Piperazine Cyclic Ureas

Abstract

Provided are piperazine cyclic 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. Also provided are pharmaceutical compositions, methods of manufacture, and methods of use, including treating a person in need thereof with an effective amount of the compound or composition 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 / 091436, 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, US2012022889, US2009099242, 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, the 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: JPEG0007760530000001.jpg6596 (in the formula, R1 is a C6 aryl containing 0 or 1 N heteroatom, or a C5 aryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein the C5 aryl and C6 aryl are optionally substituted with halogen, CN, or C1-C3 alkyl; R2 is a C6 aryl containing 0, 1 or 2 N or 3 N heteroatoms, or a C5 aryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein the C5 aryl and C6 aryl are optionally substituted with halogen, CN, C1-C3 alkoxy, or C1-C3 alkyl optionally substituted with OH; R3 is a C5-C8 aryl containing 1, 2, 3, or 4 N heteroatoms, or 1 or 2 N heteroatoms and O or S heteroatoms, and substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.

[0010] In one aspect, the present invention provides a compound of formula I, or a salt, hydrate, or stereoisomer thereof: JPEG0007760530000002.jpg5596 (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 is a C5 aryl containing 1, 2, 3, or 4 N heteroatoms, or 1 or 2 N heteroatoms and O or S heteroatoms, and substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.

[0011] In embodiments:

[0012] R3 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;

[0014] R3 includes N1, N1 / N2, N2 / N3, N3 / N4, N2 / N5, N2 / N4, S2 / N4, N2 / S4, S3 / N4, N2 / S3, N3 / O4, N2 / N3 / S5, N2 / N3 / O5, N2 / N3 / N5, N2 / N3 / N4 or N2 / N3 / N4 / N5;

[0015] Any combination of the above substituents.

[0016] In one aspect, the invention provides compounds having the structures disclosed herein.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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

[0022] Description of Specific Embodiments of the Invention

[0023] It is understood that the examples and embodiments described herein are merely illustrative of the present invention, and that various variations or modifications will be suggested to those skilled in the art based on these examples and embodiments, and that such variations or modifications are intended to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0024] 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.

[0025] 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.

[0026] 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.

[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, or 3 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 groups 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 groups selected from 5- and 6-membered carbocyclic aromatic rings (e.g., phenyl, etc.); bicyclic ring systems (e.g., 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic aromatic (e.g., bicyclic ring systems selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline); and tricyclic ring systems (e.g., 10- to 15-membered tricyclic ring systems) in which at least one ring is carbocyclic aromatic (e.g., fluorene, etc.).

[0030] For example, an aryl group may be selected from 5- and 6-membered carbocyclic aromatic rings 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, and 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 first attachment position) 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]thiazolyl (e.g., benzo[d]oxazol-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 from the first bond 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, 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-thiazepanyl, 1,4-diazepanyl Examples include, but are not limited to, 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 fused bicyclic or 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 having 0-3 heteroatoms, a C1-C3 alkyl or a C1-C2 alkyl, 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 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. For purposes of shorthand 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 considered to be present to the extent that the valence of the 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 -CHC(O)- group (keto form) may form a hydroxyl -CH=C(OH)- group (enol form) through tautomerism. Where applicable, both the keto and enol forms are intended to be included, either individually, and 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 or 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 their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting each 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 using methods such as the formation of diastereomers with an optically active resolving agent. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by suitable methods, including, for example, (1) forming ionic diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods, (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] Examples of "pharmaceutically acceptable salts" include inorganic acid salts selected from hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, and nitrates, as well as salts such as malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoates (such as acetates), and 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 recognize, without undue experimentation, a variety of synthetic methods available for preparing pharmaceutically acceptable, non-toxic addition salts.

[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 subject compounds, their stereoisomers, hydrates, and pharmaceutically acceptable salts thereof may be used alone or in combination with at least one other therapeutic agent for treatment. In some embodiments, the compounds of the present invention, their stereoisomers, hydrates, 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 that include the subject compounds, their stereoisomers, their hydrates, and / or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

[0065] Compositions containing the subject compounds, their stereoisomers, their hydrates, and / or pharmaceutically acceptable salts thereof can be administered in a variety of known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or from an implanted reservoir; however, the most appropriate route in any given case 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" includes 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 subject compounds, their stereoisomers, hydrates, and pharmaceutically acceptable salts thereof can be administered orally in solid dosage forms, such as capsules, tablets, lozenges, dragees, granules, and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The subject compounds disclosed herein, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts thereof can also be administered parenterally in sterile liquid dosage forms, such as dispersions, suspensions, and solutions. Other dosage forms can also be used to administer the subject compounds disclosed herein, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts thereof, such as ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions for ocular administration (i.e., eye drops); 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. Compressed tablets can also be prepared using similar diluents. Both tablets and capsules can 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 gastrointestinal 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, either alone or in combination. Citric acid and its salts, and sodium EDTA may also be used as suitable stabilizers. In addition, parenteral solutions may further contain at least one preservative, such as benzalkonium chloride, methyl- and 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 complexes with at least one compound and / or at least one pharmaceutically acceptable salt disclosed herein to increase solubility) can be used as pharmaceutical excipients for delivering 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 administration by inhalation, the subject compounds, 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 subject compounds, their stereoisomers, hydrates, and pharmaceutically acceptable salts thereof may be delivered as formulated powders, and such powder compositions may be inhaled with the aid of 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 subject compounds 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 formulation may be formulated as a solution or suspension containing the compound of interest, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof in an appropriate weight percentage in a suitable ophthalmic solvent, thereby maintaining contact of the compound of interest, 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 subject compounds 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 extent 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 2000 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 each standard two-piece hard gelatin capsule with 100 mg of a powdered subject compound disclosed herein, its stereoisomer, its hydrate, and / or a pharmaceutically acceptable salt thereof, 150 mg lactose, 50 mg cellulose, and 6 mg 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 a single dosage contains, for example, 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 micronized compound, 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.

[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, 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 subject compounds, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts are incorporated into pharmaceutical compositions or formulations. These compositions include 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 subject compounds, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts are administered in the morning / midday with a nighttime off-peak period.

[0083] The subject compounds, their stereoisomers, their hydrates, 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 a compound has a relatively acidic functionality, a salt can be obtained by adding a desired base in a suitable inert solvent or without a solvent. Examples of pharmaceutically acceptable base addition salts include sodium salt, potassium salt, calcium salt, ammonium salt, organic amino salt, magnesium salt, etc. When a compound has a relatively basic functionality, a salt can be obtained by adding a desired acid in a suitable inert solvent or without a 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 forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but for purposes of the present invention, the salts are otherwise equivalent to the parent forms of the compounds.

[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, for example, by hydrolysis or oxidative activation of the prodrug. Examples of prodrugs include, but are not limited to, compounds of the present invention that are administered as an ester (the "prodrug") 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 subject compounds, their stereoisomers, their hydrates, and / or pharmaceutically acceptable salts possess asymmetric carbon atoms (optical centers) or double bonds; all of their racemates, diastereomers, geometric isomers and individual isomers are intended to be encompassed within the scope of the present invention.

[0088] The compounds of the present invention may contain isotopes of atoms, such as deuterium (e.g., —CD3, CD2H, or CDH2 instead of methyl), at one or more of the constituent atoms of the compound in proportions not found in nature. For example, the compounds of the present invention may contain isotopes of atoms, such as tritium ( 3 H), iodine-125( 125 I), carbon-14 ( 14 C). All isotopically variants of the compounds of the present invention, 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 the compound of interest that will induce the biological or medical response of a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. The term "therapeutically effective amount" encompasses that amount of compound that, when administered, is sufficient 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] Such contacting is typically achieved by administering to the subject an effective amount of one or more compounds having the general formula I (see above), including the various embodiments described above. Generally, administration is adjusted to provide a therapeutic dose of about 0.1-50 mg / kg, preferably 0.5-10 mg / kg, and more preferably 1-10 mg / kg, although optimal dosages are compound-specific and 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 subject compositions 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, e.g., pancreatic cancer and melanoma.

[0093] In one aspect, the present invention provides a compound of formula Ia, or a salt, hydrate, or stereoisomer thereof: JPEG0007760530000003.jpg6496 (in the formula, R1 is a C6 aryl containing 0 or 1 N heteroatom, or a C5 aryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein the C5 aryl and C6 aryl are optionally substituted with halogen, CN, or C1-C3 alkyl; R2 is a C6 aryl containing 0, 1 or 2 N or 3 N heteroatoms, or a C5 aryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein the C5 aryl and C6 aryl are optionally substituted with halogen, CN, C1-C3 alkoxy, or C1-C3 alkyl optionally substituted with OH; R3 is a C5-C8 aryl containing 1, 2, 3, or 4 N heteroatoms, or 1 or 2 N heteroatoms and O or S heteroatoms, and substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.

[0094] In one aspect, the present invention provides a compound of formula I, or a salt, hydrate, or stereoisomer thereof: JPEG0007760530000004.jpg7096 (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 is a C5 aryl containing 1, 2, 3, or 4 N heteroatoms, or 1 or 2 N heteroatoms and O or S heteroatoms, and substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.

[0095] In embodiments: the R3 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); R2 comprises N2, N4 or N2 / N4; R3 includes N1, N1 / N2, N2 / N3, N3 / N4, N2 / N5; N2 / N4, S2 / N4, N2 / S4, S3 / N4, N2 / S3, N3 / O4, N2 / N3 / S5, N2 / N3 / O5, N2 / N3 / N5, N2 / N3 / N4 or N2 / N3 / N4 / N5; 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): JPEG0007760530000005.jpg6296In formula, R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0, 1, or 2; 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(2): JPEG0007760530000006.jpg6896In formula, R dis selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0, 1, or 2; 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(3): JPEG0007760530000007.jpg6096In formula, R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0, 1, or 2; 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(4): JPEG0007760530000008.jpg6296In formula, R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0, 1, or 2; and 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(5): JPEG0007760530000009.jpg6796In formula, R dis selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0 or 1; 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(6): JPEG0007760530000010.jpg5596In formula, R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; 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 II(1): JPEG0007760530000011.jpg6796In formula, R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0, 1, or 2; 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 II(1): JPEG0007760530000012.jpg6696In formula, R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH; where m is 0, 1, or 2; 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): JPEG0007760530000013.jpg6596In formula, R a is selected from halogen, CN, and C1-C3 alkyl; where n is 0, 1, 2, or 3; 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): JPEG0007760530000014.jpg6696In formula, R a is selected from halogen, CN, and C1-C3 alkyl; where n is 0, 1, 2, or 3; 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(3): JPEG0007760530000015.jpg6596In formula, R a is selected from halogen, CN, and C1-C3 alkyl; where n is 0, 1, 2, or 3; 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(4): JPEG0007760530000016.jpg6996, wherein X1 is S, X2 is C, and X3 is N, or X1 is S, X2 is N, and X3 is C, or X1 is N, X2 is O, and X3 is C, or X1 is N, X2 is S, and X3 is C; where R a is selected from halogen, CN, 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.

[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): JPEG0007760530000017.jpg5896In formula, R a is selected from halogen, CN, and C1-C3 alkyl; n is 0, 1, 2, or 3; where R d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH, m 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): JPEG0007760530000018.jpg5596, wherein X4 is N and X5 is C, or X4 is C and X5 is N; where R a is selected from halogen, CN, and C1-C3 alkyl; n is 0, 1, 2, or 3; where R dis selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH, m 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): JPEG0007760530000019.jpg6096, wherein X1 is S, X2 is C, and X3 is N, or X1 is S, X2 is N, and X3 is C, or X1 is N, X2 is O, and X3 is C, or X1 is N, X2 is S, and X3 is C; where R a is selected from halogen, CN, and C1-C3 alkyl, and n is 0, 1, 2, or 3; d is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl optionally substituted with OH, m 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 present disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R3 is substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl. JPEG0007760530000020.jpg96159; 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 R3 is: JPEG0007760530000021.jpg29114; 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 is 0 to 3 R e where R e is, for each occurrence, independently selected from: Halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(3-6 membered heterocyclyl), =O, -NO2, -C(=O)OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s 、 -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , and -S(=O) w NR p R q ;where: R eThe C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C2-C6 alkenyl, and C1-C6 alkoxy of -C(=O)(C1-C6 alkyl), the C3-C6 cycloalkyl of -C(=O)(C3-C6 cycloalkyl), and the 3- to 6-membered heterocyclyl of -C(=O)(3- to 6-membered heterocyclyl) are each halogen, cyano, ═O, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , -S(=O) w NR p R q , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R p , R q , R r , and R s is, for each occurrence, independently selected from hydrogen, OH, NH, C-C alkyl, C-C cycloalkyl, and 3-6 membered heterocyclyl; R p , R q , R r , and R sAny of the C1-C4 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl may be substituted by 1 to 3 groups selected from halogen, cyano, —OH, C1-C6 alkyl, —O(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)(C1-C6 alkyl), —C(═O)NH(C1-C6 alkyl), —C(═O)(3- to 6-membered heterocyclyl), —C(═O)(C3-C6 cycloalkyl), C3-C6 cycloalkyl, phenyl, and 3- to 6-membered heterocyclyl; wherein w is an integer selected from 0, 1, and 2; 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 is 0 to 3 R e where R e is, for each occurrence, independently selected from: Halogen; cyano; 4-6 membered heterocyclyl optionally substituted with =O, -NO2, or oxo; -C(=O)(C1-C3 alkyl); -C(=O)(4-6 membered heterocyclyl); -C(=O)OR s , where R s is H or C1-C3 alkyl; -OR s , where R s is H or C1-C3 alkyl; C1-C3 alkyl optionally substituted with OH, NH2, cyano, halogen, C1-C3 alkoxy, 3-4 membered cycloalkyl, 4-6 membered heterocyclyl, -C(=O)OH, -C(=O)(4-6 membered heterocyclyl), -C(=O)NH(CH2)2OH, or -C(=O)NH2; -C(=O)NR p R q , where R p and R q are each independently selected from H and C1-C3 alkyl; -NRp R q , where R p and R q are each independently selected from H and C1-C3 alkyl; -NR p C(=O)R s , where R p is selected from H and C1-C3 alkyl; and R s is selected from 3- to 4-membered cycloalkyl, and C1-C3 alkyl optionally substituted with 3- to 4-membered cycloalkyl; -NR p S(=O) w R s , where R p is selected from H and C1-C3 alkyl, R s is selected from C1-C3 alkyl, where w is 2; -S(=O) w R s , where R s is selected from C1-C3 alkyl, where w is 0 or 2; 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 R is one to three R e where R e is, for each occurrence, independently selected from: JPEG0007760530000022.jpg87159 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 R is one to three R e where R e is, for each occurrence, independently selected from: Cl, CN, methyl, —CF, —CHOH, —CHC(═O)NH, —C(═O)CH, —C(═O)NH, and —C(═O)OH; 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, salt, hydrate, or stereoisomer thereof, wherein R is one to three R e where R e is, for each occurrence, independently selected from: CN, methyl, Cl, and -C(=O)NH2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0118] In one embodiment, the present disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein the C5 aryl and C6 aryl of R1 are optionally substituted with F, Cl, Br, CN, or methyl; wherein the C5 aryl and C6 aryl of R2 are optionally substituted with F, Cl, CN, -OCH3, or -CH2OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0119] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has any of the structural formulas in Table 1 and Table 2.

[0120] Table 1: Active compounds: structure (compounds 1-142) JPEG0007760530000023.jpg207159JPEG0007760530000024.jpg218159JPEG000 7760530000025.jpg234159JPEG0007760530000026.jpg203159JPEG0007760530 000027.jpg211159JPEG0007760530000028.jpg217159JPEG0007760530000029. jpg240159JPEG0007760530000030.jpg242159JPEG0007760530000031.jpg42159

[0121] Table 2: Active compounds: structure (compounds 143-323) JPEG0007760530000032.jpg199159JPEG0007760530000033.jpg249159JPEG000 7760530000034.jpg252153JPEG0007760530000035.jpg233159JPEG0007760530 000036.jpg240159JPEG0007760530000037.jpg249159JPEG0007760530000038. jpg251153JPEG0007760530000039.jpg252153JPEG0007760530000040.jpg67159

[0122] Table 3: Cellular activity: Necrosis / necroptosis inhibitory activity (compounds 1-142) JPEG0007760530000041.jpg174159JPEG0007760530000042.jpg100159

[0123] Table 4: Cellular activity: Necrosis / necroptosis inhibitory activity (compounds 143-323) JPEG0007760530000043.jpg134159JPEG0007760530000044.jpg249153JPEG0007760530000045.jpg82159

[0124] Active Compounds: Representative Synthesis Compound 1: (S)-(4-(4-(1H-pyrazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000046.jpg75159

[0125] Step 1: To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (800 mg, 2.72 mmol) in toluene (50 mL) was added 2,4-dichloropyrimidine (446 mg, 3.0 mmol). The reaction mixture was stirred at 100° C. for 12 hours. The solvent was removed under vacuum and the crude product was purified by reverse phase chromatography. 210 mg of the desired product was obtained as a white solid. Yield: 19.0%. LC-MS (m / z) 407.1 (M+H) + ).

[0126] Step 2: To a solution of (S)-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (50 mg, 122.9 umol) in dioxane (3 mL) and HO (1 mL) was added (1H-pyrazol-3-yl)boronic acid (28 mg, 184.4 umol), Pd(dppf)Cl (20 mg, 24.6 umol), and KCO (35 mg, 245.8 umol) under argon. The reaction mixture was stirred at 80 °C for 2 h. The crude product was purified by pre-HPLC. 18 mg of the title compound 1 was obtained as a white solid. Yield: 33.4%. LC-MS (m / z) 407.1 (M+H + ).

[0127] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.37 (dd, J = 5.1, 0.9 Hz, 1H), 7.64 (d, J = 2.1, 1H), 6.93 (d, J = 5.1, 1H), 6.88-6.77 (m, 4H), 6.71-6.65 (m, 1H), 5.34 (dd, J = 11.7, 9.8 Hz, 1H), 4.02-3.96 (m, 2H), 3.90-3.76 (m, 4H), 3.69-3.62 (m, 2H), 3.36-3.27 (m, 1H), 2.72-2.64 (m, 1H).

[0128] Compound 2: (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-piperazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-imidazole-4-carbonitrile JPEG0007760530000047.jpg28159

[0129] To a solution of (S)-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (100 mg, 0.246 mmol) in DMF (5 mL) was added 1H-imidazole-4-carbonitrile (26 mg, 0.271 mmol) and CsCO3 (95 mg, 0.492 mmol). The reaction was stirred at 100 °C for 12 h. The crude product was purified by pre-HPLC to give the title compound 2 (15 mg) as a white solid. Yield: 13.2%. LC-MS (m / z) 464.1 (M+H) + ).

