and use

Abstract

The present invention provides compounds of formula I, compositions comprising same, and methods of using same, including use in the treatment of various diseases and conditions, including diseases and conditions mediated by receptor interacting protein 1 (RIP1) signaling. TIFF2024512931000306.tif31128

Description

[Technical field]

[0001] The present disclosure relates to compounds that modulate receptor interacting protein 1 (RIP1), compositions comprising the compounds, methods for preparing the compounds, and methods of using the compounds to treat various diseases or conditions, e.g., mediated by RIP1. [Background technology]

[0002] Necroptosis is a key form of programmed cell death (PCD) and is a highly regulated, caspase-independent form of cell death that plays a key role in many necrotic cell diseases manifested in various pathological forms of cell death, including ischemic brain injury, neurodegenerative diseases, viral infections, and peripheral autoimmune diseases (Dunai, et al., Dec 2011, Pathol. Oncol. Res.: POR 17(4):791-800. J. Med. Chem. 2020, 63, 4, 1490-1510. Nature Reviews Drug Discovery, 19, 553-571 (2020)). RIP1 is a multifunctional signaling agent involved in the activation of nuclear factor kappa B (NF-kappa B), apoptosis, and mediating necroptosis. The kinase activity of RIP1 plays a critical role in mediating necroptosis, a caspase-independent pathway of necrotic cell death (J. Med. Chem. 2017, 60, 3, 972-986. Holler et al. Nat Immunol 2000; 1: 489-495; Degterev et al. Nat Chem Biol 2008; 4: 313-321.). RIP1 has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases, such as psoriasis, rheumatoid arthritis, and ulcerative colitis (Pharmacol. Res. Perspect. 2017, 5, e00365, PNAS May 14, 2019 116(20)9714-9722), as well as CNS indications such as ALS and Alzheimer's disease (Nat. Rev. Neurosci. 2019, 20, 19-33). Summary of the Invention

[0003] One aspect of the present disclosure provides a compound selected from the compounds of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, which can be used in the treatment of various diseases or conditions, such as diseases or conditions mediated by receptor interacting protein 1 (RIP1). For example, a compound of the following structural formula I: [ka] [In the formula, X is C or N; When X is N, X1 and X2 are C; When X is C, then X1 and X2 are absent; When X is C then Y is O, or when X is N then Y is absent; X3 is C or N; where the valence of C is hydrogen and / or R 4 Filled with; R a is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or -OH; R b and R c are each independently hydrogen, C1-C4 alkyl, or C1-C4 heteroalkyl; Ar 1 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] but [ka] If Ar 1 cannot be furanyl; When X is C and Y is O, Ar 2 and Ar 3 are each independently phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; If X is N and Y is absent, then [ka] teeth: [ka] and; Where: (i) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, or absent; (ii) [ka] but [ka] If: Ar 1 cannot be furanyl; Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; (iii) [ka] but [ka] If [ka] teeth [ka] and; (iv) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; (v) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; (vi) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; (vii) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; (viii) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; (ix) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; R1 , R 2 , R 3 , and R 4 are each independently for each occurrence halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , and -S(=O) w NR p R q is selected from; R 1 , R 2 , R 3 , and R 4 Any one of C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkoxy, the C1-C6 alkyl of -C(=O)(C1-C6 alkyl), and the C3-C6 cycloalkyl of -C(=O)(C3-C6 cycloalkyl) are each independently selected from halogen, cyano, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR pC(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , and -S(=O) w NR p R q and optionally substituted with 1 to 3 groups selected from; R p , R q , and R r is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl; R p , R q , and R r any one of C1-C4 alkyl is optionally substituted with 1-3 groups selected from halogen, cyano, and -OH; R s is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl; R s any one of C1-C4 alkyl is optionally substituted with 1-3 groups selected from halogen, cyano, and -OH; w is an integer selected from 1 and 2; and m, n, p, and q are each integers independently selected from 0, 1, 2, and 3, or a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0004] In one aspect of the disclosure, the compound of formula I is selected from compounds 1-99 shown below, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0005] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1-99 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing. These compositions may further comprise an additional active pharmaceutical agent.

[0006] Another aspect of the present disclosure provides a method of treating a disease or condition comprising administering to a subject a therapeutically effective amount of a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing, wherein the disease or condition is selected from an inflammatory disease, an immune disease (e.g., an autoimmune disease), an allergic disease, a transplant rejection, a necrotic cell disease, a neurodegenerative disease, a central nervous system (CNS) disease, an ophthalmic disease, an infectious disease, and a malignant tumor. A further aspect of the present disclosure provides a method of treating a disease or condition mediated by RIP1, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0007] In some embodiments, the method of treatment comprises administering to a subject a compound selected from compounds 1-99 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0008] In some embodiments, the method of treatment comprises administering to a subject in need thereof an additional active pharmaceutical agent, either in the same pharmaceutical composition as a compound of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments, the method of treatment comprises administering a compound selected from compounds 1-99 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, together with the additional active pharmaceutical agent, either in the same pharmaceutical composition or in a separate composition.

[0009] Also disclosed herein is a method of mediating, e.g., inhibiting, RIP1, comprising contacting a RIP1 protein or a fragment thereof with a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, a method for inhibiting RIP1 includes contacting a RIP1 protein or a fragment thereof with a compound selected from compounds 1-99 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] I. Definition The terms "a" or "an" when referring to a noun as used herein encompass the phrase "at least one," and thus encompass both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means a single or two or more additional pharmaceutical agents.

[0011] The terms "RIP1", "RIPK1", "receptor interacting protein 1", "receptor interacting protein 1 kinase", and "receptor interacting serine / threonine protein kinase 1" all refer to the enzyme encoded by the RIPK1 gene (also called the RIP1 gene) located in humans on chromosome 6. The protein belongs to the seven-member receptor interacting protein (RIP) kinase family, with RIP1 being the first member of the family. The 671 amino acid and 76 kDa protein contains a serine / threonine kinase domain at the N-terminus of 300 amino acids, a death domain at the C-terminus of 112 amino acids, and a central region between the kinase and death domains called the intermediate domain. As used herein, "fragment", when referring to RIP1, means a peptide fragment containing any one or more of the kinase domain, death domain, and intermediate domain, or 15-100 amino acid residues.

[0012] The term "inhibitor" as used herein refers to an organic chemical small molecule compound (e.g., ≦10 kDa) that has the ability to reduce or inhibit the expression of receptor interacting protein 1 or RIP1 as defined above and / or reduce or inhibit its activity (e.g., by blocking the active site of the protein).

[0013] The term "compound", when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variations between the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains a smaller amount of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amount of such isotopic substitutions in the compounds of the present disclosure will depend on a number of factors, including, for example, the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the overall relative amount of such isotopic substitutions is less than 49.9% of the compound. In other embodiments, the overall relative amount of such isotopic substitutions is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compounds.

[0014] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of hydrogen radicals in a given structure with a specified substituent group. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0015] The term "isotopically enriched" refers to species whose chemical structures differ only in their isotopic composition. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon by C, are within the scope of this disclosure.

[0016] Unless otherwise indicated, the structures depicted herein are also meant to include all isomeric forms of the structures, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds are within the scope of the disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0017] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by the movement of an atom, e.g., a hydrogen atom or group, within the molecule.

[0018] As used herein, "stereoisomer" refers to enantiomers and diastereomers.

[0019] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, except that one or more hydrogen atoms have been replaced with a deuterium atom ("D" or " 2Deuterated derivatives of compounds of formula I refer to compounds in which at least one hydrogen has been substituted with deuterium (H"). Non-limiting examples of deuterated derivatives of compounds of formula I are compounds 60, 61, 73-78, and 97. It should be understood that some variation in natural isotopic abundance occurs in the synthesized compounds depending on the source of the chemicals used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein, despite this variation. Thus, unless otherwise indicated, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been substituted with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium designation), at least 4500 (67.5% deuterium incorporation at each deuterium designation), at least 5000 (75% deuterium incorporation at each deuterium designation), at least 5500 (82.5% deuterium incorporation at each deuterium designation), at least 6000 (90% deuterium incorporation at each deuterium designation), at least 6333.3 (95% deuterium incorporation at each deuterium designation), at least 6466.7 (97% deuterium incorporation at each deuterium designation), or at least 6600 (99% deuterium incorporation at each deuterium designation).

[0020] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0021] The term "alkyl" as used herein means a linear or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise stated, an alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-4 alkyl carbon atoms. In other embodiments, an alkyl group contains 1-3 alkyl carbon atoms. In still other embodiments, an alkyl group contains 1-2 alkyl carbon atoms. In some embodiments, an alkyl group is substituted. In some embodiments, an alkyl group is unsubstituted. In some embodiments, an alkyl group is linear or straight chain or unbranched. In some embodiments, an alkyl group is branched.

[0022] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more of the member carbon atoms is replaced by nitrogen, oxygen, or sulfur, e.g., CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5. In some embodiments, in addition to replacement of one or more of the member carbon atoms by nitrogen, oxygen, or sulfur, a heteroalkyl group is optionally further substituted as defined herein.

[0023] The term "cycloalkyl" refers to a monocyclic hydrocarbon that is fully saturated, e.g., C 3~8 ) or spirocyclic, fused, or bridged bicyclic or tricyclic hydrocarbons (e.g., C 8~14 ), for example, any individual ring in the above bicyclic or tricyclic ring systems has 3 to 7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is a C3-C 12In some embodiments, the cycloalkyl is a C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0024] The term "carbocyclyl" encompasses the term "cycloalkyl" and refers to monocyclic hydrocarbons that are fully saturated or partially saturated by containing one or more units of unsaturation but are not aromatic (e.g., C 3~8 ) or spirocyclic, fused, or bridged bicyclic or tricyclic hydrocarbons (e.g., C 8~14 ), for example, any individual ring in the above bicyclic ring system has 3-7 members. Bicyclic carbocyclyl includes the combination of a monocyclic carbocyclic ring fused to, for example, a phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is a C3-C 12 In some embodiments, the carbocyclyl is a C-C 10 In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl. In some embodiments, the carbocyclyl is a C6 carbocyclyl.

[0025] The term "alkenyl" as used herein means a linear or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is linear, straight-chained, or unbranched. In some embodiments, an alkenyl group is branched.

[0026] The term "heterocyclyl" as used herein means a non-aromatic (i.e., fully saturated or partially saturated, e.g., containing one or more units of unsaturation, but not aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl. In some embodiments, a "heterocyclyl" group contains 3 to 14 ring members in which one or more ring members are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocyclic ring has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocyclic ring has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocyclic ring has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocyclic ring has one heteroatom that is a nitrogen atom. In some embodiments, the heterocyclic ring has one heteroatom that is an oxygen atom. In some embodiments, the heterocyclic ring has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocyclic ring has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocyclic ring is substituted. In some embodiments, the heterocyclic ring is unsubstituted. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-9 membered heterocyclyl, for example a 4-9 membered heterocyclyl containing at least one N atom and optionally at least one O atom.In some embodiments, the heterocyclyl is a 5-10 membered heterocyclyl. In some embodiments, the heterocyclyl is a 5-8 membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, and the like.

[0027] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, and phosphorus, including any oxidized form of nitrogen or sulfur; the quaternized form of any basic or substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).

[0028] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are satisfied by substituents, thus causing the compound to contain one or more double or triple bonds.

[0029] The term "alkoxy" as used herein refers to an alkyl group, as defined above, wherein one carbon of the alkyl group has been replaced by an oxygen atom ("alkoxy"), provided that the oxygen atom is linked between two carbon atoms.

[0030] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0031] As used herein, a "cyano" or "nitrile" group refers to --C.ident.N.

[0032] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system having a delocalized π-electron orbital composed of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring and may be either fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, further defined as follows.

[0033] The term "aryl" used alone or as part of a larger moiety as in "arylalkyl", "arylalkoxy", or "aryloxyalkyl" refers to, for example, a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, where all rings in the system are aromatic rings containing only carbon atoms, and where each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C7). 10 In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0034] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having, for example, a total of 5-14 ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system contains 3-7 ring members. Bicyclic heteroaryls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. Non-limiting examples of bicyclic heteroaryls are isoquinolinyl, quinolinyl, quinazolinyl, and purinyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected, for example, from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3-12 membered heteroaryl. In some embodiments, the heteroaryl is a 3-10 membered heteroaryl. In some embodiments, the heteroaryl is a 3-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5 or 6 membered heteroaryl. In some embodiments, the heterocyclyl is a 5 membered heteroaryl, such as a 5 membered heteroaryl containing 1-3 nitrogen atoms. In some embodiments, the heteroaryl is a 6 membered heteroaryl, such as a 6 membered heteroaryl containing 1-3 nitrogen atoms. Non-limiting examples of monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0035] Non-limiting examples of suitable solvents that may be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0036] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0037] Pharmaceutically acceptable salts of the disclosed compounds are disclosed herein. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0038] The term "pharmaceutically acceptable" as used herein refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.

[0039] Acids commonly used to form pharma- ceutically acceptable salts include inorganic acids (e.g., hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid), and organic acids (e.g., para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid), and related inorganic and organic acids. Thus, such pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diphosphate, and the like. ester, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and those formed with organic acids, such as maleic acid.

[0040] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Suitable non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0041] The term "subject" refers to animals, including humans.

[0042] The term "therapeutically effective amount" refers to an amount of a compound that, when administered, results in a desired effect (e.g., amelioration of a disease or condition, reduction in the severity of a disease or condition, and / or reduction in the progression of a disease or condition), wherein the disease or condition is a disease or condition selected from inflammatory diseases, immune diseases (e.g., autoimmune diseases), allergic diseases, transplant rejection, necrotic cell diseases (e.g., diseases associated with necroptosis), neurodegenerative diseases, central nervous system (CNS) diseases, ischemic brain injury, eye diseases, infectious diseases, and malignant tumors (including those mediated by receptor interacting protein 1 (RIP1) signaling); a disease or condition selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infections (including those mediated by RIP1 signaling); a disease or condition mediated by RIP1 signaling. The precise amount of a therapeutically effective amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0043] As used herein, the term "treatment" and its synonyms refer to delaying or stopping disease progression. As used herein, "treatment" and its synonyms include, but are not limited to, complete or partial remission, cure, or reduction of the risk of disease or condition, where the disease or condition is selected from inflammatory disease, immune disease (e.g., autoimmune disease), allergic disease, graft rejection, necrotic cell disease, neurodegenerative disease, central nervous system (CNS) disease, ischemic brain injury, eye disease, infectious disease, and malignant tumor, including those mediated by receptor interacting protein 1 (RIP1) signaling; ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infection, including those mediated by receptor interacting protein 1 (RIP1) signaling; RIP1 signaling mediated disease or condition. Improvement or reduction in the severity of any of these symptoms can be assessed according to methods and techniques known in the art.

[0044] The terms "about" and "approximately," when used in connection with numbers, such as percentages, include the specified number as well as a range of numbers (e.g., a percentage range) that would be recognized by one of ordinary skill in the art.

