Receptor-interacting protein 1 inhibitors containing piperazine heterocyclic amide ureas

Abstract

The present disclosure provides compounds, including piperazine heterocyclic amide urea compounds (including the corresponding sulfonamides), that inhibit cell necrosis and / or human receptor-interacting protein 1 kinase (RIP1), and pharmaceutically acceptable salts, hydrates, and stereoisomers thereof. The compounds of the present invention are used in pharmaceutical compositions and methods of use and manufacturing, including treating a person in need thereof with an effective amount of a compound or composition of the present invention and detecting a resulting improvement in the person's health or condition.

Description

[Background technology]

[0001] This application claims priority to International Patent Application No. PCT / CN2020 / 091429, filed May 20, 2020, the entire contents of which are incorporated herein by reference.

[0002] <Introduction>

[0003] Tumor necrosis factor alpha (TNF-α)-induced NF-κB activation plays a central role in the immune system and inflammatory responses. Receptor-interacting protein 1 (RIP1) is a multifunctional signal transduction pathway involved in mediating nuclear factor κB (NF-κB) activation, apoptosis, and necroptosis. The kinase activity of RIP1 is critically involved in mediating necroptosis, a caspase-independent necrotic cell death pathway. Holler et al., Nat Immunol 2000;1:489-495; Degterev et al., Nat Chem Biol 2008;4:313-321.

[0004] Necroptosis plays a role in cell death in a variety of pathological conditions, including ischemic brain injury, neurodegenerative diseases, and viral infections. Dunai et al., Dec 2011, Pathol. Oncol. Res: POR 17 (4): 791-800. Necrostatin-1 (Nec-1), a small molecule inhibitor of RIP1 kinase activity, can block necroptosis. Degterev et al., Nat Chem Biol 2005; 1: 112-119.

[0005] RIP1 can contribute to D-1 immunotherapy resistance (e.g., Manguso et al., 2017 Nature 547, 413-418) and may act as a checkpoint kinase that governs tumor immunity (e.g., Wang et al., Cancer Cell 34, 757-774, Nov 12, 2018).

[0006] Related patent publications include the following: US9974762, US10092529, US6756394, US8278344, US20120122889, US20090099242, US20100317701, US20110144169, US20030083386, US201200309795, WO2009023272, WO2010075290, WO2010075561, WO2012125544 and WO2020 / 103884. Summary of the Invention

[0007] <Summary of the Invention>

[0008] The present invention provides compounds that are inhibitors of necrosis, necroptosis, ferroptosis, human receptor-interacting protein 1 kinase (RIP1) or related indications, and prodrugs thereof that are hydrolyzed, typically in the intestine or blood, to yield the corresponding inhibitor. In embodiments, these inhibitors provide unexpectedly excellent metabolic stability, as evidenced by liver microsomal and PK data.

[0009] In one aspect, the present invention provides a compound of formula Ia, or a salt, hydrate, or stereoisomer thereof: JPEG0007774579000001.jpg74127 (in the formula, R1 is a C6 aryl containing 0 or 1 N heteroatom, optionally substituted at C3 and / or C5 with halogen or CN; R2 is a C6 aryl containing 0, 1 or 2 N heteroatoms, optionally substituted at C4 with halogen or C1-C3 alkoxy; Y is O or N; When Y is N, m is 2, and JPEG0007774579000002.jpg2471, When Y is O, m is 1, and JPEG0007774579000003.jpg1371, R3 and R4 are independently H or alkyl or cycloalkyl or -OR S and for example, H or C1-C6 alkyl or cycloalkyl or -OR S and for example, H or C1-C3 alkyl or C3-C6 cycloalkyl or -OR S where R S is a C1-C6 alkyl optionally substituted with halogen and a C3-C6 cycloalkyl; wherein the alkyl and cycloalkyl, or the C1-C6 alkyl and cycloalkyl, or the C1-C3 alkyl and C3-C6 cycloalkyl, are each independently substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl, and wherein R3 and R4 may be linked to form a heterocycle.

[0010] In one aspect, the present invention provides a compound of formula I, or a salt, hydrate, or stereoisomer thereof: JPEG0007774579000004.jpg79127 (in the formula, R1 is a C6 aryl containing 0 or 1 N heteroatom, optionally substituted at C3 and / or C5 with F or CN; R2 is a C6 aryl containing 0, 1 or 2 N heteroatoms, optionally substituted at C4 with F; R3 and R4 are independently H or C1-C3 alkyl substituted with 0-3 substituents selected from halide, optionally substituted N, S or O, and optionally substituted hydrocarbyl, wherein R3 and R4 may be linked to form a heterocycle.

[0011] In embodiments:

[0012] R3 and R4 substituents are independently C0-C6: aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, or trifluoromethyl ether (OCF3);

[0013] R2 comprises N2, N4 or N2 / N4; or

[0014] Any combination of the above substituents.

[0015] In one aspect, the invention provides compounds having the structures disclosed herein.

[0016] In one aspect, the present invention provides pharmaceutical compositions, in predetermined, unit dosage form, comprising a therapeutically effective amount of a compound disclosed herein, a salt, hydrate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0017] In one aspect, the present invention provides the use of a compound, a salt, a hydrate or a stereoisomer thereof, or a composition disclosed herein in the manufacture of a medicament for inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof.

[0018] In certain aspects, the present invention provides a compound, a salt, a hydrate or a stereoisomer thereof, or a composition disclosed herein for use in inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof, or for use in the manufacture of a medicament therefor in a person in need thereof.

[0019] In certain aspects, the present invention provides methods of using a compound, a salt, a hydrate or stereoisomer thereof, or a composition disclosed herein to inhibit necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof, or in the manufacture of a medicament therefor.

[0020] The present invention includes all combinations of the specific embodiments described herein, each and every combination being contemplated as being fully described herein. DETAILED DESCRIPTION OF THE INVENTION

[0021] Description of Specific Embodiments of the Invention

[0022] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or variations will be suggested to those skilled in the art based thereon, and that such modifications or variations are intended to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0023] The term "alkyl" refers to a hydrocarbon group selected from straight-chain or branched-chain saturated hydrocarbon groups having 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0024] Lower alkyl means having 1 to 8, preferably 1 to 6, more preferably 1 to 4, for example 1 to 3 carbon atoms, and lower alkenyl or lower alkynyl means having 2 to 8, 2 to 6 or 2 to 4 carbon atoms.

[0025] The term "alkenyl" refers to a hydrocarbon group containing at least one C=C double bond and selected from straight or branched chain hydrocarbon groups having 2 to 18 carbon atoms, 2 to 12 carbon atoms, or 2 to 6 carbon atoms. Examples of alkenyl groups may be selected from ethenyl or vinyl groups, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0026] The term "alkylene" refers to a hydrocarbon group containing a ═C double bond and selected from straight and branched chain hydrocarbon groups having 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, where the point of attachment is through the ═C group of the alkylene. For example: In JPEG0007774579000005.jpg2524, the cyclobutene is substituted with a C1 alkylene, i.e., methylene, group.

[0027] The term "alkynyl" refers to a hydrocarbon group containing at least one C≡C triple bond and selected from straight or branched chain hydrocarbon groups having 2 to 18 carbon atoms, 2 to 12 carbon atoms, or 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0028] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups and partially unsaturated cyclic hydrocarbon groups, including monocyclic groups and polycyclic groups (e.g., bicyclic and tricyclic groups). For example, the cycloalkyl group may have 3 to 12, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Also, for example, the cycloalkyl group may be a monocyclic group having 3 to 12, 3 to 8, 3 to 6, or 5 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a bicyclic group selected from a [4,4], [4,5], [5,5], [5,6], and [6,6] ring system, or as a bridged bicyclic group selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. These rings may be saturated, may contain at least one double bond (i.e., may be partially unsaturated), but are not fully conjugated and are not aromatic as defined herein.

[0029] As used herein, the term "aryl" refers to a group selected from a 5- or 6-membered carbocyclic aromatic ring (such as phenyl); a bicyclic ring system (such as a 7- to 12-membered bicyclic ring system) in which at least one ring is carbocyclic aromatic (such as a bicyclic ring system selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline); and a tricyclic ring system (such as a 10- to 15-membered tricyclic ring system) in which at least one ring is carbocyclic aromatic (such as fluorene).

[0030] For example, an aryl group may be selected from a 5- or 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring or heterocycle, optionally containing at least one heteroatom selected from N, O, and S. When the carbocyclic aromatic ring is fused to a heterocycle, the point of attachment is on the carbocyclic aromatic ring; when the carbocyclic aromatic ring is fused to a cycloalkyl group, the point of attachment may be on either the carbocyclic aromatic ring or the cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are called substituted phenylene radicals. In monovalent polycyclic hydrocarbon radicals whose names end in "yl," divalent radicals derived by removing one hydrogen atom from the carbon atom having the free valence are named by adding "idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two points of attachment is called naphthylidene.

[0031] The term "halogen" or "halo" refers to F, Cl, Br, or I.

[0032] The term "heteroalkyl" refers to an alkyl that includes at least one heteroatom.

[0033] The term "heteroaryl" refers to a group selected from:

[0034] a 5- to 7-membered aromatic (e.g., 5- to 6-membered aromatic) monocyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;

[0035] an 8- to 12-membered bicyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0036] An 11- to 14-membered tricyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, in which at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0037] For example, heteroaryl groups include 5- to 7-membered heteroaromatic rings fused to 5- to 7-membered cycloalkyl rings. In such fused bicyclic heteroaryl ring systems, where only one ring contains at least one heteroatom, the point of attachment can be on either the heteroaromatic ring or the cycloalkyl ring.

[0038] When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less.

[0039] Examples of heteroaryl groups (numbered from the position of attachment 1) include pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), and the like. benzo[d]thiazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0040] The terms "heterocyclic," "heterocycle," or "heterocyclyl" refer to a 4-12-membered (e.g., 3-6, 3-5, 4-5, 5-6, or 4-6-membered), monocyclic, bicyclic, or tricyclic saturated or partially unsaturated ring containing at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen. "Heterocycle" also refers to a 5- to 7-membered heterocycle containing at least one heteroatom selected from N, O, and S fused to a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic, or heterocyclic aromatic ring; when the heterocycle is fused to a carbocyclic or heterocyclic aromatic ring, the point of attachment is on the heterocycle; when the heterocycle is fused to a cycloalkyl, the point of attachment can be on either the cycloalkyl or heterocycle.

[0041] Furthermore, "heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, where the point of attachment is at the heterocycle. These rings may be saturated or have at least one double bond (i.e., may be partially unsaturated). The heterocycle may be substituted with oxo. The point of attachment may be at a carbon or a heteroatom of the heterocycle. A heterocycle is not a heteroaryl as defined herein.

[0042] Examples of heterocyclic rings (numbered starting from the bonding position) include 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, and oxetanyl. , thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4- Examples include, but are not limited to, thiazepanyl, 1,4-diazepane, 1,4-dithianyl, 1,4-azathiyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0043] As used herein, the term "fused ring" refers to a polycyclic ring system (e.g., a bicyclic or tricyclic ring system) in which two rings share only two ring atoms and one bond. Examples of fused rings include fused bicyclic cycloalkyl rings, such as those having 7 to 12 ring atoms arranged as a bicyclic group selected from the aforementioned [4,4] ring system, [4,5] ring system, [5,5] ring system, [5,6] ring system, and [6,6] ring system; fused bicyclic aryl rings, such as the aforementioned 7- to 12-membered bicyclic aryl ring system; fused tricyclic aryl rings, such as the aforementioned 10- to 15-membered tricyclic aryl ring system; fused bicyclic heteroaryl rings, such as the aforementioned 8- to 12-membered bicyclic heteroaryl ring; fused tricyclic heteroaryl rings, such as the aforementioned 11- to 14-membered tricyclic heteroaryl ring; and the aforementioned fused bicyclic heterocyclyl rings and fused tricyclic heterocyclyl rings.

[0044] In an embodiment, the substituents are selected from optionally substituted heteroatoms and optionally substituted, heteroatom-containing, and cyclic C1-C18 hydrocarbyls. In particular, the optionally substituted, heteroatom-containing, and cyclic C1-C18 hydrocarbyl is optionally substituted, heteroatom-containing, and cyclic alkyl, alkenyl, or alkynyl, or optionally substituted, heteroatom-containing aryl; and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (alkoxy, aryloxy, etc.), optionally substituted acyl (formyl, alkanoyl, carbamoyl, carboxyl, amido, etc.), optionally substituted amino (amino, alkylamino, dialkylamino, amido, sulfamidyl, etc.), optionally substituted thiol (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyl (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0045] In embodiments, the substituents are halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SONR′″, —NR″COR′, —NH—C( The number of substituents is 0 to 3, and groups having 0, 1, or 2 substituents are particularly preferred. R', R'', and R''' each independently represent hydrogen, unsubstituted (C1 to C8) alkyl and heteroalkyl, (C1 to C8) alkyl and heteroalkyl substituted with 1 to 3 halogen atoms, unsubstituted aryl, aryl substituted with 1 to 3 halogen atoms, unsubstituted alkyl group, unsubstituted alkoxy group, unsubstituted thioalkoxy group, or aryl-(C1 to C4) alkyl group. When R' and R" are attached to the same nitrogen atom, R' and R" can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. Thus, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl, "alkyl" includes groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3), and when the aryl group is 1,2,3,4-tetrahydronaphthalene, the aryl group can be optionally substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group can be optionally substituted as defined herein for "cycloalkyl."