[0130] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.37 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 6.83-6.69 (m, 3H), 6.62 (tt, J = 8.9, 2.3 Hz, 1H), 6.47 (d, J = 5.3 Hz, 1H), 5.26 (dd, J = 11.7, 9.8 Hz, 1H), 3.95-3.53 (m, 8H), 3.25 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.62 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H).

[0131] Compound 3: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(4,5-dihydro-1H-imidazol-2-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000048.jpg68159

[0132] Step 1: To a solution of NaOH (0.32 g, 0.008 mol) in 14 mL of HO, (R)-2-hydroxy-2-phenylacetic acid (1.52 g, 0.01 mol) was added portionwise. Copper(II) chloride (0.538 g, 0.004 mol) in 14 mL of HO was added dropwise to the solution. It was stirred at room temperature for 5 minutes. The blue solid was filtered and washed with HO. It was dried in vacuum to give 1.328 g of bis((R)-2-hydroxy-2-phenylacetoxy)copper ligand as a blue solid. Yield: 90.2%.

[0133] 2-Chloropyrimidine-4-carbonitrile (52.2 mg, 0.37 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (100 mg, 0.34 mmol) were dissolved in 3 mL of DMF. 0.3 mL of DIEA was added. It was stirred at 70 °C for 32 hours. Water was added to the reaction mixture, and it was extracted with EtOAc (15 mL × 3). The organic layers were combined and evaporated to dryness, and purified by column chromatography (PE / EA = 1 / 1) to give 140 mg of (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carbonitrile as a brown oil. Yield: quantitative. LC-MS(m / z):398.2[M+H] + .

[0134] Step 2: (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carbonitrile (140 mg, 0.35 mmol) and bis((R)-2-hydroxy-2-phenylacetoxy)copper ligand (12.9 mg, 0.035 mmol), AcONa (9.8 mg, 0.12 mmol), and I2 (9 mg, 0.035 mmol) were mixed in 5 mL of toluene. Then, ethane-1,2-diamine (26.6 mg, 0.443 mmol) was added. The mixture was stirred at 90 °C for 16 hours. The mixture was filtered, and the filtrate was evaporated to dryness and recrystallized with MeOH / EA / PE to give 70 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(4,5-dihydro-1H-imidazol-2-yl)pyrimidin-2-yl)piperazin-1-yl)methanone as a white solid. Yield: 45.5%.

[0135] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.54 (d, J = 4.8 Hz, 1H), 6.99-6.93 (m, 3H), 6.82 (tt, J = 8.8, 2.4 Hz, 1H), 5.46 (dd, J = 11.6, 10.0 Hz, 1H), 4.10-4.04 (m, 2H), 4.01-3.85 (m, 8H), 3.79-3.74 (m, 2H), 3.45 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.82 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 441.3[M+H] + .

[0136] Compound 4: (S)-(4-(4-(1H-tetrazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000049.jpg35159

[0137] To a solution of (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidine-4-carbonitrile (40 mg, 100.7 umol) in DMF (4 mL) was added NaN3 (18 mg, 261.7 umol) under argon. The reaction mixture was stirred at 120 °C for 4 h. The crude product was purified by pre-HPLC to give (S)-(4-(4-(1H-tetrazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (13 mg, 29%) as an off-white solid. LC-MS (m / z) 441.1 (M+H) + ).

[0138] 1H NMR (400 MHz, DMSO) δ 8.23 ​​(d, J = 6.1 Hz, 1H), 7.15-7.05 (m, 2H), 7.05-6.94 (m, 2H), 6.72 (d, J = 6.2 Hz, 1H), 5.25 (dd, J = 11.6, 9.9 Hz, 1H), 3.87-3.52 (m, 8H), 3.35 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.64 (ddd, J = 18.3, 9.9, 1.7 Hz, 1H).

[0139] Compound 5: (S)-(4-(2-(1H-pyrrol-2-yl)pyrimidin-4-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000050.jpg83159

[0140] Step 1. 2,4-Dichloropyrimidine (360 mg, 2.416 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (608 mg, 2.073 mmol), and K2CO3 (666 mg, 4.826 mmol) were mixed in 15 mL of 1,4-dioxane / HO (9 / 1). Pd(dppf)Cl2 (180 mg, 0.246 mmol) was added. The mixture was stirred at 80 °C under nitrogen for 16 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 4 / 1) to give 85 mg of the mixture as a brown oil. Yield: 22.9%. LC-MS (m / z) 180.2 [M+H] + .

[0141] Step 2. The above mixture (73 mg, 0.408 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (120 mg, 0.408 mmol) were mixed in 8 mL of i-PrOH. 0.5 mL of DIEA was added. It was stirred at 160° C. under microwave for 1 h. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA=2 / 1) to give 10 mg of 5 as a pale yellow solid. Yield: 5.6%. LC-MS (m / z) 438.4 (M+H + ).

[0142] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.28 (d, J = 5.6 Hz, 1H), 7.50 (t, J = 2.4 Hz, 2H), 6.82-6.86 (m, 3H), 6.67-6.72 (m, 1H), 6.51 (d, J = 5.6 Hz ,1H), 6.34 (t, J = 2.4 Hz, 2H), 5.34 (dd, J = 10.0, 11.6 Hz ,1H), 3.94-4.00 (m, 2H), 3.75-3.89 (m, 4H), 3.62-3.67 (m, 2H), 3.32 (ddd, J = 2.0, 11.6, 13.6 Hz,1H), 2.69 (ddd, J = 1.6, 10.0, 11.6 Hz, 1H).

[0143] Compound 6: (S)-(4-(4-(1H-pyrrol-2-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000051.jpg91159

[0144] The title compound 6 was prepared in two steps in 7% yield from 2,4-dichloropyrimidine, tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for compound 5. LC-MS (m / z) 438.4 (M+H + ).

[0145] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 9.60 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 6.92-6.94 (m, 1H), 6.79-6.85 (m, 4H), 6.73 (d, J = 5.2 Hz, 1H), 6.66-6.74 (m, 1H), 6.29-6.31 (m, 1H), 5.33 (dd, J = 10.0, 11.6 Hz ,1H), 3.92-3.98 (m, 2H), 3.75-3.82 (m, 4H), 3.61-3.66 (m, 2H), 3.29 (ddd, J = 1.6, 11.6, 13.6 Hz, 1H), 2.66 (ddd, J = 1.6, 10.0, 11.6 Hz, 1H).

[0146] Measured value: 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).

[0147] Compound 7: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000052.jpg86159

[0148] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol) in 10 mL of 1,4-dioxane / HO (5:1), KCO (1.65 g, 11.98 mmol) and Pd(dppf)Cl (240 mg, 2.37 mmol) were added to the above solution at room temperature under nitrogen. The mixture was stirred at 80 °C for 1.0 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound (700 mg, 58%) as a white solid. (ES, m / s): 199.1 [M+H]

[0149] Step 2: To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (91 mg, 0.3 mmol) and 2-chloro-5-fluoro-4-(1H-pyrazol-3-yl)pyrimidine (68 mg, 0.3 mmol) in DMF (5 mL) was added EtN (63 mg, 0.6 mmol). The mixture was stirred at 65 °C overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 1) to give the title compound 7 (28.6 mg, 45% yield) as a white solid. LCMS (ES, m / z): 457.2 [M+H] + .

[0150] 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 7.73-7.63 (m, 1H), 7.04-6.94 (m, 1H), 6.86 - 6.80 (m, 3H), 6.72-6.66 (m, 1H), 5.34 (dd, J = 7.6, 11.2 Hz, 1H), 4.02 -3.58 (m, 8H), 3.36 (dd, J = 17.3, 12.3 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H).

[0151] Compound 8: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1H-1,2,3-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000053.jpg68159

[0152] Step 1. 2,4-Dichloro-5-fluoropyrimidine (1.699 g, 0.01 mol), Pd(PPh3)2Cl2 (176.3 mg, 0.25 mmol), CuI (128 mg, 0.66 mmol), and TEA (2.057 g, 0.02 mol) were dissolved in 100 mL of TEF. The mixture was stirred at 60 °C under nitrogen for 30 minutes. Next, ethynyltrimethylsilane (500 mg, 5.09 mmol) in 25 mL of THF was slowly added to the mixture, and the mixture was stirred at 60 °C for 16 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 10 / 1) to obtain 0.92 g of 2-chloro-5-fluoro-4-((trimethylsilyl)ethynyl)pyrimidine as a pale yellow solid. Yield: 79.2%. LC-MS(m / z)229.2[M+H] + .

[0153] Step 2. 2-Chloro-5-fluoro-4-((trimethylsilyl)ethynyl)pyrimidine (670 mg, 2.94 mmol) was dissolved in 5 mL of MeOH. 114 μl of KOH in MeOH (35 mg of KOH in 5 mL of MeOH) was added. It was stirred at room temperature for 20 minutes. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=6 / 1) to give 0.32 g of 2-chloro-4-ethynyl-5-fluoropyrimidine as a white solid. Yield: quantitative.

[0154] Step 3. 2-Chloro-4-ethynyl-5-fluoropyrimidine (220 mg, 1.41 mmol), TMSN3 (242 mg, 2.1 mmol), and CuI (13.2 mg, 0.07 mmol) were dissolved in 5 mL of DMF / MeOH (9 / 1) solution. The mixture was stirred at 100° C. for 4 hours. The solvent was evaporated to dryness, and the mixture was purified by preparative TLC (DCM / MeOH=12 / 1) to give 0.14 g of 2-chloro-5-fluoro-4-(1H-1,2,3-triazol-5-yl)pyrimidine as a brown solid. Yield: 49%. LC-MS (m / z) 200.1 [M+H] + .

[0155] Step 4. The title compound 8 was prepared in 16.1% yield from 2-chloro-5-fluoro-4-(1H-1,2,3-triazol-5-yl)pyrimidine and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for compound 7. 20 H 18 Calculated mass (ESI) for FNO: m / z 457.4, found 458.3 [M+H] + .

[0156] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.33 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 6.80-6.85 (m, 3H), 6.65-6.69 (m, 1H), 5.36 (t, J = 10.4 Hz ,1H), 3.91-3.95 (m, 2H), 3.76-3.87 (m, 4H), 3.61-3.68 (m, 2H), 3.32 (ddd, J = 1.2, 12.0, 12.8 Hz ,1H), 2.68 (ddd, J = 0.8, 9.6, 10.4 Hz, 1H).

[0157] Compound 9: (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrrole-3-carboxylate methyl JPEG0007760530000054.jpg74159

[0158] Step 1. 1-(tert-butyl)-3-methyl 5-bromo-1H-pyrrole-1,3-dicarboxylate (614 mg, 2.026 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.029 g, 4.05 mmol) were dissolved in 20 mL of 1,4-dioxane. KOAc (380.7 mg, 4.054 mmol) and Pd(PPh3)2Cl2 (66.7 mg, 0.095 mmol) were added. The mixture was stirred at 90 °C for 16 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=4 / 1) to give 1.01 g of 1-(tert-butyl)3-methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,3-dicarboxylate as a brown oil. Yield: 87.5%. LC-MS (m / z) 270.2 [M+H] + .

[0159] Step 2. 1-(tert-butyl)3-methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,3-dicarboxylate (39.6 mg, 0.147 mmol) and (S)-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (60 mg, 0.147 mmol), KCO (41 mg, 0.294 mmol), and Pd(dppf)Cl (10.7 mg, 0.014 mmol) were dissolved in 3 mL of 1,4-dioxane / HO (3 / 1). The mixture was stirred at 90 °C for 16 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=1 / 3) to give 35 mg of compound 9 as a white solid. Yield: 47.9%. Mass (ESI): m / z: C 24 H 23 Calculated for F2N7O3: 495.5, Found: 496.4 [M+H] + .

[0160] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 9.68 (brs, 1H), 8.28-8.32 (m, 1H), 7.55 (s, 1H), 7.21 (s, 1H), 6.80-6.87 (m, 3H), 6.75-6.79 (m, 1H), 6.66-6.74 (m, 1H), 5.35 (t, J = 10.4 Hz, 1H), 3.92-4.05 (m, 2H), 3.74-3.91 (m, 7H), 3.60-3.70 (m, 2H), 3.33 (dd, J = 12.4, 18.4 Hz ,1H), 2.70 (dd, J = 9.6, 18.4 Hz, 1H).

[0161] Compound 10: (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide JPEG0007760530000055.jpg3364

[0162] The title compound 10 was prepared in 16% yield from ammonium hydroxide and (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrrole-3-carbonyl chloride following the procedure outlined for compound 92. Mass (ESI): m / z C 23 H 22 Calculated for F2N8O2: 480.5, Found: 481.3 [M+H] + .

[0163] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 9.69 (brs, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.49-7.50 (m, 1H), 7.02-7.03 (m, 1H), 6.82-6.86 (m, 3H), 6.70-6.76 (m, 2H), 5.32-5.37 (m, 1H), 3.95-4.00 (m, 2H), 3.77-3.89 (m, 4H), 3.61-3.69 (m, 2H), 3.33 (ddd, J = 1.2, 12.0, 13.2Hz ,1H), 2.69 (ddd, J = 1.2, 10.0,11.2 Hz, 1H).

[0164] Compound 11: (S)-1-(2-(4-(5-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000056.jpg3464

[0165] The title compound 11 was prepared in a similar manner to the preparation of 10 in 39.1% yield as a grey solid. LC-MS (m / z) 446.4 (M+H + )

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 7.91 (brs, 1H), 7.37 - 7.19 (m, 6H), 7.09 (d, J = 5.2 Hz, 2H), 5.25 (t, J = 10.4 Hz, 1H), 3.94 - 3.51 (m, 8H), 3.44 - 3.36 (m, 1H), 2.69 - 2.54 (m, 1H).

[0167] Compound 12: (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrrole-3-carboxylate methyl JPEG0007760530000057.jpg73159

[0168] The title compound 12 was prepared in 11.5% yield from methyl 5-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrrole-3-carboxylate and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for 7. Mass (ESI): m / z C 24 H 22 Calculated for F3N7O3: 513.5, Found: 514.4 [M+H] + .

[0169] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 9.73 (brs, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.59 (dd, J = 1.2, 2.8Hz ,1H), 7.40-7.42 (m, 1H), 6.80-6.85 (m, 3H),6.66-6.72 (m, 1H), 5.33 (dd, J = 10.0, 11.6 Hz ,1H), 3.87-3.92 (m, 5H), 3.75-3.82 (m, 4H), 3.62-3.48 (m, 2H), 3.32 (ddd, J = 2.0, 12.0, 13.6 Hz,1H), 2.69 (ddd, J = 1.6, 9.6,11.2 Hz, 1H).

[0170] Compound 13: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000058.jpg90159

[0171] The title compound 13 was prepared in 9% yield from 2-chloro-5-fluoro-4-(3-methyl-1H-pyrazol-4-yl)pyrimidine and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for 7. Mass (ESI): m / z C 22 H 21 Calculated for F3NO 476.5, found 477.4 [M+H] + .

[0172] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.09-8.31 (m, 2H), 6.82-6.86 (m, 3H), 6.69-6.72 (m, 1H),5.35 (t, J = 11.6 Hz, 1H), 3.88-3.96 (m, 2H), 3.76-3.85 (m, 4H), 3.59-3.72 (m, 2H), 3.32 (dd, J = 12.0, 18.4 Hz ,1H), 2.66-2,79 (m, 4H).

[0173] Compound 14: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000059.jpg38159

[0174] Step 1. 2-Chloro-5-fluoro-4-(3-methyl-1H-pyrazol-4-yl)pyrimidine (50 mg, 0.236 mmol) was dissolved in 3 mL of DMF. NaH (28 mg, 0.699 mmol) was added in portions at 0 °C. It was stirred at 0 °C for 30 minutes. CHCl (67 mg, 0.472 mmol) was added. It was stirred at room temperature for 30 minutes. Water was added and extracted with EtOAc (10 mL × 3). Drying over NaSO, filtration, and evaporation to dryness gave 64 mg of 2-chloro-4-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidine as a pale yellow solid. This crude product was used directly in the next step without further purification. LC-MS (m / z) 227.2 [M+H] + .

[0175] Step 2. The above residue and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (83 mg, 0.282 mmol) were dissolved in 9 mL of DMF. It was stirred at 65° C. for 32 h. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA=1 / 2) to give 5 mg of 14 as a pale yellow solid. Yield: 4.4%. Mass (ESI): m / z C 23 H 23 Calculated for F3N8O: 484.5, Found: 485.4 [M+H] + .

[0176] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.16 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 6.80-6.86 (m, 3H), 6.67-6.72 (m, 1H), 5.34 (dd, J = 10.4,11.2 Hz, 1H), 3.86-3.90 (m, 5H), 3.74-3.81 (m, 4H), 3.60-3.68 (m, 2H), 3.32 (ddd, J = 1.6, 11.6, 18.4 Hz ,1H), 2.62-2,73 (m, 4H).

[0177] Compound 15: (S)-3-(1-(4-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000060.jpg52159

[0178] The title compound 15 was prepared as a brown solid in 33.3% yield from 2-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidine and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile) in a manner similar to the preparation of compound 14.

[0179] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 1.6 Hz, 1H), 7.51 (s, 1H), 7.42 (t, J = 1.2 Hz, 1H), 7.30 -7.26 (m, 1H), 7.25-7.20 (m, 1H), 6.89 (t, J = 1.2 Hz, 1H), 5.37 (dd, J = 11.6, 10.0 Hz, 1H), 3.95 (s, 3H), 3.94-3.86 (m, 2H), 3.85-3.73 (m, 4H), 3.70-3.60 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 512.8 [M+H] + .

[0180] Compound 16: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-4-methyl-1H-imidazole-2-carbonitrile JPEG0007760530000061.jpg97159

[0181] The title compound 16 was prepared in a similar manner to the preparation of 14 from 1-(2-chloro-5-fluoropyrimidin-4-yl)-4-methyl-1H-imidazole-2-carbonitrile (90 mg, 0.38 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (100 mg, 0.33 mmol), DIEA (200 mg, 1.45 mmol), and DMF (5 mL) in 32.0% yield as a white solid. LC-MS (m / z) 503.4 (M+H) + )

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 3.2 Hz, 1H), 7.80 (dd, J = 3.2, 1.2 Hz, 1H), 7.68 (ddd, J = 8.6, 2.4, 1.2 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.52 - 7.44 (m, 1H), 7.06 (d, J = 1.6 Hz, 1H), 5.22 (t, J = 10.8 Hz, 1H), 3.83 - 3.42 (m, 8H), 3.32 - 3.22 (m, 1H), 2.64 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.18 (d, J = 1.2 Hz, 3H).