[0045] II. Compounds and Compositions In a first embodiment, the compound of the present disclosure has the following structural formula I: [ka] [In the formula, X is C or N; When X is N, X1 and X2 are C; When X is C, then X1 and X2 are absent; When X is C then Y is O, or when X is N then Y is absent; X3 is C or N; where the valence of C is hydrogen and / or R 4 Filled with; R ais hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or -OH; R b and R c are each independently hydrogen, C1-C4 alkyl, or C1-C4 heteroalkyl; Ar 1 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] but [ka] If Ar 1 cannot be furanyl; When X is C and Y is O, Ar 2 and Ar 3 are each independently phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; If X is N and Y is absent, then [ka] teeth: [ka] and; Where: (i) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, or absent; (ii) [ka] but [ka] If: Ar 1 cannot be furanyl; Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; (iii) [ka] but [ka] If [ka] teeth [ka] and; (iv) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; (v) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; (vi) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; (vii) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; (viii) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; (ix) [ka] but [ka] If Ar 3 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; R 1 , R 2 , R 3 , and R 4 are each independently for each occurrence halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , and -S(=O) w NR p R q is selected from; R 1 , R 2 , R 3, and R 4 Any one of C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkoxy, the C1-C6 alkyl of -C(=O)(C1-C6 alkyl), and the C3-C6 cycloalkyl of -C(=O)(C3-C6 cycloalkyl) are each independently selected from halogen, cyano, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , and -S(=O) w NR p R q and optionally substituted with 1 to 3 groups selected from; R p , R q , and R r is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl; R p , R q , and R r any one of C1-C4 alkyl is optionally substituted with 1-3 groups selected from halogen, cyano, and -OH; R s is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl; R sany one of C1-C4 alkyl is optionally substituted with 1-3 groups selected from halogen, cyano, and -OH; w is an integer selected from 1 and 2; and m, n, p, and q are each integers independently selected from 0, 1, 2, and 3, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing. Combinations of substituents disclosed herein are those that result in the formation of stable or chemically feasible compounds. In the case of abbreviations or by convention, specific hydrogen atoms bonded to specific atoms (e.g., carbon atom C or nitrogen atom N) are not specifically shown in the chemical structures, formulas, or symbols; hydrogen atoms are considered to be present to the extent that the valence of the specific atom (e.g., C or N) is satisfied. For example, when X1 is C, X1 is R 4 and / or H, for example, X 1 can be bonded to two hydrogen atoms, or one hydrogen atom and one halogen atom, or one hydrogen atom and one methyl group, etc.

[0046] In a second embodiment, the compound of the present disclosure has the following structural formula IIa: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in the preceding embodiments.

[0047] In a third embodiment, the compound of the present disclosure has the following structural formula IIIa-1: [ka] [In the formula, Ar 1 and Ar 3are each independently phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0048] In a fourth embodiment, the compound of the present disclosure has the following structural formula IIIa-2: [ka] [In the formula, Ar 1 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; 1 cannot be furanyl; Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0049] In a fifth embodiment, the compound of the present disclosure has the following structural formula IIIa-3: [ka] [In the formula, Ar 1is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; [ka] teeth [ka] and; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0050] In a sixth embodiment, the compound of the present disclosure has the following structural formula IIIa-4: [ka] [In the formula, Ar 1 is phenyl, C5-C6 carbocyclyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl; Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0051] In a seventh embodiment, the compound of the present disclosure has the following structural formula IIIa-5: [ka] [In the formula, Ar 1 and Ar 3 are each independently phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0052] In an eighth embodiment, the compound of the present disclosure has the following structural formula IIIa-6: [ka] [In the formula, Ar 1 and Ar 3 are each independently phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0053] In a ninth embodiment, the compound of the present disclosure has the following structural formula IIIa-7: [ka] [In the formula, Ar 1 and Ar 3 are each independently phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0054] In a tenth embodiment, the compound of the present disclosure has the following structural formula IIIa-8: [ka] [In the formula, Ar 1 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; Ar 3 is phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0055] In an eleventh embodiment, the compound of the present disclosure has the following structural formula IIIa-9: [ka] [In the formula, Ar 1 and Ar 3 are each independently phenyl, C5-C6 carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0056] In a twelfth embodiment, the compound of the present disclosure has the following structural formula IVa-1: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0057] In a thirteenth embodiment, the compound of the present disclosure has the following structural formula IVa-2: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5-6 membered heteroaryl; [ka] teeth, [ka] It cannot be; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0058] In a fourteenth embodiment, the compound of the present disclosure has the following structural formula IVa-3: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; [ka] teeth [ka] and; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; band R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0059] In a fifteenth embodiment, the compound of the present disclosure has the following structural formula IVa-4: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5-6 membered heteroaryl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0060] In a sixteenth embodiment, the compound of the present disclosure has the following structural formula IVa-5: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5-6 membered heteroaryl or a 5- or 6-membered heterocyclyl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0061] In a seventeenth embodiment, the compound of the present disclosure has the following structural formula IVa-6: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5-6 membered heteroaryl or a 5- or 6-membered heterocyclyl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0062] In an eighteenth embodiment, the compound of the present disclosure has the following structural formula IVa-7: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0063] In a nineteenth embodiment, the compound of the present disclosure has the following structural formula IVa-8: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; [ka] teeth, [ka] It cannot be; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; R b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0064] In a twentieth embodiment, the compound of the present disclosure has the following structural formula IVa-9: [ka] [In the formula, R a is hydrogen, C1-C2 alkyl optionally substituted with 1-3 deuterium atoms, or -OH; Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 3 is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0065] In a twenty-first embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 1is phenyl, cyclohexyl, cyclohexenyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, or pyridinyl; each of m R 1 groups; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0066] In a twenty-second embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 1 teeth, [ka] Each of m R 1 groups; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0067] In a twenty-third embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 1 m R 1 and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0068] In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 pR 3 and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0069] In a twenty-fifth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 contains 1 to 3 nitrogen atoms and p R 3 and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0070] In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 pR 3 is a 5-membered heteroaryl optionally substituted with a group; [ka] teeth, [ka] all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0071] In a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 contains 1 to 3 nitrogen atoms and p R 3 is a 5-membered heteroaryl optionally substituted with a group; [ka] teeth, [ka] all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0072] In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 is triazolyl, thiadiazolyl, or pyrazolyl; each of p R 3 group; p is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0073] In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 is pyrazolyl, triazolyl, or thiadiazolyl; each of p R 3 group; p is an integer selected from 0, 1, and 2; [ka] teeth, [ka] all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0074] In a thirtieth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 teeth, [ka] Each of p R 3 group; p is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0075] In a thirty-first embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure, R a is hydrogen, -CH, -CD, -CHCH, or -OH; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0076] In a thirty-second embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, R b and R c is each independently hydrogen, deuterium, or -CHOH; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0077] In a thirty-third embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure: R b and R c are both hydrogen; R b and R c are both deuterium; or R b and R c one of which is hydrogen and the other is -CHOH; All other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0078] In a thirty-fourth embodiment, the compound of the present disclosure has the following structural formula IIb: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. a is hydrogen, C1-C2 alkyl optionally substituted with 1 to 3 deuterium atoms, or -OH.

[0079] In a thirty-fifth embodiment, the compound of the present disclosure has the following structural formula IIIb: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments as appropriate.

[0080] In a thirty-sixth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure: Ar 1 is phenyl, C5-C6 carbocyclyl, or 5-6 membered heteroaryl; Ar 2 is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R b and R c are each independently hydrogen, deuterium, C1-C2 alkyl, or C1-C2 heteroalkyl; b and R c C1-C2 alkyl and R b and R c each C1-C2 heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; q is an integer selected from 0 and 1; All other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0081] In a thirty-seventh embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure: Ar 1 is phenyl or C6 carbocyclyl; each of m R 1 optionally substituted with a group; Ar 2 is a 5- to 6-membered heteroaryl; each of n R 2 optionally substituted with a group; All other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0082] In a thirty-eighth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure: Ar 2 is a 6-membered heteroaryl; each of n R 2 optionally substituted with a group; All other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0083] In a thirty-ninth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure: Ar 2 is pyridinyl or pyrimidinyl; each of n R 2 optionally substituted with a group; All other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0084] In a fortieth embodiment, the compound of the present disclosure has the following structural formula IVb-1: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0085] In a forty-first embodiment, the compound of the present disclosure has the following structural formula IVb-2: [ka] wherein q is an integer selected from 0 and 1; all other variables not specifically defined herein are as defined in any one of the preceding embodiments, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0086] In a forty-second embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 1 m R 1 and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0087] In a forty-third embodiment, in the compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 is 5-6 membered heteroaryl or 5- or 6-membered heterocyclyl; each of p R 3 groups; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0088] In a forty-fourth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 pR 3 and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0089] In a forty-fifth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, Ar 3 pR 3 and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0090] In a forty-sixth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure, [ka] teeth, [ka] and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0091] In a forty-seventh embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure, R 1 , R 2 , R 3 , and R 4are each independently for each occurrence halogen, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR p R q -NR p R q -OH; R 1 , R 2 , R 3 , and R 4 Any one of C1-C4 alkyl, C2-C4 alkenyl, and C1-C4 alkoxy, and the C1-C4 alkyl of -C(=O)(C1-C4 alkyl) is optionally substituted with 1-3 groups selected from halogen, cyano, and -OH; R p , R q , and R r is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl; All other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0092] In a forty-eighth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, R 1 , R 2 , R 3 , and R 4 is, for each occurrence, independently selected from halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, and -OH; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0093] In a forty-ninth embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, R 1is independently selected for each occurrence from F, Cl, cyano, CF, CFH, and -CH; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0094] In a 50th embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, R 2 is F for each occurrence; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0095] In a fifty-first embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, R 3 is -CH3 for each occurrence; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0096] In a fifty-second embodiment, in a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt of the present disclosure, R 4 is independently selected for each occurrence from F and -CH3; all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0097] In a fifty-third embodiment, in the compounds, tautomers, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the present disclosure, p is an integer selected from 1 and 2; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0098] In certain embodiments, at least one compound of the disclosure is selected from compounds 1-99 shown in Table 1, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0099] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0100] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, and at least one pharma- ceutically acceptable carrier.

[0101] In some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant, hi some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0102] It will also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy: i.e., the pharmaceutical compositions described herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, a compound selected from compounds 1-99, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, can be administered as a separate composition, simultaneously with, prior to, or subsequent to a composition comprising an additional active pharmaceutical agent.

[0103] As mentioned above, the pharmaceutical composition disclosed herein includes a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier can be selected from adjuvants and vehicles. The pharma- ceutically acceptable carrier used herein can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders, and lubricants suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988 to 1999, Marcel Dekker, New York disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by producing any undesirable biological effects, or otherwise interacting in a deleterious manner with any of the other component(s) of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose, cellulose acetate, cellulose esters ... Ingredients that can be used include, for example, sodium cellulose, ethyl cellulose, and cellulose acetate), 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, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants.

[0104] III. Preparation of Compounds The compounds, tautomers, deuterated derivatives, and salts of the present disclosure can be made according to standard chemical techniques or as described herein. In some embodiments, the compounds of I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, their tautomers, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, can be made according to the procedures illustrated in the following general schemes and examples.

[0105] In some embodiments, Scheme 1 provides methods for preparing compounds of Formula I, IIa, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, and IVa-9. [ka] The variables X3, R shown in Scheme 1 1 , R 2 , R 3 , R 4 , R a , R b , R c , Ar 1 , Ar 2 , Ar 3 and m, n, p, and q are as defined for formula I above; Here, the reagents and conditions are: (a) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), triethylamine (TEA), DMF, room temperature (RT), 2.0 hours; (b) (i) thionyl chloride (SOCl2), THF, DMF, RT, 1 hour, (ii) dichloromethane (DCM), TEA, 0°C, then RT, 1 hour. (c) bis(trichloromethyl)carbonate (BTC), TEA, THF, RT, 2.0 hours.

[0106] In some embodiments, Scheme 2 provides methods for preparing compounds of Formula I, IIa, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, and IVa-9. [ka] The variables X3, R shown in Scheme 2 1 , R 2 , R 3 , R 4 , R a , R b , R c , Ar 1 , Ar 2 , Ar 3 and m, n, p, and q are as defined for formula I above; Here, the reagents and conditions are: (a) sodium hydride (NaH), iodomethane or iodoethane or iodomethane-d3, DMF, RT, 1 hour.

[0107] In some embodiments, Scheme 3 provides a method for preparing compounds of Formula I, IIb, IIIb, IVb-1, and IVb-2. [ka] The variable R shown in Scheme 3 1 , R 2, R 3 , R 4 , R b , R c , Ar 1 , Ar 2 , Ar 3 and m, n, p, and q are as defined for formula I above; Here, the reagents and conditions are: (a) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), triethylamine (TEA), DMF, room temperature (RT), 2.0 hours.

[0108] IV. METHODS OF TREATMENT AND USES In another aspect of the disclosure, a compound of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuteration of the compounds or the tautomers, The compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts, including derivatives, or pharma- ceutically acceptable salts of the foregoing, as described herein, or pharmaceutical compositions thereof, are for use in the treatment of a disease or condition selected from inflammatory diseases, immune diseases (e.g., autoimmune diseases), allergic diseases, graft rejection, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ischemic brain injury, eye diseases, infectious diseases, and malignancies. In some embodiments, the disease or condition is mediated by receptor interacting protein 1 (RIP1) signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infections.

[0109] In another aspect, disclosed herein is a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, as described herein, including a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for use as a medicament.

[0110] In another aspect, a compound represented by the formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IIIc, IIId, IIIe, IIIg, IIIg-10, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-60, IIIg-70, IIIg-80, IIIg-90, IIIg-11, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-60, IIIg-70, IIIg-80, IIIg-90, IIIg-12, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-60, IIIg-70, IIIg-80, IIIg-90, IIIg-13, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-60, IIIg-70, IIIg-80, IIIg-90, IIIg-14, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-60, IIIg-70, IIIg-80, IIIg-90, IIIg-15, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-16, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-17, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-18, IIIg-20, IIIg-30, IIIg-40, IIIg-50, IIIg-19, IIIg-21, IIIg-22, IIIg-23, IIIg-24, IIIg-25, IIIg-26, III Disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein, including compounds IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing. In some embodiments, the disease or condition is mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infections. In yet another aspect, a method of treating a disease or condition selected from an inflammatory disease, an immune disease (e.g., an autoimmune disease), an allergic disease, a transplant rejection, a necrotic cell disease, a neurodegenerative disease, a central nervous system (CNS) disease, an ischemic brain injury, an eye disease, an infectious disease, and a malignancy in a subject, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa-10, IVa-11, IVa-12, IVa-13, IVa-14, IVa-15, IVa-16, IVa-17, IVa-18, IVa-19, IVa-20, IVa-21, IVa-22, IVa-23, IVa-24, IVa-25, IVa-26, IVa-27, IVa-28, IVa-29, IVa-30, IVa-31, IVa-32, IVa-33, IVa-34, IVa-35, IVa-36, IVa-37, IVa-38, IVa-39, IVa-40, IVa-41, IVa-42, IVa-43, IVa-44, IVa-45, IVa-46, IVa-47, IVa-48, IVa-49, IVa-49, IVa- Disclosed herein are methods that include administering a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, including compound of formula (I)-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing.In some embodiments, the disease or condition is mediated by RIP1 signaling, hi some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and viral infection.

[0111] In a further aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts described herein, including compounds of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in the treatment of a disease or condition mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and a viral infection. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutically acceptable salt thereof, as described herein, including a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease or condition mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and a viral infection.In yet another aspect, disclosed herein is a method of treating a disease or condition mediated by RIP1 signaling in a subject, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative of the compound or tautomer, or pharma- ceutical composition thereof, as described herein, including a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutical acceptable salts thereof. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and a viral infection.

[0112] In another aspect of the disclosure, a compound of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable derivatives of the foregoing. The compounds, tautomers, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts, or pharmaceutical compositions thereof described herein, including salts that are capable of binding to RIP1, are for use in mediating, e.g., inhibiting, RIP1 by contacting a RIP1 protein or fragment thereof (e.g., the kinase domain, the intermediate domain, and / or the death domain) with the compound, tautomer, deuterated derivative of the compound or tautomer, pharma- ceutically acceptable salt, or pharmaceutical composition. In yet another aspect, disclosed herein is a method of inhibiting RIP1 comprising contacting a RIP1 protein or a fragment thereof (e.g., the kinase domain, the intermediate domain, and / or the death domain) with a subject with a compound, tautomer, deuterated derivative of the compound or tautomer, or a pharma- ceutical composition thereof, including a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutical acceptable salts of the foregoing.

[0113] The compounds of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1 to 99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be used to treat, for example, the diseases or conditions described above, for example, inflammatory diseases, immune disorders, and the like. The compound may be administered once daily, twice daily, or three times daily for the treatment of a disease or condition selected from the group consisting of a disease (e.g., an autoimmune disease), an allergic disease, a transplant rejection, a necrotic cell disease, a neurodegenerative disease, a CNS disease, an ischemic brain injury, an eye disease, an infectious disease, and a malignant tumor (including those mediated by RIP1 signaling); a disease or condition selected from the group consisting of ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and a viral infection (including those mediated by RIP1 signaling); or a disease or condition mediated by RIP1 signaling.