[0046] Preferred substituents are selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″COR′, —NR′-SONR″R′″, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, where R′ and R″ are as defined above.

[0047] Preferred substituents are disclosed herein, specific examples of which are given in the tables, structures, examples, and claims, and may be applied to a variety of different compounds of the invention, i.e., the substituents of a given compound may be used in combination with another compound.

[0048] In certain embodiments, applicable substituents are each independently a substituted or unsubstituted heteroatom, a substituted or unsubstituted C1-C6 alkyl, C1-C3 alkyl, or C1-C2 alkyl having 0-3 heteroatoms, a substituted or unsubstituted C2-C6 alkenyl having 0-3 heteroatoms, a substituted or unsubstituted C2-C6 alkynyl having 0-3 heteroatoms, or a substituted or unsubstituted C5-C14 aryl, C6-C14 aryl, or C5-C6 aryl having 0-3 heteroatoms, and each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0049] In more specific embodiments, each applicable substituent is independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamide, carboxyl, cyanyl, ester, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, or trifluoromethyl ether (OCF3).

[0050] Combinations of substituents disclosed herein are those that result in the formation of stable or chemically feasible compounds. If, by omission or convention, a hydrogen atom bonded to an atom (e.g., a carbon atom C or a nitrogen atom N) is not specifically designated in a chemical structure, formula, or representation, the hydrogen atom is deemed to be present to the extent that the valence of that atom (e.g., C or N) is satisfied.

[0051] The compounds of the present invention may have asymmetric centers and therefore may exist as enantiomers. When the compounds of the present invention have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers are included in the broader definition of stereoisomers. All possible stereoisomers, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers, are intended to be included in the present invention. Also, all possible stereoisomers of the compounds of the present invention and / or pharmaceutically acceptable salts thereof are intended to be included in the present invention. Unless otherwise specified herein, a reference to one isomer applies to all possible isomers. If the isomeric composition is not specified, all possible isomers are included.

[0052] The term "substantially pure" means that the stereoisomer of interest contains no more than 35% by weight of other stereoisomers, such as no more than 30% by weight, further such as no more than 25% by weight, further such as no more than 20% by weight. In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains no more than 10% by weight of other stereoisomers, such as no more than 5% by weight, for example no more than 1% by weight.

[0053] Unless otherwise specified specifically herein, when compounds of the invention contain olefinic double bonds, such double bonds are meant to include both E and Z geometric isomers.

[0054] Some compounds of the present invention may have different points of attachment of hydrogen, and such compounds are called tautomers. For example, a compound having a carbonyl group (-CHC(O)-) (keto form) may form a hydroxyl group (-CH=C(OH)-) (enol form) through tautomerism. Where applicable, both the keto and enol forms are intended to be included, both individually and as mixtures of the keto and enol forms.

[0055] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products from each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a single solvent or a mixture of solvents, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase chromatography; size-exclusion chromatography; ion-exchange chromatography; high-, medium-, and low-pressure liquid chromatography methods and devices; small-volume analytical chromatography; simulated moving bed ("SMB") chromatography; preparative thin-layer chromatography; preparative thick-layer chromatography; and small-volume thin-layer and flash chromatography techniques. One skilled in the art will be able to apply the technique most likely to achieve the desired separation.

[0056] Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomeric mixtures can be converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting each resulting diastereomer into its corresponding pure enantiomer (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0057] Single stereoisomers (e.g., substantially pure enantiomers) may be obtained by resolving a racemic mixture, such as by forming diastereomers using an optically active resolving agent. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including, for example, (1) forming ionic diastereomeric salts with chiral compounds and separating them by methods such as fractional crystallization, (2) forming diastereomeric compounds with chiral derivatizing reagents, separating the diastereomers, and converting them to pure stereoisomers, and (3) directly isolating substantially pure or enriched stereoisomers under chiral conditions.

[0058] The "pharmaceutically acceptable salt" includes, for example, inorganic acid salts selected from hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, etc.; and, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoate (acetate, etc.), HOOC-(CH2) n -COOH (n is selected from 0 to 4), and the like. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0059] Furthermore, if a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) may be prepared by dissolving the free base in a suitable organic solvent and treating the resulting solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be aware of the various synthetic methods available for preparing pharmaceutically acceptable, non-toxic addition salts without undue experimentation.

[0060] "Treating," "treat," or "treatment" refers to administering at least one compound, and / or at least one stereoisomer thereof, and / or at least one hydrate thereof, and / or at least one pharmaceutically acceptable salt thereof to a subject identified in need thereof.

[0061] An "effective amount" refers to an amount of at least one compound, and / or at least one stereoisomer thereof, and / or at least one hydrate thereof, and / or at least one pharmaceutically acceptable salt thereof, sufficient to be effective in "treating" a disease or disorder in a subject, e.g., when administered, to induce to some significant extent a desired biological or medical response in a tissue, system, animal, or human, and to prevent the development of, or alleviate to some extent, one or more symptoms of, the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0062] The term "at least one substituent" includes, for example, 1 to 4 substituents, such as 1 to 3 substituents, and further, for example, 1 or 2 substituents. For example, as used herein, "at least one substituent R 16 " is R 16 The group may contain 1 to 4 substituents, for example 1 to 3 substituents, further for example 1 or 2 substituents selected from the list of:

[0063] The compounds of the present invention, their stereoisomers, hydrates thereof, and pharmaceutically acceptable salts thereof may be used alone to provide therapy, or may be used in combination with at least one other therapeutic agent to provide therapy. In some embodiments, the compounds of the present invention, their stereoisomers, hydrates thereof, and pharmaceutically acceptable salts thereof may be used in combination with at least one additional therapeutic agent. The compounds disclosed herein and / or one pharmaceutically acceptable salt may be administered together with at least one other therapeutic agent in a single dosage form, or in separate dosage forms. When administered in separate dosage forms, the at least one other therapeutic agent may be administered before, simultaneously with, or after the administration of the compounds disclosed herein and / or one pharmaceutically acceptable salt.

[0064] Additionally, compositions are provided comprising a compound of the present invention, a stereoisomer thereof, a hydrate thereof, and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0065] Compositions containing the compounds of the present invention, their stereoisomers, hydrates thereof, and / or pharmaceutically acceptable salts thereof can be administered by a variety of known methods, including oral, topical, rectal, parenteral, inhalation spray, and implanted reservoirs. In each case, the most appropriate route will depend on the individual host and the nature and severity of the condition for which the active ingredient is being administered. As used herein, the term "parenteral" encompasses subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently provided in unit dosage form and may be prepared by any method well known in the art.

[0066] The compounds of the present invention, their stereoisomers, hydrates thereof, and pharmaceutically acceptable salts thereof can be orally administered in solid dosage forms such as capsules, tablets, troches, dragees, granules, powders, etc., or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, suspensions, etc. The compounds of the present invention disclosed herein, their stereoisomers, hydrates thereof, and / or pharmaceutically acceptable salts thereof can also be parenterally administered in sterile liquid dosage forms such as dispersions, suspensions, solutions, etc. The compounds of the invention disclosed herein, their stereoisomers, hydrates thereof, and / or pharmaceutically acceptable salts thereof may also be administered using other dosage forms, such as ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions (i.e., eye drops) for ophthalmic administration; aerosol spray or powder compositions for inhalation or intranasal administration; and creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0067] Gelatin capsules containing the compounds disclosed herein and / or at least one pharmaceutically acceptable salt thereof and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid can also be used. Similar diluents can also be used to prepare compressed tablets. Tablets and capsules can also be prepared as sustained-release formulations for continuous release of the drug over a period of time. Compressed tablets can be sugar-coated or film-coated to mask unpleasant tastes or protect the tablet from the atmosphere, or enteric-coated to selectively disintegrate in the digestive tract.

[0068] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring agents and flavoring agents to facilitate patient administration.

[0069] In general, examples of suitable carriers for parenteral solutions include water, suitable oils, saline, aqueous dextrose (glucose), related sugar solutions, and glycols (such as propylene glycol or polyethylene glycol). Solutions for parenteral administration may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Examples of suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, which may be used alone or in combination. Examples of suitable stabilizers include citric acid and its salts and sodium EDTA. Furthermore, parenteral solutions may contain at least one preservative, such as benzalkonium chloride, methylparaben, propylparaben, and chlorobutanol.

[0070] Pharmaceutically acceptable carriers are selected from carriers that are compatible with the active ingredients in the composition (and, in some embodiments, can stabilize the active ingredients) and are not harmful to the subject being treated. For example, solubilizing agents such as cyclodextrins (which can form specific, highly soluble complexes with at least one compound and / or at least one pharmaceutically acceptable salt disclosed herein) can be used as pharmaceutical excipients for delivery of the active ingredients. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (such as D&C Yellow #10). Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0071] For inhalation administration, the compounds of the present invention, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts thereof may be conveniently delivered in the form of an aerosol spray from a pressurized container or inhaler. Alternatively, the compounds of the present invention, their stereoisomers, hydrates, and pharmaceutically acceptable salts thereof may be formulated and delivered as powders, and such powder compositions may be inhaled using an insufflation powder inhaler. An example of a delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution containing the compounds of the present invention disclosed herein, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts thereof in at least one suitable propellant, such as fluorocarbons and hydrocarbons.

[0072] For ocular administration, the ophthalmic preparation may be formulated as a suspension or solution containing the compound of the present invention, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof in an appropriate weight percentage in an appropriate ophthalmic solvent, thereby maintaining contact of the compound of the present invention, its stereoisomer, its hydrate, and / or at least one pharmaceutically acceptable salt thereof with the surface of the eye for a sufficient period of time to allow the compound to penetrate the cornea and the interior of the eye.

[0073] Pharmaceutical dosage forms useful for administering the compounds of the invention disclosed herein, their stereoisomers, hydrates thereof, and / or pharmaceutically acceptable salts thereof include, but are not limited to, hard gelatin capsules, soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

[0074] The dosage will depend on factors such as the recipient's age, health, and weight, the severity of the disease, the type of treatment, if any, the frequency of treatment, and the characteristics of the desired effect. Generally, the daily dosage of the active ingredient may vary, but may be, for example, 0.1 to 2,000 mg per day. For example, 10 to 500 mg administered once or multiple times daily may be effective to achieve the desired results.

[0075] In some embodiments, for example, a number of unit capsules can be prepared by filling a standard two-piece hard gelatin capsule with 100 mg of a powdered compound of the invention disclosed herein, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

[0076] In some embodiments, a soft gelatin capsule containing 100 mg of the active ingredient can be prepared by preparing a mixture of the compound of the present invention, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof with a digestible oil such as soybean oil, cottonseed oil, or olive oil, and injecting the mixture into gelatin using a positive displacement pump.The capsules are then washed and dried.

[0077] In some embodiments, bulk tablets can be prepared by conventional methods so that, for example, a single dosage contains 100 mg of the compound of the present invention, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate coatings may be applied to improve palatability or delay absorption.

[0078] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound disclosed herein and / or at least one enantiomer, diastereomer, or pharmaceutically acceptable salt thereof in 10% by volume propylene glycol. The solution is made up to volume with water for injection and sterilized.

[0079] In some embodiments, an aqueous suspension for oral administration can be prepared, for example, 5 mL of an aqueous suspension containing 100 mg of a micronized compound of the present invention, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP), and 0.025 mL of vanillin can be used.

[0080] When the compound of the present invention, its stereoisomer, its hydrate, and / or their pharmaceutically acceptable salts are administered stepwise or together with at least one other therapeutic agent, the same dosage form can usually be used. When the drugs are administered in physical combination, the dosage form and administration route should be selected according to the compatibility of the combined drugs. Therefore, the term "co-administration" is understood to include simultaneous or sequential administration of at least two drugs, or administration of at least two active ingredients as a fixed-dose combination.

[0081] The compounds disclosed herein, their stereoisomers, hydrates thereof, and / or pharmaceutically acceptable salts thereof can be administered as the sole active ingredient or can be administered in combination with at least one second active ingredient.

[0082] The compounds of the present invention, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts are incorporated into pharmaceutical compositions or formulations. These compositions contain a pharmaceutically acceptable diluent and / or carrier, i.e., a diluent or carrier that is physiologically compatible and substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing administrable compositions are known or apparent to those skilled in the art and are described in further detail in publications such as Remington's Pharmaceutical Science, Mack Publishing Co., NJ (1991). These compositions may also be in the form of controlled-release or sustained-release compositions known in the art. In many applications, the compounds of the present invention, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts are administered in the morning / midday with a nighttime off-peak period.