[0183] Compound 17: (S)-1-(2-(4-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000062.jpg3064

[0184] In a similar manner to the preparation of 10, the title compound 17 was prepared as a white solid in 17.0% yield. LC-MS (m / z) 464.4 (M+H + )

[0185] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.51 (dd, J = 5.2, 1.2 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.84 (brs, 1H), 7.43 - 7.33 (m, 1H), 7.30 (brs, 1H), 7.15 - 7.03 (m, 5H), 5.26 (dd, J = 11.6, 9.8 Hz, 1H), 3.93 - 3.51 (m, 8H), 3.43 - 3.35 (m, 1H), 2.68 - 2.59 (m, 1H).

[0186] Compound 18: (S)-2-(4-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-3-methyl-1H-pyrazol-1-yl)acetamide JPEG0007760530000063.jpg38159

[0187] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(3-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone (55 mg, 0.117 mmol), 2-bromoacetamide (17.7 mg, 0.128 mmol), and CsCO (76 mg, 0.234 mmol) were mixed in 2 mL of DMF. It was stirred at room temperature for 16 hours. Water was added to the solution, and it was extracted with EtOAc (10 mL × 3). The solvent was washed with brine. It was filtered and evaporated to dryness, and purified by preparative HPLC to give 3 mg of 18 as a white solid. Yield: 4.9%. Mass (ESI): m / z C 24 H 24 Calculated for F3N9O2: 527.5, Found: 528.6 [M+H] + .

[0188] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.19 (d, J = 3.2 Hz, 1H), 8.07 (d, J = 3.2 Hz, 1H), 6.81-6.86 (m, 3H), 6.67-6.72 (m, 1H), 6.36 (brs, 1H), 5.59 (brs,1H),5.35 (t, J = 10.8 Hz, 1H), 4.80 (s, 2H), 3.86-3.94 (m, 2H), 3.79 (q, J = 7.2 Hz, 4H), 3.61-3.69 (m, 2H), 3.32 (ddd, J = 2.0, 12.0, 13.6 Hz,1H), 2.69 (ddd, J = 1.6, 10.0, 11.2 Hz,1H), 2.65 (s, 3H).

[0189] Compound 19: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-2',6'-dimethoxy-[4,4'-bipyrimidin]-2-yl)piperazin-1-yl)methanone JPEG0007760530000064.jpg62159

[0190] Step 1. 2,4-Dichloro-5-fluoropyrimidine (1.14 g, 6.82 mmol), 4-bromo-2,6-dimethoxypyrimidine (1.5 g, 6.84 mmol), and (Sn-Bu3)2 (3.984 g, 6.87 mmol) were dissolved in 17.5 mL of water. Nitrogen was bubbled through the mixture for 5 minutes. Pd(PPh3)4 (528 mg, 0.342 mmol) was then added. The mixture was stirred at 150 °C for 90 minutes under microwave irradiation. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 4 / 1) to give 240 mg of 2-chloro-5-fluoro-2',6'-dimethoxy-4,4'-bipyrimidine as a white solid. Yield: 19.5%. LC-MS (m / z) 271.2 [M+H] + .

[0191] Step 2. 2-Chloro-5-fluoro-2',6'-dimethoxy-4,4'-bipyrimidine (101 mg, 0.374 mmol) and S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)ethenone (100 mg, 0.34 mmol) and 60 μL of TEA were dissolved in 13 mL of DMF. It was stirred at 65°C for 32 hours. Water was added to the solution and extracted with EtOAc (10 mL x 3). The solvent was washed with brine. Filtration and evaporation to dryness and purification by preparative TLC (PE / EA = 1 / 1.2) gave 42 mg of 19 as a white solid. Yield: 21.4%. Mass (ESI): m / z C 24 H 23 Calculated for F3N8O3: 528.5, Found: 529.4 [M+H] + .

[0192] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.35-8.36 (m, 1H), 7.1-7.33 (m, 1H), 6.80-6.88 (m, 3H), 6.69-6.72 (m, 1H), 5.30-5.37 (m, 1H), 4.40 (s, 6H), 3.88-3.96 (m, 2H), 3.75-3.84 (m, 4H), 3.60-3.70 (m, 2H), 3.27-3.40 (m, 1H), 2.64-2.75 (m, 1H).

[0193] Compound 20: (S)-(5-(3,5-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(5-iodo-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000065.jpg62159

[0194] Step 1. 2-Chloro-4-ethynyl-5-fluoropyrimidine (186 mg, 1.192 mmol), NIS (318 mg, 1.413 mmol), and AgNO (20 mg, 0.118 mmol) were suspended in 10.5 mL of acetone. It was stirred at room temperature for 2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was redissolved in 30 mL of EtOAc and washed with saturated NH Cl solution, saturated Na SO solution, and water. Drying over Na SO , filtering, and evaporation to dryness gave 340 mg of 2-chloro-5-fluoro-4-(iodoethynyl)pyrimidine as a white solid. Yield: quantitative. It was used in the next step without further purification. LC-MS (m / z) 283.3 [M+H] + .

[0195] Step 2. 2-Chloro-5-fluoro-4-(iodoethynyl)pyrimidine (220 mg, 0.78 mmol), TMSN3 (134.8 mg, 1.17 mmol), and CuI (11 mg, 0.058 mmol) were dissolved in 5 mL of DMF / MeOH (9 / 1) solution. The mixture was stirred at 100° C. for 2 hours. The solvent was evaporated to dryness, and the mixture was purified by preparative TLC (DCM / MeOH=12 / 1) to give 20 mg of 2-chloro-5-fluoro-4-(5-iodo-2H-1,2,3-triazol-4-yl)pyrimidine as a brown solid. Yield: 7.9%. LC-MS (m / z) 326.2 [M+H] + .

[0196] Step 3. The title compound 20 was prepared in 5% yield from 2-chloro-5-fluoro-4-(5-iodo)-2H-1,2,3-triazol-4-yl)pyrimidine and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for 7. Mass (ESI): m / z C 20 H 17 Calculated for F3IN9O 583.3, found 584.4 [M+H] + .

[0197] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.36 (d, J = 2.8 Hz, 1H), 6.80-6.89 (m, 3H), 6.67-6.72 (m, 1H), 5.36 (t, J = 10.0, 1H), 3.99-4.05 (m, 2H), 3.89-3.94 (m, 2H), 3.78-3.84 (m, 2H), 3.64-3.70 (m, 2H), 3.33 (ddd, J = 2.0, 12.0, 13.6 Hz ,1H), 2.69 (ddd, J = 1.6, 9.6, 11.2Hz,1H).

[0198] Compound 21: (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid JPEG0007760530000066.jpg38159

[0199] The title compound 21 was prepared in 86.2% yield from (S)-methyl 5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrrole-3-carboxylate following the procedure outlined for 10. Mass (ESI): m / z C 23 H 20 Calculated for F3N7O3: 499.5, Found: 500.4 [M+H] + .

[0200] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.20-8.22 (m, 1H), 7.60-7.65 (m, 1H), 7.39-7.41 (m, 1H), 6.87-6.92 (m, 2H), 6.77-6.80 (m, 2H), 6.67-6.69 (m, 1H), 5.25-5.31 (m, 1H), 4.08-4.19 (m, 2H), 3.96-4.04 (m, 2H), 3.78-3.92 (m, 2H), 3.66-3.74 (m, 2H), 3.28-3.32 (m, 1H), 2.66-2.72 (m, 1H).

[0201] Compound 22: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000067.jpg85159

[0202] The title compound 22 was prepared in a similar manner to the preparation of compound 7.

[0203] 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.4 Hz, 1H), 7.92-7.64 (m, 1H), 7.42-7.41 (m, 1H), 7.33-7.20 (m, 2H), 7.00-6.97 (m, 1H), 6.91-8.89 (m, 1H), 5.33 (dd, J = 10, 11.2 Hz, 1H), 4.02-3.50 (m, 8H), 3.36 (ddd, J = 18.2, 11.7, 1.8 Hz, 1H), 2.70 (ddd, J = 18.2, 10.0, 1.6 Hz. 1H).

[0204] Compound 23: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(5-methyl-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000068.jpg29159

[0205] The title compound 23 was prepared in a similar manner to the preparation of 7.

[0206] 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 2.4 Hz, 1H), 6.90-6.75 (m, 3H), 6.74-6.55 (m, 1H), 5.33 (dd, J = 10, 12 Hz, 1H), 3.97-3.56 (m, 8H), 3.33 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.80 (s, 3H), 2.70 (ddd, J = 18.2, 10.0, 1.6 Hz. 1H).

[0207] Compound 24: (S)-(4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000069.jpg28159

[0208] The title compound 24 was prepared in a similar manner to the preparation of compound 7.

[0209] 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.43 (d, J = 3.2 Hz, 1H), 6.96-6.75 (m, 3H), 6.70 (m, 1H), 5.33 (dd, J = 9.6, 11.2 Hz, 1H), 4.02-3.53 (m, 8H), 3.33 (ddd, J = 18.2, 11.7, 1.7 Hz, 1H), 2.70 (ddd, J = 18.3, 9.7, 1.5 Hz, 1H).

[0210] Compound 25: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(6-hydroxypyridin-3-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000070.jpg33159

[0211] The title compound 91 was prepared in a manner similar to the preparation of compound 7.

[0212] 1 H NMR (400 MHz, CDCl3) δ 13.14 (brs, 1H), 8.39-8.02 (m, 3H), 6.87-6.53 (m, 5H), 5.33 (dd, J = 10, 11.6 Hz, 1H), 4.00-3.40 (m, 8H), 3.32-3.09 (m, 1H), 2.74 (m, 1H).

[0213] Compound 26: (S)-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(5-methyl-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000071.jpg71159

[0214] The title compound 26 was prepared as a pale yellow solid in 41.1% yield from 4-chloro-2-(5-methyl-1H-tetrazol-1-yl)pyrimidine and (S)-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone in a manner similar to the preparation of compound 7.

[0215] 1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 7.67 (dt, J = 8.4, 2.4 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 6.96 (t, J = 1.6 Hz, 1H), 5.47 (dd, J = 11.2, 10.6 Hz, 1H), 4.02-3.91 (m, 2H), 3.89-3.75 (m, 4H), 3.74-3.63 (m, 2H), 3.44 (ddd, J = 18.4, 11.6, LC-MS (m / z): 438.3 [M+H]+.

[0216] Compound 27: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000072.jpg28159

[0217] The title compound 27 was prepared in a similar manner to the preparation of compound 7.

[0218] 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.9 Hz, 1H), 7.56-7.57 (m, 1H), 6.87 (ddd, J = 16.2, 6.2, 4.0 Hz, 4H), 6.72-6.66 (m, 1H), 5.35 (dd, J = 13.4, 8.1 Hz, 1H), 4.28 (s, 3H), 4.03-3.54 (m, 8H), 3.38-3.29 (m, 1H), 2.69 (ddd, J = 18.4, 9.9, 1.5 Hz, 1H).

[0219] Compound 28: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000073.jpg28159

[0220] The title compound 28 was prepared in a similar manner to the preparation of compound 7. 1 H NMR (400 MHz, CDCl3) δ 8.35-8.12 (m, 1H), 7.58-7.52 (m, 1H), 7.00-6.77 (m, 4H), 6.74-6.66 (m, 1H), 5.36-5.31 (m, 1H), 4.04 (s, 3H), 3.99-3.56 (m, 8H), 3.37-3.25 (m, 1H), 2.74-7.64 (m, 1H).

[0221] Compound 29: (S)-2-(3-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)acetamide JPEG0007760530000074.jpg24159

[0222] The title compound 29 was prepared in a similar manner to the preparation of compound 7.

[0223] 1 H NMR (400 MHz, CDCl3) δ 8.41-8.02 (m, 1H), 7.69-7.41 (m, 1H), 7.25-6.98 (m, 3H), 6.95-6.48 (m, 2H), 5.36-5.31 (m, 1H), 4.95 (s, 2H), 4.09-3.46 (m, 8H), 3.32 (dd, J = 17.4, 12.7 Hz, 1H), 2.69 (dd, J = 19.1, 10.8 Hz, 1H).

[0224] Compound 30: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(5-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000075.jpg31159

[0225] The title compound 30 was prepared in a similar manner to the preparation of compound 7.

[0226] 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 4 Hz, 1H), 6.92-6.77 (m, 5H), 6.74-6.62 (m, 1H), 5.37-5.32 (m, 1H), 4.04-3.51 (m, 8H), 3.39-3.26 (m, 1H), 2.74-2.68 (m, 1H), 2.67 (s,3H).

[0227] Compound 31: (S)-2-(4-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-1,2,3-triazol-1-yl)acetamide JPEG0007760530000076.jpg75159

[0228] The title compound 31 was prepared in a similar manner to the preparation of compound 7.

[0229] 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 4 Hz, 1H), 6.72-6.67 (m, 3H), 6.86-8.81 (m, 1H), 5.42-5.25 (m, 1H), 5.17 (s, 2H), 3.92-3.64 (m, 8H), 3.36-3.29 (m, 1H), 2.73-2.67 (m, 1H), 2.67 (s, 3H).

[0230] Compound 32: (S)-2-(4-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-2H-1,2,3-triazol-2-yl)acetamide JPEG0007760530000077.jpg76159

[0231] The title compound 32 was prepared in a manner similar to the preparation of compound 7.

[0232] 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 4.0 Hz, 1H), 6.90-6.77 (m, 3H), 6.72-6.67 (m, 1H), 5.42-5.25 (m, 1H), 5.07 (s, 2H), 3.92-3.64 (m, 8H), 3.36-3.29 (m, 1H), 2.73-2.67 (m, 1H), 2.67 (s, 3H).

[0233] Compound 33: (S)-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000078.jpg68159

[0234] Step 1: To a solution of 2,4-dichloropyrimidine (10 g, 67.1 mmol) in toluene (80 mL) was added tert-butyl piperazine-1-carboxylate (12.5 g, 67.1 mmol). The reaction mixture was stirred at 110° C. for 10 hours. The crude product was purified by flash chromatography. tert-Butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate was obtained as a white solid (4.2 g), yield: 20.9%. LC-MS (m / z) 299.1 (M+H) + ).

[0235] Step 2: To a solution of tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (1 g, 3.35 mmol) in dioxane (20 mL) and HO (6 mL) was added (1H-pyrazol-3-yl)boronic acid (412 mg, 3.68 mmol), Pd(dppf)Cl (246 mg, 0.034 mmol), and KCO (926 mg, 6.7 mmol). The reaction mixture was stirred at 80 °C under argon for 12 h. The crude product was purified by flash chromatography. tert-Butyl 4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (640 mg) was obtained as a white solid. Yield: 57.9%. LC-MS (m / z) 331.1 (M+H) + ).

[0236] Step 3: To a solution of tert-butyl 4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 605.3 umol) 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) 231.1 (M+H + ).

[0237] Step 4: To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (100 mg, 362 umol) in THF (6 mL) was added 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine (84 mg, 362 umol) and EtN (2 mL). The reaction mixture was stirred at 75° C. for 12 hours. The crude product was purified by flash chromatography. The title compound 33 was obtained as a white solid (43 mg), yield: 27.1%. LC-MS (m / z) 439.1 (M+H + ).

[0238] 1 H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 5.1, 1.1 Hz, 1H), 7.64 (s, 1H), 7.42-7.41 (m, 1H), 7.34-7.21 (m, 2H), 6.94 (dd, J = 5.0, 1.1 Hz, 1H), 6.92-6.82 (m, 2H), 5.37 (t, J = 10.8 Hz, 1H), 4.04-3.60 (m, 8H), 3.35 (ddt, J = 18.2, 11.7, 1.4 Hz, 1H), 2.68 (ddt, J = 18.2, 10.0, 1.4 Hz, 1H).

[0239] Compound 34: (S)-3-(1-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000079.jpg38159

[0240] The title compound 34 was prepared in 35.2% yield from 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine following the procedure outlined for compound 33. LC-MS (M / z) 446.1 (M+H + ).

[0241] 1 H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 5.1, 1.1 Hz, 1H), 7.58 (s, 1H), 7.34 (t, J = 1.4 Hz, 1H), 7.27-7.14 (m, 2H), 6.88 (dd, J = 5.0, 1.1 Hz, 1H), 6.85-6.76 (m, 2H), 5.31 (t, J = 10.8 Hz, 1H), 3.97-3.53 (m, 8H), 3.28 (ddt, J = 18.2, 11.7, 1.4 Hz, 1H), 2.62 (ddt, J = 18.2, 10.0, 1.4 Hz, 1H).

[0242] Compound 35: (S)-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000080.jpg36159

[0243] The title compound 35 was prepared in 32.7% yield from 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine in a manner similar to that used to prepare compound 33. LC-MS (m / z) 421.1 (M+H) + ).

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 5.2, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.32 (td, J = 8.0, 5.9 Hz, 1H), 7.19-7.07 (m, 2H), 7.03-6.94 (m, 2H), 6.93-6.87 (m, 2H), 5.41 -5.30 (m, 1H), 4.04-3.61 (m, 8H), 3.37 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.72 (ddd, J = 18.3, 9.8, 1.7 Hz, 1H).

[0245] Compound 36: (S)-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000081.jpg39159

[0246] The title compound 36 was prepared in 26.2% yield from 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine in a similar manner to the preparation of compound 33. LC-MS (m / z) 422.1 (M+H + ).

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.39-8.31 (m, 2H), 7.60 (dd, J = 2.2, 0.6 Hz, 1H), 7.41 (dt, J = 9.3, 2.3 Hz, 1H), 7.11 (dd, J = 5.2, 0.6 Hz, 1H), 7.04-6.95 (m, 1H), 6.89 (dd, J = 2.3, 0.6 Hz, 1H), 5.46-5.35 (m, 1H), 4.04-3.60 (m, 8H), 3.49-3.36 (m, 1H), 2.84-2.71 (m, 1H).

[0248] Compound 37: (S)-3-(1-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000082.jpg37159

[0249] The title compound 37 was prepared in 28.6% yield from 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine prepared in a similar manner to the preparation of 33. LC-MS (m / z) 428.1 (M+H + ).