[0114] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, is administered once daily, twice daily, or three times daily.

[0115] A compound of Formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, compounds 1-99, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, vaginally, transdermally, by patch, pump administration, or via an implanted reservoir, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intraspinal, intrarectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Other modes of administration contemplated in the present disclosure are as described in WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142, and WO2015 / 023915. EXAMPLES

[0116] In order that the disclosure set forth herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any way.

[0117] Example 1. Synthesis of exemplary compounds Compounds of the disclosure selected from compounds of formula I, IIa, IIb, IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8, IIIa-9, IIIb, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVb-1, or IVb-2, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, can be made according to standard chemical methods or as described herein, including the following synthetic schemes for compounds 1-99 as representative examples of compounds of formula I.

[0118] compound 1 N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] Step 1: Synthesis of 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine To a stirred solution of 2,4-dichloro-5-fluoropyrimidine (5 g, 29.95 mmol) and 3,5-dimethyl-1H-1,2,4-triazole (3.2 g, 32.94 mmol) in dimethylformamide, i.e., DMF (80 mL), cesium carbonate Cs2CO3 (17.3 g, 89.85 mmol) was added at room temperature. The resulting mixture was stirred at 80° C. for another 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc) (1:1) to give 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine (3 g, 44.1%) as a tan solid. MS(m / z): 228.6[M+H] + .

[0119] Step 2: Synthesis of methyl 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylate To a stirred solution of 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine (3 g, 13.18 mmol) and methyl piperidine-4-carboxylate (2.08 g, 14.50 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine or DIEA (5.1 g, 39.54 mmol) at room temperature. The resulting mixture was stirred at 80° C. for another 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate or Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (PE:EtOAc) (1:1) to give methyl 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (2.6 g, 59%) as a yellow oil. MS(m / z): 335.3[M+H] + .

[0120] Step 3: Synthesis of 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid To a stirred solution of methyl 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (2.6 g, 7.78 mmol) in tetrahydrofuran or THF (10 mL) was added 1N sodium hydroxide or NaOH (5 mL) at room temperature. The resulting mixture was stirred at 25° C. for another 2 h. The mixture was acidified with 1N hydrochloric acid or HCl to pH 3-4. The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc) (1:2) to give 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid (1.9 g, 76.3%) as a tan solid. LC-MS (m / z) 321.3 [M+H] + .

[0121] Step 4: Synthesis of N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide (Compound 1) To a stirred solution of 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid (70 mg, 0.22 mmol) and N-(3,5-difluorobenzyl)hydroxylamine (38 mg, 0.24 mmol) in DMF (2 mL) was added hexafluorophosphate azabenzotriazole tetramethyluronium or HATU (125 mg, 0.33 mmol) and triethylamine or TEA (67 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at 25° C. for another 2 h. The resulting mixture was diluted with water (4 mL). The resulting mixture was extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: spherical C18 40-60 μm, 40 g; Mobile phase B: acetonitrile or ACN; Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. The fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title compound 1 (40 mg, 39.6%) as an off-white solid. LC-MS (m / z): 462.4 [M+H] + . 1 H NMR(400MHz,DMSO)δ10.12(brs,1H),8.67(d,J=3.0Hz,1H),7.20-7.10(m,1H),6.95(t,J=4.3,3.8Hz,2H),4.73(s,2H),4.54(d,J=13 .1Hz,2H),3.05(td,J=13.2,2.8Hz,2H),2.61(s,3H),2.29(s,3H),2.08(s,1H),1.84(d,J=12.8Hz,2H),1.53(d,J=12.4,4.0Hz,2H).

[0122] compound 2 N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide [ka] Step 1: Synthesis of 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride 1-(4-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid (75 mg, 0.234 mmol), as described above in the synthesis of compound 1, was dissolved in 3 mL of tetrahydrofuran or THF. 1 mL of thionyl chloride or SOCl2 was added at room temperature. One drop of DMF was added. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and used in the next step without further purification.

[0123] Step 2: Synthesis of N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide (compound 2) 1-(4-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride was dissolved in 3 mL of dichloromethane or DCM. It was slowly added to a mixture of (3,5-difluorophenyl)methanamine (36.9 mg, 0.258 mmol) and TEA (0.2 mL) in 2 mL of DCM at 0° C. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=1 / 3) to give 60 mg of a white solid, which is the title compound 2. Yield: 57.7%. LC-MS (m / z): 446.5 [M+H] + . 1H NMR(400MHz,CDCl3)δ8.37(d,J=2.4Hz,1H),6.81-6.76(m,2H),6.71(tt,J=8.8,2.4Hz,1H),5.85(t,J=6.0Hz,1H),4.74-4.64(m,2H) ),4.44(d,J=6.0Hz,2H),3.05-2.95(m,2H),2.68(s,3H),2.49-2.38(m,4H),2.01-1.91(m,2H),1.77(ddd,J=24.8,12.0,4.4Hz,2H).

[0124] compound 3 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide [ka] Step 1: Synthesis of tert-butyl ((tert-butoxycarbonyl)oxy) ((1-methyl-1H-pyrazol-4-yl)methyl)carbamate (1-Methyl-1H-pyrazol-4-yl)methanol (1 g, 8.918 mmol), tert-butyl ((tert-butoxycarbonyl)oxy)carbamate (2.5 g, 10.717 mmol), and triphenylphosphine PPh3 (2.8 g, 10.687 mmol) were mixed in 30 mL of THF. Diisopropyl azodiformate (2.164 g, 10.7 mmol) was slowly added to the solution at 0° C. The mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=2 / 1) to give 2.4 g of a white solid. Yield: 82.3%. LC-MS (m / z): 328.4 [M+H] + .

[0125] Step 2. Synthesis of N-((1-methyl-1H-pyrazol-4-yl)methyl)hydroxylamine tert-Butyl ((tert-butoxycarbonyl)oxy) ((1-methyl-1H-pyrazol-4-yl)methyl)carbamate (186 mg, 0.569 mmol) was dissolved in 2 mL of DCM. 2 mL of dichloromethane / trifluoroacetic acid, i.e. DCM / TFA (1 / 1), was added. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and used in the next step without further purification. LC-MS (m / z): 128.3 [M+H] + .

[0126] Step 3. Synthesis of 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide (compound 3) 1-(4-(1,4-Dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid (70 mg, 0.219 mmol) was dissolved in 3 mL of tetrahydrofuran or THF and 1 mL of thionyl chloride or SOCl2 was added at room temperature. One drop of DMF was added. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and used in the next step without further purification. The above residue was dissolved in 3 mL of DCM. It was slowly added to a mixture of N-((1-methyl-1H-pyrazol-4-yl)methyl)hydroxylamine (144.6 mg, 0.6 mmol) and trifluoroacetate of TEA (0.2 mL) in 2 mL of DCM at 0° C. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and purified by preparative TLC (DCM / MeOH=18 / 1) to give 7 mg of a white solid. Yield: 7.5%. LC-MS(m / z):429.3[M+H] + . 1H NMR(400MHz,CDCl3)δ8.29(d,J=1.6Hz,1H),7.44-7.37(m,2H),7.36(s,1H),5.35(t,J=4.8Hz,2H),4.80-4.65(m ,4H),3.92(s,3H),3.87(s,3H),3.20-3.07(m,1H),3.04-2.94(m,2H),2.08(d,J=2.4Hz,3H),1.88-1.73(m,4H).

[0127] Preparation of the intermediate 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid and other intermediates [ka] Step 1: Synthesis of 2-chloro-4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine 2,4-Dichloro-5-fluoropyrimidine (200 mg, 1.19 mmol) was dissolved in 6 mL of 1,4-dioxane / H2O (5:1). 1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (293 mg, 1.32 mmol), sodium carbonate Na2CO3 (1.8 mL, 2N), and palladium-tetrakis(triphenylphosphine) Pd(PPh3)4 (138 mg, 0.12 mmol) were added to the above mixture at room temperature under nitrogen. The mixture was stirred at 80° C. for 12 hours. The mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under vacuum. Purification by silica gel chromatography gave 2-chloro-4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (150 mg, 55%) as a white solid. LC-MS (m / z): 227.2 [M+H] + .

[0128] Step 2: Synthesis of ethyl 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylate 2-Chloro-4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (150 mg, 0.66 mmol) was dissolved in 10 mL of DMF, and ethyl piperidine-4-carboxylate (157 mg, 1.00 mmol) and Cs2CO3 (326 mg, 1.00 mmol) were added to the above solution at room temperature. The mixture was stirred at 100° C. for 2 h. The mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under vacuum. Purification by silica gel chromatography afforded ethyl 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (200 mg, 87%) as a white solid. LC-MS (m / z): 348.4 [M+H] + .

[0129] Step 3: Synthesis of 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid Ethyl-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylate (200 mg, 0.57 mmol) was dissolved in 10 mL of THF, and NaOH(aq) (2.0 mL, 1N) was added to the above solution at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N HCl to pH 3-4. The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with (PE:EtOAc) (1:2) to give intermediate 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid (150 mg, 81.9%) as a yellow solid. LC-MS(m / z):320.3[M+H] + .

[0130] The following intermediates used in the preparation of compounds 4, 20-28, 31-52, 56-62 were synthesized using methods similar to the preparation of 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid above. [ka]

[0131] compound 4 N-(3,5-difluorobenzyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 4 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 17.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 461.3 [M+H] +1 H NMR(400MHz,chloroform-d)δ8.31(s,1H),7.40-7.33(m,1H),6.84(d,J=6.6Hz,2H),6.80-6.69(m,1H),4.9 3-4.80(m,2H),4.75(d,J=13.1Hz,2H),3.93(s,3H),3.35-2.61(m,3H),2.08(s,3H),1.95-1.65(m,4H).

[0132] compound 5 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 5 was prepared as a white solid in 54.9% yield from 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z): 464.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.37(d,J=2.8Hz,1H),6.90-6.78(m,2H),5.92(t,J=5.2Hz,1H),4.72-4.64(m,2H),4.50(d,J =5.6Hz,2H),3.05-2.93(m,2H),2.68(s,3H),2.44(s,3H),2.43-2.37(m,1H),1.97-1.89(m,2H),1.80-1.72(m,2H).

[0133] compound 6 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 6 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride as a white solid in 57.2% yield following the procedure outlined for compound 2. LC-MS (m / z): 463.4 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.29(d,J=1.6Hz,1H),7.37(s,1H),6.89-6.79(m,2H),5.92(t,J=5.6Hz,1H),4.79-4.71(m,2H),4.50(d,J=5.6Hz,2H), 3.93(s,3H),3.01-2.91(m,2H),2.42(tt,J=11.6,4.0Hz,1H),2.07(d,J=2.4Hz,3H),1.98-1.85(m,2H),1.74(ddd,J=25.2,12.4,4.0Hz,2H).

[0134] compound 7 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide [ka] The title compound 7 was prepared as an off-white solid in 6.5% yield from 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z): 427.5 [M+H] + . 1 H NMR(400MHz,DMSO)δ10.16(brs,1H),8.67(d,J=3.2Hz,1H),8.60(d,J=5.2Hz,1H),7.96(t,J=7.2Hz,1H),7.48-7.32(m,2H) ),4.87(s,2H),3.31-2.99(m,4H),2.62(s,3H),2.30(s,3H),2.08-1.97(m,1H),1.87(d,J=11.2Hz,2H),1.62-1.49(m,2H).

[0135] compound 8 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((3-fluoropyridin-2-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 8 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride as a white solid in 24.7% yield following the procedure outlined for compound 2. LC-MS (m / z): 444.5 [M+H] + . 1H NMR(400MHz,CDCl3)δ9.13(brs,1H),8.30(dd,J=8.4,3.2Hz,2H),7.45(ddd,J=9. 2,8.4,1.2Hz,1H),7.39-7.34(m,1H),7.30(dt,J=8.8,4.4Hz,1H),5.18-5.06(m,2 H),4.75(d,J=13.2Hz,2H),3.93(s,3H),3.36(t,J=9.4Hz,1H),3.05(t,J=12.8Hz ,2H),2.08(d,J=2.4Hz,3H),1.94(d,J=12.4Hz,2H),1.76(qd,J=12.4,4.0Hz,2H).

[0136] compound 9 N-((3-chloropyridin-2-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 9 was prepared as a white solid in 4.0% yield from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z): 460.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.36(d,J=4.8Hz,1H),8.22(d,J=2.0Hz,1H),7.78-7.62(m,1H),7.30(s,1H),7.27-7.20(m,1H),5.08(s,2H),4.68(d,J=1 3.2Hz,2H),3.87(s,3H),3.30(t,J=11.6Hz,1H),2.99(t,J=12.8Hz,2H),2.01(d,J=2.4Hz,3H),1.89(d,J=13.6Hz,2H),1.69(d,J=12.4Hz,2H).

[0137] compound 10 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((5-fluoropyridin-2-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 10 was prepared as a white solid in 6.7% yield from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z): 444.5 [M+H] + . 1 H NMR(400MHz,DMSO)δ10.17(brs,1H),8.57(dd,J=20.8,1.8Hz,2H),8.34(t,J=46.2Hz,1H),7.39(s,1H),7.32-7.17(m,1H),4.82(s,2H),4.60(d ,J=13.2Hz,2H),3.86(s,3H),3.18(s,1H),3.03(t,J=11.6Hz,2H),2.01(d,J=2.0Hz,3H),1.83(d,J=11.2Hz,2H),1.53(qd,J=12.4,3.6Hz,2H).

[0138] compound 11 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((3-fluoropyridin-4-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 11 was prepared as a white solid in 6.7% yield from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z): 444.5 [M+H] + . 1H NMR(400MHz,DMSO)δ10.03(brs,1H),8.60(d,J=2.0Hz,1H),8.50(dd,J=7.0,2 .8Hz,1H),7.84-7.64(m,1H),7.40(s,1H),7.30(dd,J=8.4,4.4Hz,1H),4.79(d ,J=13.2Hz,2H),4.61(d,J=13.2Hz,2H),3.86(s,3H),3.20(s,1H),3.03(t,J= 11.6Hz,2H),2.01(d,J=2.0Hz,3H),1.84(d,J=11.2Hz,2H),1.62-1.43(m,2H).

[0139] compound 12 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] The title compound 12 was prepared as a white solid in 8.4% yield from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z): 432.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.87(brs,1H),8.22(d,J=2.0Hz,1H),7.59(s,1H),7.32-7.28(m,1H),7.26(s,1H),7.19(s,1H),5.11(s,2H) ,4.75-4.61(m,2H),3.86(s,3H),3.22(s,1H),2.96(t,J=13.2Hz,2H),2.01(s,3H),1.85(d,J=13.2Hz,2H),1.69(d,J=13.2Hz,2H).

[0140] compound 13 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-((3-fluoropyridin-2-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 13 was prepared from 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl chloride as an off-white solid in 3.5% yield following the procedure outlined for compound 2. LC-MS (m / z): 445.5 [M+H] + . 1 H NMR(400MHz,DMSO)δ9.89(brs,1H),8.67(d,J=3.0Hz,1H),8.39(d,J=4.4Hz,1H),7.78-7.57(m,1H),7.43(dt,J=8.4,4.4Hz,1H),4.91(s,2H) ,4.53(d,J=13.2Hz,2H),3.17(s,1H),3.05(t,J=11.6Hz,2H),2.62(s,3H),2.32(d,J=15.2Hz,3H),1.83(d,J=11.2Hz,2H),1.61-1.48(m,2H).

[0141] compound 14 N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-4-fluoro-N-hydroxypiperidine-4-carboxamide [ka] The title compound 14 was prepared from 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-4-fluoropiperidine-4-carbonyl chloride as a yellow solid in 57.2% yield following the procedure outlined for compound 2. LC-MS (m / z) 480.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ8.41(d,J=2.36Hz,1H),6.89-6.82(m,2H),6.80-6.73(m,1H),5.04(s,2H),4. 63-4.46(m,2H),3.40-3.29(m,2H),2.72(s,3H),2.46(s,3H),2.34-2.18(m,2H),2.05-1.97(m,2H).