[0083] The compounds of the present invention, their stereoisomers, hydrates thereof, and / or pharmaceutically acceptable salts may be used as they are or in the form of a pharmaceutically acceptable salt such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compounds of the present invention have a relatively acidic functional group, a salt can be obtained by adding a desired base in a solvent-free or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salt, potassium salt, calcium salt, ammonium salt, organic amino salt, magnesium salt, etc. When the compounds of the present invention have a relatively basic functional group, a salt can be obtained by adding a desired acid in a solvent-free or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginate and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0084] The neutral compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in physical properties such as solubility in polar solvents, but for purposes of the present invention, the salts are otherwise equivalent to the parent form of the compound.

[0085] In addition to salt forms, the present invention provides compounds in prodrug forms. Prodrugs of the compounds described herein are compounds that are readily chemically altered under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. In some situations, prodrugs are often useful because they are easier to administer than the parent drug. For example, prodrugs may have better oral bioavailability than the parent drug. Prodrugs may also have improved solubility in pharmacological compositions compared to the parent drug. Various prodrug derivatives are known in the art, including, for example, prodrugs that utilize hydrolysis or oxidative activation. Examples of prodrugs include, but are not limited to, compounds of the present invention that are administered as esters ("prodrugs") and then metabolically hydrolyzed to the active carboxylic acid.

[0086] Certain compounds of the present invention may exist in unsolvated form or in solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is intended to be included within the scope of the present invention.Certain compounds of the present invention may exist in various crystalline forms or amorphous forms.In general, all physical forms are equivalent for the use envisioned by the present invention, and all are intended to be included within the scope of the present invention.

[0087] Some of the compounds of the present invention, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts contain asymmetric carbon atoms (optical centers) or double bonds; all of the racemates, diastereomers, geometric isomers, and individual isomers thereof are intended to be encompassed within the scope of the present invention.

[0088] The compounds of the present invention may contain isotopes such as deuterium at one or more of the constituent atoms of the compound in proportions not found in nature, for example, -CD3, CD2H, or CDH2 in place of methyl. For example, the compounds of the present invention may contain isotopes such as tritium ( 3 H), iodine-125( 125 I), carbon-14 ( 14 The compounds of the present invention may be radiolabeled with a radioisotope such as C. All compounds of the present invention that contain isotopes, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present invention.

[0089] The compounds of the invention are typically administered in a "therapeutically effective amount," i.e., an amount of a compound of the invention that will induce in a tissue, system, animal, or human the biological or medical response desired by a researcher, veterinarian, physician, or other clinician. The term "therapeutically effective amount" encompasses that amount of compound sufficient, when administered, to prevent the development of, or alleviate to some extent, one or more symptoms of, the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0090] The contacting is typically achieved by administering to the subject an effective amount of one or more compounds having general formula I (see above), including the various embodiments described above. Generally, the administration is adjusted to provide a therapeutic dose of about 0.1 to 50 mg / kg, preferably 0.5 to 10 mg / kg, and more preferably 1 to 10 mg / kg, although the optimal dose is compound-specific and is generally determined empirically for each compound.

[0091] The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include ampoules or syringes filled with premeasured amounts of liquid compositions, or pills, tablets, capsules, lozenges, and the like for solid compositions. In such compositions, the mimetic is typically present as a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being processing aids and various vehicles or carriers to facilitate the formation of the desired dosage form. Unit dosage formulations are preferably about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, or about 1,000 mg per unit. In one particular embodiment, the unit dosage forms are packaged in a multi-pack package suitable for successive use, for example a blister pack containing sheets containing at least 6, 9 or 12 unit dosage forms.

[0092] The compositions of the present invention may also be co-formulated and / or co-administered with different compounds to treat applicable indications or to treat programmed cell death, which in embodiments include brain injury, neurodegenerative diseases, viral infections, immune tolerance, and promoting tumor immunity in cancer, such as pancreatic cancer and melanoma.

[0093] In one aspect, the present invention provides a compound of formula Ia, or a salt, hydrate, or stereoisomer thereof: JPEG0007774579000006.jpg73127R1 is a C6 aryl containing 0 or 1 N heteroatom, optionally substituted at C3 and / or C5 with halogen or CN; R2 is a C6 aryl containing 0, 1 or 2 N heteroatoms, optionally substituted at C4 with halogen or C1-C3 alkoxy; Y is O or N; When Y is N, m is 2, and JPEG0007774579000007.jpg2471, When Y is O, m is 1, and JPEG0007774579000008.jpg2383, R3 and R4 are independently H or alkyl or cycloalkyl or -OR S and for example, H or C1-C6 alkyl or cycloalkyl or -OR S , for example, H or C1-C3 alkyl or C3-C6 cycloalkyl or -OR S where R S is a C1-C6 alkyl optionally substituted with halogen and a C3-C6 cycloalkyl; wherein the alkyl and cycloalkyl, or the C1-C6 alkyl and cycloalkyl, or the C1-C3 alkyl and C3-C6 cycloalkyl are each independently substituted with 0 to 3 substituents selected from halide, optionally substituted N, S or O, and optionally substituted hydrocarbyl, and wherein R3 and R4 may be linked to form a heterocycle.

[0094] In one aspect, the present invention provides a compound of formula I, or a salt, hydrate, or stereoisomer thereof: JPEG0007774579000009.jpg83127R1 is a C6 aryl containing 0 or 1 N heteroatom, optionally substituted at C3 and / or C5 with F or CN; R2 is a C6 aryl containing 0, 1 or 2 N heteroatoms, optionally substituted at C4 with F; R3 and R4 are independently H or C1-C3 alkyl substituted with 0-3 substituents selected from halide, optionally substituted N, S or O, and optionally substituted hydrocarbyl, wherein R3 and R4 may be linked to form a heterocycle.

[0095] In an embodiment: the R3 and R4 substituents are independently C0-C6: aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, or trifluoromethyl ether (OCF3). R2 comprises N2, N4 or N2 / N4; or Any combination of the above substituents.

[0096] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula II(1): JPEG0007774579000010.jpg78127, where Rd is selected from H, halogen, and C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0097] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula II(1)a: JPEG0007774579000011.jpg78127, wherein R and R, for each occurrence, are independently selected from: H, C-C alkyl, C-C cycloalkyl, and —O(C-C alkyl), where C-C alkyl and C-C cycloalkyl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, and 3-6 membered heterocyclyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0098] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula II(1)b: JPEG0007774579000012.jpg78127 (wherein R5 is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR s ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or NR p R q or C1-C3 alkylene optionally substituted with CN; wherein R S is C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, and R p and R q are each independently selected from H and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0099] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula II(2): JPEG0007774579000013.jpg78127 All other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0100] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula II(2)a: JPEG0007774579000014.jpg78127, where R and R, for each occurrence, are independently selected from: H, C-C alkyl, C-C cycloalkyl, and —O(C-C alkyl), where C-C alkyl and C-C cycloalkyl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, and 3-6 membered heterocyclyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0101] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula II(2)b: JPEG0007774579000015.jpg79127 (wherein R5 is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR S ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, or NR p R q or C1-C3 alkylene optionally substituted with CN; wherein R S is C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, and R p and R q are each independently selected from H and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0102] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(1): JPEG0007774579000016.jpg76127 (wherein R2 is a C6 aryl containing 0, 1 or 2 N heteroatoms, optionally substituted with halogen or C1-C3 alkoxy; R b and R c are each independently selected from H, halogen, and CN; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0103] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(1)a: JPEG0007774579000017.jpg80127, where R and R, for each occurrence, are independently selected from: H, C-C alkyl, C-C cycloalkyl, and —O(C-C alkyl), where C-C alkyl and C-C cycloalkyl are each optionally substituted with 1-3 groups selected from halogen, cyano, and 3-6-membered heterocyclyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0104] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(1)b: JPEG0007774579000018.jpg72127 (wherein R5 is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR s ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or NR p R q or C1-C3 alkylene optionally substituted with CN. Sis C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, and R p and R q are each independently selected from H and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0105] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(2): JPEG0007774579000019.jpg66127 (wherein R2 is a C6 aryl containing 0, 1 or 2 N heteroatoms, optionally substituted with halogen or C1-C3 alkoxy; R b is selected from H, halogen, and CN; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0106] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(2)a: JPEG0007774579000020.jpg73127, where R and R, for each occurrence, are independently selected from: H, C-C alkyl, C-C cycloalkyl, and —O(C-C alkyl), where C-C alkyl and C-C cycloalkyl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, and 3-6 membered heterocyclyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0107] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(2)b: JPEG0007774579000021.jpg72127 (wherein R5 is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR S ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or -NR p R q or C1-C3 alkylene optionally substituted with CN. S is C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, and R p and R q are each independently selected from H and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0108] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula IV(1): JPEG0007774579000022.jpg73127 (in the formula, R b and R c are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; R3 and R4 are linked together to form n R e forming a 5-membered heterocyclyl substituted with R e is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR S ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or -NR p R q or C1-C3 alkylene optionally substituted with CN; wherein Rs is C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, where R p and R q are each independently selected from H and C1-C3 alkyl; where n is 0, 1, or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0109] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula IV(2): JPEG0007774579000023.jpg78127 (in the formula, R b and R c are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; R3 and R4 are linked together to form n R e forming a 4-membered heterocyclyl substituted with R e is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR s ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or -NR p R q C1-C3 alkyl optionally substituted with C1-C3 alkylene optionally substituted with C1-C3 alkyl, s is C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, and R p and R q are each independently selected from H and C1-C3 alkyl; n is 0, 1, or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0110] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula IV(3): JPEG0007774579000024.jpg75127 (in the formula, R b and R c are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; X is C, N, or O; R3 and R4 are linked to form n R e forming a 6-membered heterocyclyl substituted with R e is OH; CN; C3-C6 cycloalkyl; 3-6 membered heterocyclyl; OR s ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or -NR p R q or C1-C3 alkylene optionally substituted with CN; where R s is C1-C3 alkyl optionally substituted with halogen and C3-C6 cycloalkyl, and R p and R q are each independently selected from H and C1-C3 alkyl; n is 0, 1, or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0111] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula IV(4): JPEG0007774579000025.jpg78127 (in the formula, R b and R care each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; where R3 and R4, for each occurrence, are independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, and —O(C1-C3 alkyl), where C1-C3 alkyl and C3-C6 cycloalkyl are each optionally substituted with 1-3 groups selected from halogen, cyano, and 3-6-membered heterocyclyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0112] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R and R, for each occurrence, are independently selected from: H; C-C alkyl; and C-C cycloalkyl; and -OR s wherein the C1-C6 alkyl and C3-C6 cycloalkyl of R3 and R4 are each optionally substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; or R3 and R4, when linked together, represent OH; CN; C3-C6 cycloalkyl; 3- to 6-membered heterocyclyl; ORs; -C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or -NR p R q C1-C3 alkyl optionally substituted with; or forming a 4-6 membered heterocyclyl optionally substituted with C1-C3 alkylene optionally substituted with CN; where R s is C1-C6 alkyl optionally substituted with halogen and C3-C6 cycloalkyl; R p and R qare each independently selected from H and C1-C6 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0113] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R and R, for each occurrence, are independently selected from: H; C-C alkyl; and C-C cycloalkyl; and -OR s wherein the C1-C3 alkyl and C3-C4 cycloalkyl of R3 and R4 are each optionally substituted with 1 to 3 groups selected from cyano and 3- to 6-membered heterocycles; or R3 and R4 are linked together to form OH; CN; C3-C6 cycloalkyl; 3- to 6-membered heterocyclyl; OR s ;-C(=O)NR p R q ;-NR p R q CN, C3-C6 cycloalkyl, 3-6 membered heterocyclyl or -NR p R q or a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkylene optionally substituted with CN; s is C1-C3 alkyl optionally substituted with halogen and C3-C4 cycloalkyl; R p and R q are each independently selected from H and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0114] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R and R, for each occurrence, are independently selected from the following: H, OH, methyl, ethyl, —CHCN, —OCH, JPEG0007774579000026.jpg3167; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0115] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R3 and R4 are linked to form the following: JPEG0007774579000027.jpg74159; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0116] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R1 is optionally substituted with F, Cl, or CN; R2 is optionally substituted with F, Cl, or —OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0117] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has one of the structural formulas in Table 1.

[0118] Table 1: Active compounds: Structure [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0119] The cellular RIP1 inhibitory activities of test compounds 1 to 67 are summarized in Table 2. In Table 2, the activities are provided as follows: +++=0.1 nM≦EC50<100 nM; ++=100 nM≦EC50<1000 nM; +=1000 nM≦EC50<10000 nM.