[0250] 1 H NMR (400 MHz, CDCl3) δ 8.28 (dt, J = 5.2, 0.6 Hz, 1H), 7.57-7.45 (m, 4H), 7.38 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 5.1 Hz, 1H), 6.85-6.78 (m, 2H), 5.31 (dd, J = 11.7, 10.0 Hz, 1H), 3.99-3.53 (m, 8H), 3.29 (ddd, J = 18.4, 11.7, 1.8 Hz, 1H), 2.63 (ddd, J = 18.2, 10.1, 1.6 Hz, 1H).

[0251] Compound 38: (S)-5-(1-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)nicotinonitrile JPEG0007760530000083.jpg33159

[0252] The title compound 38 was prepared in 22.5% yield from 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine in a similar manner to the preparation of compound 33. LC-MS (m / z) 429.1 (M+H + ).

[0253] 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 2.2 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.04 (t, J = 2.1 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 5.1 Hz, 1H), 7.05-7.01 (m, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.46-5.37 (m, 1H), 4.09-3.62 (m, 8H), 3.45(ddd, J = 18.3, 10.2, 1.6 Hz, 1H), 2.80 (ddd, J = 18.3, 10.2, 1.6 Hz, 1H).

[0254] Compound 39: (S)-(4-(4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazin-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000084.jpg37159

[0255] The title compound 39 was prepared in 29.2% yield from 2-(piperazin-1-yl)-4-(1H-pyrazol-3-yl)pyrimidine in a similar manner to the preparation of compound 33. LC-MS (m / z) 403.1 (M+H + ).

[0256] 1 H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 5.1, 0.6 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.30-7.14 (m, 5H), 7.02 (d, J = 5.1 Hz, 1H), 6.82 (q, J = 1.9 Hz, 2H), 5.33-5.24 (m, 1H), 3.97-3.51 (m, 8H), 3.34-3.21 (m, 1H), 2.73-2.62 (m, 1H).

[0257] Compound 40: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000085.jpg78159

[0258] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (10 g, 59.9 mmol) in THF (200 mL) under argon was added EtN (24.2 g, 239.6 mmol), CuI (1.48 g, 7.79 mmol), Pd(PPh)Cl (2.1 g, 2.99 mmol), and ethynyltrimethylsilane (2.94 g, 29.4 mmol). The reaction mixture was stirred under argon at 70 °C for 16 h. The crude product was purified by flash chromatography. 2-Chloro-5-fluoro-4-((trimethylsilyl)ethynyl)pyrimidine (5 g) was obtained as a pale yellow oil. Yield: 36.5%. LC-MS (m / z) 229.1 (M+H) + ).

[0259] Step 2: To a solution of 2-chloro-5-fluoro-4-((trimethylsilyl)ethynyl)pyrimidine (5 g, 21.86 mmol) in MeOH (70 mL) was added KOH (62 mg, 1.09 mmol). The reaction mixture was stirred at 25° C. for 10 min. The crude product was purified by flash chromatography. 2-Chloro-4-ethynyl-5-fluoropyrimidine (2.9 g) was obtained as a pale yellow oil. Yield: 84.7%. LC-MS (m / z) 156.9 (M+H + ).

[0260] Step 3: To a solution of 2-chloro-4-ethynyl-5-fluoropyrimidine (2 g, 12.78 mmol) in DMF (30 mL) and MeOH (3 mL) under argon, CuI (243 mg, 128 mmol) and TMSN3 (4.42 g, 38.33 mmol) were added. The reaction mixture was stirred at 100° C. under argon for 2 hours. The crude product was purified by flash chromatography. 2-Chloro-5-fluoro-4-(2H-1,2,3-triazol-4-yl)pyrimidine (1.2 g) was obtained as a pale yellow solid. Yield: 47.1%. LC-MS (m / z) 200.1 (M+H + ).

[0261] Step 4: To a solution of (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (1 g, 3.32 mmol) in DMF (10 mL) was added DIPEA (1.72 g, 13.27 mmol) and 2-chloro-5-fluoro-4-(2H-1,2,3-triazol-4-yl)pyrimidine (660 mg, 3.32 mmol). The reaction mixture was stirred at 65° C. for 12 h. The crude was purified by flash chromatography. (S)-3-Fluoro-5-(1-(4-(5-fluoro-4-(2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (1.1 g) was obtained as a white solid. Yield: 71.6%. LC-MS (m / z) 465.1 (M+H + ).

[0262] Step 5: To a solution of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (0.8 g, 1.73 mmol) in MeCN (20 mL) was added KCO (595 mg, 4.31 mmol) and MeI (269 mg, 1.9 mmol). The reaction mixture was stirred at 25 °C for 2 h. The crude was purified by pre-HPLC. (S)-3-Fluoro-5-(1-(4-(5-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (126 mg) was obtained as a white solid. Yield: 15.3%. LC-MS (m / z) 479.1 (M+H + ).

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.5 Hz, 1H), 8.54 (d, J = 2.9 Hz, 1H), 7.74 (ddd, J = 8.5, 2.6, 1.4 Hz, 1H), 7.65 (s, 1H), 7.53 (ddd, J = 9.8, 2.5, 1.4 Hz, 1H), 7.12 (s, 1H), 5.29 (dd, J = 11.5, 10.2 Hz, 1H), 4.14 (s, 3H), 3.87-3.58 (m, 6H), 3.41-3.33 (m, 2H), 3.37 (ddd, J = 18.3, 11.6, 1.9 Hz, 1H), 2.71 (ddd, J = 18.3, 10.2, 1.6 Hz, 1H).

[0264] Compound 41: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000086.jpg40159

[0265] The title compound 41 was prepared in 32.2% yield from (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile following the procedure outlined for compound 40. LC-MS (m / z) 479.1 (M+H + ).

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.6 Hz, 1H), 8.26 (d, J = 4.0 Hz, 1H), 7.74 (ddd, J = 8.5, 2.6, 1.3 Hz, 1H), 7.65 (s, 1H), 7.53 (ddd, J = 9.8, 2.5, 1.4 Hz, 1H), 7.12 (s, 1H), 5.29 (dd, J = 11.5, 10.1 Hz, 1H), 4.38 (s, 3H), 3.84-3.65 (m, 6H), 3.60-3.54 (m, 2H), 3.37 (ddd, J = 18.3, 11.6, 1.8 Hz, 1H), 2.70 (ddd, J = 18.3, 10.1, 1.6 Hz, 1H).

[0267] Compound 42: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000087.jpg40159

[0268] The title compound 42 was prepared in 17.2% yield from (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile following the procedure outlined for compound 40. LC-MS (m / z) 479.1 (M+H + ).

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 2.8 Hz, 1H), 8.35 (d, J = 1.2 Hz, 1H), 7.74 (ddd, J = 8.5, 2.5, 1.3 Hz, 1H), 7.65 (s, 1H), 7.57-7.49 (m, 1H), 7.12 (s, 1H), 5.29 (dd, J = 11.5, 10.1 Hz, 1H), 4.27 (s, 3H), 3.84-3.63 (m, 6H), 3.57-3.52 (m, 2H), 3.36 (ddd, J = 18.3, 11.6, 1.8 Hz, 1H), 2.71 (ddd, J = 18.3, 10.1, 1.6 Hz, 1H).

[0270] Compound 43: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000088.jpg77159

[0271] The title compound 43 was prepared in a similar manner to the preparation of compound 40.

[0272] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.30 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 6.80-6.85 (m, 3H), 6.67-6.71 (m, 1H), 5.33 (dd, J = 10.0,11.6 Hz, 1H), 4.21 (s, 3H), 3.93-3.99 (m, 2H), 3.76-3.88 (m, 4H), 3.62-3.68 (m, 2H), 3.32 (ddd, J = 2.0, 12.0, 13.6 Hz ,1H), 2.69 (ddd, J = 1.6, 10.0, 11.6 Hz ,1H). Mass (ESI): m / z calcd for C 21 H 20 F3N9O 471.5, found 472.4 [M+H] + .

[0273] Compound 44: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000089.jpg38159

[0274] The title compound 44 was prepared in a similar manner to the preparation of compound 40. 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.35 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 6.79-6.89 (m, 3H), 6.68-6.72 (m, 1H), 5.35 (t, J = 10.8, 1H), 4.47 (s, 3H), 3.88-3.94 (m, 2H), 3.76-3.84 (m, 4H), 3.62-3.70 (m, 2H), 3.33 (ddd, J = 2.0, 12.0, 14.0 Hz ,1H), 2.70 (ddd, J = 1.6, 9.6, 11.6 Hz ,1H). Mass (ESI): m / z calcd for C 21 H 20 F3N9O 471.5, found 472.3 [M+H] + .

[0275] Compound 45: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000090.jpg38159

[0276] The title compound 45 was prepared in a similar manner to the preparation of compound 40.

[0277] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.31 (d, J = 2.8 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 6.80-6.86 (m, 3H), 6.67-6.72 (m, 1H), 5.34 (dd, J = 10.0, 11.6, 1H), 4.32 (s, 3H), 3.90-3.97 (m, 2H), 3.76-3.86 (m, 4H), 3.62-3.69 (m, 2H), 3.32 (ddd, J = 1.6, 11.6, 13.6 Hz ,1H), 2.69 (ddd, J = 1.6, 10.0, 11.6 Hz, 1H).

[0278] Compound 46: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000091.jpg77159

[0279] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (5 g, 29.95 mmol) in DMF (40 mL) was added 3,5-dimethyl-1H-1,2,4-triazole (3 g, 30.84 mmol) and CsCO3 (11.6 g, 59.89 mmol). The reaction mixture was stirred at 110 °C for 1 h. The mixture was purified by flash chromatography. 2-Chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine was obtained as a white solid (6, 1 g, 89.5%). LC-MS (m / z) 228.1 (M+H) + ).

[0280] Step 2: To a solution of 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine (86 mg, 373.8 umol) in DMF (5 mL) was added (S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (100 mg, 339.8 umol) and CsCO3 (132 mg, 629.6 umol). The reaction mixture was stirred at 110°C for 1 hour. The mixture was purified by flash chromatography. The title compound 46 (86 mg) was obtained as a white solid. Yield: 48.6%. LC-MS (m / z) 486.1 (M+H) + ).

[0281] 1 H NMR (400 MHz, CDCl3) δ (ppm): δ 8.38 (s, 1H), 6.90-6.56 (m, 4H), 5.35-5.28 (m, 1H), 3.98-3.50 (m, 8H), 3.41-3.18 (m, 1H), 2.82-2.57 (m, 4H), 2.42 (s, 3H).

[0282] Compound 47: (S)-3-(1-(4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000092.jpg82159

[0283] The title compound 47 was prepared following the procedure outlined for compound 46. LC-MS (m / z) 493.1 (M+H + ).

[0284] 1H NMR (400 MHz, CDCl3) δ (ppm): δ 8.28 (d, J = 1.0 Hz, 1H), 7.11 (m, 3H), 6.74 (s, 1H), 5.21 (t, J = 10.8 Hz, 1H), 3.82-3.40 (m, 9H), 3.21 (m, 1H), 2.65-2.46 (m, 4H), 2.32 (s, 3H).

[0285] Compound 48: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(6-hydroxypyridin-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000093.jpg66159

[0286] Step 1: 2,4-Dichloro-5-fluoropyrimidine (697 mg, 4.20 mmol), (6-hydroxypyridin-3-yl)boronic acid (700 mg, 5.04 mmol), and Pd(PPh3)4 (485 mg, 0.42 mmol) were dissolved in 10 mL of 1,4-dioxane. 2N Na2CO3 (6.25 mL) was added. It was stirred at 85 °C for 16 h. The solvent was evaporated to dryness and purified by column chromatography (EA) to give 800 mg of 5-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-ol as a pale yellow solid. Yield: 84.6%. LC-MS (m / z): 256.3 [M+H] + .

[0287] Step 2: tert-Butyl piperazine-1-carboxylate (447 mg, 2.5 mmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-ol (450 mg, 2 mmol) were dissolved in 10 mL of DMF. 0.5 mL of DIEA was added. It was stirred at 65° C. for 16 hours. Water was added to the reaction mixture, and it was extracted with EtOAc (30 mL×3). The organic layers were combined, evaporated to dryness, and purified by preparative TLC (DCM / MeOH=12 / 1) to give 350 mg of tert-butyl 4-(5-fluoro-4-(6-hydroxypyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate as a brown solid. Yield: 46.7%. LC-MS (m / z): 376.2 [M+H] + .

[0288] Steps 3 and 4: tert-Butyl 4-(5-fluoro-4-(6-hydroxypyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (92 mg, 0.245 mmol) was dissolved in 3 mL of DCM. 2 mL of TFA / DCM (1 / 1) was added to the solution at 0° C. It 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): 276.3 [M+H] + .

[0289] The residue from above, (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (69.4 mg, 0.245 mmol) and DABCO (110 mg, 0.98 mmol) were mixed in 3 mL of THF. The mixture was evaporated to dryness and directly irradiated with a 100 W filament lamp for 2 hours. The solid was purified by preparative TLC (DCM / MeOH=14 / 1) to give 35 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(6-hydroxypyridin-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a pale yellow solid. Total yield for two steps: 29.1%.

[0290] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.35 (d, J = 2.8 Hz, 1H), 8.33-8.30 (m, 1H), 8.23 ​​(d, J = 3.6 Hz, 1H), 7.42 (t, J = 1.2 Hz, 1H), 7.29 (s, 1H), 6.89 (t, J = 1.6 Hz, 1H), 6.73-6.69 (m, 1H), 5.37 (dd, J = 11.2, 10.4 Hz, 1H), 3.96-3.86 (m, 2H), 3.84-3.75 (m, 4H), 3.69-3.62 (m, 2H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 491.3 [M+H] + .

[0291] Compound 49: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-2',4',6'-trimethoxy-[4,5'-bipyrimidin]-2-yl)piperazin-1-yl)methanone JPEG0007760530000094.jpg87159

[0292] Step 1: 2,4,6-Trimethoxypyrimidine (1 g, 5.88 mmol) was dissolved in 20 mL of THF. n-BuLi (2.85 mL, 6.84 mmol, 2.4 M in hexane) was slowly added to the solution at -78 °C. It was stirred at -78 °C for 30 min. Then, a solution of ZnCl (6.3 mL, 6.3 mmol, 1 M in THF) was added dropwise at -78 °C. It was stirred at -78 °C for 30 min, then warmed to room temperature, and stirred at room temperature for 1 h. 2,4-Dichloro-5-fluoropyrimidine (286 mg, 1.71 mmol) and Pd(PPh) (224 mg, 0.194 mmol) in 6 mL of THF were added in one portion to the solution. It was stirred at 70 °C for 16 h. The reaction was quenched by adding water and extracted with EtOAc (60 mL x 3). The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 85 / 15) to give 160 mg of 2-chloro-5-fluoro-2',4',6'-trimethoxy-4,5'-bipyrimidine as a pale yellow solid. Yield: 31.2%. LC-MS (m / z): 301.4 [M+H] + .

[0293] Step 2: 2-Chloro-5-fluoro-2',4',6'-trimethoxy-4,5'-bipyrimidine (28 mg, 0.093 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (25 mg, 0.085 mmol) were dissolved in 2 mL of DMF. 0.2 mL of DIEA was added. It was stirred at 65 °C for 32 hours. Water was added to the reaction mixture, and it was extracted with EtOAc (50 mL x 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=1 / 3) to obtain 17 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-2',4',6'-trimethoxy-[4,5'-bipyrimidin]-2-yl)piperazin-1-yl)methanone as a white solid. Yield: 36.2%.

[0294] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.20 (d, J = 1.2 Hz, 1H), 6.85-6.80 (m, 2H), 6.69 (tt, J = 8.8, 2.0 Hz, 1H), 5.33 (dd, J = 11.6, 10.0 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 6H), 3.91-3.82 (m, 2H), 3.81-3.71 (m, 4H), 3.67- 3.58 (m, 2H), 3.31 (ddd, J = 18.4, 12.0, 2.0 Hz, 1H), 2.67 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 559.3 [M+H] + .

[0295] Compound 50: (S)-3-fluoro-5-(1-(4-(5-fluoro-2',6'-dihydroxy-[4,4'-bipyrimidin]-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000095.jpg33159

[0296] Step 1: 2-Chloro-5-fluoro-2',6'-dimethoxy-4,4'-bipyrimidine (80 mg, 0.296 mmol) was dissolved in 2 mL of MeOH. 0.3 mL of concentrated hydrochloric acid was added to the solution. It was stirred at 60°C for 10 hours. The solvent was evaporated to dryness and purified by recrystallization (EA / PE) to give 60 mg of 2'-chloro-5'-fluoro-[4,4'-bipyrimidine]-2,6-diol as a white solid. Yield: 83.8%. LC-MS (m / z): 243.2 [M+H] + .

[0297] Step 2: 2'-Chloro-5'-fluoro-[4,4'-bipyrimidine]-2,6-diol (60 mg, 0.199 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (47.8 mg, 0.198 mmol) were dissolved in 2 mL of DMF. 0.2 mL of DIEA was added to the solution, which was stirred at 65°C for 32 hours. 1 mL of water was added to the solution, and it was extracted with EtOAc (10 mL x 3). The organic layers were combined, evaporated to dryness, and purified by preparative TLC (DCM / MeOH=14 / 1) to give 50 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-2',6'-dihydroxy-[4,4'-bipyrimidin]-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a brown solid. Yield: 51.5%.

[0298] 1 H NMR (400 MHz, CDCl3) δ (ppm): 9.00 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 7.42 (t, J = 1.6 Hz, 1H), 6.92 (t, J = 1.6 Hz, 1H), 6.64 (t, J = 2.0 Hz, 1H), 5.37 (dd, J = 11.2, 10.4 Hz, 1H), 3.99-3.86 (m, 2 H), 3.85-3.75 (m, 4H), 3.72 -3.62 (m, 2H), 3.37 (ddd, J = 18.4, 11.6, 1.6Hz, 1H), 2.72 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 508.3 [M+H] + .

[0299] Compound 51: (S)-3-fluoro-5-(1-(4-(5-fluoro-1',3'-dimethyl-2',6'-dioxo-1',2',3',6'-tetrahydro-[4,4'-bipyrimidin]-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000096.jpg37159

[0300] (S)-3-Fluoro-5-(1-(4-(5-fluoro-2',6'-dihydroxy-[4,4'-bipyrimidin]-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (25 mg, 0.049 mmol) was dissolved in 2 mL of DMF. NaH (6 mg, 0.15 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, CHCl (0.05 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water and extracted with EtOAc (5 mL × 3). The organic layers were combined, evaporated to dryness, and purified by preparative TLC (PE / EA=1 / 3) to give 6 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-1′,3′-dimethyl-2′,6′-dioxo-1′,2′,3′,6′-tetrahydro-[4,4′-bipyrimidin]-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a pale yellow solid. Yield: 22.8%.