[0142] compound 15 N-(3,5-difluorobenzyl)-1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 15 was prepared as an off-white solid in 11.7% yield from 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 448.4 [M+H + ]. 1 H NMR(400MHz,CDCl3)δ10.12(brs,1H),8.41(d,J=2.4Hz,1H),8.01(d,J=17.8Hz,1H),6.89-6.80( m,2H),6.76(s,1H),4.69(s,2H),4.22(s,3H),3.04(d,J=57.2Hz,4H),2.74(s,1H),1.26(s,4H).

[0143] compound 16 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(thiazol-5-ylmethyl)piperidine-4-carboxamide [ka] The title compound 16 was prepared from 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperidine-4-carbonyl chloride as an off-white solid in 20.2% yield following the procedure outlined for compound 2. LC-MS (m / z) 432.4 [M+H] + .

[0144] compound 17 N-(3,5-difluorobenzyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-4-fluoro-N-hydroxypiperidine-4-carboxamide [ka] The title compound 17 was prepared in 2.0% yield as an off-white solid from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-4-fluoropiperidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 479.4 [M+H + ]. 1 H NMR(400MHz,DMSO)δ10.24(s,1H),8.62(d,J=2.0Hz,1H),7.40(s,1H),7.25-7.07(m,2H),6.95(dd,J=4.4,2.4Hz,1 H),4.76(s,2H),4.45(d,J=13.2Hz,2H),3.86(s,3H),2.98-2.81(m,2H),2.25-2.06(m,4H),2.01(d,J=2.4Hz,3H).

[0145] compound 18 N-(3,5-difluorobenzyl)-1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-hydroxy-4-methylpiperidine-4-carboxamide [ka] The title compound 18 was prepared from 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carbonyl chloride as an off-white solid in 10.0% yield following the procedure outlined for compound 2. LC-MS (m / z) 462.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.39(d,J=6.4Hz,1H),8.04(s,1H),6.83-6.79(m,2H),6.74-6.68(m,1H),4.81(s,2 H),4.19(s,3H),4.10-4.02(m,2H),3.54-3.46(m,2H),2.38-2.30(m,2H),1.60-1.52(m,2H),1.35(s,3H).

[0146] compound 19 N-(3,5-difluorobenzyl)-4-fluoro-1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 19 was prepared from 4-fluoro-1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 10.0% yield following the procedure outlined for compound 2. LC-MS (m / z) 466.1 [M+H] + .

[0147] compound 20 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2-fluoropyridin-4-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 20 was prepared as a brown solid in 11.7% yield from the trifluoroacetate of N-((2-fluoropyridin-4-yl)methyl)hydroxylamine following the procedure outlined for compound 1. LC-MS (m / z): 444.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.30(d,J=1.6Hz,1H),8.03(s,1H),7.32(s,1H),7.11(d,J=4.8Hz,1H),6.85(s,1H),5.39-5.31(m,1H),4. 97-4.82(m,2H),4.80-4.69(m,2H),3.91(s,3H),3.33-3.19(m,1H),3.07-2.90(m,2H),2.08(d,J=2.0Hz,3H),1.94-1.75(m,4H).

[0148] compound 21 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 21 was prepared from 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid as a pale yellow solid in 58.6% yield following the procedure outlined for compound 1. LC-MS (m / z) 450.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.67(d,J=2.4Hz,1H),8.53(brs,1H),8.15(s,1H),7.43(dd dd,J=11.2,9.2,6.4,3.2Hz,1H),6.96(ddq,J=10.2,5.2,2.4Hz,1H),4.58(dt,J=13. 0,3.6Hz,2H),4.33(d,J=5.6Hz,2H),4.15(s,3H),3.02(td,J=12.8,2.8Hz,2H),2.57 (dt,J=11.6,3.6Hz,1H),1.82(dd,J=13.6,3.6Hz,2H),1.56(qd,J=12.4,4.0Hz,2H).

[0149] compound 22 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)piperidine-4-carboxamide [ka] The title compound 22 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 70.5% yield following the procedure outlined for compound 1. LC-MS (m / z) 444.5 [M+H] + . 1 H NMR(400MHz,DMSO)δ8.59(d,J=2.0Hz,1H),8.45(brs,1H),7.40(s,1H),4.57(dt,J=13.6,3.6Hz,2H),4.30(d,J=5.6Hz,2H),3.86(s,3H),2.96(t d,J=12.8,2.8Hz,2H),2.48(s,3H),2.43(ddt,J=11.6,7.2,3.6Hz,1H),2 .25(s,3H),2.01(d,J=2.4Hz,3H),1.79-1.68(m,2H),1.58-1.45(m,2H).

[0150] compound 23 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(oxazol-5-ylmethyl)piperidine-4-carboxamide [ka] The title compound 23 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a yellow solid in 24.5% yield following the procedure outlined for compound 1. LC-MS (m / z) 416.3 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.30(d,J=2.0Hz,1H),7.74(s,1H),7.32(s,1H),6.96(s,1H),4.88(s,2H),4.74(d,J=13 .2Hz,2H),3.90(s,3H),3.21(s,1H),3.07-2.93(m,2H),2.07(d,J=2.4Hz,3H),1.87(d,J=3.6Hz,2H),1.78(s,2H).

[0151] compound 24 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-((2-methylthiazol-5-yl)methyl)piperidine-4-carboxamide [ka] The title compound 24 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 38.6% yield following the procedure outlined for compound 1. LC-MS (m / z) 446.3 [M+H] +1H NMR(400MHz,chloroform-d)δ10.04(s,1H),8.29(d,J=2.0Hz,1H),7.34(s,1H),7.29(s,1H),4.89(s,2H),4.74(dt,J=13.6,3 .6Hz,2H),3.92(s,3H),3.23(s,1H),3.02(td,J=13.2,2.8Hz,2H),2.50(s,3H),2.08(d,J=2.4Hz,3H),1.98-1.73(m,4H).

[0152] compound 25 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2-fluoropyridin-3-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 25 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 23.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 444.3 [M+H] +1 H NMR(400MHz,chloroform-d)δ9.21(s,1H),8.37-7.93(m,2H),7.82(d,J=29.6Hz,1H),7.30(s,1H),7.13(s,1H),5.01-4.64 (m,4H),3.90(d,J=5.2Hz,3H),3.17(d,J=55.8Hz,1H),3.06-2.72(m,2H),2.06(d,J=2.3Hz,3H),1.82(d,J=35.7Hz,4H)

[0153] compound 26 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2-fluoropyridin-3-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 26 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 27.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 444.3 [M+H] +1 H NMR(400MHz,chloroform-d)δ9.68(s,1H),8.28(d,J=1.6Hz,1H),8.02(s,1H),7.80(td,J=8.0,2.5Hz,1H),7.27(s,1H),6.79( d,J=8.4Hz,1H),4.91-4.67(m,4H),3.87(s,3H),3.24(s,1H),3.03-2.93(m,2H),2.06(d,J=2.3Hz,3H),1.93-1.66(m,4H).

[0154] compound 27 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-((1-methyl-1H-pyrazol-5-yl)methyl)piperidine-4-carboxamide [ka] The title compound 27 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 27.4% yield following the procedure outlined for compound 1. LC-MS (m / z) 429.3 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.30(d,J=1.9Hz,1H),7.33(s,1H),7.23(s,1H),6.28(s,1H),4.80(d,J=34.5Hz,4H),3.92( s,3H),3.53(s,3H),3.28(s,1H),3.04(t,J=12.4Hz,2H),2.08(d,J=2.3Hz,3H),1.93(s,2H),1.83(d,J=11.9Hz,2H).

[0155] compound 28 N-(cyclohexylmethyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide [ka] The title compound 28 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a yellow solid in 36.1% yield following the procedure outlined for compound 1. LC-MS (m / z) 415.3 [M+H] +1 H NMR (400MHz, chloroform-d) δ8.29(d,J=1.9Hz,1H),7.37(s,1H),5.52(s,1H),4.74(dt,J=13.4,3.3Hz,2H),3.93(s,3H),3.16-3.06(m,2H),3.00-2.89( m,2H),2.35(tt,J=11.6,3.9Hz,1H),2.08(d,J=2.3Hz,3H),1.98(s,1H),1 .94-1.87(m,2H),1.79-1.59(m,8H),1.25-1.16(m,2H),1.00-0.82(m,2H).

[0156] compound 29 N-(3,5-difluorobenzyl)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperazine-1-carboxamide [ka] Step 1. Synthesis of tert-butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate 2-Chloro-4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (410 mg, 1.809 mmol) was dissolved in 12 mL of DMF, and tert-butyl piperazine-1-carboxylate (371 mg, 1.992 mmol) and Cs2CO3 (1.18 g, 3.63 mmol) were added to the above solution at room temperature. The mixture was stirred at 100° C. for 2 h. The mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under vacuum. Purification by silica gel chromatography afforded tert-butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (360 mg, 52.9%) as a white oil. LC-MS (m / z): 377.3 [M+H] + .

[0157] Step 2. Synthesis of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoro-2-(piperazin-1-yl)pyrimidine tert-Butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (360 mg, 0.956 mmoL) was dissolved in 5 mL of DCM. 4 mL of dichloromethane / trifluoroacetic acid, i.e. DCM / TFA (1 / 1), was added. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and used in the next step without further purification. LC-MS (m / z): 277.4 [M+H] + .

[0158] Step 3. Synthesis of N-(3,5-difluorobenzyl)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperazine-1-carboxamide (Compound 29) N-(3,5-difluorobenzyl)hydroxylamine (41 mg, 0.258 mmoL), trifluoroacetate of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoro-2-(piperazin-1-yl)pyrimidine (100 mg, 0.257 mmoL) and bis(trichloromethyl)carbonate (38 mg, 0.128 mmoL) were dissolved in 10 mL of THF. The mixture was stirred at room temperature for 2 h. The solvent was evaporated to dryness and C 18 Purification by column gave 32 mg of product as a white solid. Yield: 27%. LC-MS(m / z): 462.3[M+H] +1 H NMR (400MHz, chloroform-d) δ8.33(d,J=2.0Hz,1H),7.13-6.98(m,1H),6.97-6.87(m,2H),6.74(tt,J=8 .8,2.4Hz,1H),4.39(s,2H),3.90(s,3H),3.88-3.84(m,4H),3.66-3.58(m,4H),2.09-2.04(m,4H).

[0159] compound 30 N-(3,5-difluorobenzyl)-1-(5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 30 was prepared from 1-(5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 35.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 367.2 [M+H] +1 H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.44(d,J=0.8Hz,2H),7.15(tt,J=9.4,2.4Hz,1H),7.02-6.90(m,2H), 4.72(s,2H),4.61-4.52(m,2H),3.20-3.10(m,1H),3.02-2.91(m,2H),1.86-1.73(m,2H),1.55-1.42(m,2H).

[0160] compound 31 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide [ka] The title compound 31 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 53.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 426.3 [M+H] +1 H NMR (400MHz, chloroform-d) δ8.75(d,J=5.7Hz,1H),8.35(t,J=7.8Hz,1H),8.29(d,J=1.9Hz,1H),7.86(d,J=7.4Hz,1H),7.81(t,J=6.6Hz,1H),7.42(s,1 H),5.15(s,2H),4.65-4.73(m,2H),3.94(s,3H),3.30-3.19(m,1H),3.05- 2.92(m,2H),2.07(d,J=2.3Hz,3H),1.93-1.84(m,2H),1.69-1.56(m,2H).

[0161] compound 32 N-(3-cyano-5-fluorobenzyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 32 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a beige solid in 18.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 468.3 [M+H] +1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.59(d,J=2.1Hz,1H),7.81-7.76(m,1H),7.58-7.55(m,1H),7.47-7.42(m,1H),7.40-7.38(m,1H),4.77(s, 2H),4.60(d,J=13.3Hz,2H),3.85(s,3H),3.23-3.12(m,1H),3.08-2.97( m,2H),2.01(d,J=2.3Hz,3H),1.83(d,J=13.0Hz,2H),1.58-1.45(m,2H).

[0162] compound 33 N-Benzyl-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 33 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 42.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 425.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ8.29(d,J=1.9Hz,1H),7.42-7.17(m,6H),4.88(d,J=28.4Hz,2H),4.73(d,J=13.3Hz, 2H),3.87(s,3H),3.21(s,0.5H),3.04-2.85(m,2H),2.75(s,0.5H),2.06(d,J=2.3Hz,3H),1.96-1.56(m,4H).

[0163] compound 34 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(1-phenylethyl)piperidine-4-carboxamide [ka] The title compound 34 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 22.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 438.3 [M+H] +1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.58(d,J=2.1Hz,1H),7.41-7.37(m,1H),7.36-7.27(m,4H),7.27-7.22(m,1H),5.59(q,J=7.1Hz,1H) ),4.58(t,J=13.1Hz,2H),3.85(s,3H),3.18-3.06(m,1H),3.06-2.93(m,2H),2.00(d,J=2.3Hz,3H),1.86-1.70(m,2H),1.59-1.38(m,4H).

[0164] compound 35 (R)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(2-hydroxy-1-phenylethyl)piperidine-4-carboxamide [ka] The title compound 35 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 66.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 439.3 [M+H] +1 H NMR (400MHz, chloroform-d) δ8.29(d,J=1.9Hz,1H),7.42-7.33(m,3H),7.34-7.27(m,3H),6.20(d,J=7.1Hz,1H),5.12-5.05(m,1H),4.81-4.70(m,2H) ),3.94(s,3H),3.93-3.89(m,2H),3.03-2.93(m,2H),2.47(tt,J=11.5, 3.8Hz, 1H), 2.08 (d, J=2.2Hz, 3H), 2.02-1.89 (m, 2H), 1.84-1.67 (m, 2H).

[0165] compound 36 (S)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(2-hydroxy-1-phenylethyl)piperidine-4-carboxamide [ka] The title compound 36 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 70.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 439.3 [M+H] +1 H NMR (400MHz, chloroform-d) δ8.29(d,J=2.0Hz,1H),7.40-7.34(m,3H),7.33-7.27(m,3H),6.21(d,J=7.0Hz,1H),5.12-5.05(m,1H),4.82-4.71(m,2H) ),3.94(s,3H),3.92-3.89(m,2H),3.04-2.93(m,2H),2.47(tt,J=11.5, 3.8Hz, 1H), 2.08 (d, J=2.4Hz, 3H), 2.00-1.90 (m, 2H), 1.85-1.68 (m, 2H).

[0166] compound 37 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((5-fluoropyridin-3-yl)methyl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 37 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a pale yellow solid in 27.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 444.3 [M+H] +1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.59(d,J=2.1Hz,1H),8.51(d,J=2.8Hz,1H),8.39-8.34(m,1H),7.59-7.53(m,1H),7.39(s,1H),4.78 (s,2H),4.64-4.55(m,2H),3.85(s,3H),3.21-3.10(m,1H),3.07-2.95(m,2H),2.01(d,J=2.3Hz,3H),1.85-1.76(m,2H),1.59-1.44(m,2H).

[0167] compound 38 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(pyridin-3-ylmethyl)piperidine-4-carboxamide [ka] The title compound 38 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a pale yellow solid in 27.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 426.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.68-8.64(m,1H),8.63(s,1H),8.5 9(d,J=2.1Hz,1H),8.02-7.97(m,1H),7.68(dd,J=8.0,5.2Hz,1H),7.39(s, 1H),4.82(s,2H),4.64-4.55(m,2H),3.85(s,3H),3.21-3.10(m,1H),3.08 -2.96(m,2H),2.01(d,J=2.2Hz,3H),1.85-1.76(m,2H),1.58-1.45(m,2H).

[0168] compound 39 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-((1-methyl-1H-imidazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 39 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a yellow solid in 3.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 429.3 [M+H] +1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.59(d,J=2.2Hz,1H),7.70(d,J=2.0Hz,1H),7.64(d,J=1.9Hz,1H),7.39(s,1H),5.06(s,2H),4.63- 4.54(m,2H),3.85(s,3H),3.75(s,3H),3.20-3.10(m,1H),3.06-2.96(m,2H),2.00(d,J=2.3Hz,3H),1.85-1.76(m,2H),1.56-1.43(m,2H).