[0120] Table 2: Cellular activity; necrosis or necroptosis inhibitory activity [Table 2-1] [Table 2-2] [Example]

[0121] Example 1

[0122] Synthesis of representative compounds The above intermediate was synthesized and isolated as a racemate. Chiral HPLC separation afforded the S-enantiomer of the intermediate (ee%>98%). Compound 1: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylic acid Step 1: To a solution of ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (3.5 g, 17.0 mmol) in DMF (0 mL) was added (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (5 g, 17.0 mmol) and TEA (3.44 g, 34.0 mmol). The reaction was stirred at 45 °C for 4 h. The mixture was purified by flash column chromatography (EtOAc / PE = 0% to 10%). 2.2 g of ethyl 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylate was obtained as a yellow solid. Yield: 27.8%. LC-MS (m / z) 463.1 (M+H + ). Step 2: To a solution of ethyl 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylate (2.1 g) in THF (25 mL) was added 1N NaOH (25 mL). The reaction mixture was stirred at 50° C. for 2 hours. 1.7 g of (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylic acid was obtained as a yellow solid. Yield: 86.2%. LC-MS (m / z) 435.3 (M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12 (d, J = 2.2 Hz, 1H), 6.65 (t, J = 1.7 Hz, 1H), 6.62-6.56 (m, 2H), 6.45 (tt, J = 8.9, 2.3 Hz, 1H), 5.07 (dd, J = 11.7, 9.9 Hz, 1H), 3.70-3.60 (m, 2H), 3.59-3.45 (m, 4H), 3.43-3.32 (m, 2H), 3.14-3.06 (m, 1H), 2.49-2.41 (m, 1H). Compound 2: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-hydroxypyrimidine-4-carboxamide JPEG0007774579000036.jpg67159 Step 1: To a solution of 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylic acid (600 mg, 1.38 mmol) in THF (20 mL) was added 1 drop of DMF and SOCl2 (822 mg, 6.91 mmol). The reaction was stirred at 0° C. to 40° C. for 1 h. The solvent was removed in vacuo and the crude product was used directly in the next step. Step 2: To a solution of 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride (100 mg, 220.8 umol) in DCM (5 mL) at 0° C. under Ar, DIPEA (5 mL) and hydroxylamine hydrochloride (31 mg, 441.7 umol) were added. The reaction mixture was stirred at 20° C. for 1 h. The mixture was purified by reverse phase chromatography. 36 mg of (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-hydroxypyrimidine-4-carboxamide was obtained as a pale yellow solid. Yield: 36.3%. LC-MS (m / z) 450.1 (M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 11.35 (s, 1H), 9.34 (brs, 1H), 8.58 (d, J = 2.4 Hz, 1H), 7.14 - 7.06 (m, 2H), 7.02 - 6.94 (m, 2H), 5.24 (dd, J = 11.6, 9.9 Hz, 1H), 3.84-3.45 (m, 8H), 3.35 (ddd, J = 18.3, 11.7, 1.9 Hz, 1H), 2.63 (ddd, J = 18.3, 10.0, 1.6 Hz, 1H). Compound 3: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-methoxypyrimidine-4-carboxamide JPEG0007774579000037.jpg27159 The title compound 3 was prepared in 62.1% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 464.1(M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 11.83 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.14-7.05 (m, 2H), 7.02-6.94 (m, 2H), 5.24 (dd, J = 11.6, 9.9 Hz, 1H), 3.86-3.45 (m, 11H), 3.35 ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.63 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 4: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-methoxypyrimidine-4-carboxamide JPEG0007774579000038.jpg27159 The title compound 4 was prepared in 65.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 448.1(M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (d, J = 4.9 Hz, 1H), 8.60 (d, J = 2.8 Hz, 1H), 7.17-7.07 (m, 2H), 7.00 (dt, J = 7.0, 2.2 Hz, 2H), 5.26 (dd, J = 11.6, 9.9 Hz, 1H), 3.89-3.48 (m, 8H), 3.37 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.66 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 5: 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N,N-dimethylpyrimidine-4-carboxamide JPEG0007774579000039.jpg31159 The title compound 5 was prepared in 56.3% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 462.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.26 (d, J = 1.1 Hz, 1H), 6.87-6.77 (m, 3H), 6.72-6.66 (m, 1H), 5.33 (dd, J = 11.7, 9.9 Hz, 1H), 3.92-3.81 (m, 2H), 3.81-3.68 (m, 4H), 3.66-3.56 (m, 2H), 3.31 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 3.12 (s, 3H), 2.96 (s, 3H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 6: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-N-ethyl-5-fluoro-N-methylpyrimidine-4-carboxamide JPEG0007774579000040.jpg37159 The title compound 6 was prepared in 58.1% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 476.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.26-8.25 (m, 1H), 6.88-6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 9.9 Hz, 1H), 3.92-3.81 (m, 2H), 3.80-3.69 (m, 4H), 3.65-3.54 (m, 2H), 3.37-3.20 (m, 3H), 3.09 (s, 2H), 2.92 (s, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 1.29-1.21 (m, 2H), 1.18 (t, J = 7.1 Hz, 2H). Compound 7: (S)-Azetidin-1-yl(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)methanone JPEG0007774579000041.jpg29159 The title compound 7 was prepared in 69.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 474.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.30 (d, J = 1.9 Hz, 1H), 6.89-6.78 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.33(dd, J = 11.7, 9.9 Hz, 1H), 4.37-4.29 (m, 2H), 4.28-4.19 (m, 2H), 3.93-3.56 (m, 8H), 3.32 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.43-2.29 (m, 2H). Compound 8: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(pyrrolidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000042.jpg30159 The title compound 8 was prepared in 73.5% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 488.1(M+H + ).1 H NMR (400 MHz, CDCl3) δ (ppm): 8.30 (d, J = 1.9 Hz, 1H), 6.89-6.78 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.33(dd, J = 11.7, 9.9 Hz, 1H), 4.37-4.29 (m, 2H), 4.28-4.19 (m, 2H), 3.93-3.56 (m, 12H), 3.37-3.34 (m, 1H), 2.73-2.63 (m, 1H), 1.99-1.91 (m, 4H). Compound 9: (S)-N-Cyclopropyl-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-methylpyrimidine-4-carboxamide JPEG0007774579000043.jpg28159 The title compound 9 was prepared in 63.7% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 488.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.25 (d, J = 1.9 Hz, 1H), 6.87 - 6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.32 (dd, J = 11.7, 9.9 Hz, 1H), 3.90-3.82 (m, 2H), 3.80-3.70 (m, 4H), 3.66 -3.57 (m, 2H), 3.31 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 3.11 (s, 3H), 2.81-2.75 (m, 1H), 2.68 (ddd, J = 18.2, 9.9, 1.6 Hz, 1H), 0.64 - 0.55 (m, 4H). Compound 10: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000044.jpg28159 The title compound 10 was prepared in 63.7% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 557.2(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.30 (d, J = 2.0 Hz, 1H), 6.88-6.77 (m, 3H), 6.68 (tt, J = 8.8, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 9.9 Hz, 1H), 4.57 (t, J = 8.6 Hz, 1H), 4.36 (dd, J = 10.8, 7.8 Hz, 1H), 4.19 (dd, J = 9.8, 4.7 Hz, 1H), 3.96-3.56 (m, 9H), 3.31 (ddd, J = 18.3, 11.8, 1.8Hz, 1H), 3.19-3.17 (m, 3H), 3.00-2.93 (d, J = 28.0 Hz, 4H), 2.68 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H), 2.01-1.97 (m, 4H). Compound 11: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-N-ethyl-5-fluoro-N-hydroxypyrimidine-4-carboxamide JPEG0007774579000045.jpg38159 The title compound 11 was prepared in 43.5% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 478.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.72 (d, J = 1.8 Hz, 1H), 7.27-7.16 (m, 3H), 7.09 (tt, J = 9.1, 2.4 Hz, 1H), 5.72 (dd, J = 11.7, 10.0 Hz, 1H), 4.33-3.94 (m, 8H), 3.79-3.63 (m, 1H), 3.15-3.00 (m, 1H), 2.12 - 1.96 (br, 1H), 1.78-1.67 (m, 2H), 1.63 (t, J = 7.0 Hz, 3H). Compound 12: (S)-(3,3-Difluoroazetidin-1-yl)(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)methanone JPEG0007774579000046.jpg38159 The title compound 12 was prepared in 39.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 510.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.37 (d, J = 2.2 Hz, 1H), 6.89-6.79 (m, 3H), 6.70 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.73 (td, J = 11.8, 1.4 Hz, 2H), 4.50 (td, J = 11.8, 1.4 Hz, 2H), 3.90-3.59 (m, 8H), 3.33 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 13: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-hydroxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000047.jpg35159 The title compound 13 was prepared in 67.3% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 490.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.31 (d, J = 2.0 Hz, 1H), 6.88-6.79 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.76-4.71 (m, 1H), 4.56-4.50 (m, 1H), 4.49-4.41 (m, 1H), 4.26-4.22 (m, 1H), 4.08- 4.04 (m, 1H), 3.91-3.56 (m, 8H), 3.32 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 14: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000048.jpg38159 The title compound 14 was prepared in 42.6% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 516.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.32 (d, J = 2.0 Hz, 1H), 6.89 - 6.80 (m, 3H), 6.70 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.87-4.77 (m, 4H), 4.51 (d, J = 1.2 Hz, 2H), 4.35 (d, J = 1.1 Hz, 2H), 3.92-3.58 (m, 8H), 3.33 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 15: (3S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)pyrrolidine-3-carbonitrile JPEG0007774579000049.jpg37159 The title compound 15 was prepared in 63.8% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 513.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.32 (dd, J = 4.5, 1.3 Hz, 1H), 6.87 - 6.77 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.10-3.54 (m, 11H), 3.39-3.15 (m, 2H), 2.69 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.48-2.25 (m, 2H). Compound 16: (3R)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)pyrrolidine-3-carbonitrile JPEG0007774579000050.jpg36159 The title compound 16 was prepared in 65.3% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 513.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.32 (dd, J = 4.5, 1.3 Hz, 1H), 6.87 - 6.77 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.10-3.54 (m, 11H), 3.39-3.15 (m, 2H), 2.69 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.48-2.25 (m, 2H). Compound 17: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(piperidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000051.jpg38159 The title compound 17 was prepared in 68.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 502.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 1.0 Hz, 1H), 6.86-6.78 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 3.93-3.53 (m, 12H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 1.93-1.53 ​​(m, 6H). Compound 18: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(morpholine-4-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000052.jpg38159 The title compound 18 was prepared in 61.7% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 504.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.27 (d, J = 1.0 Hz, 1H), 6.87-6.79 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 3.91-3.54 (m, 16H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 19: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(4-methylpiperazine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000053.jpg36159 The title compound 19 was prepared in 56.3% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 517.2(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.26 (d, J = 1.0 Hz, 1H), 6.88 - 6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 3.91-3.54 (m, 12H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.50 (t, J = 5.1 Hz, 2H), 2.44 - 2.37 (m, 2H), 2.33 (s, 3H). Compound 20: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-hydroxy-N-methylpyrimidine-4-carboxamide JPEG0007774579000054.jpg40159 The title compound 20 was prepared in 45.8% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 464.1(M+H + ).1 H NMR (400 MHz, CDCl3) δ (ppm): 8.31 (dd, J = 13.6, 1.3 Hz, 1H), 6.88 - 6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.4 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 3.93-3.58 (m, 8H), 3.41 (s, 3H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.9, 1.7 Hz, 1H). Compound 21: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000055.jpg37159 The title compound 21 was prepared in 46.1% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 504.