[0301] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.38 (d, J = 1.2 Hz, 1H), 7.41 (t, J = 1.2 Hz, 1H), 7.29 (s, 1H), 6.89 (s, 1H), 5.87 (s, 1H), 5.37 (d, J = 11.2, 10.4 Hz, 1H), 3.90-3.85 (m, 2H), 3.81-3.74 (m, 4H), 3.68-3.60 (m, 2H), 3.41 (s, 3H), 3.34 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 3.31 (s, 3H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 508.3 [M+H] + .

[0302] Compound 52: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000097.jpg137159

[0303] Step 1: 2,4-Dichloro-5-fluoropyrimidine (6.74 g, 40.6 mmol), (1H-pyrazol-4-yl)boronic acid (5 g, 44.7 mmol), and K2CO3 (11.2 g, 81.16 mmol) were mixed in 120 mL of 1,4-dioxane / HO (3 / 1). Pd(dppf)Cl2 (2.97 g, 4.06 mmol) was added. The mixture was stirred at 85 °C for 16 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 3 / 1) to give 3.28 g of 2-chloro-5-fluoro-4-(1H-pyrazol-4-yl)pyrimidine as an orange oil. Yield: 40.8%. LC-MS (m / z): 199.3 [M+H] + .

[0304] Step 2: tert-Butyl piperazine-1-carboxylate (960 mg, 5.15 mmol) and 2-chloro-5-fluoro-4-(1H-pyrazol-4-yl)pyrimidine (1 g, 5.05 mmol) were dissolved in 23 mL of DMF. 1 mL of DIEA was added. It was stirred at 65° C. for 32 hours. Water was added to the reaction mixture, and it was extracted with EtOAc (50 mL×3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=1 / 2) to give 800 mg of tert-butyl 4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carboxylate as a yellow oil. Yield: 45.5%. LC-MS (m / z): 349.3 [M+H] + .

[0305] Step 3 and Step 4: tert-Butyl 4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carboxylate (400 mg, 1.15 mmol) was dissolved in 5 mL of DCM. 3 mL of TFA / DCM (1 / 1) was added to the solution at 0° C. It was stirred at room temperature for 1 hour. The solvent was evaporated to dryness to give 650 mg of 5-fluoro-2-(piperazin-1-yl)-4-(1H-pyrazol-4-yl)pyrimidine as a brown oil, which was used in the next step without further purification. LC-MS (m / z): 249.2 [M+H] + .

[0306] The above residue (325 mg, 1.305 mmol), (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (317.4 mg, 1.146 mmol), and DABCO (514.2 mg, 4.584 mmol) were mixed in 8 mL of THF. The mixture was evaporated to dryness and irradiated directly with a 100 W filament lamp for 1 hour. The solid was purified by preparative TLC (PE / EA=1 / 3) to give 42 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone as a white solid. Yield: 8%.

[0307] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.31 (s, 1H), 8.24-8.22 (m, 1H), 6.86-6.81 (m, 3H ), 6.70(tt, J = 11.2, 2.0 Hz , 1H)), 5.34 (dd, J = 11.6, 10.0 Hz, 1H), 4.02-3.89 (m, 2H), 3.89-3.75 (m, 4H), 3.71-3.61 (m, 2H), 3.33 (ddd, J = 18.4, 12.0, 2.0 Hz, 1H), 2.70 (ddd, J = 18.4, 9.6, 1.6 Hz, 1H).LC-MS (m / z): 457.5 [M+H] + .

[0308] Compound 53: (S)-2-(4-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)acetamide JPEG0007760530000098.jpg39159

[0309] (S)-(5-(3,5-Difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone (100 mg, 0.219 mmol), 2-bromoacetamide (33.3 mg, 0.241 mmol), and CsCO (144 mg, 0.439 mmol) were mixed in 2 mL of CHCN and stirred at room temperature for 16 h. The solvent was evaporated to dryness and purified by column chromatography (DCM / MeOH=17 / 3) to give 21 mg of (S)-2-(4-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)acetamide as a white solid. Yield: 18.6%.

[0310] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.27 (d, J = 0.8 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 6.88-6.80 (m, 2H), 6.70 (tt, J = 8.8, 2.4 Hz, 1H), 6.23 (brs, 1H), 5.52 (brs, 1H), 5.34 (dd, J = 11.2, 10.0 Hz, 1H), 4.89 (s, 2H), 3.99-3.90 (m, 2H), 3.86-3.77 (m, 4H), 3.72-3.61 (m, 2H), 3.33 (ddd, J = 18.4, 12.0, 2.0 Hz, 1H), 2.70 (ddd, J = 18.3, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 514.3 [M+H] + .

[0311] Compound 54: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000099.jpg50159

[0312] 5-Fluoro-2-(piperazin-1-yl)-4-(1H-pyrazol-4-yl)pyrimidine (325 mg, 1.305 mmol), (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (325.5 mg, 1.146 mmol), and DABCO (514.2 mg, 4.584 mmol) were mixed in 8 mL of THF. The mixture was evaporated to dryness and irradiated with direct light using a 100 W filament lamp for 1 hour. The solid was purified by preparative TLC (PE / EA=1 / 3) to obtain 152 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a pale yellow solid. Yield: 28.6%.

[0313] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.35-8.27 (m, 2H), 8.23 ​​(d, J = 2.8 Hz, 1H), 7.42 (t, J = 1.2 Hz, 1H), 7.29 (s, 1H), 6.90 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.6, 10.0 Hz, 1H), 4.00-3.92 (m, 2H), 3.90-3.75 (m, 4H), 3.70-3.64 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 2.0 Hz, 1H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 464.3 [M+H] + .

[0314] Compound 55: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(2,4-dimethylthiazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000100.jpg116159

[0315] Step 1: 2,5-Dimethylthiazole (300 mg, 2.65 mmol) was dissolved in 10 mL of THF. n-BuLi (1.3255 mL, 3.18 mmol, 2.4 M in hexane) was slowly added to the solution at −78 °C. It was stirred at −78 °C for 30 min. Then, a solution of ZnCl (2.91 mL, 2.91 mmol, 1 M in THF) was added dropwise at −78 °C. It was stirred at −78 °C for 30 min, then warmed to room temperature, and stirred at room temperature for 1 h. 2,4-Dichloro-5-fluoropyrimidine (310 mg, 1.856 mmol) and Pd(PPh) (152 mg, 0.13 mmol) in 6 mL of THF were added in one portion to the solution. It was stirred at 70 °C for 16 h. The reaction was quenched by adding water and extracted with EtOAc (30 mL x 3). The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 85 / 15) to give 75 mg of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2,4-dimethylthiazole as an orange solid. Yield: 16.6%. LC-MA (m / z): 244.3 [M+H] + .

[0316] Step 2: The title compound 55 was prepared in 35.2% yield from 5-(2-chloro-5-fluoropyrimidin-4-yl)-2,4-dimethylthiazole and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone as a pale yellow solid following the procedure outlined for compound 7.

[0317] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.24 (d, J = 2.4 Hz, 1H), 6.94-6.78 (m, 2H), 6.69 (t, J = 8.8 Hz, 1H), 5.34 (t, J = 10.4 Hz, 1H), 3.95-3.85 LC-MS (m / z): 502.4 [M+H] + .

[0318] Compound 56: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(2-methylthiazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000101.jpg105159

[0319] Step 1: 2-Methylthiazole (300 mg, 3.03 mmol) was dissolved in 10 mL of THF. n-BuLi (1.388 mL, 3.33 mmol, 4 M in hexane) was slowly added to the solution at −78 °C. It was stirred at −78 °C for 30 minutes. Then, a solution of ZnCl (3.3 mL, 3.3 mmol, 1 M in THF) was added dropwise at −78 °C. It was stirred at −78 °C for 30 minutes, then warmed to room temperature, and stirred at room temperature for 1 hour. 2,4-Dichloro-5-fluoropyrimidine (354.2 mg, 2.12 mmol) and Pd(PPh) (175 mg, 0.152 mmol) in 6 mL of THF were added in one portion to the solution. It was stirred at 70 °C for 16 hours. The reaction was quenched by adding water and extracted with EtOAc (30 mL x 3). The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 1 / 1) to give 328 mg of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylthiazole as a gray solid. Yield: 67.6%. LC-MS (m / z): 230.4 [M+H]+ .

[0320] Step 2: The title compound 56 was prepared in 70% yield from 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylthiazole and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone as a pale yellow solid following the procedure outlined for compound 7.

[0321] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.32 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 6.86-6.81 (m, 2H), 6.70 (dt, J = 8.8, 2.4 Hz, 1H), 5.34 (dd, J = 11.6, 10.0 Hz, 1H), 3.93-3.84 (m, 2H), 3.78 (q, J = 7.6 Hz, 4H), 3.68-3.58 (m, 2H), 3.32 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.77 (s, 3H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 488.3 [M+H] + .

[0322] Compound 57: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(2-methylthiazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000102.jpg56159

[0323] The title compound 57 was prepared as a brown solid in 42.1% yield from 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylthiazole and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile following the procedure outlined for compound 56.

[0324] 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.37-7.28 (m, 2H), 6.89 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.2, 10.4 Hz, 1H), 3.92-3.84 (m, 2H), 3.82-3.72 (m, 4H), 3.69-3.60 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.77 (s, 3H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 495.4 [M+H] + .

[0325] Compound 58: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000103.jpg99159

[0326] Step 1: 4-Bromo-1,3,5-trimethyl-1H-pyrazole (500 mg, 2.64 mmol) was dissolved in 10 mL of THF. n-BuLi (1.323 mL, 3.168 mmol, 2.4 M in hexanes) was slowly added to the solution at −78° C. It was stirred at −78° C. for 30 minutes. Then, a solution of ZnCl (2.91 mL, 2.91 mmol, 1 M in THF) was added dropwise at −78° C. It was stirred at −78° C. for 30 minutes, then warmed to room temperature, and stirred at room temperature for 1 hour. 2,4-Dichloro-5-fluoropyrimidine (397.6 mg, 2.38 mmol) and Pd(PPh) (305.8 mg, 0.265 mmol) in 6 mL of THF were added to the solution in one portion. It was stirred at 70°C for 16 hours. Water was added to quench the reaction, and it was extracted with EtOAc (40 mL x 3). The solvent was evaporated to dryness, and purified by column chromatography (PE / EA = 2 / 1) to give 300 mg of 2-chloro-5-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine as a white solid. Yield: 52.5%. LC-MS (m / z): 241.3 [M+H] + .

[0327] Step 2: The title compound was prepared in 20.7% yield as a pale yellow solid from 2-chloro-5-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for compound 7.

[0328] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.22 (d, J = 2.4 Hz, 1H), 6.86-6.81 (m, 2H), 6.69 (tt, J = 8.8, 2.4 Hz, 1H), 5.33 (dd, J = 11.2, 10.0 Hz, 1H), 3.95-3.84 (m, 2H), 3.82-3.72 (m, 7H), 3.68-3.60 (m, 2H), 3.32 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.33 (d, J = 1.6 Hz, 6H). LC-MS (m / z): 499.3 [M+H] + .

[0329] Compound 59: (S)-3-Fluoro-5-(1-(4-(5-fluoro-4-(5-methyl-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000104.jpg3564

[0330] The title compound 59 was prepared following the procedure outlined for compound 56. LC-MS (m / z): 480.5 [M+H] + .

[0331] Compound 60: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000105.jpg68159

[0332] Step 1: 2-Chloro-5-fluoro-4-(1H-pyrazol-4-yl)pyrimidine (400 mg, 2.02 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (531.6 mg, 2.22 mmol) were dissolved in 5 mL of DMF. Cs2CO3 (1.313 g, 4.04 mmol) was added. It was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with EtOAc (40 mL x 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA = 17 / 3) to give 100 mg of 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-chloro-5-fluoropyrimidine as a white solid. Yield: 13.9%. LC-MS(m / z):357.6[M+H] + .

[0333] Step 2 and Step 3: 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-chloro-5-fluoropyrimidine (40 mg, 0.11 mmol) was dissolved in 2 mL of DCM. 1 mL of TFA was slowly added to the solution at 0° C. Then it was stirred at room temperature for 6 hours. The solvent was evaporated to dryness and used in the next step without further purification. LC-MS (m / z): 257.6 [M+H] + .

[0334] The residue was dissolved in 2 mL of DMF. (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (44 mg, 0.15 mmol) and 0.2 mL of DIEA were added to the solution. The solvent was evaporated to dryness and purified by preparative HPLC to give 15 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone as a brown oil. Yield for two steps: 27.3%.

[0335] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.18 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 6.90-6.79 (m, 3H), 6.69 (tt, J = 8.8, 2.4 Hz, 1H), 5.34 (dd, J = 11.6, 10.0 Hz, 1H), 4.32 (t, J = 4.8 Hz, 2H), 4.05 (t, J = 4.8 Hz, 2H), 3.94-3.85 (m, 2H), 3.82-3.77 (m, 2H), 3.69-3.60 (m, 4H), 3.32 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 501.4[M+H] + .

[0336] Compound 61: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000106.jpg117159

[0337] Step 1: 2,4-Dichloro-5-fluoropyrimidine (300 mg, 1.796 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (399 mg, 1.797 mmol), and 2N Na2CO3 (2.69 mL, 5.38 mmol) were mixed in 5 mL of 1,4-dioxane. Pd(PPh3)4 (207 mg, 0.179 mmol) was added. The mixture was stirred at 85 °C for 16 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 4 / 1) to give 140 mg of 2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine as a white solid. Yield: 34.5%. LC-MS(m / z):227.5[M+H]+ .

[0338] Step 2: tert-Butyl piperazine-1-carboxylate (126.7 mg, 0.68 mmol) and 2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (140 mg, 0.62 mmol) were dissolved in 4 mL of DMF. 0.2 mL of DIEA was added. It was stirred at 65 °C for 16 hours. Water was added to the reaction mixture and extracted with EtOAc (15 mL × 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA = 17 / 3) to give 213 mg of tert-butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate as a brown oil. Yield: 91%. LC-MS (m / z): 377.3 [M+H] + .

[0339] Step 3 and Step 4: tert-Butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (85 mg, 0.226 mmol) was dissolved in 3 mL of DCM. 2 mL of TFA / DCM (1 / 1) was added to the solution at 0° C. It 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): 277.4 [M+H] + .

[0340] The residue, (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (68.6 mg, 0.248 mmol), and DABCO (101.4 mg, 0.904 mmol) were mixed in 3 mL of THF. The mixture was evaporated to dryness and irradiated with direct light using a 100 W filament lamp for 3 hours. The solid was purified by preparative TLC (PE / EA=1 / 3) to obtain 60 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone as a white solid. Two-step yield: 54.8%.

[0341] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.32 (s, 1H), 7.37 (s, 1H), 6.97-6.74 (m, 3H), 6.69 (t, J = 8.4 Hz, 1H), 5.33 (t, J = 10.8 Hz, 1H), 3.93 (s, 3H), 3.91-3.85 (m, 2H), 3.84-3.71 (m, 4H), 3.69-3.56 (m, 2H), 3.32 (dd, J = 18.4, 12.0 Hz, 1H), 2.69 (dd, J = 18.0, 10.0 Hz, 1H), 2.08 (s, 3H). LC-MS (m / z): 485.3 [M+H] + .

[0342] Compound 62: (S)-3-(1-(4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000107.jpg56159

[0343] The title compound 62 was prepared as a pale yellow solid in 51.8% yield from the trifluoroacetate salt of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoro-2-(piperazin-1-yl)pyrimidine and (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile following the procedure outlined for compound 61.

[0344] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.33 (d, J = 2.0 Hz, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.38 (s, 1H), 7.28 (dd, J = 5.2, 1.2 Hz, 1H), 6.89 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.65, 10.4 Hz, 1H), 3.94 (s, 3H), 3.92-3.86 (m, 2H), 3.83-3.74(m, 4H), 3.69-3.59 (m, 2H), 3.35 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.08 (d, J = 2.4 Hz, 3H). LC-MS (m / z): 492.4 [M+H] + .

[0345] Compound 63: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000108.jpg90159

[0346] Step 1: 2,4-Dichloro-5-fluoropyrimidine (200 mg, 1.197 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (214.8 mg, 1.197 mmol), 1,1,1,2,2,2-hexamethyldistannane (392 mg, 1.196 mmol), and Pd(PPh3)4 (68.8 mg, 0.06 mmol) were mixed in 8 mL of 1,4-dioxane. The mixture was stirred at 150 °C under microwave irradiation for 90 minutes. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 1 / 1) to give 79 mg of 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-methyl-1,3,4-thiadiazole as a brown oil. Yield: 25.4%. LC-MS (m / z): 231.4 [M+H] + .

[0347] Step 2: 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-methyl-1,3,4-thiadiazole (40 mg, 0.173 mmol) (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (50.9 mg, 0.173 mmol) was dissolved in 3 mL of DMF. 0.2 mL of DIEA was added. It was stirred at 70 °C for 32 hours. Water was added to the reaction mixture and it was extracted with EtOAc (10 mL × 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=1 / 2) to obtain 12 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)piperazin-1-yl)methanone as a brown solid. Yield: 14.2%.

[0348] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.43 (d, J = 2.4 Hz, 1H), 6.86 (t, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 6.69 (tt, J = 8.8, 2.0 Hz, 1H), 5.34 (dd, J = 11.6, 9.6 Hz, 1H), 3.94-3.86 (m, 2H), 3.84-3.73 (m, 4H), 3.70-3.61 (m, 2H), 3.33 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.85 (s, 3H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 489.3 [M+H] + .

[0349] Compound 64: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000109.jpg3964

[0350] The title compound 64 was prepared as a brown solid in 25.5% yield from 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-methyl-1,3,4-thiadiazole and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile following the procedure outlined for compound 63.

[0351] 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.4 Hz, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.31-7.27 (m, 2H), 6.90 (t, J = 1.6 Hz, 1H), 5.38 (dd, J = 11.6, 10.4 Hz, 1H), 3.96-3.86 (m, 2H), 3.85-3.73 (m, 4H), 3.70-3.61 (m, 2H), 3.37 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.86 (s, 3H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 496.4 [M+H] + .