[0169] compound 40 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-((1-methyl-1H-imidazol-5-yl)methyl)piperidine-4-carboxamide [ka] The title compound 40 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a brown solid in 48.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 429.3 [M+H] +1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.08-9.03(m,1H),8.59(d,J=2.2Hz,1H),7.67-7.62(m,1H),7.39(s,1H),4.83(s,2H),4.63-4.5 4(m,2H),3.85(s,3H),3.75(s,3H),3.19-3.08(m,1H),3.06-2.95(m,2H),2.00(d,J=2.3Hz,3H),1.84-1.75(m,2H),1.56-1.42(m,2H).

[0170] compound 41 N-(3,5-difluorobenzyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 41 was prepared from 1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)piperidine-4-carboxylic acid as a dark orange solid in 23.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 443.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.72(s,1H),7.41(s,1H),7.20-7.09(m,2H),6.99-6.91(m,2H),4.7 3(s,2H),4.57(s,2H),3.89(s,3H),3.35-3.12(m,3H),2.09(s,3H),1.94-1.86(m,2H),1.66-1.50(m,2H).

[0171] compound 42 N-(3,5-difluorobenzyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)piperidine-4-carboxamide [ka] The title compound 42 was prepared from 1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)piperidine-4-carboxylic acid as a white solid in 80.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 427.3 [M+H] + .

[0172] compound 43 N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide [ka] The title compound 43 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 93.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 427.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.58(d,J=2.1Hz,1H),8.16(t,J=5.8Hz,1H),7.40-7.38(m,1H),5.85-5.83(m,1H),4.62-4.53(m,2H),4.09(d,J=5.7Hz) ,2H),3.85(s,3H),3.63(s,3H),2.99-2.89(m,2H),2.56-2.41(m,1H),2 .18(s,3H),2.00(d,J=2.4Hz,3H),1.77-1.69(m,2H),1.58-1.45(m,2H).

[0173] compound 44 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-carboxamide [ka] The title compound 44 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 92.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 413.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.58(d,J=2.1Hz,1H),8.21(t,J=5.8Hz,1H),7.56( d,J=2.1Hz,1H),7.40-7.38(m,1H),6.04(d,J=2.2Hz,1H),4.62-4.53(m,2H) ),4.17(d,J=5.7Hz,2H),3.85(s,3H),3.76(s,3H),3.00-2.89(m,2H),2.55 -2.42(m,1H),2.00(d,J=2.3Hz,3H),1.78-1.69(m,2H),1.59-1.46(m,2H).

[0174] compound 45 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide [ka] The title compound 45 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 86.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 413.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.58(d,J=2.1Hz,1H),8.14(t,J=5.6Hz,1H),7.51(s,1H),7.40-7.38(m,1H),7.28-7.26(m,1H),4.62-4.53(m,2H),4.0 6(d,J=5.6Hz,2H),3.85(s,3H),3.77(s,3H),2.99-2.89(m,2H),2.55-2 .38(m,2H),2.00(d,J=2.2Hz,3H),1.78-1.69(m,2H),1.58-1.45(m,2H).

[0175] compound 46 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 46 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 94.0% yield following the procedure outlined for compound 1. LC-MS (m / z) 431.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.81(t,J=6.0Hz,1H),8.59(d,J=2.1Hz,1H),7.39(s,1H),4.63-4.52(m,4H),3.85(s,3H) ,3.04-2.94(m,2H),2.66(s,3H),2.53-2.45(m,1H),2.00(d,J=2.3Hz,3H),1.81-1.72(m,2H),1.59-1.47(m,2H).

[0176] compound 47 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 47 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 82.9% yield following the procedure outlined for compound 1. LC-MS (m / z) 430.5 [M+H + ]. 1 H NMR(400MHz,DMSO)δ8.76(t,J=6.1Hz,1H),8.59(brs,J=2.1Hz,1H),7.39(d,J= 0.7Hz,1H),7.14-7.11(m,1H),4.58(dt,J=13.3,3.5Hz,2H),4.48(d,J=6.0Hz,2 H),3.86(s,3H),3.01(td,J=12.8,2.7Hz,2H),2.56(dd,J=7.6,3.8Hz,1H),2.3 1(d,J=1.0Hz,3H),2.01(d,J=2.2Hz,3H),1.85-1.73(m,2H),1.61-1.49(m,2H).

[0177] compound 48 N-(cyclohex-1-en-1-ylmethyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] The title compound 48 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid in 35.2% yield following the procedure outlined for compound 1. LC-MS (m / z) 429.3 [M+H] + . 1H NMR(400MHz,DMSO)δ9.62(s,1H),8.58(d,J=2.0Hz,1H),7.39(s,1H),5.51(s,1H),4.59(d,J=13.2Hz,2H),3.99(s,2H),3.85(s, 3H),3.14(t,J=12.0Hz,2H),3.00(t,J=12.0Hz,2H),2.00(d,J=2.0Hz,3H),1.96(s,2H),1.84-11.72(m,4H),1.60-1.41(m,6H).

[0178] compound 49 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4,5-dimethylthiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 49 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 56.3% yield following the procedure outlined for compound 1. LC-MS (m / z) 444.4 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.29(d,J=2.0Hz,1H),7.37(s,1H),6.37(t,J=5.2Hz,1H),4.74(d,J=13.6Hz,2H),4.63(d,J=5.6Hz,2H),3.93(s,3H),3.06-2 .90(m,2H),2.49-2.41(m,1H),2.32(s,6H),2.30(s,3H),2.08(d,J=2.4H z,3H),1.93(dd,J=12.8,2.4Hz,2H),1.75(ddd,J=16.4,12.0,4.0Hz,2H).

[0179] compound 50 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2-methylthiazol-5-yl)methyl)piperidine-4-carboxamide [ka] The title compound 50 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 52.6% yield following the procedure outlined for compound 1. LC-MS (m / z) 430.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.29(d,J=2.0Hz,1H),7.44(s,1H),7.36(s,1H),5.92(t,J=5.2Hz,1H),4.73(d,J=13.6Hz,2H),4.56(d,J=5.6Hz,2H),3 .92(s,3H),3.01-2.86(m,2H),2.66(s,3H),2.43-2.31(m,1H),2.07(d ,J=2.4Hz,3H),1.93-1.86(m,2H),1.75(ddd,J=16.4,12.4,4.0Hz,2H).

[0180] compound 51 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxy-N-(isothiazol-4-ylmethyl)piperidine-4-carboxamide [ka] The title compound 51 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 46.8% yield following the procedure outlined for compound 1. LC-MS (m / z) 432.3 [M+H] + . 1H NMR(400MHz,DMSO)δ10.08(brs,1H),8.85(s,1H),8.59(d,J=2.0Hz,1H),8.46(s,1H),7.39(s,1H),4.77(s,2H),4.58(d,J=12). 8Hz,2H),3.85(s,3H),3.17-3.07(m,1H),3.03-2.94(m,2H),2.00(d,J=2.0Hz,3H),1.78(d,J=11.2Hz,2H),1.56-1.41(m,2H).

[0181] compound 52 N-((5-cyanopyridin-3-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] Following the procedure outlined for compound 1, 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid and 5-((hydroxyamino)methyl)nicotinonitrile afforded the title compound 52 as an off-white solid in 36.7% yield. 5-((hydroxyamino)methyl)nicotinonitrile was obtained from tert-butyl((tert-butoxycarbonyl)oxy)((5-cyanopyridin-3-yl)methyl)carbamate in the presence of TFA and DCM. 1 H NMR(400MHz,chloroform-d)δ8.79(s,2H),8.31(d,J=1.9Hz,1H),7.97(s,1H),7.31(s,1H),4.90(s,2H),4.74(d,J=13.3Hz,2H),3.90(s, 3H),3.25-3.10(m,1H),3.01(t,J=13.9Hz,2H),2.08(d,J=2.3Hz,3H),1.87-1.82(m,2H),1.67-1.63(m,2H).Mass(m / z):451.2[M+H] + .

[0182] compound 53 N-(3-cyano-5-fluorobenzyl)-3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)-N-hydroxycyclobutane-1-carboxamide [ka] Step 1: Synthesis of methyl 3-((2-chloro-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylate Methyl 3-hydroxycyclobutane-1-carboxylate (2.86 g, 22 mmol), 2-chloro-5-fluoropyridin-4-ol (2.94, 20 mmol), diisopropyl azodicarboxylate, i.e., DIAD (4.85 g, 24 mmol), and PPh3 (6.29 g, 24 mmol) were dissolved in THF (40 mL) at 0° C. The mixture was stirred at 70° C. for 4 h, then concentrated and purified by flash (PE / EA=85 / 15) to give methyl 3-((2-chloro-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylate as a colorless oil (3.47 g, yield: 67.0%).

[0183] Step 2: Synthesis of methyl 3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylate Methyl 3-((2-chloro-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylate (3.47 g, 13.4 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.27 g, 14.7 mmol), tris(dibenzylideneacetone)dipalladium(0) or Pd2(dba)3 (1.23 g, 1.34 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl or XPhos (638 mg, 1.34 mmol), and 2N potassium phosphate or K3PO4 (20 mL, 40.2 mmol) were dissolved in dioxane (40 mL) under nitrogen gas or N2(g) atmosphere. The mixture was stirred at 90° C. for 2 h. Concentration and purification by flash (PE / EA=90 / 10) gave methyl 3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylate as a colorless oil (2.0 g, yield: 46.8%).

[0184] Step 3: Synthesis of 3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylic acid Lithium hydroxide, LiOH (225 mg, 9.4 mmol) was added to a solution of methyl 3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylate (2.0 g, 6.3 mmol) in MeOH (20 mL). The mixture was stirred at room temperature for 3 h. The pH was adjusted to pH 2 by adding 2N HCl and extracted with EtOAc to give 3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylic acid as a yellow oil (1.3 g, yield: 68.4%). Following the procedure outlined for compound 1, 3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)cyclobutane-1-carboxylic acid and N-(3,5-difluorobenzyl)hydroxylamine afforded the title compound 53 as an off-white solid in 7.0% yield. 1 H NMR (400MHz, chloroform-d) δ8.38(d,J=2.9Hz,1H),7.22(s,1H),6.80(m,4H),5.13-4.90(m,1H),4.77(s,2H),3 .85(s,3H),3.80-3.70(m,1H),2.90-2.72(m,2H),2.62-2.46(m,2H),2.06(s,3H).LC-MS(m / z):447.2[M+H] + .

[0185] compound 54 N-(3,5-difluorobenzyl)-3-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluoropyridin-3-yl)oxy)-N-hydroxycyclobutane-1-carboxamide [ka] Following the procedure outlined for compound 53, 3-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluoropyridin-3-yl)oxy)cyclobutane-1-carboxylic acid and N-(3,5-difluorobenzyl)hydroxylamine afforded the title compound 54 as an off-white solid in 10.2% yield. 1H NMR (400MHz, chloroform-d) δ7.31-7.27(m,1H),7.19(d,J=7.7Hz,2H),6.92-6.70(m,3H),5.02(d,J=46.9Hz,1H),4.81 (s,2H),3.94(s,3H),3.83-3.67(m,1H),2.90-2.72(m,2H),2.58-2.49(m,2H),2.11(s,3H).Mass(m / z):447.2[M+H] + .

[0186] compound 55 N-(3,5-difluorobenzyl)-1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)-N-hydroxypiperidine-4-carboxamide [ka] Step 1: Synthesis of 2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-amine A mixture of 2-chloro-5-fluoropyrimidin-4-amine (1.13 g, 7.66 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.04 g, 9.19 mmol), Pd2(dba)3 (705 mg, 0.77 mmol), X-Phos (735 mg, 1.54 mmol), and K3PO4 (8.1 g, 38.3 mmol) in dioxane (20 mL) and water (19 mL) was stirred at 100° C. for 4 h under Ar. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by silica column with DCM / MeOH=40 / 1 to give the product as a yellow oil (1.3 g, yield: 82%).

[0187] Step 2: Synthesis of 4-chloro-2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine 2-(1,4-Dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-amine (1.3 g, 6.3 mmol) was added to a mixture of anhydrous copper(II) chloride (1.02 g, 7.6 mol), tert-butyl nitrite (1.3 g, 12.6 mmol) in acetonitrile (800 mL) at 80° C. with stirring. After 3 h, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate, washed with water, brine and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by silica column with DCM / MeOH=30 / 1 to give the product as a yellow solid. (370 mg, yield: 26%)

[0188] Step 3: Synthesis of methyl 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate A mixture of 4-chloro-2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (100 mg, 0.44 mmol), methyl piperidine-4-carboxylate (76 mg, 0.53 mmol), and Cs2CO3 (433 mg, 1.33 mmol) in DMF (10 mL) was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the crude product was used directly in the next step.

[0189] Step 4: Synthesis of 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylic acid To a solution of methyl 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate (140 mg, 0.42 mmol) in THF was added NaOH (15%, 5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the reaction was acidified to pH 3 with 1N HCl. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuum and the crude product was used directly in the next step.

[0190] Step 5: Synthesis of N-(3,5-difluorobenzyl)-1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)-N-hydroxypiperidine-4-carboxamide (compound 55) A mixture of 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylic acid (133 mg, 0.42 mmol), N-(3,5-difluorobenzyl)hydroxylamine (60 mg, 0.38 mmol), HATU (160 mg, 0.42 mmol), and N,N-diisopropylethylamine or DIPEA in DMF was stirred at room temperature for 16 h. The reaction mixture was diluted with water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2SO4. The crude product was purified by preparative HPLC (high performance liquid chromatography) to give 60 mg of the desired product, compound 55, as a white solid. Yield: 31%. LC-MS (m / z) 461.3 (M+H + ). 1 H NMR (400MHz, chloroform-d) δ8.14(d,J=6.5Hz,1H),7.23(s,1H),6.87-6.79(m,2H),6.72(s,1H),4.78(s,2) H),4.60(d,J=13.5Hz,2H),4.07(s,3H),3.25(s,1H),3.13(t,J=14.0Hz,2H),2.26(s,3H),1.90(s,3H).

[0191] compound 56 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,5-dimethylthiazol-4-yl)methyl)piperidine-4-carboxamide [ka] The title compound 56 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid as an off-white solid in 37.6% yield following the procedure outlined for compound 1. LC-MS (m / z) 444.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.28(d,J=2.0Hz,1H),7.36(s,1H),6.32(s,1H),4.77-4.69(m,2H),4.37(d,J=4.8Hz,2H),3.93( s,3H),2.99-2.92(m,2H),2.61(s,3H),2.45-2.35(m,4H),2.08(d,J=2.4Hz,3H),1.96-1.87(m,2H),1.75-1.70(m,2H).

[0192] compound 57 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-4-ylmethyl)piperidine-4-carboxamide [ka] To a stirred solution of 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid (prepared above) (468 mg, 1.46 mmol) and thiazol-4-ylmethanamine hydrochloride (200 mg, 1.33 mmol) in DMF (3 mL) was added HATU (758 mg, 1.99 mmol) and DIEA (515 mg, 3.99 mmol) at rt. The resulting mixture was stirred at 25° C. for an additional 2 h. The resulting mixture was diluted with water (6 mL). The resulting mixture was extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column: spherical C18 40-60 μm, 80 g; mobile phase B: ACN; flow rate: 50 mL / min; gradient: 30% B to 60% B in 20 min; detector: 254 nm. The fractions containing the desired product were collected at 48% B and concentrated under reduced pressure to give the title compound 57 (300 mg, 49.3%) as an off-white solid. 1 H NMR (400MHz, chloroform-d) δ8.84(d,J=2.1Hz,1H),8.24(d,J=1.9Hz,1H),7.36(d,J=0.7Hz, 1H),7.30(d,J=2.1Hz,1H),6.77-6.68(brs,1H),4.65(dt,J=13.7,3.5Hz,2H),4.54(d,J =5.7Hz,2H),3.88(s,3H),2.89(ddd,J=13.4,12.1,2.8Hz,2H),2.37(tt,J=11.7,3.8Hz, 1H),2.01(d,J=2.3Hz,3H),1.86-1.82(m,2H),1.70-1.60(m,2H).LC-MS(m / z)416.4[M+H] + .