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.31 (d, J = 2.0 Hz, 1H), 6.88-6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.52-4.32 (m, 2H), 4.3-4.18 (m, 2H), 4.07 (ddd, J = 11.1, 3.8, 1.4 Hz, 1H), 3.93-3.56 (m, 8H), 3.36-3.28 (m, 4H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 22: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methoxy-3-methylazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000056.jpg38159 The title compound 22 was prepared in 42.5% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 518.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.31 (d, J = 2.0 Hz, 1H), 6.88-6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.30 (dd, J = 9.8, 3.6 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 4.04 (ddd, J = 9.7, 3.6, 1.5 Hz, 1H), 3.95 (dd, J = 10.7, 1.4 Hz, 1H), 3.90-3.56 (m, 11H), 3.32 (ddd, J = 18.3, 11.7, 1.9 Hz, 1H), 3.26 (d, J = 0.4 Hz, 3H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 23: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3-ethoxyazetidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000057.jpg36159 The title compound 23 was prepared in 39.4% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 518.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.31 (d, J = 2.0 Hz, 1H), 6.88-6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 10.0 Hz, 1H), 4.5-4.43 (m, 1H), 4.41-4.30 (m, 2H), 4.27-4.19 (m, 1H), 4.13-4.02 (m, 1H), 3.92-3.56 (m, 8H), 3.53-3.39 (m, 2H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H), 1.23 (td, J = 7.0, 2.5 Hz, 3H). Compound 24: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-isopropoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000058.jpg36159 The title compound 24 was prepared in 45.3% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 532.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.30 (d, J = 1.9 Hz, 1H), 6.87-6.79 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 10.0 Hz, 1H), 4.51-4.34 (m, 3H), 4.26 - 4.18 (m, 1H), 4.11 - 4.02 (m, 1H), 3.92 - 3.54 (m, 9H), 3.32 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H), 1.16 (dd, J = 8.5, 6.1 Hz, 6H). Compound 25: (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)azetidine-3-carbonitrile JPEG0007774579000059.jpg38159 The title compound 25 was prepared in 56.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 499.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.36 (d, J = 2.2 Hz, 1H), 6.89-6.78 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 10.0 Hz, 1H), 4.77-4.67 (m, 2H), 4.56-4.47 (m, 1H), 4.42 (dd, J = 10.5, 6.4 Hz, 1H), 3.89-3.52 (m, 9H), 3.39-3.26 (m, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 26: (S)-1-(2-(4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)pyrrolidine-3-carboxamide JPEG0007774579000060.jpg35159 The title compound 26 was prepared in 53.6% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 531.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.28 (d, J = 1.2 Hz, 1H), 6.89-6.78 (m, 3H), 6.69 (dddt, J = 10.4, 8.0, 2.5, 1.3 Hz, 1H), 5.65 (br, 1H), 5.50 (br, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.07-3.44 (m, 12H), 3.38-3.20 (m, 1H), 3.03 (ddd, J = 12.7, 8.1, 4.7 Hz, 1H), 2.68 (ddt, J = 18.1, 10.0, 1.6 Hz, 1H), 2.37-2.12 (m, 2H). Compound 27: (R)-1-(2-(4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)pyrrolidine-3-carboxamide JPEG0007774579000061.jpg35159 The title compound 27 was prepared in 55.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 531.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.28 (d, J = 1.2 Hz, 1H), 6.89-6.78 (m, 3H), 6.69 (dddt, J = 10.4, 8.0, 2.5, 1.3 Hz, 1H), 5.65 (br, 1H), 5.50 (br, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.07-3.44 (m, 12H), 3.38-3.20 (m, 1H), 3.03 (ddd, J = 12.7, 8.1, 4.7 Hz, 1H), 2.68 (ddt, J = 18.1, 10.0, 1.6 Hz, 1H), 2.37-2.12 (m, 2H). Compound 28: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3-((dimethylamino)methyl)azetidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000062.jpg36159 The title compound 28 was prepared in 37.6% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 531.2(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.30 (d, J = 1.9 Hz, 1H), 6.89 - 6.77 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.44 (t, J = 9.0 Hz, 1H), 4.36 - 4.27 (m, 1H), 3.99 (t, J = 7.7 Hz, 1H), 3.91-3.55 (m, 12H), 3.32 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 3.00 - 2.85 (m, 1H), 2.76 - 2.62 (m, 1H), 2.31 (s, 6H). Compound 29: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(2-azaspiro[3.3]heptane-2-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000063.jpg38159 The title compound 29 was prepared in 41.5% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 531.2(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.29 (d, J = 2.0 Hz, 1H), 6.88-6.79 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.22 (s, 2H), 4.15 (s, 2H), 3.92-3.57 (m, 8H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.24-2.14 (m, 2H), 1.26-1.20 (m, 4H). Compound 30: (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)azetidine-3-carboxamide JPEG0007774579000064.jpg39159 The title compound 30 was prepared in 63.1% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 517.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.33 (d, J = 2.1 Hz, 1H), 6.88-6.78 (m, 3H), 6.74-6.64 (m, 1H), 5.79 (br, 1H), 5.64 (br, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.70-4.60 (m, 1H), 4.56-4.51 (m, 1H), 4.43-4.33 (m, 2H), 3.94-3.55 (m, 8H), 3.43-3.40 (m, 1H), 3.32 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 31: ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-((S)-3-(dimethylamino)pyrrolidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000065.jpg36159 The title compound 31 was prepared in 76.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 531.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.29 (dd, J = 5.3, 1.3 Hz, 1H), 6.86-6.77 (m, 3H), 6.69 (ttd, J = 8.9, 2.4, 1.2 Hz, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.06 - 3.44 (m, 12H), 3.31(ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.92-2.83 (m, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.23-2.15 (m, 1H), 2.02-1.82 (m, 1H). Compound 32: ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000066.jpg36159 The title compound 32 was prepared in 78.1% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 531.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.29 (dd, J = 5.3, 1.3 Hz, 1H), 6.86-6.77 (m, 3H), 6.69 (ttd, J = 8.9, 2.4, 1.2 Hz, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.06 - 3.44 (m, 12H), 3.31(ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.92-2.83 (m, 1H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.23-2.15 (m, 1H), 2.02-1.82 (m, 1H). Compound 33: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3-(dimethylamino)azetidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000067.jpg39159 The title compound 33 was prepared in 75.8% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 517.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.26 (dd, J = 7.3, 1.0 Hz, 1H), 6.87-6.78 (m, 3H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 3.94-3.54 (m, 13H), 3.31(ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 3.22 (s, 3H), 2.68 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.31 (s, 3H). Compound 34: (S)-N-(cyanomethyl)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoro-N-methylpyrimidine-4-carboxamide JPEG0007774579000068.jpg37159 The title compound 34 was prepared in 82.4% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 487.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.33 (dd, J = 13.1, 1.1 Hz, 1H), 6.89-6.78 (m, 3H), 6.74-6.64 (m, 1H), 5.33 (dd, J = 11.7, 9.8 Hz, 1H), 4.53 (s, 2H), 3.96-3.57 (m, 8H), 3.32 (ddt, J = 18.2, 11.7, 2.1 Hz, 1H), 3.24 (s, 1H), 3.12 (s, 2H), 2.68 (ddt, J = 18.3, 9.9, 1.9 Hz, 1H). Compound 35: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-N-ethylpyrimidine-4-carboxamide JPEG0007774579000069.jpg25159 The title compound 35 was prepared in 25.6% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxylic acid following the procedure outlined for compound 2. LC-MS (m / z) 444.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.53 (d, J = 4.8 Hz, 1H), 7.70 (brs, 1H), 7.33 (d, J = 4.8 Hz ,1H), 6.82-6.87 (m, 3H), 6.68-6.73 (m, 1H), 5.34 (dd, J = 10.0, 12.0 Hz,1H), 3.92-3.98 (m, 2H), 3.77-3.87 (m, 4H), 3.64-3.70 (m, 2H), 3.49 (q, J = 7.2 Hz, 2H), 3.33 (ddd, J = 2.0, 12.0, 13.6 Hz,1H), 2.70 (ddd, J = 1.6, 9.6, 11.2 Hz, 1H), 1.27 (t, J = 7.2 Hz ,3H). Mass (ESI): m / z calcd for C 21 H 23 F2N7O2443.5, found 444.6 [M+H] + . Compound 36: (S)-Azetidin-1-yl(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)methanone JPEG0007774579000070.jpg26159 The title compound 36 was prepared in a manner similar to the preparation of compound 2. 1 H NMR (400 MHz, CDCl3) δ 7.76-7.49 (m, 1H), 6.90-6.49 (m, 4H), 5.48-5.13 (m, 2H), 4.70-4.00 (m, 8H), 3.36 (dd, J = 18.3, 12.5 Hz, 1H), 2.71 (dd, J = 18.8, 6.4 Hz, 1H), 2.38-2.16 (m, 2H), 1.81-1.51 (m, 2H), 1.07-0.64 (m, 2H). Compound 37: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3-isopropoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000071.jpg23159 The title compound 37 was prepared in a manner similar to the preparation of compound 2. 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 6.89 -6.76 (m, 2H), 6.72-6.65 (m, 1H), 5.33 (dd, J = 10, 11.6 Hz, 1H), 4.92-4.74 (m, 1H), 4.58-4.45 (m, 1H), 4.46-4.24 (m, 2H), 4.12-3.99 (m, 1H), 3.96-3.55 (m,8H), 3.32 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 1.21-1.11 (m, 6H). Compound 38: 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxamide JPEG0007774579000072.jpg75159 Step 1: (S)-(5-(3,5-Difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (1 g, 3.62 mmol) was dissolved in 30 mL of dry THF and piperazine (6.24 g, 72.4 mmol) was added. The mixture was stirred at 100 °C for 12 h. The mixture was extracted with DCM, washed with brine, dried (NaSO), and concentrated to dryness to give the desired product. LC-MS (m / z) 295.1 (M+H + ). Step 2: To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (200 mg, 0.680 mmol) in DMF (3 mL) was added 2-chloropyrimidine-4-carboxamide (118 mg, 0.748 mmol). The reaction mixture was stirred at 120° C. for 12 h. The crude was purified by reverse phase chromatography. 180 mg of the target compound 38 was obtained as a white solid. Yield: 63.8%. LC-MS (m / z) 416.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.55 (d, J = 4.8, 1H), 7.56 (s, 1H), 7.31 (d, J = 4.8, 1H), 6.86-6.81 (m, 3H), 6.72-6.67 (m, 1H), 5.67 (s, 1H), 5.34 (dd, J = 11.7, 9.8 Hz, 1H), 3.98-3.93 (m, 2H), 3.87-3.76 (m, 4H), 3.68-3.63 (m, 2H), 3.33 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.70 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 39: (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrazine-2-carboxamide JPEG0007774579000073.jpg38159To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (200 mg, 679.6 μmol) in DMF (5 mL), 6-chloropyrazine-2-carboxamide (117.7 mg, 747.5 μmol) and CsCO3 (263 mg, 1.36 mmol) were added. The reaction mixture was stirred at 120°C for 12 hours. The crude product was purified by pre-HPLC. 130 mg of the desired product was obtained as a white solid. Yield: 46.1%. LC-MS (m / z) 416.3(M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.46 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.65 (s, 1H), 7.16-7.05 (m, 2H), 6.98 (dt, J = 7.0, 2.1 Hz, 2H), 5.24 (dd, J = 11.6, 9.9 Hz, 1H), 3.83-3.47 (m, 8H), 3.35 (ddd, J = 18.3, 11.6, 1.9 Hz, 1H), 2.64 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H). Compound 40: (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxamide JPEG0007774579000074.jpg39159 The title compound 40 was prepared in 67.1% yield from 6-chloropyrimidine-4-carboxamide and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for compound 38. LC-MS (m / z) 416.1(M+H + ) 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.62 (d, J = 0.9 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.42 (S, 1H), 7.15-7.04 (m, 2H), 7.00-6.97 (m, 2H), 5.24 (dd, J = 11.6, 9.9 Hz, 1H), 3.86-3.51 (m, 8H), 3.35 (ddd, J = 18.4, 11.7, 1.9 Hz, 1H), 2.64 (ddd, J = 18.4, 9.9, 1.7 Hz, 1H). Compound 41: (S)-2-(4-(5-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxamide JPEG0007774579000075.jpg67159 The title compound 41 was prepared in 53.1% yield in two steps from (S)-(1H-imidazol-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone following the procedure outlined for compound 38. LC-MS (m / z) 380.