[0352] Compound 65: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000110.jpg43159

[0353] Step 1: 2,4-Dichloro-5-fluoropyrimidine (300 mg, 1.796 mmol), 5-bromo-1-methyl-1H-1,2,4-triazole (291 mg, 1.796 mmol), 1,1,1,2,2,2-hexamethyldistannane (588.5 mg, 1.796 mmol), and Pd(PPh3)4 (103.8 mg, 0.317 mmol) were mixed in 8 mL of 1,4-dioxane. The mixture was stirred at 150 °C under microwave irradiation for 90 minutes. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 4 / 1) to give 28 mg of 2-chloro-5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine as a pale yellow solid. Yield: 7.3%. LC-MS(m / z) 214.4[M+H] + .

[0354] Step 2: 2-Chloro-5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine (28 mg, 0.131 mmol) (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (38.5 mg, 0.131 mmol) was dissolved in 3 mL of DMF. 0.2 mL of DIEA was added. It was stirred at 70 °C for 32 hours. Water was added to the reaction mixture and it was extracted with EtOAc (10 mL × 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=1 / 2) to give 16 mg of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone as a brown solid. Yield: 25.9%.

[0355] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.42 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 6.86 (t, J = 1.6 Hz, 1H), 6.83-6.81 (m, 1H), 6.69 (tt, J = 8.8, 2.0 Hz, 1H), 5.33 (dd, J = 11.6, 10.0 Hz, 1H), 4.24 (s, 3H), 3.95-3.85 (m, 2H), 3.83-3.74 (m, 4H), 3.70-3.61 (m, 2H), 3.32 (ddd, J = 18.4, 11.6, 1.6Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 472.3 [M+H] + .

[0356] Compound 66: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000111.jpg4264

[0357] The title compound 66 was prepared in 17.9% yield as a pale yellow solid from 2-chloro-5-fluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile following the procedure outlined for compound 65.

[0358] 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.30-7.25 (m, 2H), 6.90 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.6, 10.4 Hz, 1H), 4.24 (s, 3H), 3.95-3.86 (m, 2H), 3.85-3.74 (m, 4H), 3.72-3.60 (m, 2H), 3.37 (ddd, J = 18.4, 12.0, 2.0 Hz, 1H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 479.3 [M+H] + .

[0359] Compound 67: (S)-5-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile JPEG0007760530000112.jpg41159

[0360] Step 1: 2,4-Dichloro-5-fluoropyrimidine (673 mg, 4.03 mmol), 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (750 mg, 4.03 mmol), 1,1,1,2,2,2-hexamethyldistannane (1.318 g, 4.03 mmol), and Pd(PPh3)4 (232.9 mg, 0.2 mmol) were mixed in 20 mL of 1,4-dioxane. The mixture was stirred at 150 °C for 90 minutes under microwave irradiation. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 3 / 1) to give 150 mg of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile as a pale yellow solid. Yield: 15.6%. LC-MS (m / z): 238.3 [M+H] + .

[0361] Step 2: 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile (60 mg, 0.252 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (76 mg, 0.252 mmol) were dissolved in 3 mL of DMF. 0.2 mL of DIEA was added. It was stirred at 70 °C for 32 hours. Water was added to the reaction mixture and it was extracted with EtOAc (10 mL × 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=1 / 3) to give 10 mg of (S)-5-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile as a brown solid. Yield: 7.9%.

[0362] 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 1.6 Hz, 1H), 7.88 (s, 1H), 7.41 (t, J = 1.6 Hz, 1H), 7.30-7.27 (m, 1H), 7.25-7.23 (m, 1H), 6.89 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.6, 10.4 Hz, 1H), 4.04 (d, J = 1.2 Hz, 3H), 3.97-3.87 (m, 2H), 3.83-3.74 (m, 4H), 3.71-3.61 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 503.2 [M+H] + .

[0363] Compound 68: (S)-(4-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000113.jpg62159

[0364] Step 1: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.1 g, 14.899 mmol) was dissolved in 40 mL of DMF. It was stirred at 50° C. for 8 hours. Water was added to the reaction mixture and extracted with EtOAc (60 mL×3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=2 / 1) to give 2.14 g of (4-chloro-1-methyl-1H-pyrazol-5-yl)boronic acid as a white solid. Yield: 89.8%. LC-MS (m / z): 161.2 [M+H] + .

[0365] Step 2: 2,4-Dichloro-5-fluoropyrimidine (191.6 mg, 1.198 mmol), (4-chloro-1-methyl-1H-pyrazol-5-yl)boronic acid (200 mg, 1.198 mmol), (t-BuP)2Pd (61.2 mg, 0.12 mmol), and 0.2 mL of DIEA were mixed in 8 mL of 1,4-dioxane / HO (5 / 1). The mixture was stirred at 110 °C for 1 hour under microwave irradiation. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 7 / 1) to give 80 mg of 2-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidine as a pale yellow solid. Yield: 27%. LC-MS (m / z): 248.2 [M+H] + .

[0366] Step 3: 2-Chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (35 mg, 0.142 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (41.7 mg, 0.142 mmol) were dissolved in 3 mL of DMF. 0.2 mL of DIEA was added. It was stirred at 70 °C for 32 hours. Water was added to the reaction mixture and it was extracted with EtOAc (10 mL × 3). The organic layers were combined, evaporated to dryness, and purified by column chromatography (PE / EA=1 / 2) to give 35 mg of (S)-(4-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone as a brown solid. Yield: 48.9%.

[0367] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.37 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 6.86 (t, J = 1.6 Hz, 1H), 6.84-6.81 (m, 1H), 6.70 (tt, J = 8.8, 2.4 Hz, 1H), 5.34 (dd, J = 11.6, 10.0 Hz, 1H), 3.95 (s, 3H), 3.93-3.86 (m, 2H), 3.84-3.75(m, 4H), 3.69-3.61 (m, 2H), 3.32 (ddd, J = 18.4, 11.6, 1.6Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 505.6 [M+H] + .

[0368] Compound 69: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000114.jpg97159

[0369] Step 1: 2,4-Dichloro-5-fluoropyrimidine (400 mg, 2.395 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (498 mg, 2.393 mmol), and 2N Na2CO3 (3.95 mL, 7.18 mmol) were mixed in 8 mL of 1,4-dioxane. Pd(PPh3)4 (276.88 mg, 0.24 mmol) was added. The mixture was stirred at 85 °C for 16 hours. The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 3 / 1) to give 228 mg of 2-chloro-5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)pyrimidine as a white solid. Yield: 44.9%. LC-MS(m / z):213.4 [M+H] + .

[0370] Step 2: 2-Chloro-5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)pyrimidine (120 mg, 0.563 mmol) (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (165.6 mg, 0.563 mmol) was dissolved in 5 mL of DMF. 0.5 mL of DIEA was added. It was stirred at 70 °C for 32 hours. Water was added to the reaction mixture and it was extracted with EtOAc (30 mL × 3). The organic layers were combined, evaporated to dryness, and purified by preparative HPLC to give 80 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a white solid. Yield: 30.2%.

[0371] 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.30 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.30-7.27 (m, 1H), 6.92-6.88 (m, 2H), 5.37 (dd, J = 11.6, 10.0 Hz, 1H), 4.28 (s, 3H), 3.96-3.85 (m, 2H), 3.85-3.74 (m, 4H), 3.72-3.59 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 1.6Hz, 1H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 471.3 [M+H] + .

[0372] Compound 70: (S)-3-(1-(4-(4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000115.jpg116159

[0373] Step 1: 1,4-Dimethyl-1H-1,2,3-triazole (350 mg, 3.60 mmol) was dissolved in 10 mL of THF. n-BuLi (1.653 mL, 3.97 mmol, 2.4 M in hexane) was slowly added to the solution at −78 °C. It was stirred at −78 °C for 30 min. Then, a solution of ZnCl (3.97 mL, 3.97 mmol, 1 M in THF) was added dropwise at −78 °C. It was stirred at −78 °C for 30 min, then warmed to room temperature, and stirred at room temperature for 1 h. 2,4-Dichloro-5-fluoropyrimidine (543 mg, 3.25 mmol) and Pd(PPh) (417.1 mg, 0.36 mmol) in 10 mL of THF were added to the solution in one portion. It was stirred at 70°C for 16 hours. Water was added to quench the reaction, and it was extracted with EtOAc (40mL x 3). The solvent was evaporated to dryness, and purified by column chromatography (PE / EA = 4 / 1) to give 396mg of 2-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyrimidine as a pale yellow solid. Yield: 53.5%. LC-MS (m / z): 228.4 [M+H] + .

[0374] Step 2: The title compound 70 was prepared from 2-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyrimidine and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a pale yellow solid in 31% yield following the procedure outlined for compound 69.

[0375] 1H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 1.6 Hz, 1H), 7.41 (t, J = 1.6 Hz, 1H), 7.29-7.27 (m, 1H), 7.25-7.24 (m, 1H), 6.89 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.6, 10.0 Hz, 1H), 4.15 (s, 3H), 3.94-3.84 (m, 2H), 3.84-3.73 (m, 4H), 3.70-3.60 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 1.8Hz, 1H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.40 (d, J = 2.4 Hz, 3H). LC-MS (m / z): 493.3 [M+H] + .

[0376] Compound 71: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000116.jpg3264

[0377] The title compound 71 was prepared in 46.9% yield as a pale yellow solid from 2-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyrimidine and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone following the procedure outlined for compound 70.

[0378] 1H NMR (300 MHz, Chloroform-d) δ 8.36 (d, J = 1.8 Hz, 1H), 6.88- 6.80 (m, 3H), 6.70 (tt, J = 9.0, 2.4 Hz, 1H), 5.34 (dd, J = 11.7, 10.2 Hz, 1H), 4.15 (s, 3H), 3.99-3.86 (m, 2H), 3.85 - 3.72 (m, 4H), 3.71 - 3.60 (m, 2H), 3.33 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.70 (ddd, J = 18.3, 9.9, 1.5 Hz, 1H), 2.39 (d, J = 2.4 Hz, 3H). LC-MS (m / z): 486.3 [M+H] + .

[0379] Compound 72: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000117.jpg69159

[0380] Step 1: (1-Methyl-1H-1,2,4-triazol-3-yl)methanol (600 mg, 5.31 mmol), tert-butylchlorodiphenylsilane (1.605 g, 5.836 mmol), and imidazole (722 mg, 10.618 mmol) were mixed in 10 mL of DCM. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA=1 / 2) to give 1.6 g of 3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazole as a white solid. Yield: 85.7%. LC-MS (m / z): 352.3 [M+H] + .

[0381] Step 2: 3-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazole (300 mg, 0.852 mmol) was dissolved in 10 mL of THF. n-BuLi (0.426 mL, 1.022 mmol, 2.4 M in hexane) was slowly added to the solution at −78° C. It was stirred at −78° C. for 30 minutes. Then, a solution of ZnCl (0.852 mL, 0.852 mmol, 1 M in THF) was added dropwise at −78° C. It was stirred at −78° C. for 30 minutes, then warmed to room temperature and stirred at room temperature for 1 hour. 2,4-Dichloro-5-fluoropyrimidine (113.8 mg, 0.681 mmol) and Pd(PPh3)4 (98.5 mg, 0.078 mmol) in 6 mL of THF were added to the solution in one portion. It was stirred at 70 °C for 16 h. Water was added to quench the reaction, and it was extracted with EtOAc (30 mL × 3). The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 2 / 1) to give 220 mg of 4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazol-5-yl)-2-chloro-5-fluoropyrimidine as a pale yellow color. Yield: 61%. LC-MS (m / z): 404.3 [M+H-ph] + .

[0382] Step 3: The title compound 72 was prepared as a pale yellow solid in 33.1% yield from 4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazol-5-yl)-2-chloro-5-fluoropyrimidine and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile following the procedure outlined for compound 7.

[0383] 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 2.4 Hz, 1H), 7.41 (t, J = 1.6 Hz, 1H), 7.30-7.27 (m, 1H), 7.25-7.22 (m, 1H), 6.89 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.6, 10.2 Hz, 1H), 4.82 (s, 2H), 4.20 (s, 3H), 3.94-3.85 (m, 2H), 3.84-3.75 (m, 4H), 3.71-3.64 (m, 2H), 3.36 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.70 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 509.3 [M+H] + .

[0384] Compound 73: (S)-4-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrazole-3-carboxylate ethyl JPEG0007760530000118.jpg73159

[0385] Step 1: tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (4 g, 12.658 mmol), 1,1,1,2,2,2-hexamethyldistannane (4.97 g, 15.17 mmol), and 1,1'-bis(di-:tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (4 g, 12.7 mmol), 1,1,1,2,2,2-hexamethyldistannane (4.97 g, 15.17 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium Dichloride (0.414 g, 0.633 mmol) was mixed in 25 mL of 1,4-dioxane. It was stirred at 120° C. for 16 hours. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=2 / 1) to give 3 g of tert-butyl 4-(5-fluoro-4-(trimethylstannyl)pyrimidin-2-yl)piperazine-1-carboxylate as a white solid. Yield: 53.3%. LC-MS (m / z): 446.3 [M+H] + .

[0386] Step 2: tert-Butyl 4-(5-fluoro-4-(trimethylstannyl)pyrimidin-2-yl)piperazine-1-carboxylate (2.4 g, 2.696 mmol) and 1-(tert-butyl)3-ethyl 4-bromo-5-methyl-1H-pyrazole-1,3-dicarboxylate (1 g, 3.0 mmol) and Pd(PPh3)4 were mixed in 30 mL of toluene. The mixture was stirred at 120 °C for 48 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA=1 / 1) to obtain 240 mg of tert-butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate as a brown oil. Yield: 20.5%. LC-MS(m / z):435.4[M+H] + .

[0387] Step 3 and Step 4: tert-Butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (40 mg, 0.092 mmol) was dissolved in 3 mL of DCM. 1 mL of TFA / DCM (1 / 1) was added to the solution at 0° C. It 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): 335.3 [M+H] + .

[0388] The above residue, (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (30 mg, 0.106 mmol) and DABCO (41 mg, 0.366 mmol) were mixed in 3 mL of THF. The mixture was evaporated to dryness and irradiated with direct light using a 100 W filament lamp for 3 hours. The solid was purified by preparative HPLC to give 10 mg of ethyl (S)-4-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrazole-3-carboxylate as a white solid. Yield for two steps: 19.8%.

[0389] 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 1.6 Hz, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.30-7.27 (m, 1H), 7.25-7.22 (m, 1H), 6.89 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.2, 10.4 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.93-3.83 (m, 2H), 3.82-3.71 (m, 4H), 3.68 -3.61 (m, 2H), 3.35 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.42 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS (m / z): 550.4 [M+H] + .

[0390] Compound 74: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000119.jpg77159

[0391] Step 1: 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (150 mg, 0.146 mmol) was dissolved in 4 mL of THF. LiAlH (0.6 mL, 0.6 mmol, 1 M in THF solution) was slowly added to the solution at 0 °C. It was stirred at room temperature for 8 h. The reaction was quenched by adding 0.6 mL of HO and 0.6 mL of 1 N NaOH solution. The reaction mixture was filtered, and the filtrate was evaporated to dryness to give 180 mg of 4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carboxylate as a crude brown oil, which was used in the next step without further purification. LC-MS(m / z):393.4[M+H] + .

[0392] Step 2 and Step 3: tert-Butyl 4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carboxylate (180 mg, 0.459 mmol) was dissolved in 3 mL of DCM. 2 mL of TFA / DCM (1 / 1) was added to the solution at 0° C. It 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): 293.5 [M+H] + .

[0393] The above residue, (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (75 mg, 0.265 mmol) and DABCO (150 mg, 1.339 mmol) were mixed in 3 mL of THF. The mixture was evaporated to dryness and irradiated with direct light using a 100 W filament lamp for 1 hour. The solid was purified by preparative HPLC to give 5 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a white solid. Yield for two steps: 3.7%.

[0394] 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.42 (s, 1H), 7.31-7.28 (m, 1H), 7.25-7.21 (m, 1H), 6.89 (s, 1H), 5.35 (dd, J = 11.6, 10.4 Hz, 1H), 4.90-4.75 (m, 2H), 3.94-3.82 (m, 2H), 3.81-3.70 (m, 4H), 3.68-3.58 (m, 2H), 3.35 (ddd, J = 18.4, 11.6 , 1.6 Hz), 2.69 (ddd, J = 18.4, 9.6, 1.6 Hz, 1H), 2.43 (s, 3H). LC-MS (m / z): 508.4 [M+H] + .

[0395] Compound 75: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(5-methyl-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000120.jpg27159

[0396] To a solution of (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (50 mg, 0.2 mmol) and 2-chloro-5-fluoro-4-(5-methyl-1H-tetrazol-1-yl)pyrimidine (43 mg, 0.2 mmol) in DMF (2 mL) was added EtN (25 mg, 0.2 mmol). The mixture was stirred at 65° C. overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by preTLC (petroleum ether / EtOAc=1 / 1) to give the title compound (31 mg, 38% yield) as a white solid. LCMS (ES, m / z): 480.2 [M+H] + .

[0397] 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 2.0 Hz, 1H), 7.41 (t, J = 1.4 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.26 - 7.23 (m, 1H), 6.96 - 6.73 (m, 1H), 5.36 (dd, J = 11.6, 10.1 Hz, 1H), 4.02 - 3.50 (m, 8H), 3.37 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.80 (s, 3H), 2.70 (ddd, J = 18.3, 9.9, 1.6Hz, 1H)

[0398] Compound 76: (S)-2-(3-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)acetamide JPEG0007760530000121.jpg34159

[0399] The title compound 76 was prepared in a similar manner to the preparation of compound 7 as a white solid (8 mg, 14% yield). LCMA (ES, m / z): 521.2 [M+H] + .

[0400] 1 H NMR (400 MHz, dmso) δ 8.47 (s, 1H), 7.83 - 7.44 (m, 3H), 7.29 (s, 1H), 7.09 (s, 1H), 6.90 (s, 1H), 5.28 (d, J = 10.9 Hz, 1H), 4.88 (s, 2H), 3.82 - 3.49 (m, 8H), 3.36 (dd, J = 17.4, 12.6 Hz, 1H), 2.59 (dd, J = 18.3, 10.9 Hz, 1H).

[0401] Compound 77: (S)-2-(3-(5-fluoro-2-(4-(5-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetamidoyl)acetamide JPEG0007760530000122.jpg2964

[0402] The title compound 77 was prepared in a similar manner to the preparation of compound 76 as a white solid (9 mg, 16% yield). LCMA (ES, m / z): 478.2 [M+H] + .