[0193] compound 58 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(thiazol-5-ylmethyl)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 1, 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid and thiazol-5-ylmethanamine afforded the title compound 58 as an off-white solid in 51.1% yield. 1 H NMR (400MHz, chloroform-d) δ8.75(d,J=0.8Hz,1H),8.31(d,J=1.9Hz,1H),7.76(d,J=0.9Hz,1H ),7.38(d,J=0.7Hz,1H),6.13(brs,1H),4.75(dt,J=14.0,3.4Hz,2H),4.68(dd,J=6.0,0.9 Hz,2H),3.94(d,J=0.6Hz,3H),2.98(ddd,J=13.4,12.0,2.8Hz,2H),2.42(tt,J=11.6,3.8H z,1H),2.09(d,J=2.3Hz,3H),1.97-1.88(m,2H),1.81-1.69(m,2H).LC-MS(m / z)416.4[M+H] + .

[0194] compound 59 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 1, 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid and thiazol-2-ylmethanamine afforded the title compound 59 as an off-white solid in 55.2% yield. 1H NMR (400MHz, chloroform-d) δ8.31(d,J=1.9Hz,1H),7.73(d,J=3.3Hz,1H),7.39(d,J =0.7Hz,1H),7.33(d,J=3.3Hz,1H),6.56-6.47(brs,1H),4.82-4.73(m,4H),3.9 5(s,3H),3.00(ddd,J=13.4,12.0,2.8Hz,2H),2.49(tt,J=11.5,3.8Hz,1H),2.1 0(d,J=2.3Hz,3H),2.01-1.93(m,2H),1.84-1.79(m,2H).LC-MS(m / z)416.4[M+H] + .

[0195] compound 60 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] Step 1: Synthesis of (2,3,5-trifluorophenyl)methane-d2-amine To a stirred solution of lithium aluminum deuteride, LiAlD4 (1.0 g, 24.82 mmol) in THF (40 mL) was added 2,3,5-trifluorobenzonitrile (1.3 g, 8.27 mmol) under N2 atmosphere at 0°C. The resulting mixture was stirred at 70°C for another 16 h. The reaction was quenched by adding water (10 mL) and 1N NaOH (5 mL). The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give (2,3,5-trifluorophenyl)methane-d2-amine (1.1 g, 81.5%) as a pale yellow oil. LC-MS (m / z) 164.1 [M+H] + .

[0196] Step 2: Synthesis of 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide (compound 60) Following the procedure outlined for compound 1, the title compound 60 was obtained as an off-white solid in 49% yield. 1 H NMR(400MHz,DMSO-d6)δ8.62(brs,J=3.1,0.9Hz,1H),8.42(s,1H),7.45-7.34(m,1H),6.92(dddd,J=9.0,5.1,3.2,2.0Hz,1H),4.48(dt,J=13.2,3.4Hz, 2H),2.96(td,J=12.9,2.7Hz,2H),2.57(s,3H),2.52-2.48(m,1H),2.25(s,3 H),1.83-1.71(m,2H),1.50(qd,J=12.3,4.2Hz,2H).LC-MS(m / z)466.4[M+H] + .

[0197] compound 61 1-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 1, 1-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid and (2,3,5-trifluorophenyl)methan-d2-amine afforded the title compound 61 as an off-white solid in 20.2% yield. LC-MS (m / z) 469.3 [M+H] + .

[0198] compound 62 N-(3,5-difluorobenzyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide [ka] Following the procedure from compound 1, 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxylic acid and (3,5-difluorophenyl)methanamine gave the title compound 62 as a white solid in 56% yield. LC-MS (m / z): 445.3 [M+H] + .1H NMR (400MHz, chloroform-d) δ8.30(d,J=2.0Hz,1H),7.38-7.36(m,1H),6.81-6.76(m,2H),6.71(tt,J=9.0,2.3Hz,1H),5.91-5.79(m,1H),4.82-4.7 3(m,2H),4.44(d,J=5.9Hz,2H),3.93(s,3H),3.04-2.92(m,2H),2.50-2 .39(m,1H),2.08(d,J=2.3Hz,3H),1.99-1.91(m,2H),1.83-1.70(m,2H).

[0199] compound 63 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] Step 1: Synthesis of 1-(2-chloro-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid 2-Chloro-5-fluoro-4-iodopyridine (5.14 g, 20 mmol), methyl piperidine-4-carboxylate (2.58 g, 18 mmol), Pd2(dba)3 (1.83 g, 2.0 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or Xantphos (2.30 g, 4.0 mmol), and t-BuONa (4.8 g, 50.0 mmol) were placed in toluene (100 mL). The mixture was stirred at 125 °C under N2 for 1 h. The mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under vacuum. Purification by silica gel chromatography afforded 1-(2-chloro-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (6.0 g, 85%) as an orange solid. LC-MS(m / z)259.1[M+H] + .

[0200] Step 2: Synthesis of 1-(2-chloro-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide 1-2-Chloro-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (258 mg, 1.0 mmol), thiazol-2-ylmethanamine (225 mg, 1.2 mmol), HATU (570 mg, 1.5 mmol), and DIPEA (645 mg, 5.0 mmol) were dissolved in THF (5 mL) and stirred at 25° C. for 1 h. The mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under vacuum. Purification by silica gel chromatography afforded 1-(2-chloro-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (353 mg, 99%) as a yellow solid. LC-MS (m / z) 354.8 [M+H] + .

[0201] Step 3: Synthesis of 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (compound 63) 1-(2-chloro-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (353 mg, 0.99 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (266 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), X-phos (95 mg, 0.2 mmol), K3PO4 (2N, 1.5 mL, 3.0 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at 110° C. under N2 for 2 h. The mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave the title compound 63 (360 mg, crude, 87%) as a yellow solid. Purification (120 mg) was performed by preparative HPLC to give 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (50 mg, 36.5%) (compound 63) as a white solid. LC-MS (m / z) 415.2 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.30(d,J=5.4Hz,1H),7.71(d,J=3.3Hz,1H),7.33(d ,J=0.6Hz,1H),7.31(d,J=3.3Hz,1H),6.81(d,J=7.4Hz,1H),6.51(t,J=5.6Hz, 1H),4.78(d,J=5.5Hz,2H),3.92(s,3H),3.86-3.79(m,2H),2.95(ddd,J=12.6, 10.5,3.8Hz,2H),2.43(tt,J=9.9,4.8Hz,1H),2.10(s,3H),2.04-1.93(m,4H).

[0202] compound 64 N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-methylpiperidine-4-carboxamide [ka] N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide (compound 2) (40 mg, 0.09 mmol) was dissolved in 2 mL of DMF. Sodium hydride, NaH (8 mg, 0.2 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 min. Iodomethane, MeI (0.1 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction was quenched by adding water and extracted with EtOAc (10×3 mL). The solvent was evaporated to dryness and purified by preparative TLC (PE / EA=1 / 2) to give 10 mg of a brown solid. Yield: 24.2%. LC-MS (m / z): 460.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.38(d,J=2.8Hz,1H),6.78-6.67(m,3H),4.74-4.62(m,2H),4.56(s ,2H),3.12-2.96(m,5H),2.91-2.82(m,1H),2.69(s,3H),2.44(s,3H),1.91-1.81(m,4H).

[0203] compound 65 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 65 was prepared from 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide (compound 5) following the procedure outlined for compound 64 as a pale yellow solid in 14.2% yield. LC-MS (m / z): 478.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ8.37(d,J=2.8Hz,1H),6.89-6.80(m,1H),6.78-6.67(m,1H),4.72-4.66(m,2H),4.6 5(s,2H),3.10(s,3H),3.08-2.98(m,2H),2.89-2.81(m,1H),2.69(s,3H),2.44(s,3H),1.89-1.77(m,4H).

[0204] compound 66 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 66 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide (compound 6) following the procedure outlined for compound 64 in 61.3% yield as a pale yellow solid. LC-MS (m / z): 477.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.30(d,J=2.0Hz,1H),7.37(s,1H),6.88-6.79(m,1H),6.78-6.72(m,1H),4.82-4.71(m,2H),4. 64(s,2H),3.93(s,3H),3.11(s,3H),3.05-2.96(m,2H),2.89-2.77(m,1H),2.08(d,J=2.0Hz,3H),1.88-1.77(m,4H).

[0205] compound 67 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 67 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide (compound 6) following the procedure outlined for compound 64 in 56.5% yield as a pale yellow solid. LC-MS (m / z): 491.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.29(d,J=2.0Hz,1H),7.36(s,1H),6.88-6.77(m,1H),6.76-6.70(m,1H),4.84-4.70(m,2H),4.62(s,2H),3.92 (s,3H),3.41(q,J=7.2Hz,2H),3.05-2.90(m,2H),2.87-2.76(m,1H),2.08(d,J=2.4Hz,3H),1.94-1.73(m,4H),1.25(t,J=7.2Hz,3H).

[0206] compound 68 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-methyl-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide [ka] The title compound 68 was prepared from 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-(2,3,5-trifluorobenzyl)piperidine-4-carboxamide (compound 21) in 59.0% yield as a pale yellow solid following the procedure outlined for compound 64. LC-MS (m / z) 464.4 [M+H + ]. 1H NMR(400MHz,DMSO-d6)δ8.66(t,J=3.0Hz,1H),8.15(d,J=1.1Hz,1H),7.57-7.39(m,1H),6.96-6.75(m,1H),4.60(d,J=14.4Hz) ,4H),4.15(d,J=4.9Hz,3H),3.11(s,3H),3.08-2.94(m,2H),2.79(s,1H),1.81(d,J=12.7Hz,2H),1.55(qt,J=12.4,7.3Hz,2H)

[0207] compound 69 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)-N-methylpiperidine-4-carboxamide [ka] The title compound 69 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)piperidine-4-carboxamide (compound 22) following the procedure outlined for compound 64 in 36.6% yield as an off-white solid. LC-MS (m / z) 458.5 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.1Hz,1H),7.41-7.38(m,1H),4.65-4.55(m,2H),4.54(s,2H),3.86(s,3H),3.2 6(s,3H),3.00-2.88(m,2H),2.75(s,1H),2.29(s,3H),2.01(d,J=2.4Hz,3H),1.75-1.65(m,2H),1.58-1.44(m,2H).

[0208] compound 70 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)-N-ethylpiperidine-4-carboxamide [ka] The title compound 70 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)piperidine-4-carboxamide (compound 22) following the procedure outlined for compound 64 in 36.7% yield as an off-white solid. LC-MS (m / z) 472.6 [M+H + ].H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.1Hz,1H),7.40(s,1H),4.61(d,J=13.1Hz,2H),4.53(s,2H),3.86(s,3H),3.26-2.82(m,4H),2 .57(s,1H),2.29(s,3H),2.02(d,J=2.2Hz,3H),1.67(dd,J=13.1,3.7Hz,2H),1.55(qd,J=12.5,4.1Hz,2H),1.15(s,J=7.0Hz,3H).

[0209] compound 71 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 71 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide (compound 47) following the procedure outlined for compound 64 in 46.4% yield as an off-white solid. LC-MS (m / z) 444.5 [M+H] + . 1H NMR(400MHz,DMSO)δ8.59(dd,J=4.6,2.1Hz,1H),7.41-7.38(m,1H),7.28-7.15(m,1H),4.60(d,J=12.9Hz,2H),3.85(d,J=3.7Hz,3H),3.15(s, 3H),3.10-2.93(m,4H),2.36(d,J=1.1Hz,1H),2.33(d,J=1.1Hz,3H),2.01(s,J=2.2Hz,3H),1.72(dd,J=24.8,12.7Hz,2H),1.61-1.46(m,2H).

[0210] compound 72 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 72 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide (compound 47) following the procedure outlined for compound 64 in 42.8% yield as an off-white solid. LC-MS (m / z) 458.5 [M+H + ]. 1 H NMR(400MHz,DMSO)δ8.59(t,J=2.3Hz,1H),7.39(d,J=1.3Hz,1H),7.19(dd,J=43.3 ,1.1Hz,1H),4.68(s,2H),4.60(dd,J=13.1,9.9Hz,2H),3.85(d,J=3.6Hz,3H),3.5 0(q,J=7.0Hz,2H),3.08-2.95(m,2H),2.36(s,1H),2.32(d,J=1.0Hz,3H),2.01(d, J=2.2Hz,3H),1.77-1.65(m,2H),1.64-1.48(m,2H),1.08(dt,J=66.7,7.0Hz,3H).

[0211] compound 73 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)-N-(methyl-d3)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] The title compound 73 was prepared as a white solid in 40.5% yield from 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide following the procedure outlined for compound 64. 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide was prepared following the procedure outlined for compound 60. LC-MS (m / z) 482.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.16(d,J=6.62Hz,1H),7.31(s,1H),6.87-6.80(m,1H),6.78-6.73(m,1H),4. 65-4.59(m,2H),4.13(s,3H),3.18-3.11(m,2H),2.92-2.85(m,1H),2.27(s,3H),2.00-1.76(m,4H).

[0212] compound 74 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(methyl-d3)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] The title compound 74 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide (compound 60) following the procedure outlined for compound 64 in 30.0% yield as a white solid. LC-MS (m / z) 482.4 [M+H] + .

[0213] compound 75 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-(methyl-d3)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] The title compound 75 was prepared as a white solid in 30.0% yield from 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide following the procedure outlined for compound 64. 1-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide was prepared following the procedure outlined for compound 60. LC-MS (m / z) 469.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.39(d,J=2.36Hz,1H),8.03(s,1H),6.95-6.60(m,2H),4.80-4.65(m,2H),4.23(s,3H),3.12-2.72(m,3H),1.95-1.71(m,4H).

[0214] compound 76 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-(methyl-d3)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] The title compound 76 was prepared as a white solid in 30.0% yield from 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide following the procedure outlined for compound 64. 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide was prepared following the procedure outlined for compound 60. LC-MS (m / z) 483.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.35(d,J=2.74Hz,1H),6.86-6.79(m,1H),6.77-6.72(m,1H),4.72-4. 2(m,2H),3.05-2.96(m,2H),2.86-2.78(m,1H),2.66(s,3H),2.41(s,3H),1.86-1.76(m,4H).

[0215] compound 77 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(methyl-d3)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] The title compound 77 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (compound 59) following the procedure outlined for compound 64 in 30.0% yield as a white solid. LC-MS (m / z) 433.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.31(d,J=2.0Hz,1H),7.72(d,J=3.3Hz,1H),7.40(s,1H),7.33(d,J=3.3Hz,1H),4.89(s,3H),4. 79-4.72(m,2H),3.94(s,3H),3.05-2.97(m,1H),2.91-2.70(m,2H),2.09(s,3H),1.87-1.76(m,2H),1.35-1.22(m,2H).

[0216] compound 78 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(methyl-d3)-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 78 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4-methylthiazol-2-yl)methyl)piperidine-4-carboxamide (compound 47) following the procedure outlined for compound 64 in 30.0% yield as a white solid. LC-MS (m / z) 447.1 [M+H] + .

[0217] compound 79 N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methylpiperidine-4-carboxamide [ka] The title compound 79 was prepared from N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide (compound 43) following the procedure outlined for compound 64 in 52.0% yield as a white solid. LC-MS (m / z) 441.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.58(dd,J=2.9,2.1Hz,1H),7.39(s,1H),5.93(s,0 .5H),5.77(s,0.5H),4.59(d,J=13.1Hz,2H),4.46(s,1H),4.31(s,1H),3.8 5(d,J=2.1Hz,3H),3.65(d,J=12.3Hz,3H),3.15-2.90(m,4H),2.77(s,2H), 2.24-2.15(m,3H),2.02-1.99(m,3H),1.75-1.65(m,2H),1.58-1.44(m,2H).