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.54 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.37 - 7.28 (m, 6H), 6.86 (t, J = 1.7 Hz, 1H), 5.63 (s, 1H), 5.38 (dd, J = 11.8, 9.7 Hz, 1H), 3.98-3.58 (m, 8H), 3.33 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.76 (ddd, J = 18.3, 9.7, 1.6 Hz, 1H). Compound 42: (S)-2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxamide JPEG0007774579000076.jpg76159 The title compound 42 was prepared in two steps in 65.2% yield from (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile following the procedure outlined for compound 38. LC-MS (m / z) 443.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.55 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.42 (t, J = 1.5 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.30 - 7.21 (m, 2H), 6.91 - 6.87 (m, 1H), 5.67 (s, 1H), 5.37 (dd, J = 11.7, 10.0 Hz, 1H), 4.02 - 3.59 (m, 8H), 3.36 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.70 (ddd, J = 18.3, 10.0, 1.6 Hz, 1H). Compound 43: (S)-2-(4-(5-(5-cyanopyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxamide JPEG0007774579000077.jpg73159 The title compound 43 was prepared in 42.6% yield in two steps from (S)-5-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)nicotinonitrile following the procedure outlined for compound 38. LC-MS (m / z) 406.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.80 (dd, J = 3.8, 2.1 Hz, 2H), 8.55 (d, J = 4.8 Hz, 1H), 7.91 (t, J = 2.1 Hz, 1H), 7.56 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 6.94 (t, J = 1.7 Hz, 1H), 5.64 (s, 1H), 5.42 (dd, J = 11.7, 10.3 Hz, 1H), 4.08 - 3.52 (m, 8H), 3.40 (ddd, J = 18.2, 11.7, 1.9 Hz, 1H), 2.75 (ddd, J = 18.2, 10.2, 1.6 Hz, 1H). Compound 44: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxylic acid JPEG0007774579000078.jpg37162 The title compound 44 was prepared in 76.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 38. LC-MS (m / z) 417.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.62 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 6.87 (t, J = 1.6 Hz, 1H), 6.81-6.84 (m, 2H), 6.68-6.73 (m, 1H), 5.34 (dd, J = 10.0, 11.6 Hz ,1H), 3.93-4.00 (m, 2H), 3.78-3.89 (m, 4H), 3.65-3.70 (m, 2H), 3.34 (ddd, J = 1.6, 11.6, 13.6 Hz ,1H), 2.71 (ddd, J = 1.6, 9.6, 11.2 Hz, 1H). Compound 45: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-N-(2-morpholinoethyl)pyrimidine-4-carboxamide JPEG0007774579000079.jpg71159 The title compound 45 was prepared in 32.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxylic acid following the procedure outlined for compound 2. Mass (ESI): m / z calculated for C 25 H30 F2N8O3528.6, found 529.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.69 (t, J = 1.2 Hz, 1H), 8.52 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.85 (t, J = 1.6 Hz, 1H), 6.77-6.82 (m, 2H), 6.67-6.73 (m, 1H), 5.31 (dd, J = 9.6, 11.6 Hz ,1H), 3.78-4.05 (m, 10 H), 3.58-3.77 (m, 6H), 3.49 (t, J = 5.6 Hz, 2H), 3.32 (ddd, J = 2.0, 12.0, 13.2 Hz, 1H), 2.92-3.05 (m, 2H), 2.68 (ddd, J = 1.6, 9.6, 11.2 Hz, 1H). Compound 46: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-N-methylpyrimidine-4-carboxamide JPEG0007774579000080.jpg25159 The title compound 46 was prepared in 30.4% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxylic acid following the procedure outlined for compound 2. Mass (ESI): m / z calculated for C 20 H 21 F2N7O2429.4, found 430.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.51 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 4.4 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H), 6.79-6.85 (m, 3H), 6.66-6.71 (m, 1H), 5.32 (dd, J = 10.0, 11.6 Hz ,1H), 3.89-3.96 (m, 2H), 3.74-3.85 (m, 4H), 3.61-3.68 (m, 2H), 3.31 (ddd, J = 2.0, 11.6, 13.6 Hz, 1H), 3.00 (d, J = 4.2 Hz,3H), 2.68 (ddd, J = 1.6, 9.6, 11.2 Hz, 1H). Compound 47: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylate JPEG0007774579000081.jpg34159 (S)-(5-(3,5-Difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (6 mg, 0.204 mmol) and ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (38.9 mg, 0.19 mmol) were dissolved in 11.7 mL of DMF. TEA (59 µl) was added. The mixture was stirred at 60 °C under nitrogen for 16 h. The solvent was evaporated to dryness, and the mixture was purified by prep-TLC (PE / EA = 1 / 2) to give 20 mg of 47 as a pale yellow solid. Yield: 21.2%. Mass (ESI): m / z calculated for C 21 H 21 F3N6O3462.4, found 463.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.34 (d, J = 2.0 Hz, 1H), 6.78-6.85 (m, 3H), 6.66-6.71 (m, 1H), 5.32 (dd, J = 10.0, 11.2 Hz ,1H), 4.43 (q, J = 7.2 Hz, 2H), 3.86-3.91 (m, 2H), 3.72-3.81 (m, 4H), 3.59-3.65 (m, 2H), 3.30 (ddd, J = 1.6, 11.6, 13.6 Hz ,1H), 2.68 (ddd, J = 1.6, 10.0, 11.6Hz, 1H), 1.40 (t, J = 7.2 Hz, 3H). Compound 48: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxamide JPEG0007774579000082.jpg29159 Following the procedure outlined for compound 2, the title compound 48 was prepared in 66.67% yield from ammonium hydroxide and (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)iperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride. Mass (ESI): m / z calcd for C19H18F3N7O2 433.4, found 434.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.40 (d, J = 3.2 Hz, 1H), 7.37 (brs, 1H), 6.80-6.86 (m, 3H), 6.67-6.72 (m, 1H), 5.90 (brs, 1H),5.33 (dd, J = 10.0, 11.6 Hz ,1H), 3.86-3.91 (m, 2H), 3.74-3.81 (m, 4H), 3.63-3.67 (m, 2H), 3.32 (ddd, J = 1.6, 11.6, 13.6 Hz ,1H), 2.69 (ddd, J = 1.6, 10.0, 11.2 Hz, 1H). Compound 49: Methyl (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carboxylate To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (500 mg, 1.7 mmol) in DMF (5 mL) was added methyl 2-chloropyrimidine-4-carboxylate (350 mg, 2.0 mmol) and EtN (0.7 mL, 5.1 mmol). The resulting mixture was stirred at 45 °C for 12 h. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and then extracted with DCM (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether = 1:1) to give the title compound as a white solid (500 mg, 68%). yield :68%. LCMS (ES, m / z): 431.16 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.8 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 6.91- 6.78 (m, 2H), 6.72-6.65 (m, 1H), 5.33 (dd, J = 11.6, 9.9 Hz, 1H), 4.06-3.97 (m, 2H), 3.96 (s, 3H), 3.88 (ddd, J = 13.2, 7.2, 3.4 Hz, 2H), 3.83-3.69 (m, 2H), 3.64 (ddd, J = 13.2, 6.6, 3.4Hz, 2H), 3.32 (ddd, J = 18.2, 11.7, 1.8 Hz, 1H), 2.69 (ddd, J = 18.4, 9.8, 1.6 Hz, 1H). Compound 50: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-hydroxy-3-methylazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone To a solution of (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylic acid (50 mg, 115.1 umol) in DCM (3 mL) was added HATU (66 mg, 172.7 umol), DIPEA (25 mg, 172.7 umol), and 3-methylazetidin-3-ol (22 mg, 172.7 umol). The reaction mixture was stirred at 35° C. for 12 hours. The crude product was purified by reverse phase chromatography. The title compound 50 (26 mg) was obtained as a yellow solid. Yield: 44.9%. LC-MS (m / z) 504.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 0.7 Hz, 1H), 6.89-6.77 (m, 3H), 6.70 (tt, J = 8.9, 2.4 Hz, 1H), 5.37-5.30 (m, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.18 (dd, J = 9.9, 6.4 Hz, 1H), 4.13 (s, 2H), 3.91-3.56 (m, 8H), 3.33 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H), 1.57 (s, 3H). Compound 51: (S)-3-Fluoro-5-(1-(4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007774579000085.jpg56159 Step 1: To a solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylic acid (300 mg, 919.3 umol) in DCM (10 mL) was added DIPEA (328 mg, 2.76 mmol), HATU (525 mg, 1.38 mmol), and 3-methoxyazetidine (124 mg, 1.01 mmol). The reaction mixture was stirred at 25 °C for 12 h. The mixture was purified by flash chromatography. tert-Butyl 4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carboxylate was obtained as a yellow solid (310 mg, 85.3%). LC-MS (m / z) 396.2 (M+H + ). Step 2: To a solution of tert-butyl 4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 252.89 μmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo and used directly in the next step. LC-MS (m / z) 296.1 (M+H + ). Step 3: To a solution of the compound (5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone (52 mg, 172.5 umol) in THF (6 mL) was added (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (50 mg, 172.5 umol) and EtN (2 mL). The reaction mixture was stirred at 75 °C for 12 hours. The crude product was purified by reverse phase chromatography. The title compound 51 (63 mg) was obtained as a yellow solid. Yield: 69.9%. LC-MS (m / z) 511.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 1.9 Hz, 1H), 7.34 (t, J = 1.5 Hz, 1H), 7.24-7.14 (m, 2H), 6.84 (d, J = 1.6 Hz, 1H), 5.60 (brs, 1H), 5.31 (dd, J = 11.6, 9.8 Hz, 1H), 4.44-4.40 (m, 1H), 4.33 (dd, J = 11.2, 5.5 Hz, 1H), 4.26-4.11 (m, 2H), 4.05-4.01 (m, 1H), 3.87-3.50 (m, 8H), 3.35-3.28 (m, 1H), 3.26 (s, 3H), 2.64 (ddd, J = 18.4, 9.7, 1.6 Hz, 1H). Compound 52: (S)-(5-Fluoro-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone JPEG0007774579000086.jpg34159 The title compound 52 was prepared from (5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone following the procedure outlined for compound 51. LC-MS (m / z) 487.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.39 (dd, J = 2.8, 0.9 Hz, 1H), 8.32 (dd, J = 2.1, 1.0 Hz, 1H), 7.34 (dt, J = 9.1, 2.6 Hz, 1H), 6.90 (s, 1H), 5.41 (t, J = 10.9 Hz, 1H), 4.51-4.41 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.19 (m, 1H), 4.13-4.03 (m, 1H), 3.91-3.56 (m, 8H), 3.38 (ddt, J = 18.3, 10.3, 1.3 Hz, 1H), 3.32 (s, 3H), 2.75 (ddt, J = 18.3, 10.3, 1.3 Hz, 1H). Compound 53: (S)-5-(1-(4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)nicotinonitrile JPEG0007774579000087.jpg32159 The title compound 53 was prepared from (5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone following the procedure outlined for compound 51. LC-MS (m / z) 494.1(M+H + ). 1H NMR (400 MHz, CDCl3) δ 8.83-8.77 (m, 2H), 8.32 (dd, J = 1.9, 0.7 Hz, 1H), 7.91 (t, J = 2.2 Hz, 1H), 6.94 (s, 1H), 5.42 (t, J = 10.9 Hz, 1H), 4.46 (ddd, J = 10.4, 5.3, 3.1 Hz, 1H), 4.42-4.34 (m, 1H), 4.33-4.18 (m, 2H), 4.08 (ddd, J = 11.2, 3.8, 1.3 Hz, 1H), 3.91-3.58 (m, 8H), 3.47-3.35 (m, 1H), 3.32 (s, 3H), 2.81-2.68 (m, 1H). Compound 54: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)azetidine-3-carbonitrile JPEG0007774579000088.jpg56159 Following the procedure outlined for compound 51, the title compound 54 was prepared. LC-MS (m / z) 506.1(M+H + ). 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.2 Hz, 1H), 7.33-7.32 (m, 1H), 7.21 (d, J = 1.4 Hz, 1H), 7.19-7.18 (m, 2H), 6.85 (s, 1H), 6.31 (brs, 1H), 5.31 (dd, J = 11.7, 9.6 Hz, 1H), 4.67 (dd, J = 7.5, 4.3 Hz, 2H), 4.46 (t, J = 9.9 Hz, 1H), 4.38 (dd, J = 10.6, 6.1 Hz, 1H), 3.85-3.47 (m, 8H), 3.39-3.25 (m, 1H), 2.64 (ddd, J = 18.4, 9.6, 1.5 Hz, 1H). Compound 55: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methyleneazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000089.jpg32159 The title compound 55 was prepared in 69.2% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 486.1(M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 2.3 Hz, 1H), 7.14-7.07 (m, 2H), 7.05-6.94 (m, 2H), 5.26 (dd, J = 11.5, 10.0 Hz, 1H), 5.10 (dt, J = 7.8, 2.6 Hz, 2H), 4.92-4.89 (m, 2H), 4.65-4.63 (m, 2H), 3.79-3.47 (m, 8H), 3.36 (ddd, J = 18.3, 11.6, 1.9 Hz, 1H), 2.64 (ddd, J = 18.3, 10.0, 1.6 Hz, 1H). Compound 56: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methylazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000090.jpg25159 The title compound 56 was prepared in 72.5% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 488.1(M+H + ).1 H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 5.9 Hz, 1H), 7.17 (d, J = 5.9 Hz, 1H), 7.09 (t, J = 6.4 Hz, 2H), 7.00-6.94 (m, 1H), 5.54 (td, J = 11.0, 6.3 Hz, 1H), 4.67 (t, J = 8.1 Hz, 1H), 4.50 (d, J = 8.5 Hz, 1H), 4.18-3.75 (m, 10H), 3.61 (ddd, J = 18.2, 11.7, 6.0 Hz, 1H), 3.09-3.02 (m, 1H), 2.97-2.88 (dt, J = 17.6, 8.1 Hz, 1H), 2.85-2.78 (m, 1H), 1.52 (s, 3H). Compound 57: (S)-2-(1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)azetidin-3-ylidene)acetonitrile JPEG0007774579000091.jpg31159 The title compound 57 was prepared in 63.7% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 511.1(M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (t, J = 1.9 Hz, 1H), 7.16-7.05 (m, 2H), 7.04-6.94 (m, 2H), 5.94-5.89 (m, 1H), 5.26 (t, J = 10.7 Hz, 1H), 5.21-5.18 (m, 1H), 5.16-5.13 (m, 1H), 4.91-4.88 (m, 1H), 4.83-4.81 (m, 1H), 3.80-3.48 (m, 8H), 3.36 (ddd, J = 18.3, 11.6, 1.8 Hz, 1H), 2.65 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 58: (S)-2-(1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl)acetonitrile JPEG0007774579000092.jpg29159 The title compound 58 was prepared in 62.1% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 513.1(M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 8.61(d, J = 2.2 Hz, 1H), 7.18-7.05 (m, 2H), 7.02-6.97 (m, 2H), 5.25 (dd, J = 11.5, 9.9 Hz, 1H), 4.46 (ddd, J = 10.5, 8.6, 3.1 Hz, 1H), 4.20 (dd, J = 10.4, 8.