[0403] 1 H NMR (400 MHz, dmso) δ 8.47 (d, J = 3.2 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.58 (s, 1H), 7.37 - 7.14 (m, 4H), 7.05 (s, 1H), 6.90 (s, 1H), 5.27 - 5.12 (m, 1H), 4.88 (s, 2H), 3.67 (m, 8H), 3.36 (dd, J = 17.4, 12.6 Hz, 1H), 2.59 (dd, J = 18.3, 10.9 Hz, 1H)

[0404] Compounds 78 and 79: (S)-2-(4-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-2H-1,2,3-triazol-2-yl)acetamide and (S)-2-(4-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-1,2,3-triazol-1-yl)acetamide JPEG0007760530000123.jpg112159

[0405] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (254 mg, 1.5 mmol) in dioxane (200 mL) under nitrogen, tributyl(prop-1-yn-1-yl)stannane (500 mg, 1.52 mmol) and trans-Pd(dppf)Cl2 (107 mg, 0.15 mmol) were added. The resulting mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether = 2:1) to give 2-chloro-5-fluoro-4-(prop-1-yn-1-yl)pyrimidine as a white solid (234 mg, 46%). LCMS (ES, m / z): 171.0 [M+H] + .

[0406] Step 2: To a solution of 2-chloro-5-fluoro-4-(prop-1-yn-1-yl)pyrimidine (234 mg, 1.4 mmol) in 10 mL of DMF / MeOH (9:1) was added TMSN3 (238 mg, 2.0 mmol) and CuI (500 mg, 1.52 mmol) under nitrogen. The resulting mixture was stirred at 100 °C for 12 h, diluted with ethyl acetate (20 mL), washed with water (10 mL) and brine (10 mL), dried (NaSO), filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether = 1:1) to give 2-chloro-5-fluoro-4-(5-methyl-2H-1,2,3-triazol-4-yl)pyrimidine as a white solid (62 mg, 21%). LCMS (ES, m / z): 214.6 [M+H] + .

[0407] Step 3: To a solution of (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (53 mg, 0.25 mmol) and 2-chloro-5-fluoro-4-(5-methyl-2H-1,2,3-triazol-4-yl)pyrimidine (50 mg, 0.17 mmol) in DMF (5 mL) was added EtN (25 mg, 0.24 mmol). The mixture was stirred at 65 °C overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 4) to give the title compound (60 mg, 81% yield) as a white solid. LCMS (ES, m / z): 479.2 [M+H].

[0408] Step 4: To (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(5-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (25 mg, 0.10 mmol) in DMF (2 mL) was added 2-aminoacetamide (11 mg, 0.10 mmol) and CsCO (26 mg, 0.10 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (DCM / MeOH=20 / 1) to give the title compounds (8.7 mg, 23% yield and 2.1 mg, 14% yield) as a white solid. LCMS(ES,m / z):536.4[M+H] + .

[0409] Compound 78: 1 H NMR (400 MHz, cdcl3) δ 8.33 (d, J = 2.7 Hz, 1H), 7.67 (dd, J = 12.1, 6.9 Hz, 1H), 7.57 - 7.44 (m, 1H), 7.42 (s, 1H), 6.89 (s, 1H), 5.41 - 5.32 (m, 1H), 5.17 (s, 2H), 3.90 (dd, J = 14.6, 7.7 Hz, 2H), 3.80 (d, J = 9.5 Hz, 4H), 3.67 (dd, J = 14.5, 7.9 Hz, 2H), 3.41 - 3.31 (m, 1H), 2.69 (dd, J = 19.1, 10.7 Hz, 1H), 2.63 (s, 3H).

[0410] Compound 79: 1H NMR (400 MHz, cdcl3) δ 8.33 (d, J = 2.7 Hz, 1H), 7.67 (dd, J = 12.1, 6.9 Hz, 1H), 7.57 - 7.44 (m, 1H), 7.42 (s, 1H), 6.89 (s, 1H), 5.41 - 5.32 (m, 1H), 5.08 (s, 2H), 3.93 - 3.83 (m, 2H), 3.78 (d, J = 9.9 Hz, 4H), 3.70 - 3.60 (m, 2H), 3.36 (dd, J = 16.5, 11.9 Hz, 1H), 2.70 (dd, J = 15.8, 7.4 Hz, 1H), 2.65 (d, J = 13.1 Hz, 3H).

[0411] Compound 80: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(5-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000124.jpg3664

[0412] The title compound 80 (10 mg, 6% yield) as a white solid was prepared in a similar manner to the preparation of compound 78. LCMS (ES, m / z): 479.2 [M+H] + .

[0413] 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 9.2, 1.5 Hz, 1H), 7.27 (d, J = 1.4 Hz, 1H), 6.91 (d, J = 11.4 Hz, 1H), 5.45 - 5.31 (m, 1H), 3.94 (td, J = 10.1, 6.4 Hz, 2H), 3.84 (dd, J = 10.9, 8.1 Hz, 4H), 3.75 - 3.61 (m, 2H), 3.45 - 3.29 (m, 1H), 2.77 - 2.71 (m, 1H), 2.71 - 2.67 (m, 3H).

[0414] Compound 81: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000125.jpg78159

[0415] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol) in 10 mL of 1,4-dioxane / HO (5:1), (3-methyl-1H-pyrazol-4-yl)boronic acid (900 mg, 7.2 mmol), KCO (1.65 g, 11.98 mmol), and Pd(dppf)Cl (240 mg, 2.37 mmol) were added at room temperature under nitrogen. The mixture was stirred at 80 °C for 1.0 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound (700 mg, 58%) as a white solid. (ES, m / s): 213.2 [M+H].

[0416] Step 2: To a solution of (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (165 mg, 0.78 mmol) and 2-chloro-5-fluoro-4-(1H-pyrazol-3-yl)pyrimidine (258 mg, 0.86 mmol) in DMF (5 mL) was added EtN (118 mg, 1.17 mmol). The mixture was stirred at 65 °C overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 1) to give the title compound 81 (65 mg, 26% yield) as an off-white solid. LCMS (ES, m / z): 462.2 [M+H].

[0417] Compound 82: (S)-3-Fluoro-5-(1-(4-(5-fluoro-4-(1H-pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000126.jpg33159

[0418] To a solution of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (30 mg, 0.06 mmol) and 2-bromoacetamide (13 mg, 0.09 mmol) in DMF (2 mL) was added CsCO (30 mg, 0.09 mmol). The mixture was stirred at room temperature for 16 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (2 mg, 6% yield) as a white solid. LCMS (ES, m / z): 535.2 [M+H].

[0419] 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 3.1 Hz, 1H), 8.09 (d, J = 3.1 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J = 12.1 Hz, 2H), 6.92 (s, 1H), 6.37 (brs, 1H), 5.58 (brs, 1H), 5.43 - 5.32 (m, 1H), 4.83 (s, 2H), 3.97 - 3.86 (m, 2H), 3.83 (t, J = 9.0 Hz, 4H), 3.72 - 3.63 (m, 2H), 3.38 (dd, J = 17.5, 12.6 Hz, 1H), 2.76 - 2.69 (m, 1H), 2.68 (s, 3H).

[0420] Compound 83: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000127.jpg37159

[0421] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.19 mmol) in 6 mL of 1,4-dioxane / HO (5:1), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (293 mg, 1.32 mmol), NaCO (1.8 mL, 2 M), and Pd(PPh) (138 mg, 0.12 mmol) were added at room temperature under nitrogen. The mixture was stirred at 80 °C overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound (150 mg, 55%) as a white solid. (ES, m / s): 227.2 [M+H]

[0422] Step 2: To a solution of 2-chloro-4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidine (50 mg, 0.31 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (60 mg, 0.28 mmol) in DMF (5 mL) was added EtN (56 mg, 0.58 mmol). The mixture was stirred at 65 °C overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 1) to give the title compound 83 (47 mg, 47% yield) as an off-white solid. LCMS (ES, m / z): 485.2 [M+H] + .

[0423] 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 2.9 Hz, 1H), 6.81 - 6.69 (m, 3H), 6.66 - 6.58 (m, 2H), 5.27 (dd, J = 11.6, 10.0 Hz, 1H), 4.13 (s, 3H), 3.87 - 3.79 (m, 2H), 3.76 - 3.66 (m, 4H), 3.62 - 3.52 (m, 2H), 3.26 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.62 (ddd, J = 18.3, 9.9, 1.5 Hz, 1H), 2.24 (s, 3H).

[0424] Compound 84: (S)-3-(1-(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000128.jpg3364

[0425] The title compound 84 was prepared in a 22% yield from (S)-3-(1-(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (24 mg) in a manner similar to the preparation of compound 83 as a white solid. LC-MS (m / z) 492.1 (M+H + )

[0426] 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 2.9 Hz, 1H), 7.34 (s, 1H), 7.23 - 7.19 (m, 1H), 7.18 - 7.15 (m, 1H), 6.81 (s, 1H), 6.60 (d, J = 4.3 Hz, 1H), 5.37 - 5.22 (m, 1H), 4.13 (s, 3H), 3.85 - 3.76 (m, 2H), 3.76 - 3.64 (m, 4H), 3.61 - 3.47 (m, 2H), 3.28 (ddd, J = 18.3, 11.7, 1.7 Hz, 1H), 2.61 (ddd, J = 18.3, 10.1, 1.5 Hz, 1H), 2.24 (s, 3H).

[0427] Compound 85: (S)-(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000129.jpg2964

[0428] The title compound 85 was prepared in a similar manner to the preparation of 83 from (S)-(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone (34 mg) as a white solid in 34% yield. LC-MS (m / z) 449.2 (M+H + )

[0429] 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 2.9 Hz, 1H), 7.29 - 7.18 (m, 5H), 6.78 (t, J = 1.6 Hz, 1H), 6.60 (d, J = 4.4 Hz, 1H), 5.31 (dd, J = 11.7, 9.8 Hz, 1H), 4.13 (s, 3H), 3.87 - 3.77 (m, 2H), 3.75 - 3.62 (m, 4H), 3.59 - 3.51 (m, 2H), 3.26 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.68 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H), 2.24 (s, 3H).

[0430] Compound 86: (S)-(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000130.jpg2864

[0431] The title compound 86 was prepared as a white solid from (S)-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone in a manner similar to the preparation of 83. LCMS (ES, m / z): 468.2 [M+H] + .

[0432] Compound 87: (S)-3-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)pyridin-2(1H)-one JPEG0007760530000131.jpg78159

[0433] Step 1: 2,4-Dichloro-5-fluoropyrimidine (300 mg, 1.80 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (300 mg, 2.17 mmol) were dissolved in 5 mL of 1,4-dioxane. To the solution was added Na2CO3 (2.7 mL, 2N) and Pd(PPh3)4 (207 mg, 0.18 mmol) under nitrogen at room temperature. The mixture was stirred at 80 °C for 1.0 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound (100 mg, 24%) as a white solid. LC-MS (ES, m / s): 226.1 [M+H]+

[0434] Step 2: To (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (100 mg, 0.34 mmol) and 2-chloro-5-fluoro-4-(1H-pyrazol-3-yl)pyrimidine (84 mg, 0.37 mmol) in DMF (5 mL) was added EtN (68 mg, 0.68 mmol). The mixture was stirred at 65 °C overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 5 / 1) to give the title compound 87 (42 mg, 19% yield) as a white solid. LCMS (ES, m / z): 484.2 [M+H] + .

[0435] 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 5.1 Hz, 1H), 7.47 (dd, J = 13.7, 5.8 Hz, 1H), 6.73 (ddd, J = 18.7, 9.8, 4.6 Hz, 3H), 6.62 (tt, J = 8.9, 2.3 Hz, 1H), 6.39 (t, J = 6.6 Hz, 1H), 5.24 (dd, J = 19.9, 9.9 Hz, 1H), 3.81 (td, J = 10.1, 6.4 Hz, 2H), 3.76 - 3.63 (m, 4H), 3.56 (td, J = 10.0, 6.3 Hz, 2H), 3.24 (ddd, J = 18.2, 11.7, 1.8 Hz, 1H), 2.61 (ddd, J = 18.2, 9.9, 1.5 Hz, 1H).

[0436] Compound 88: (S)-3-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1-methylpyridin-2(1H)-one JPEG0007760530000132.jpg35159

[0437] (S)-3-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)pyridin-2(1H)-one (22 mg, 0.05 mmol) was dissolved in 3 mL of DMF. NaH (2 mg, 0.05 mmol) was added in portions at 0 °C. It was stirred at 0 °C for 30 minutes. CHCl (10 mg, 0.06 mmol) was added. It was stirred at room temperature for 30 minutes. Water was added and extracted with EtOAc (10 mL × 3). Drying over NaSO, filtration, and evaporation to dryness gave 64 mg of 2-chloro-4-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidine as a pale yellow solid. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 5) to give the title compound 88 (5.6 mg, 21% yield) as a white solid. LCMS (ES, m / z): 498.2 [M+H] +

[0438] 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.71 - 7.52 (m, 1H), 7.44 (dd, J = 21.9, 14.9 Hz, 2H), 6.82 - 6.67 (m, 2H), 6.68 - 6.48 (m, 1H), 6.23 (s, 1H), 5.34 - 5.11 (m, 1H), 3.82 (s, 2H), 3.77 - 3.63 (m, 4H), 3.56 (s, 5H), 3.23 (dd, J = 17.6, 12.4 Hz, 1H), 2.60 (dd, J = 18.2, 9.8 Hz, 1H).

[0439] Compound 89: (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1-methylpyridin-2(1H)-one JPEG0007760530000133.jpg40159

[0440] (S)-5-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1-methylpyridin-2(1H)-one (20 mg, 0.05 mmol) was dissolved in 3 mL of DMF. NaH (2 mg, 0.05 mmol) was added in portions at 0 °C. It was stirred at 0 °C for 30 minutes. CHCl (10 mg, 0.06 mmol) was added. It was stirred at room temperature for 30 minutes. Water was added and extracted with EtOAc (10 mL × 3). Drying over NaSO, filtration, and evaporation to dryness gave 64 mg of 2-chloro-4-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidine as a pale yellow solid. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 5) to give the title compound 89 (5.0 mg, 18% yield) as a white solid. LCMS (ES, m / z): 498.2 [M+H] +

[0441] 1 H NMR (400 MHz, CDCl3) δ 8.24 - 8.15 (m, 1H), 8.11 (dd, J = 11.3, 3.2 Hz, 2H), 6.75 (dd, J = 11.0, 5.0 Hz, 3H), 6.65 - 6.46 (m, 2H), 5.32 - 5.20 (m, 1H), 3.82 (dd, J = 14.7, 8.0 Hz, 2H), 3.76 - 3.65 (m, 4H), 3.62 - 3.49 (m, 5H), 3.25 (ddd, J = 18.4, 11.8, 1.8 Hz, 1H), 2.67 - 2.55 (m, 1H).

[0442] Compound 90: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methanone JPEG0007760530000134.jpg90159

[0443] Step 1: To 4,6-dichloropyrimidine (200 mg, 1.34 mmol) and 3,5-dimethyl-1H-1,2,4-triazole (105 mg, 0.17 mmol) in DMF (5 mL) was added CsCO (654 mg, 2.01 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 4) to give the title compound (90 mg, 32% yield) as a white solid. LCMS (ES, m / z): 210.2 [M+H].

[0444] Step 2: To 4,6-dichloropyrimidine (90 mg, 0.43 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (138 mg, 0.47 mmol) in DMF (5 mL) was added EtN (65 mg, 0.64 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 4) to give the title compound 90 (76.9 mg, 32% yield) as a white solid. LCMS (ES, m / z): 468.2 [M+H] + .

[0445] 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 0.7 Hz, 1H), 6.94 (t, J = 3.5 Hz, 1H), 6.80 - 6.70 (m, 3H), 6.63 (tt, J = 8.8, 2.3 Hz, 1H), 5.25 (dd, J = 11.6, 9.9 Hz, 1H), 3.85 - 3.69 (m, 4H), 3.69 - 3.54 (m, 4H), 3.26 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.79 (s, 3H), 2.63 (ddd, J = 18.3, 9.8, 1.6 Hz, 1H), 2.32 (s, 3H).

[0446] Compound 91: (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrrole-3-carboxylate methyl JPEG0007760530000135.jpg80159

[0447] Step 1: To 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.20 mmol) and 5-methyl-1H-pyrrole-3-carboxylate (166 mg, 1.2 mmol) in DMF (5 mL) was added CsCO (584 mg, 1.79 mmol). The mixture was stirred at 60 °C for 12 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc = 1 / 4) to give the title compound (181 mg, 60% yield) as a white solid. LCMS (ES, m / z): 252.2 [M+H] + .

[0448] Step 2: To methyl 1-(2-chloropyrimidin-4-yl)-5-methyl-1H-pyrrole-3-carboxylate (181 mg, 0.67 mmol) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (256 mg, 0.87 mmol) in DMF (5 mL) was added EtN (102 mg, 1.01 mmol). The mixture was stirred at 60° C. for 12 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-TLC (petroleum ether / EtOAc=1 / 4) to give the title compound 91 (27.3 mg, 8% yield) as a white solid. LCMS (ES, m / z): 528.2 [M+H] + .

[0449] Compound 92: (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrrole-3-carboxamide JPEG0007760530000136.jpg62159

[0450] Step 1: To methyl (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrrole-3-carboxylate (80 mg, 0.15 mmol) in MeOH (5 mL) was added 1 N NaOH (1 mL). The reaction mixture was stirred at room temperature overnight. 50 mg of (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrrole-3-carboxylic acid was obtained as a white solid. Yield: 74%. LC-MS (m / z) 514.2 (M+H+).

[0451] Step 2: To (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (50 mg, 0.10 mmol) in DMF (15 mL) was added NH4Cl (17 mg, 0.3 mmol), HATU (111 mg, 0.3 mmol) and TAE (29 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound 92 (12 mg, 24% yield) as a white solid. LCMS (ES, m / z): 513.2 [M+H] + .

[0452] 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.68 (s, 1H), 6.79 (dd, J = 36.2, 30.1 Hz, 4H), 6.35 (s, 1H), 5.33 (t, J = 10.4 Hz, 1H), 3.98 - 3.52 (m, 8H), 3.37 - 3.21 (m, 1H), 2.69 (dd, J = 18.3, 9.8 Hz, 1H), 2.40 (s, 3H).

[0453] Compound 93: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000137.jpg73159

[0454] Step 1: 2,4-Dichloro-5-fluoropyrimidine (500 mg, 2.99 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (731 mg, 3.29 mmol), and K2CO3 (826 mg, 5.98 mmol) were mixed in 20 mL of 1,4-dioxane / HO (5:1). Pd(dppf)2Cl2 (219 mg, 0.30 mmol) was added. The mixture was stirred at 85 °C for 16 h. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 1 / 3) to give 300 mg of crude 2-chloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidine as a pale yellow solid. LC-MS(m / z):227.2[M+H]+.