[0218] compound 80 N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethylpiperidine-4-carboxamide [ka] The title compound 80 was prepared from N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide (compound 43) in 52.0% yield as a white solid following the procedure outlined for compound 64. LC-MS (m / z) 455.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.58(dd,J=3.1,2.1Hz,1H),7.40-7.38(m,1H),5.94(d,J=0.9Hz,0.5H),5.7 6(d,J=0.9Hz,0.5H),4.65-4.53(m,2H),4.42(s,1H),4.31(s,1H),3.85(d,J=2.0Hz,3H),3.65(d,J= 14.1Hz,3H),3.38-3.30(m,1H),3.24(q,J=7.0Hz,1H),3.11-2.84(m,3H),2.23-2.15(m,3H),2.03-1 .97(m,3H),1.72-1.63(m,2H),1.62-1.46(m,2H),1.11(t,J=7.0Hz,1.5H),0.96(t,J=7.0Hz,1.5H).

[0219] compound 81 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-carboxamide [ka] The title compound 81 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-carboxamide (compound 44) ​​following the procedure outlined for compound 64 in 48.0% yield as a white solid. LC-MS (m / z) 427.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.58(dd,J=2.8,2.1Hz,1H),7.64(d,J=2.2Hz,0.5H),7.57(d,J= 2.2Hz,0.5H),7.40-7.38(m,1H),6.14(d,J=2.2Hz,0.5H),5.97(d,J=2.1Hz,0.5H),4.63 -4.55(m,2H),4.53(s,1H),4.39(s,1H),3.85(d,J=2.2Hz,3H),3.79(d,J=12.8Hz,3H),3 .16-2.92(m,4H),2.79(s,2H),2.05-1.98(m,3H),1.78-1.64(m,2H),1.59-1.45(m,2H).

[0220] compound 82 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-carboxamide [ka] The title compound 82 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-carboxamide (compound 44) ​​following the procedure outlined for compound 64 in 63.0% yield as a white solid. LC-MS (m / z) 441.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.58(dd,J=3.0,2.1Hz,1H),7.64(d,J=2.2Hz,0.5H),7.55(d,J=2.2Hz,0.5H),7.40 -7.37(m,1H),6.14(d,J=2.2Hz,0.5H),5.95(d,J=2.2Hz,0.5H),4.65-4.54(m,2H),4.50(s,1H),4.38(s,1H) ,3.85(d,J=2.2Hz,3H),3.78(d,J=14.6Hz,3H),3.41-3.31(m,1H),3.27(q,J=7.0Hz,1H),3.11-2.85(m,3H) ,2.03-1.99(m,3H),1.72-1.63(m,2H),1.63-1.45(m,2H),1.11(t,J=7.1Hz,1.5H),0.96(t,J=7.0Hz,1.5H).

[0221] compound 83 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide [ka] The title compound 83 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide (compound 45) following the procedure outlined for compound 64 in 42.0% yield as a white solid. LC-MS (m / z) 427.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.61-8.56(m,1H),7.68(s,0.4H),7.54(s,0.6H),7.41-7.37(m,1.4H),7.27(s,0.6H),4.59(d,J=13.1Hz,2H),4.45(s,0 .7H),4.27(s,1.3H)3.85(s,3H),3.82-3.75(m,3H),3.13-2.86(m,5H),2 .77(s,1H),2.01(d,J=2.3Hz,3H),1.74-1.63(m,2H),1.59-1.44(m,2H).

[0222] compound 84 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide [ka] The title compound 84 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxamide (compound 45) following the procedure outlined for compound 64 in 34.0% yield as a white solid. LC-MS (m / z) 441.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.60-8.57(m,1H),7.67(s,0.4H),7.52(s,0.6H),7.39(s,1H),7.38-7.36 (m,0.4H),7.26(d,J=0.8Hz,0.6H),4.65-4.53(m,2H),4.42(s,0.8H),4.25(s,1.2H),3.87-3.84(m ,3H),3.82-3.75(m,3H),3.37-3.29(m,1H),3.24(q,J=7.0Hz,1H),3.07-2.81(m,3H),2.01(d,J=2 .3Hz,3H),1.71-1.62(m,2H),1.61-1.47(m,2H),1.13(t,J=7.0Hz,1.8H),0.96(t,J=7.0Hz,1.2H).

[0223] compound 85 N-(3,5-difluorobenzyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methylpiperidine-4-carboxamide [ka] The title compound 85 was prepared from N-(3,5-difluorobenzyl)-1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide (compound 62) following the procedure outlined for compound 64 in 36.0% yield as a white solid. LC-MS (m / z) 459.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.35-8.28 (m, 1H), 7.38 (s, 1H), 6.77-6.67 (m, 3H), 4.85-4.69 (m, 2H), 4.63-4.52 (m, 2H), 3.98-3.91 (m, 3H), 3.10-2.81 (m, 6H), 2.13-2.05 (m, 3H), 1.94-1.74 (m, 4H).

[0224] compound 86 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)-N-methyl-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] The title compound 86 was prepared from 1-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (compound 63) following the procedure outlined for compound 64 in 11.0% yield as a white solid. LC-MS (m / z) 429.3 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 8.30 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 3.3 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 4.88 (d, J = 4.0 Hz, 2H), 3.92 (d, J=2.9Hz,3H),3.86(d,J=12.6Hz,2H),3.17(s,3H),3.00(td,J=12.1,2.7Hz,2H),2.8 5-2.76(m,1H),2.10(d,J=3.9Hz,3H),2.04(t,J=5.9Hz,2H),1.88(d,J=13.6Hz,2H).

[0225] compound 87 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)piperidine-4-carboxamide [ka] The title compound 87 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)piperidine-4-carboxamide (compound 46) following the procedure outlined for compound 64 in 61.0% yield as a white solid. LC-MS (m / z) 445.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.61-8.57(m,1H),7.39(s,1H),4.78(s,2H),4.63-4.54(m,2H),3.87-3.84(m,3H),3.13(s ,3H),3.09-2.94(m,2H),2.86-2.70(m,1H),2.67(s,3H),2.03-1.97(m,3H),1.77-1.64(m,2H),1.58-1.43(m,2H).

[0226] compound 88 N-(3,5-difluorobenzyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-N-methylpiperidine-4-carboxamide [ka] The title compound 88 was prepared from N-(3,5-difluorobenzyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)piperidine-4-carboxamide (compound 42) as a white solid in 69.0% yield following the procedure outlined for compound 64. LC-MS (m / z) 441.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.61-8.59(m,1H),7.34(s,1H),6.98-6.92(m,1H),6.92-6.89(m,2H),6.89-6.86 (m,1H),4.51(s,2H),3.91(s,3H),3.13-2.93(m,8H),2.11(s,3H),1.85-1.75(m,2H),1.57-1.50(m,2H).

[0227] compound 89 N-(3,5-difluorobenzyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-N-ethylpiperidine-4-carboxamide [ka] The title compound 89 was prepared from N-(3,5-difluorobenzyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-4-yl)piperidine-4-carboxamide (compound 42) as a white solid in 45.0% yield following the procedure outlined for compound 64. LC-MS (m / z) 455.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.60(d,J=1.1Hz,1H),7.34-7.33(m,1H),6.99-6.92 (m,1H),6.92-6.88(m,2H),6.88-6.86(m,1H),4.50(s,2H),3.91(s,3H),3.4 1(q,J=7.0Hz,2H),3.26(q,J=7.0Hz,1H),3.18-3.01(m,3H),3.00-2.86(m,1 H),2.11(s,3H),1.83-1.74(m,2H),1.65-1.54(m,2H),1.14(t,J=7.0Hz,3H).

[0228] compound 90 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4,5-dimethylthiazol-2-yl)methyl)-N-methylpiperidine-4-carboxamide [ka] The title compound 90 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((4,5-dimethylthiazol-2-yl)methyl)piperidine-4-carboxamide (compound 49) following the procedure outlined for compound 64 in 45.5% yield as a white solid. LC-MS (m / z) 458.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.29(d,J=2.0Hz,1H),7.37(s,1H),4.79-4.71(m,4H),3.93(d,J=3.2Hz,3H),3.16(s,2H),3. 06-2.90(m,3H),2.87-2.79(m,1H),2.34(d,J=13.6Hz,2H),2.30(s,4H),2.08(d,J=2.0Hz,3H),1.92-1.73(m,4H).

[0229] compound 91 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-((2-methylthiazol-5-yl)methyl)piperidine-4-carboxamide [ka] The title compound 91 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2-methylthiazol-5-yl)methyl)piperidine-4-carboxamide (compound 50) following the procedure outlined for compound 64 in 38.2% yield as a white solid. LC-MS (m / z) 444.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.29(d,J=2.0Hz,1H),7.46(s,1H),7.37(s,1H),4.81-4.71(m,2H),4.66(d,J=24Hz,2H),3.93(s,3H) ,3.10-3.01(m,3H),3.00-2.90(m,2H),2.82-2.74(m,1H),2.68(d,J=20.0Hz,3H),2.08(d,J=2.4Hz,3H),1.80-1.72(m,4H).

[0230] compound 92 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,5-dimethylthiazol-4-yl)methyl)-N-methylpiperidine-4-carboxamide [ka] The title compound 92 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-((2,5-dimethylthiazol-4-yl)methyl)piperidine-4-carboxamide (compound 56) following the procedure outlined for compound 64 in 47.2% yield as a white solid. LC-MS (m / z) 458.4 [M+H] + . 1H NMR(400MHz,CDCl3)δ8.28(d,J=1.6Hz,1H),7.36(s,1H),4.80-4.71(m,2H),4.54(d,J=34.8Hz,2H),3.93(s,3H),3.15(s,2H) ,3.03-2.92(m,2H),2.85-2.75(m,1H),2.59(d,J=6.4Hz,3H),2.39(d,J=6.8Hz,3H),2.08(d,J=1.6Hz,3H),1.88-1.73(m,4H).

[0231] compound 93 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(thiazol-4-ylmethyl)piperidine-4-carboxamide [ka] The title compound 93 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(thiazol-4-ylmethyl)piperidine-4-carboxamide (compound 57) following the procedure outlined for compound 64 in 37.4% yield as an off-white solid. 1 H NMR (400MHz, chloroform-d) δ8.76(d,J=2.1Hz,1H),8.29(d,J=2.0Hz,1H),7.37(s,1H),7.20(d,J=2.0Hz,1H),4.74(s,2H),3. 93(s,3H),3.20(s,3H),3.02-2.95(m,4H),2.87-2.81(m,1H),2.08(s,3H),1.82(t,J=4.6Hz,4H).LC-MS(m / z)430.5[M+H] + .

[0232] compound 94 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-(thiazol-4-ylmethyl)piperidine-4-carboxamide [ka] The title compound 94 was prepared from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(thiazol-4-ylmethyl)piperidine-4-carboxamide (compound 57) following the procedure outlined for compound 64 in 33.6% yield as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ8.79(dd,J=43.8,2.0Hz,1H),8.29(dd,J=4.2,1.9Hz,1H), 7.37(d,J=1.7Hz,1H),7.22-7.10(m,1H),4.80-4.73(m,2H),3.93(d,J=2.5Hz,3H), 3.51(dq,J=21.7,7.1Hz,2H),3.06-2.74(m,3H),2.08(t,J=2.3Hz,3H),1.87(dd,J= 12.1,4.6Hz,1H),1.81-1.72(m,4H),1.25(t,J=7.1Hz,3H).LC-MS(m / z)444.5[M+H] + .

[0233] compound 95 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 64, the title compound 95 was obtained from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (compound 59) and iodomethane as an off-white solid in 47.5% yield. 1H NMR (400MHz, chloroform-d) δ8.31(dd,J=4.1,1.9Hz,1H),7.72(d,J=3.3Hz,1H),7.39(s,1H),7.33(d,J=3.3Hz,1H),4.90(d,J=3.7Hz,2H),4.84-4. 71(m,2H),3.95(d,J=3.6Hz,3H),3.21(d,3H),3.08(s,1H),3.06-2.80( m,2H),2.10(d,J=2.4Hz,3H),1.88-1.81(m,2H).LC-MS(m / z)430.5[M+H] + .

[0234] compound 96 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 64, the title compound 96 was obtained from 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-2-ylmethyl)piperidine-4-carboxamide (compound 59) and iodoethane in 60.4% yield as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ8.32(dd,J=5.6,1.9Hz,1H),7.74(d,J=3.4Hz,1H),7.43( s,1H),7.35(d,J=3.4Hz,1H),4.91(s,2H),4.80(d,J=13.7Hz,2H),3.97(d,J=4.3Hz ,3H),3.54(q,J=7.1Hz,2H),3.09-2.96(m,2H),2.84(td,J=11.0,5.6Hz,1H),2.11 (d,J=2.4Hz,3H),1.93-1.79(m,4H),1.28(t,J=7.1Hz,3H).LC-MS(m / z)444.5[M+H] + .

[0235] compound 97 1-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)-N-(methyl-d3)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 64, the title compound 97 was obtained from 1-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)-N-((2,3,5-trifluorophenyl)methyl-d2)piperidine-4-carboxamide (compound 61) and iodomethane in 17.2% yield as an off-white solid. LC-MS (m / z) 486.4 [M+H] + .

[0236] compound 98 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-methyl-N-(thiazol-5-ylmethyl)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 64, 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-5-ylmethyl)piperidine-4-carboxamide (compound 58) and iodomethane afforded the title compound 98 as an off-white solid in 44.2% yield. 1 H NMR(400MHz,CDCl3)δ8.75(s,1H),8.30(d,J=1.9Hz,1H),7.80-7.75(m,1H),7.37(s,1H),4.84-4.75(m,2H),3.94(s,3H),3.09(s,3H) ),3.05-2.93(m,4H),2.80(tt,J=10.3,4.8Hz,1H),2.09(d,J=2.3Hz,3H),1.80(qd,J=10.3,9.8,4.7Hz,4H).LC-MS(m / z)430.5(M+H) + .

[0237] compound 99 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-ethyl-N-(thiazol-5-ylmethyl)piperidine-4-carboxamide [ka] Following the procedure outlined for compound 64, 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)-N-(thiazol-5-ylmethyl)piperidine-4-carboxamide (compound 58) and iodoethane afforded the title compound 99 as an off-white solid in 29.1% yield. 1 H NMR(400MHz,CDCl3)δ8.73(s,1H),8.30(d,J=1.9Hz,1H),7.76(s,1H),7.37(s,1H),4.71(s,2H),3.94(s,3H),3.40(q,J=7 .2Hz,3H),3.04-2.91(m,3H),2.76(ddt,J=11.2,7.3,3.9Hz,1H),1.90-1.75(m,4H),1.26(s,3H).LC-MS(m / z)444.5[M+H] + .

[0238] Example 2. Biological Assays Compounds 1-99 of the present disclosure (represented as Compound Nos. 1-99 in Table 2 below) were tested for binding and cellular RIP1 inhibitory activity according to the experimental procedures described below.

[0239] material Cell line: HT-29 (ATCC (registered trademark) HTB-38 (trademark)) Culture medium: McCoy's 5A, Gibco, Cat. No. 16600-082 FBS, Gibco, Catalog No. 10099-141C Trypsin: Gibco, Catalog Number 25200-056 DMSO: Sigma, Catalog No. 67-68-5, 1L Assay plate: Corning #3903 Compound dilution plate: Corning #3357 Inducer: TNFα, GenScript, Catalog No. Z01001-50 SmacM, Catalog No. HY-15989, MedChemExpress (MCE) Z_VAD FMK, TargetMol, T6013 Cell Titer-Glo® Luminescent Cell Viability Assay Kit: Promega, Catalog No. G7573 EnVision:PerkinElmer, 2105-0010

[0240] method

[0241] Cell seeding 1. HT-29 cells were checked daily to ensure they were healthy and growing as expected. They were subcultured when they were approximately 80% confluent. 2. The culture medium, McCoy's 5A Medium (Gibco, Catalog No. 16600-082) containing 10% Fetal Bovine Serum or FBS (Gibco, Catalog No. 10099-141C), was pre-warmed in a 37° C. water bath for at least 30 minutes. 3. Once the cells reached the desired level of 80% confluence in the T75 flask, the medium was aspirated and the cells were washed twice with warm phosphate buffered saline or PBS. 4. Add 2-3 mL of freshly warm trypsin (Gibco, Cat. No. 25200-056) solution to the washed cells. Transfer the flask with cells to a 37°C incubator. After 5.5 minutes, the flask was examined under a microscope for cell detachment from the flask by tapping the side of the flask. If necessary, the cells were kept in the incubator for an additional 5-10 minutes with occasional tapping until lifting was complete. Neutralize the trypsin reaction by transferring 6.6-9 mL of cell culture medium to a sterile 15 mL conical tube and centrifuging the cell culture at 300 x g for 7 min to pellet the cells (decant the supernatant). 7. The cells were resuspended in fresh cell culture medium and the cell number was counted using a hemocytometer. 8. 100 μL of the resuspended cell culture medium containing approximately 5,000 cells was transferred to each well of a sterile 96-well cell culture plate (Corning 3903) and incubated overnight at 37° C. with 5% CO 2 .