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.84-3.59 (m, 7H), 3.59-3.49 (m, 2H), 3.36 (ddd, J = 18.3, 11.6, 1.8Hz, 1H), 3.01-2.96 (m, 1H), 2.89 (d, J = 6.4 Hz, 2H), 2.64 (ddd, J = 18.4, 9.9, 1.6 Hz, 1H). Compound 59: (S)-3-(1-(4-(4-(3-(cyclopropylmethoxy)azetidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile Step 1: To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol) in DMF (10 mL) was added NaH (60% in oil, 900 mg, 22.5 mmol) at 0 °C. The mixture was stirred at room temperature for 1.5 h, and then bromomethylcyclopropane (2.80 g, 20.7 mmol) was slowly added and stirred for 12 h. The mixture was diluted with EtOAc, washed twice with HO and once with saturated aqueous NaCl, the layers were separated, the organic extract was dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with a gradient of 0-20% EtOAc in hexane to give the title compound (1.7 g) as a colorless oil after solvent evaporation. Yield: 43.2%. LC-MS (m / z) 228.1(M+H + ). Step 2: To a solution of tert-butyl 3-(cyclopropylmethoxy)azetidine-1-carboxylate (300 mg, 1.32 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at 25° C. for 1 h. The crude was concentrated in vacuo and used directly in the next step. LC-MS (m / z) 128.1(M+H + ). Step 3: Following the procedure outlined for compound 2, the title compound 59, (S)-3-(1-(4-(4-(3-(cyclopropylmethoxy)azetidine-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile, was prepared from 3-(cyclopropylmethoxy)azetidine in 36.2% yield. LC-MS (m / z) 551.1(M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 2.2 Hz, 1H), 7.78-7.68 (m, 1H), 7.64 (s, 1H), 7.56-7.44 (m, 1H), 7.11 (s, 1H), 5.29 (t, J = 10.9 Hz, 1H), 4.51-4.42 (m, 1H), 4.39-4.34 (m, 1H), 4.30-4.21 (m, 1H), 4.14-4.07 (m, 1H), 3.86 (ddd, J = 11.0, 3.9, 1.4 Hz, 1H), 3.79-3.48 (m, 9H), 3.22 (d, J = 6.9 Hz, 2H), 1.21-1.13 (m, 1H), 0.51-0.43 (m, 2H), 0.20-0.13 (m, 2H). Compound 60: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-(trifluoromethoxy)azetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone Step 1: tert-Butyl 3-hydroxyazetidine-1-carboxylate (2.189 g, 12.653 mmol), Zn(NTf) (537.1 mg, 0.837 mmol), and 1-(trifluoromethyl)-11-3-benzo[d][1,2]iodaoxol-3(1H)-one (800 mg, 2.532 mmol) were dissolved in 16.9 mmL of CHCl. ​​The mixture was stirred at room temperature for 48 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 10 / 1) to give 45 mg of tert-butyl 3-(trifluoromethoxy)azetidine-1-carboxylate as a yellow oil. LC-MS (m / z): 242.1[M+H] + . Step 2 and Step 3: tert-Butyl 3-(trifluoromethoxy)azetidine-1-carboxylate (45 mg, 0.186 mmol) was dissolved in 1 mL of DCM. 0.2 mL of TFA / DCM (1 / 1) was added to the solution at 0 °C. This was stirred at room temperature for 1 hour. The solvent was evaporated to dryness and used in the next step without further purification. LC-MS (m / z): 142.2[M+H] + . The residue, (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carboxylic acid (10 mg, 0.02 mmol), HATU (11.6 mg, 0.03 mmol), and 0.1 mL of TEA were dissolved in 2 mL of DMF. The mixture was stirred at room temperature for 16 hours. 1 mL of water was added to the solution, and the mixture was extracted with EtOAc (5 mL × 3). The organic layers were combined, evaporated to dryness, and purified by prep-HPLC to give 3 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-(trifluoromethoxy)azetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone as a white solid. Overall yield for two steps: 27%. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.35 (d, J = 2.4 Hz, 1H), 6.86 (t, J = 1.6 Hz, 1H), 6.83-6.81 (m, 1H), 6.70 (tt, J = 8.8, 2.0 Hz, 1H), 5.33 (dd, J = 11.2, 10.0 Hz, 1H), 5.06-5.00 (m, 1H), 3.89-3.82 (m, 3H), 3.81-3.70 (m, 6H), 3.68-3.57 (m, 3H), 3.33 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 558.2 [M+H] + . Compound 61: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-)yl)(4-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007774579000095.jpg27159 The title compound 61 was prepared in 55.7% yield from (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidine-4-carbonyl chloride following the procedure outlined for compound 2. LC-MS (m / z) 486.1(M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 1.5 Hz, 1H), 7.15-7.05 (m, 2H), 7.02-6.97 (m, 2H), 5.97-5.94 (m, 1H), 5.88-5.85 (m, 1H), 5.25 (dd, J = 11.5, 10.0 Hz, 1H), 4.29-4.21 (m, 4H), 3.80-3.48 (m, 8H), 3.36 (ddd, J = 18.3, 11.6, 1.9 Hz, 1H), 2.64 (ddd, J = 18.3, 10.0, 1.6 Hz, 1H). Compound 62: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-methoxypyrimidine-4-carboxamide JPEG0007774579000096.jpg25159 The title compound 62 was prepared following the procedure outlined for compound 67. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.39 (brs, 1H), 6.94-6.77 (m, 3H), 6.79-6.57 (m, 1H), 5.74 (brs, 1H), 5.33 (dd, J = 11.7, 9.9 Hz, 1H), 3.94 (s, 3H), 3.92-3.52 (m, 8H), 3.32 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.69 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H). Compound 63: (S)-3-(1-(4-(5-chloro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007774579000097.jpg112159 Step 1: To a solution of tert-butyl piperazine-1-carboxylate (303 mg, 1.63 mmol) in DMF (10 mL) was added ethyl 2,5-dichloropyrimidine-4-carboxylate (360 mg, 1.63 mmol) and DIPEA (315 mg, 2.44 mmol). The reaction mixture was stirred at 50 °C for 12 h. The crude product was purified by column chromatography on silica gel. Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chloropyrimidine-4-carboxylate (230 mg, 38%) was obtained as a pale yellow solid. MS (m / z): 371.1 [M+H] + . Step 2: To a solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chloropyrimidine-4-carboxylate (150 mg, 404.5 umol) in THF (6 mL) was added 1N NaOH (6 mL). The reaction mixture was stirred at 45° C. for 1 h. The reaction mixture was acidified by adding 1N HCl. The aqueous layer was extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. The solvent was concentrated under vacuum. The crude was used directly in the next step. MS (m / z): 343.1 [M+H] + . Step 3: To a solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chloropyrimidine-4-carboxylic acid (100 mg, 291.7 umol) in DCM (5 mL) was added 3-methoxyazetidine (31 mg, 350.1 umol), HATU (333 mg, 875.2 umol), and DIPEA (0.5 mL). The reaction mixture was stirred at room temperature for 12 hours. The crude product was purified by column chromatography on silica gel. tert-Butyl 4-(5-chloro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 83%) was obtained as a pale yellow solid. MS (m / z): 412.1 [M+H]+ . Step 4: To a solution of tert-butyl 4-(5-chloro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 242.8 umol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo. The crude material was used directly in the next step. MS (m / z): 312.1 [M+H] + . Step 5: To a solution of (S)-3-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (60 mg, 211.8 μmol) in THF (3 mL) was added (5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone (66 mg, 211.8 μmol) and DIPEA (137 mg, 1.06 mmol). The reaction mixture was stirred at 70° C. for 12 hours. The crude product was purified by pre-HPLC. (S)-3-(1-(4-(5-chloro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (15 mg, 13%) was obtained as a pale yellow solid. MS (m / z): 527.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 6.66 (s, 1H), 5.34 - 5.22 (m, 1H), 4.35-4.15 (m, 2H), 3.95-3.35 (m, 11H), 3.36-3.28 (m, 1H), 2.90-2.84 (m, 1H). Compound 64: (S)-(5-chloro-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone Following the procedure outlined for compound 63, the title compound 64, (S)-(5-chloro-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone, was prepared from (S)-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone in 31% yield. LC-MS (m / z) 503.1(M+H + ). 1 H NMR (400 MHz, DMSO) δ 8.59-8.36 (m, 3H), 7.65 (d, J = 9.9 Hz, 1H), 7.14 (s, 1H), 5.31 (t, J = 10.9 Hz, 1H), 4.26 (d, J = 9.0 Hz, 5H), 3.95-3.48 (m, 8H), 3.39 (dd, J = 18.3, 11.8 Hz, 1H), 3.21 (s, 3H), 2.82-2.65 (m, 1H). Compound 65: (5-chloro-2-(4-(5-(5-chloropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone Following the procedure outlined for compound 63, the title compound 65, (5-chloro-2-(4-(5-(5-chloropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)(3-methoxyazetidin-1-yl)methanone, was prepared from (5-(5-chloropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone in 33% yield. LC-MS (m / z) 519.1(M+H + ). 1 H NMR (300 MHz, DMSO-d6) δ 8.59-8.41 (m, 2H), 8.35-8.23 (m, 1H), 7.82 (t, J = 2.0 Hz, 1H), 7.13-7.11 (m, 1H), 5.25(t, J = 10.8 Hz, 1H), 4.26-4.19 (m, 3H), 3.91-3.81 (m, 1H), 3.77-3.28 (m, 8H), 3.18 (s, 3H), 3.16-3.07 (m, 2H), 2.78-2.71 (m, 1H). Compound 66: (5-(5-chloropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone Following the procedure outlined for compound 63, the title compound 66, (5-(5-chloropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methoxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazin-1-yl)methanone, was prepared from (5-(5-chloropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone in 35% yield. LC-MS (m / z) 503.1(M+H + ). 1H NMR (300 MHz, DMSO-d6) δ 8.60-8.46 (m, 3H), 7.83 (t, J = 2.1 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 5.27 (t, J = 10.8 Hz, 1H), 4.47-4.40 (m, 1H), 4.28-4.20 (m, 3H), 4.10-4.03 (m, 1H), 3.88-3.82 (m, 1H), 3.78-3.48 (m, 8H), 3.42-3.31 (m, 1H), 3.21 (s, 3H), 2.78-2.71 (m, 1H). Compound 67: (S)-4-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropicolinamide Step 1: 2-Chloro-5-fluoro-4-iodopyridine (1.84 g, 7.16 mmol) and tert-butyl piperazine-1-carboxylate (2.0 g, 10.7 mmol), Pd2(dba)3 (655 mg), Xphos (341 mg), and Cs2CO3 (3.49 g, 10.74 mmol) were mixed in 30 mL of toluene. The mixture was stirred at 110 °C for 16 h. The solvent was evaporated to dryness, and the product was purified by chromatography (PE / EA = 4 / 1) to give 1.5 g of a brown oil. Yield: 66.4%. LC-MS (m / z): 316.4 [M+H] + . Step 2: To a stirred solution of tert-butyl 4-(2-chloro-5-fluoropyridin-4-yl)piperazine-1-carboxylate (640 mg, 2 mmol) and Zn(CN) (240 mg, 2 mmol) in DMF (10 mL) was added Zn powder (30 mg, 0.5 mmol), Pd(dba) (180 mg, 0.2 mmol), and DPPF (110 mg, 0.2 mmol) at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EA (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=82 / 18) to give 400 mg of tert-butyl 4-(2-cyano-5-fluoropyridin-4-yl)piperazine-1-carboxylate as a yellow solid (yield: 35.3%). LC-MS (m / z): 307.4 [M+H] + . Step 3 and Step 4: Following the procedure for compound 63, (S)-4-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropicolinonitrile was synthesized as an off-white solid. Yield: 21.7%. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.87 (t, J = 1.7 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.71 (tt, J = 8.8, 2.3 Hz, 1H), 5.32 (dd, J = 11.7, 9.6 Hz, 1H), 3.87 (ddd, J = 13.4, 7.3, 3.3 Hz, 2H), 3.72 (ddd, J = 13.4, 6.7, 3.3 Hz, 2H), 3.45 (ddd, J = 12.4, 6.7, 3.3 Mass (m / z): 415.2 [M+H] + . Step 5: (S)-4-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropicolinonitrile (61 mg, 0.147 mmol) was dissolved in 2 mL of MeOH. 0.3 mL of 30% HO and 0.15 mL of 2 N NaOH were added. This was stirred at room temperature for 30 minutes. The solvent was evaporated to dryness and purified by Prep-TLC (DCM / MeOH=25 / 1) to give 35 mg of compound 67 as a white solid. Yield: 54.9%. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 7.7 Hz, 2H), 6.89 - 6.78 (m, 3H), 6.70 (tt, J = 8.9, 2.3 Hz, 1H), 5.68 (s, 1H), 5.32 (dd, J = 11.7, 9.8 Hz, 1H), 3.85 (ddd, J = 13.3, 7.2, 3.2 Hz, 2H), 3.70 (ddd, J = 13.3, 6.7, 3.2 Hz, 2H), 3.45 (ddd, J = 12.4, 6.8, 3.3Hz, 2H), 3.41 - 3.23 (m, 3H), 2.69 (ddd, J = 18.3, 9.8, 1.7 Hz, 1H). Mass (m / z): 433.2[M+H] + .