[0242] Compound titration and treatment 1. All test compounds were dissolved in DMSO (dimethyl sulfoxide) to prepare 20 mM stocks. 2.3 μL of each compound 20 mM stock was mixed with 27 μL of DMSO and compound solutions were further diluted in titration ratios of 1:3 (20 μL compound solution + 40 μL DMSO) until 10 points were completed. 3. All culture medium was removed from the assay plate filled with HT-29 cell cultures. The cells were then washed with 1×PBS and resuspended in fresh FBS-free McCoy's 5A medium containing a cocktail of TNF-α (10 ng / mL), SMAC mimetic compound (6 μM), and Z-VAD-fluoromethylketone, or zVAD-FMK (10 μM), to stimulate HT-29 cells to increase RIP1 kinase levels and necroptosis. 4. 0.5 μL of the diluted compound solution was added to the corresponding 96-well assay plate. 5. The assay plate was incubated at 37° C. with 5% CO2 for 20 hours.

[0243] Cell viability detection 1. The CellTiter-Glo® Luminescent Cell Viability Assay Kit was used to detect ATP levels in live HT-29 cells. 2. CellTiter-Glo® buffer and lyophilized substrate were equilibrated to room temperature prior to use. 3. CellTiter-Glo® Substrate was resuspended in CellTiter-Glo® Buffer and then mixed by gentle vortexing to obtain a homogenous solution. 4. 20 μL of the enzyme / substrate mixture was transferred to a 96-well assay plate by multichannel pipetting. 5. The assay plate was placed on an orbital shaker and the contents were shaken for 3 minutes to induce cell lysis. 6. The assay plate was incubated at room temperature for 10 minutes to stabilize the luminescent signal. 7. The luminescence signal was read and recorded using EnVision. 8. Geometric mean EC 50 Values ​​were calculated from 10 replicate response doses.

[0244] The cellular RIP1 inhibitory activity of the test compounds is summarized in Table 2. In Table 2, activity is provided as follows: +++ = 0.1 nM ≦ EC 50 <100nM;++=100nM≦EC 50 <1000nM; +=1000nM ≤ EC 50 <10000nM.

[0245] [Table 2]

[0246] All publications, including but not limited to disclosures and disclosed applications, cited herein are incorporated by reference as if fully set forth. In the event that the specific content of a publication cited herein contradicts or is inconsistent with the present disclosure, the present disclosure shall control.

[0247] Those skilled in the art will readily recognize from the disclosure and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure, as defined in the following claims.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, X is C or N; When X is N, X １ and X ２ is C; If X is C, then X １ and X ２ does not exist; When X is C then Y is O, or when X is N then Y is absent; X ３ is C or N; Here, the valence of C is a hydrogen atom and / or R ４ Filled with; R ａ is hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, or -OH; R ｂ and R ｃ are each independently hydrogen, C １ ~C ４ Alkyl, or C １ ~C ４ is heteroalkyl; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; 【Chemistry 2】 but 【Chemistry 3】 If Ar １ cannot be furanyl; When X is C and Y is O, Ar ２ and Ar ３ are each independently phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; When X is N and Y is absent, 【Chemistry 4】 teeth: 【Chemistry 5】 and Where: (i) 【Chemistry 6】 but 【Chemistry 7】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, or absent; (ii) 【Chemistry 8】 but 【Chemistry 9】 If: Ar １ cannot be furanyl; Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; however, 【Chemistry 10】 teeth, 【Chemistry 11】 cannot be; (iii) 【Chemistry 12】 but 【Chemistry 13】 If 【Chemistry 14】 teeth 【Chemistry 15】 and (iv) 【Chemistry 16】 but 【Chemistry 17】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; however, 【Chemistry 18】 teeth, 【Chemistry 19】 cannot be; (v) 【Chemistry 20】 but 【Chemistry 21】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; (vi) 【Chemical 22】 but 【Chemistry 23】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; (vii) 【Chemistry 24】 but 【Chemistry 25】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; (viii) 【Chemistry 26】 but 【Chemical 27】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; however, 【Chemistry 28】 teeth, 【Chemical 29】 cannot be; (ix) 【Chemistry 30】 but 【Chemistry 31】 If Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; R １ , R ２ , R ３ , and R ４ is, for each occurrence, independently selected from halogen, cyano, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)(C ３ ~C ６ cycloalkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , and -S(=O) ｗ N.R. ｐ R ｑ is selected from: R １ , R ２ , R ３ , and R ４ Any one of the C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, the C ２ ~C ６ Alkenyl, and the C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl) １ ~C ６ Alkyl, and -C(=O)(C ３ ~C ６ Cycloalkyl) ３ ~C ６ Cycloalkyl is independently halogen, cyano, -C(=O)R ｓ , -C(=O)OR ｓ , -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , and -S(=O) ｗ N.R. ｐ R ｑ and optionally substituted with 1 to 3 groups selected from R ｐ , R ｑ , and R ｒ is, for each occurrence, independently selected from hydrogen and C １ ~C ４ alkyl; R ｐ , R ｑ , and R ｒ Any one of the C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R ｓ is, for each occurrence, independently selected from hydrogen and C １ ~C ４ alkyl; R ｓ Any one of the C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; w is an integer selected from 1 and 2; m, n, p, and q are each integers independently selected from 0, 1, 2, and 3, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

2. The compound has the following structural formula IIa: 【Chemistry 32】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

3. The compound has the following structural formula IIIa-1: 【Chemical 33】 [In the formula, Ar １ and Ar ３ are each independently phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

4. The compound has the following structural formula IIIa-2: 【Chemical 34】 [In the formula, Ar １ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; １ cannot be furanyl; Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; 【Chemistry 35】 teeth, 【Chemical 36】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

5. The compound has the following structural formula IIIa-3: 【Chemical 37】 [In the formula, Ar １ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; 【Chemical Formula 38】 teeth, 【Chemical 39】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

6. The compound has the following structural formula IIIa-4: 【Chemistry 40】 [In the formula, Ar １ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; 【Chemistry 41】 teeth, 【Chemistry 42】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

7. The compound has the following structural formula IIIa-5: 【Chemistry 43】 [In the formula, Ar １ and Ar ３ are each independently phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

8. The compound has the following structural formula IIIa-6: 【Chemistry 44】 [In the formula, Ar １ and Ar ３ are each independently phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

9. The compound has the following structural formula IIIa-7: 【Chemistry 45】 [In the formula, Ar １ and Ar ３ are each independently phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

10. The compound has the following structural formula IIIa-8: 【Chemistry 46】 [In the formula, Ar １ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; Ar ３ is phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; 【Chemistry 47】 teeth, 【Chemistry 48】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

11. The compound has the following structural formula IIIa-9: 【Chemistry 49】 [In the formula, Ar １ and Ar ３ are each independently phenyl, C ５ ~C ６ carbocyclyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

12. The compound has the following structural formula IVa-1: 【Chemistry 50】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

13. The compound has the following structural formula IVa-2: 【Chemistry 51】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5-6 membered heteroaryl; 【Chemistry 52】 teeth, 【Chemistry 53】 cannot be; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

14. The compound has the following structural formula IVa-3: 【Chemical 54】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; 【Chemistry 55】 teeth 【Chemistry 56】 and R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

15. The compound has the following structural formula IVa-4: 【Chemistry 57】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5-6 membered heteroaryl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

16. The compound has the following structural formula IVa-5: 【Chemistry 58】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5-6 membered heteroaryl or a 5- or 6-membered heterocyclyl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

17. The compound has the following structural formula IVa-6: 【Chemistry 59】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5-6 membered heteroaryl or a 5- or 6-membered heterocyclyl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

18. The compound has the following structural formula IVa-7: 【Chemistry 60】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

19. The compound has the following structural formula IVa-8: 【Chemistry 61】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; 【Chemistry 62】 teeth, 【Chemistry 63】 cannot be; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

20. The compound has the following structural formula IVa-9: 【Chemistry 64】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ alkyl, or -OH; Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ３ is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ heteroalkyl; where R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; and q is an integer selected from 0 and 1; a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

21. Ar １ is phenyl, cyclohexyl, cyclohexenyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, or pyridinyl; each of m R １ 21. The compound of claim 1, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt, optionally substituted with a group.

22. Ar １ teeth, 【Chemistry 65】 each of m R １ 22. The compound of claim 1, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt, optionally substituted with a group.

23. Ar １ is m R １ 23. The compound of any one of claims 1 to 22, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt thereof, wherein R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11, R is 12, R is 13, R is 1

24. Ar ３ is p R ３ 24. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1-3, 6-9, 11, 12, 15-18, and 20-23, wherein R is a 5-membered heteroaryl optionally substituted with a group.

25. Ar ３ contains 1 to 3 nitrogen atoms and p R ３ 25. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1-3, 6-9, 11, 12, 15-18, and 20-24, wherein R is a 5-membered heteroaryl optionally substituted with a group.

26. Ar ３ is p R ３ is a 5-membered heteroaryl optionally substituted with a group; 【Chemistry 66】 teeth, 【Chemistry 67】 14. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1, 2, 4, and 13, wherein

27. Ar ３ contains 1 to 3 nitrogen atoms and p R ３ is a 5-membered heteroaryl optionally substituted with a group; 【Chemistry 68】 teeth, 【Chemistry 69】 30. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1, 2, 4, 13, and 26, wherein

28. Ar ３ is triazolyl, thiadiazolyl, or pyrazolyl; each of p R ３ 26. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1-3, 6-9, 11, 12, 15-18, and 20-25, wherein:

29. Ar ３ is pyrazolyl, triazolyl, or thiadiazolyl; each of p R ３ group; p is an integer selected from 0, 1, and 2; 【Chemistry 70】 teeth, 【Chemistry 71】 30. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1, 2, 4, 13, 26, and 27, wherein

30. Ar ３ teeth, 【Chemical Formula 72】 each of p R ３ 29. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1-4, 6-13, and 15-28, wherein:

31. R ａ is hydrogen, -CH ３ , -CD ３ , -CH ２ CH ３ or -OH.

32. R ｂ and R ｃ are each independently hydrogen, deuterium, or -CH ２ 32. The compound of any one of claims 1 to 31, wherein R is 0, R is 1 or R is 2.

32. The compound of any one of claims 1 to 31, wherein R is 0, R is 1 or R is 2.

33. R ｂ and R ｃ are both hydrogen; R ｂ and R ｃ are both deuterium; or R ｂ and R ｃ One of the groups is hydrogen and the other is -CH ２ 33. The compound of any one of claims 1 to 32, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt thereof, wherein R is 0, R is 1 or R is 2;

34. The compound has the following structural formula IIb: 【Chemical 73】 [In the formula, R ａ is hydrogen, C optionally substituted with 1 to 3 deuterium atoms １ ~C ２ 2. The compound of claim 1, wherein: R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R,

35. The compound has the following structural formula IIIb: 【Chemical Formula 74】 35. The compound of claim 1 or 34, which is a compound of the formula:

36. Ar １ is phenyl, C ５ ~C ６ carbocyclyl, or 5-6 membered heteroaryl; Ar ２ is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R ｂ and R ｃ are each independently hydrogen, deuterium, C １ ~C ２ Alkyl, or C １ ~C ２ is heteroalkyl; Here, R ｂ and R ｃ The above C １ ~C ２ Alkyl and R ｂ and R ｃ The above C １ ~C ２ Each heteroalkyl is independently optionally substituted with 1 to 3 deuterium atoms; 36. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1, 34, and 35, wherein q is an integer selected from 0 and 1.

37. Ar １ is phenyl or C ６ carbocyclyl; each of m R １ is optionally substituted with a group; Ar ２ is a 5-6 membered heteroaryl; each n R ２ 37. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1 and 34-36, optionally substituted with a group.

38. Ar ２ is a 6-membered heteroaryl; each of n R ２ 37. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1 and 34-36, optionally substituted with a group.

39. Ar ２ is pyridinyl or pyrimidinyl; each of n R ２ 40. The compound of any one of claims 1 and 34-38, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt, optionally substituted with a group.

40. The compound has the following structural formula IVb-1: 【Chemistry 75】 or a tautomer thereof; a deuterated derivative of said compound or said tautomer; or a pharma- ceutically acceptable salt of the foregoing.

41. The compound has the following structural formula IVb-2: 【Chemical 76】 wherein q is an integer selected from 0 and 1, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

42. Ar １ is m R １ 42. The compound of any one of claims 1 and 34-41, wherein R is phenyl optionally substituted with a group, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt.

43. Ar ３ is a 5- to 6-membered heteroaryl, or a 5- or 6-membered heterocyclyl; ３ 43. The compound of any one of claims 1 and 34-42, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt, optionally substituted with a group.

44. Ar ３ is p R ３ 44. The compound of any one of claims 1 and 34-43, wherein R is a 5-membered heteroaryl optionally substituted with a group, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt.

45. Ar ３ is p R ３ 45. The compound of any one of claims 1 and 34-44, wherein R is a pyrazolyl optionally substituted with a group, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt.

46. 【Catalogue 77】 teeth, 【Chemical 78】 46. ​​The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1 and 34-45,

47. R １ , R ２ , R ３ , and R ４ is, for each occurrence, independently selected from halogen, cyano, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenyl, C １ ~C ４ Alkoxy, -C(=O)(C １ ~C ４ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ and —OH; Here, R １ , R ２ , R ３ , and R ４ Any one of the C １ ~C ４ Alkyl, the C ２ ~C ４ Alkenyl, and the C １ ~C ４ Alkoxy, and -C(=O)(C １ ~C ４ alkyl) １ ~C ４ each alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R ｐ , R ｑ , and R ｒ is, for each occurrence, independently selected from hydrogen and C １ ~C ４ 47. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1 to 46, wherein:

48. R １ , R ２ , R ３ , and R ４ is, for each occurrence, independently selected from halogen, cyano, C １ ~C ２ Alkyl, C １ ~C ２ 48. The compound, tautomer, deuterated derivative of said compound or said tautomer, or pharma- ceutically acceptable salt of any one of claims 1 to 47, wherein said compound is selected from -alkoxy, and -OH.

49. R １ For each occurrence, F, Cl, cyano, CF ３ , C.F. ２ H, and -CH ３ 49. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1 to 48, independently selected from:

50. R ２ is F for each occurrence, a tautomer, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt thereof.

51. R ３ For each occurrence, -CH ３ 51. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1 to 50,

52. R ４ For each occurrence, F and -CH ３ 52. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1 to 51, independently selected from:

53. 53. The compound, tautomer, deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of any one of claims 1 to 52, wherein p is an integer selected from 1 and 2.

54. The compound comprising: 【Chemical Formula 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemistry 84】 2. The compound of claim 1 selected from: a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

55. 55. A pharmaceutical composition comprising a compound according to any one of claims 1 to 54, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and at least one pharma- ceutically acceptable carrier.

56. 56. A pharmaceutical composition according to claim 55 for use in the treatment of a disease or condition, comprising The pharmaceutical composition, wherein the disease or condition is selected from an inflammatory disease, an immune disease, an allergic disease, a transplant rejection, a necrotic cell disease, a neurodegenerative disease, a central nervous system (CNS) disease, an ischemic brain injury, an eye disease, an infectious disease, and a malignant tumor.

57. 57. The pharmaceutical composition of claim 56, wherein the disease or condition is mediated by receptor interacting protein 1 (RIP1) signaling.

58. 56. The pharmaceutical composition of claim 55 for use in the treatment of a disease or condition mediated by receptor interacting protein 1 (RIP1) signaling.

59. 59. The pharmaceutical composition of any one of claims 56 to 58, wherein the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infection.

60. 56. The pharmaceutical composition of claim 55 for use in inhibiting receptor interacting protein 1 (RIP1).

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