[0123] <Example 2> Biological Assays Compounds 1 to 67 of the present disclosure (referred to as Compound Nos. 1 to 67 in Table 1) were tested for binding and cellular RIP1 inhibitory activity according to the experimental procedures described below.

[0124] material Cell line: HT-29 (ATCC (registered trademark) HTB-38 (trademark)) Media: McCoy's 5A, Gibco, Cat. No. 16600-082 FBS: Gibco, catalog number 10099-141C Trypsin: Gibco, catalog number 25200-056 DMSO: Sigma, Cat. No. 67-68-5, 1L Assay plate: Corning #3903 Compound dilution plate: Corning #3357 Inducer: TNFα, GenScript, Catalog No. Z01001-50 SmacM: Catalog number HY-15989, MedChemExpress (MCE) Z_VAD FMK, TargetMol, T6013 Cell Titer-Glo® Luminescent Cell Viability Assay Kit: Promega, catalog number G7573 EnVision: PerkinElmer, 2105-0010

[0125] method Cell seeding 1. HT-29 cells were checked daily to ensure they were healthy and growing as expected. When they reached approximately 80% confluence, they were subcultured. 2. The 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. When 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. 2-3 mL of freshly warmed trypsin (Gibco, Cat. No. 25200-056) solution was added to the washed cells. The flask containing the cells was transferred to a 37°C incubator. After 5 minutes, the flask was tapped on the side and examined under a microscope to see if the cells had detached from the flask. If necessary, the cells were kept in the incubator for another 5-10 minutes, tapping occasionally, until the cells had completely detached. 6. Neutralize the trypsin reaction by transferring 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 minutes 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 resuspended cell culture medium containing ∼5000 cells was transferred to each well of a sterile 96-well cell culture plate (Corning 3903) and incubated overnight at 37°C, 5% CO .

[0126] Compound titration and treatment 1. All test compounds were dissolved in DMSO (dimethyl sulfoxide) to prepare 20 mM stocks. 2. 3 μL of 20 mM stock solution of each compound was mixed with 27 μL of DMSO, and this compound solution was further diluted in a titration ratio of 1:3 (20 μL of compound solution + 40 μL of DMSO) until 10 points were completed. 3. All medium was removed from the assay plates containing HT-29 cell cultures. The cells were then washed with 1 mL of PBS and resuspended in fresh FBS-free McCoy's 5A medium containing a cocktail of TNF-α (10 ng / mL), a 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 diluted compound solution was added to the corresponding 96-well assay plate. 5. The assay plate was incubated at 37°C, 5% CO2 for 20 hours. Cell viability detection 1. The CellTiter-Glo® luminescent cell viability assay was employed to detect ATP levels in live HT-29 cells. 2. CellTiter-Glo® buffer and lyophilized substrate were equilibrated to room temperature before use. 3. CellTiter-Glo® Substrate was resuspended in CellTiter-Glo® Buffer and 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 allow the luminescent signal to stabilize. 7. The luminescence signal was read and recorded using EnVision. 8. The geometric mean of EC50 values ​​was calculated from the 10 response doses in duplicate. The range of EC50 values ​​for compounds 1-67 is shown in Table 2.

Claims

1. A compound of formula Ia, or a salt, hydrate or stereoisomer thereof: (In the formula, R1 is a 6-membered aryl or a 6-membered heteroaryl containing one N heteroatom, wherein the 6-membered aryl or 6-membered heteroaryl is unsubstituted or substituted at C3 and / or C5 with halogen or CN; R2 is a 6-membered aryl or a 6-membered heteroaryl containing 1 or 2 N heteroatoms, wherein the 6-membered aryl or 6-membered heteroaryl is unsubstituted or substituted with halogen or C1-C3 alkoxy; Y is O or N; When Y is N, m is 2, and When Y is O, m is 1, and R3 and R4 are independently H or C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl or —OR Ｓ and R Ｓ is unsubstituted or halogen and / or C ３ ~C ６ Cycloalkyl-substituted C １ ~C ６ alkyl; １ ~C ６ Alkyl and C ３ ~C ６ Cycloalkyl includes halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′″, —NR′-SO2NR′″, —NR″COR′, —NH -C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S02R', -S02NR'R'', -NR''S02R, -CN, and 0 to 3 substituents selected from -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; R', R" and R'" are each independently hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1 to 3 halogens, C1-C8 heteroalkyl substituted with 1 to 3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1 to 3 halogens, unsubstituted C1-C8 alkoxy group, unsubstituted C1-C8 thioalkoxy group, or C6-C14 aryl-(C1-C4)alkyl group, and when R' and R" are bonded to the same nitrogen atom, R' and R" can form a 5-, 6- or 7-membered ring together with the nitrogen atom, and R3 and R4 can be linked to form a heterocycle.

2. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(1): wherein Rd is selected from H, halogen, and C1-C3 alkoxy.

3. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(1)a: wherein R and R, for each occurrence, are independently selected from the following: H, C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, and —O(C １ ~C ３ alkyl), wherein said C １ ~C ３ Alkyl and C ３ ~C ６ Each cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl.

4. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(1)b: wherein R5 is heterocyclyl; The heterocyclyl may be unsubstituted or substituted with OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ is substituted with alkylene, The R Ｓ is unsubstituted or halogen and / or C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and ｐ and R ｑ are each independently H and C １ ~C ３ alkyl.)

5. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(2):

6. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(2)a: wherein R3 and R4, for each occurrence, are independently selected from the following: H; C which is unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; １ ~C ３ alkyl; unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; ３ ~C ６ cycloalkyl; and —O(C １ ~C ３ alkyl).

7. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(2)b: wherein R5 is heterocyclyl; The heterocyclyl may be unsubstituted or substituted with OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR Ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ is substituted with alkylene, The R Ｓ is unsubstituted or halogen and / or C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and ｐ and R ｑ are each independently H and C １ ~C ３ alkyl.)

8. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(1): wherein R2 is a 6-membered aryl or a 6-membered heteroaryl containing one or two N heteroatoms, and the 6-membered aryl or 6-membered heteroaryl is unsubstituted or is substituted with a halogen or C １ ~C ３ is substituted with alkoxy, and ｂ and R ｃ are each independently selected from H, halogen, and CN.

9. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(1)a: wherein R3 and R4, for each occurrence, are independently selected from the following: H; C which is unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; １ ~C ３ alkyl; unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; ３ ~C ６ cycloalkyl; and —O(C １ ~C ３ alkyl).

10. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(1)b: wherein R5 is heterocyclyl; The heterocyclyl may be unsubstituted or substituted with OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ is substituted with alkylene, The R Ｓ is unsubstituted or halogen and / or C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and ｐ and R ｑ are each independently H and C １ ~C ３ alkyl.)

11. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(2): (Wherein, R2 is a 6-membered aryl or a 6-membered heteroaryl, and the 6-membered aryl or the 6-membered heteroaryl is unsubstituted or is substituted with halogen or C １ ~C ３ is substituted with alkoxy, and ｂ is selected from H, halogen and CN.

12. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(2)a: wherein R3 and R4, for each occurrence, are independently selected from the following: H; C which is unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; １ ~C ３ alkyl; unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; ３ ~C ６ cycloalkyl; and —O(C １ ~C ３ alkyl).

13. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(2)b: wherein R5 is heterocyclyl; The heterocyclyl may be unsubstituted or substituted with OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR Ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ is substituted with alkylene, The R Ｓ is unsubstituted or halogen and / or C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and ｐ and R ｑ are each independently H and C １ ~C ３ alkyl.)

14. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula IV(1): (In the formula, R ｂ and R ｃ are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; R3 and R4 are linked to form n R ｅ forming a 5-membered heterocyclyl substituted with R ｅ is OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR Ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl, unsubstituted or substituted with CN １ ~C ３ alkylene; ｓ is unsubstituted or halogen and / or C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and the R ｐ and R ｑ are each independently H and C １ ~C ３ alkyl; and n is 0, 1, or 2.

15. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula IV(2): (In the formula, R ｂ and R ｃ are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; R3 and R4 are linked to form n R ｅ forming a 4-membered heterocyclyl substituted with R ｅ is OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR s -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ alkyl; and unsubstituted or substituted with CN １ ~C ３ alkylene; ｓ is unsubstituted or is a halogen and C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and the R ｐ and R ｑ are each independently H and C １ ~C ３ alkyl; and n is 0, 1, or 2.

16. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula IV(3): (In the formula, R ｂ and R ｃ are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; X is C, N, or O; R3 and R4 are linked to form n R ｅ forming a 6-membered heterocyclyl substituted with R ｅ is OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ alkylene; ｓ is unsubstituted or is a halogen and C ３ ~C ６ C substituted with cycloalkyl １ ~C ３ alkyl, and ｐ and R ｑ are each independently H and C １ ~C ３ alkyl; and n is 0, 1, or 2.

17. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula IV(4): (In the formula, R ｂ and R ｃ are each independently selected from H, halogen, and CN; Rd is selected from H, halogen, and C1-C3 alkoxy; and wherein R3 and R4, for each occurrence, are independently selected from: H; C that is unsubstituted or substituted with 1-3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; １ ~C ３ alkyl; unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; ３ ~C ６ cycloalkyl; and —O(C １ ~C ３ alkyl).

18. 10. The compound, salt, hydrate or stereoisomer of claim 1, R3 and R4, for each occurrence, are independently selected from the following: H; C which is unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; １ ~C ６ alkyl; unsubstituted or substituted with 1 to 3 groups selected from halogen, cyano, and 3- to 6-membered heterocyclyl; ３ ~C ６ cycloalkyl; and —OR ｓ or R3 and R4 are linked to form a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or selected from the group consisting of OH; CN; C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ is substituted with alkylene, The R ｓ is unsubstituted or is a halogen and C ３ ~C ６ C substituted with cycloalkyl １ ~C ６ alkyl; and said R ｐ and R ｑ are each independently H and C １ ~C ６ selected from alkyl, Compounds, salts, hydrates or stereoisomers.

19. 10. The compound, salt, hydrate or stereoisomer of claim 1, R3 and R4, for each occurrence, are independently selected from the following: H; C which is unsubstituted or substituted with 1 to 3 groups selected from cyano, and 3- to 6-membered heterocyclyl; １ ~C ３ alkyl; C 3 -C 4 cycloalkyl; C 3 -C 4 cycloalkyl substituted with 1 to 3 groups selected from cyano, and 3- to 6-membered heterocyclyl; and —OR ｓ or R3 and R4 are linked to form a 4- to 6-membered heterocyclyl, or OH;CN;C ３ ~C ６ Cycloalkyl; 3- to 6-membered heterocyclyl; OR ｓ -C(=O)NR ｐ R ｑ ;-NR ｐ R ｑ unsubstituted or CN, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or —NR ｐ R ｑ C substituted with １ ~C ３ Alkyl; unsubstituted or substituted with CN １ ~C ３ alkylene; forming a 4- to 6-membered heterocyclyl substituted with; The R ｓ is unsubstituted or is a halogen and C ３ ~C ４ C substituted with cycloalkyl １ ~C ３ alkyl; and said R ｐ and R ｑ are each independently H and C １ ~C ３ selected from alkyl, Compounds, salts, hydrates or stereoisomers.

20. 10. The compound, salt, hydrate or stereoisomer of claim 1, R3 and R4, for each occurrence, are independently one of the following: H, OH, methyl, ethyl, —CH ２ CN, -OCH ３ , A compound, salt, hydrate or stereoisomer selected from:

21. 10. The compound, salt, hydrate or stereoisomer of claim 1, R3 and R4, when linked, are: A compound, salt, hydrate or stereoisomer forming a 4- to 6-membered heterocyclyl selected from:

22. R1 is unsubstituted or substituted with F, Cl, or CN; and R2 is unsubstituted or substituted with F, Cl, or —OCH ３ 22. The compound, salt, hydrate or stereoisomer of any one of claims 1 to 21, substituted with:

23. 2. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has a structure selected from the following:

24. A pharmaceutical composition in a predetermined unit dosage form comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21 and 23 and one or more pharmaceutically acceptable excipients.

25. 24. Use of a compound according to any one of claims 1 to 21 and 23 in the manufacture of a medicament for inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof.

26. Use of the composition of claim 24 in the manufacture of a medicament for inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof.

27. 24. A compound according to any one of claims 1 to 21 and 23 for use in inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof, or in the manufacture of a medicament thereof in a person in need thereof.

28. The composition of claim 24 for use in inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof, or in the manufacture of a medicament therefor in a person in need thereof.

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