[0455] Step 2: To (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (150 mg, 0.41 mmol) and 2-chloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidine (126 mg, 0.56 mmol) in DMF (5 mL) was added EtN (68 mg, 0.68 mmol). The mixture was stirred at 65° C. overnight. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound 93 (10 mg, 4% yield) as a white solid. LC-MS (ES, m / z): 485.2 [M+H] +

[0456] 1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 5.9, 1.9 Hz, 1H), 6.83 (ddd, J = 13.8, 8.4, 3.7 Hz, 3H), 6.73 - 6.56 (m, 1H), 5.33 (dd, J = 18.3, 8.3 Hz, 1H), 3.88 (dt, J = 15.3, 7.5 Hz, 2H), 3.82 - 3.68 (m, 4H), 3.64 (dd, J = 9.9, 6.9 Hz, 2H), 3.33 (ddd, J = 18.3, 11.7, 1.7 Hz, 1H), 2.70 (ddd, J = 18.3, 9.8, 1.5 Hz, 1H), 2.53 (d, J = 1.5 Hz, 6H).

[0457] Compound 94: (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000138.jpg3964

[0458] The title compound 94 was prepared from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile in a manner similar to the preparation of 93 as a white solid in 4% yield. LC-MS (m / z) 492.2 (M+H+).

[0459] 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 7.2, 1.9 Hz, 1H), 7.41 (d, J = 1.3 Hz, 1H), 7.33 - 7.20 (m, 2H), 6.90 (s, 1H), 5.43 - 5.30 (m, 1H), 3.95 - 3.81 (m, 2H), 3.78 (d, J = 10.0 Hz, 4H), 3.69 - 3.57 (m, 2H), 3.41 - 3.29 (m, 1H), 2.70 (dd, J = 18.3, 10.0 Hz, 1H), 2.52 (d, J = 1.5 Hz, 6H).

[0460] Compound 95: (S)-2-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one JPEG0007760530000139.jpg64159

[0461] Step 1: Methylamine hydrochloride (2.70 g, 40 mmol) was dissolved in anhydrous EtOH (200 mL) and a suspension of sodium ethoxide (2.72 g, 40 mmol) in anhydrous EtOH (70 mL) was added, and the reaction was stirred at room temperature for 5 minutes. A solution of (E)-ethyl 2-(1-ethoxyethylidene)hydrazinecarboxylate (3.48 g, 20 mmol) in anhydrous EtOH (50 mL) was added dropwise, and the reaction was refluxed for 4 hours. The reaction was then cooled to room temperature and filtered through a Celite pad. The eluate was dried under reduced pressure, and the resulting residue was recrystallized from EtOAc (via hot filtration) to give the pure product. Isolated yield: 904 mg (40%, 20 mmol scale); white crystals (recrystallized from EtOAc); LCMS (ES, m / z): 114.1 [M+H] + .

[0462] Step 2: To tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.63 mmol) in DMF (20 mL) was added 4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.75 mmol), CsCO (2.5 g, 7.62 mmol). The reaction was stirred at 120 °C for 3 h. Water was added and extracted with EA, washed with brine, and dried over (NaSO). The resulting mixture was evaporated in vacuo, and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-(3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate as a yellow solid. (281mg,41%)LC-MS(m / z):394.2(M+H + ).

[0463] Step 3: tert-Butyl 4-(4-(3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (281 mg, 0.71 mmol) was dissolved in 5 mL of DCM. 1 mL of TFA / DCM (1 / 5) was added to the solution at 0° C. It 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): 294.2 [M+H] + .

[0464] Step 4: The residue above, (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (100 mg, 0.36 mmol) and DABCO (61 mg, 0.55 mmol) were mixed in 3 mL of THF. The mixture was evaporated to dryness and irradiated with direct light using a 100 W filament lamp for 2 hours. The solid was purified by preparative HPLC to give 48.8 mg of ((S)-2-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid. Overall yield for two steps: 14%. LC-MS (m / z): 502.2 [M+H] + .

[0465] 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 2.6 Hz, 1H), 6.80 - 6.71 (m, 3H), 6.62 (tt, J = 8.9, 2.3 Hz, 1H), 5.26 (dd, J = 11.5, 10.0 Hz, 1H), 3.86 - 3.76 (m, 2H), 3.70 (tdd, J = 9.7, 7.2, 2.8 Hz, 4H), 3.60 - 3.50 (m, 2H), 3.29 - 3.19 (m, 1H), 3.22 (s, 3H), 2.61 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H), 2.26 (s, 3H).

[0466] Compound 96: (S)-3-(1-(4-(4-(3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000140.jpg38159

[0467] 2-(5-Fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (124 mg, 0.42 mmol), (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.35 mmol), and DABCO (60 mg, 0.55 mmol) were mixed in 2 mL of THF. The mixture was evaporated to dryness and irradiated with direct light using a 100 W filament lamp for 1 hour. The solid was purified by preparative HPLC to give 150 mg of (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile as a pale yellow solid. Yield: 28%. LC-MS (m / z): 509.2 [M+H] + .

[0468] 1 H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H), 7.22 - 7.17 (m, 2H), 6.80 (t, J = 1.5 Hz, 1H), 5.29 (dd, J = 11.3, 10.4 Hz, 1H), 3.85 - 3.76 (m, 2H), 3.70 (qd, J = 7.0, 3.5 Hz, 4H), 3.59 - 3.50 (m, 2H), 3.28 (ddd, J = 18.2, 11.7, 1.8 Hz, 1H), 3.22 (s, 3H), 2.61 (ddd, J = 18.2, 10.1, 1.5 Hz, 1H), 2.26 (s, 3H).

[0469] Compound 97: (S)-3-(1-(4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000141.jpg65159

[0470] Step 1: Ethanamine hydrochloride (2.0 g, 10 mmol) was dissolved in anhydrous EtOH (200 mL) and a suspension of sodium ethoxide (1.33 g, 19.5 mmol) in anhydrous EtOH (70 mL) was added, and the reaction was stirred at room temperature for 5 minutes. A solution of (E)-ethyl 2-(1-ethoxyethylidene)hydrazinecarboxylate (1.6 g, 19.5 mmol) in anhydrous EtOH (50 mL) was added dropwise, and the reaction was refluxed for 4 hours. The reaction was then cooled to room temperature and filtered on a Celite pad. The eluate was dried under reduced pressure, and the resulting residue was recrystallized from EtOAc (via hot filtration) to give the pure product. Isolated yield: 183 mg (10%); white crystals (recrystallized from EtOAc); LC-MS (ES, m / z): 128.1 [M+H] + .

[0471] Step 2: tert-Butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 0.95 mmol) in DMF (20 mL) was added to 4-ethyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (128 mg, 1.42 mmol), CsCO (462 mg, 1.42 mmol). The reaction was stirred at 120 °C for 3 h. Water was added and extracted with EA, washed with brine, and dried over (NaSO). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 77%) as a yellow solid. LC-MS (m / z) 408.2 (M+H + ).

[0472] Step 3: tert-Butyl 4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 0.73 mmol) was dissolved in 5 mL of DCM. 1 mL of TFA / DCM (1 / 5) was added to the solution at 0° C. It 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): 308.2 [M+H] + .

[0473] Step 4: The residue above, 4-ethyl-2-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (260 mg, 0.84 mmol) and DABCO (53 mg, 1.06 mmol) were mixed in 3 mL of THF, evaporated to dryness and irradiated directly with a 100 W filament lamp for 2 hours. The solid was purified by preparative HPLC to give 20 mg of (S)-3-(1-(4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile as a white solid. Overall yield for two steps: 6%. LC-MS (m / z): 523.2 [M+H] + .

[0474] 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 2.7 Hz, 1H), 7.34 (s, 1H), 7.26 - 7.11 (m, 2H), 6.80 (s, 1H), 5.36 - 5.21 (m, 1H), 3.89 - 3.77 (m, 2H), 3.77 - 3.60 (m, 6H), 3.61 - 3.48 (m, 2H), 3.28 (ddd, J = 18.2, 11.7, 1.7 Hz, 1H), 2.62 (ddd, J = 18.2, 10.0, 1.5 Hz, 1H), 2.28 (s, 3H), 1.26 (q, J = 7.4 Hz, 3H).

[0475] Compound 98: (S)-2-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-4-ethyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one JPEG0007760530000142.jpg3364 The title compound 98 was prepared in a similar manner to the preparation of 97 from (S)-2-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-4-ethyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (25 mg) in 8% yield as a white solid. LC-MS (m / z) 516.2 (M+H + )

[0476] 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 2.7 Hz, 1H), 6.79 - 6.69 (m, 3H), 6.69 - 6.53 (m, 1H), 5.26 (dd, J = 11.4, 10.1 Hz, 1H), 3.86 - 3.77 (m, 2H), 3.70 (tdd, J = 14.4, 9.2, 5.0 Hz, 6H), 3.60 - 3.51 (m, 2H), 3.24 (ddd, J = 18.2, 11.7, 1.7 Hz, 1H), 2.61 (ddd, J = 18.3, 9.9, 1.5 Hz, 1H), 2.27 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0477] Compound 99: (S)-5-(1-(4-(4-(5-methyl-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)nicotinonitrile JPEG0007760530000143.jpg84159

[0478] The title compound 99 was prepared from 2-chloro-4-(5-methyl-1H-tetrazol-1-yl)pyrimidine and (S)-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)nicotinonitrile in a manner similar to the preparation of compound 7 as a pale yellow solid in 20.7% yield.

[0479] 1H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 2H), 8.56 (d, J = 5.2 Hz, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.26 (t, J = 2.8 Hz, 1H), 6.98 (t, J = 1.6 Hz, 1H), 5.46 (dd, J = 11.6, 10.0 Hz, 1H), 4.01-3.91 m, 2H), 3.90-3.76 (m, 4H), 3.73-3.63 (m, 2H), 3.44 (ddd, J = 18.4, 11.6, 2.0 Hz, 1H), 2.98 (s, 3H), 2.78 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H). LC-MS (m / z): 445.3 [M+H]+

[0480] Compound 100: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000144.jpg27159

[0481] Step 1: To a solution of (S)-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (30 mg, 0.07 mmol) in DMF (20 mL) was added 3,5-dimethyl-4H-1,2,4-triazole (14 mg, 0.14 mmol), CsCO (48 mg, 0.14 mmol) at 30° C. The reaction was stirred at 110° C. for 2.0 h. Water was added and extracted with EA, washed with brine, and dried over (NaSO). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone (4.0 mg, 10.4%) as a white solid. LC-MS (m / z) 468.4 (M+H + ).

[0482] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 5.2 Hz, 1H), 7.15-7.11 (m, 1H), 7.11-7.08 (m, 1H), 7.03 - 7.01 (m, 2H), 7.01-6.99 (m, 1H), 5.26 (dd, J = 11.6, 10.0 Hz, 1H), 3.88 - 3.53 (m, 8H), 3.49 - 3.42 (m, 1H), 2.79 (s, 3H), 2.65 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.29 (s, 3H).

[0483] Compound 101: (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000145.jpg64159

[0484] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (1.0 g, 5.98 mmol) in DMF (20 mL) was added methyl 1H-pyrazole-4-carboxylate (950 mg, 7.53 mmol), DIEA (1.54 g, 11.93 mmol) at 30° C. The reaction was stirred at 50° C. for 3.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was evaporated under vacuum, and the crude product was purified by silica gel chromatography to give methyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxylate (1.2 g, 85.5%) as a gray solid. LC-MS (m / z) 257.6 (M+H) + ).

[0485] Step 2: To a solution of methyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxylate (130 mg, 0.51 mmol) in DMF (3 mL) was added (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (100 mg, 0.34 mmol), DIEA (87 mg, 0.67 mmol) at 30° C. The reaction was stirred at 65° C. for 1.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxylate (100 mg, 57.4%) as a yellow oil. LC-MS (m / z) 515.4 (M+H + ).

[0486] Step 3: To a solution of (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxylate (100 mg, 0.19 mmol) in MeOH (10 mL) and THF (10 mL) was added NH (23 w% in HO) (2 mL) at 30° C. The reaction was stirred at 100° C. overnight. Water was added and extracted with EA, washed with brine, and dried over (NaSO). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-1-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxamide (2.7 mg, 2.7%) as a white solid. LC-MS (m / z) 500.4 (M+H + ).

[0487] Compound 102: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000146.jpg37159

[0488] The title compound 102 was prepared from ((S)-3-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (20 mg, 0.07 mmol) and 1-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide (30 mg, crude) following the procedure outlined for compound 95 in 9.0% yield as a white solid. LC-MS (m / z) 489.4 (M+H + ).

[0489] 1H NMR (400 MHz, DMSO-d6) δ 9.21 (brs, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.85 (s, 1H), 7.78-7.72 (m, 1H), 7.65 (s, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.31 (s, 1H), 7.14 - 7.06 (m, 2H), 5.30 (t, J = 10.8 Hz, 1H), 3.94-3.52 (m, 8H), 3.42 - 3.35 (m, 1H), 2.72 (dd, J = 18.6, 10.8 Hz, 1H).

[0490] Compound 103: (S)-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000147.jpg62159

[0491] Step 1: To a solution of 2,4-dichloropyrimidine (5.0 g, 33.56 mmol) in dioxane (100 mL) was added tert-butyl piperazine-1-carboxylate (7.48 g, 40.00 mmol), DIEA (8.65 g, 67.05 mmol) at 30° C. The reaction was stirred at 80° C. for 2.0 hours. Water was added and extracted with EA, washed with brine, and dried (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (1.4 g, 14.0%) as a yellow solid. LC-MS (m / z) 299.6 (M+H) + ).

[0492] Step 2: To a solution of tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (900 mg, 3.01 mmol) in DMF (20 mL) was added 5-(trifluoromethyl)-1H-tetrazole, sodium salt (1.0 g, crude), TFA (1.8 mL) at 30° C. The reaction was stirred at 100° C. for 2.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (500 mg, 41.6%) as a yellow solid. LC-MS (m / z) 401.4 (M+H + ).

[0493] Step 3: To a solution of tert-butyl 4-(4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (500 mg, 1.25 mmol) in dioxane (5 mL) was added HCl (4 M in dioxane) (20 mL) at 30° C. The reaction was stirred at 30° C. for 1.0 h. The resulting mixture was removed under vacuum and the crude product was used in the next step reaction without purification. 2-(piperazin-1-yl)-4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidine hydrochloride (600 mg, crude) as a grey solid. LC-MS (m / z) 301.4 (M+H + ).

[0494] Step 4: To a solution of 2-(piperazin-1-yl)-4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidine hydrochloride (100 mg, crude) in THF (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (300 mg, 2.67 mmol), (S)-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (60 mg, 0.23 mmol) at 30° C. The solvent was removed under vacuum and the reaction mixture was left at 80° C. for 2.0 h. The crude product was purified by silica gel chromatography to give (S)-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone (14.7 mg, 12.0%) as a yellow solid. LC-MS (m / z) 491.4 (M+H + ).

[0495] Compound 104: (S)-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000148.jpg31159

[0496] The title compound 104 was prepared in a similar manner to the preparation of compound 103 from (S)-(1H-imidazol-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone (60 mg, 0.25 mmol) and 2-(piperazin-1-yl)-4-(5-(trifluoromethyl)-1H-tetrazol-1-yl)pyrimidine (100 mg, crude) in 6.7% yield as a yellow solid. LC-MS (m / z) 473.4 (M+H + ).

[0497] Compound 105: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000149.jpg34159

[0498] The title compound 105 was prepared in a similar manner to the preparation of compound 103 from (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (100 mg, 0.36 mmol) and 5-fluoro-2-(piperazin-1-yl)-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl)pyrimidine (150 mg, crude) in 2.7% yield as a yellow solid. LC-MS (m / z) 526.4 (M+H) + )

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.8 Hz, 1H), 7.14 - 7.04 (m, 2H), 7.01 - 6.91 (m, 2H), 5.22 (dd, J = 11.6, 10.0 Hz, 1H), 3.52 - 3.18 (m, 9H), 2.62 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H).

[0500] Compound 106: (S)-1-(2-(4-(5-(3-cyanophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000150.jpg33159

[0501] The title compound 106 was prepared from (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (20 mg, 0.07 mmol) and 1-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide (30 mg, crude) in a manner similar to the preparation of compound 103 as a white solid in 4.4% yield. LC-MS (m / z) 471.6 (M+H + )

[0502] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.85 (brs, 1H), 7.77 - 7.71 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.31 (brs, 1H), 7.14 - 7.07 (m, 2H), 5.30 (dd, J = 11.6, 10.0 Hz, 1H), 3.95 - 3.51 (m, 8H), 3.44 - 3.37 (m, 1H), 2.74 - 2.64 (m, 1H).

[0503] Compound 107: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000151.jpg37159

[0504] The title compound was prepared from (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (20 mg, 0.08 mmol) and 1-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide (30 mg, crude) in a manner similar to the preparation of 103. The title compound was prepared as a white solid in 5.4% yield from 107. LC-MS (m / z) 507.4 (M+H). + )

[0505] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 2.8 Hz, 1H), 8.65 (d, J = 3.2 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.88 (brs, 1H), 7.78-7.71 (m, 1H), 7.66-7.62 (m, 1H), 7.56-7.49 (m, 1H), 7.34 (brs, 1H), 7.12 (s, 1H), 5.29 (t, J = 10.8 Hz, 1H), 3.91 - 3.52 (m, 8H), 3.44-3.33 (m, 1H), 2.71 (dd, J = 18.8, 10.8 Hz, 1H).

[0506] Compound 108: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethylisoxazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000152.jpg67159

[0507] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (334 mg, 2.00 mmol) in dioxane (12 mL) and HO (3 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (448 mg, 2.00 mmol), Pd(dppf)Cl (146 mg, 0.20 mmol), and KCO (276 mg, 2.00 mmol) under argon at 30 °C. The reaction was stirred at 60 °C for 2.0 h. The solvent was removed in vacuo, and the crude product was purified by silica gel chromatography to give 4-(2-chloro-5-fluoropyrimidin-4-yl)-3,5-dimethylisoxazole (180 mg, 39.4%) as a white solid. LC-MS (m / z) 228.6 (M+H + ).

[0508] Step 2: To a solution of 4-(2-chloro-5-fluoropyrimidin-4-yl)-3,5-dimethylisoxazole (25 mg, 0.11 mmol) in DMF (10 mL) was added (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (29 mg, 0.10 mmol) and DIEA (60 mg, 0.46 mmol) at 30° C. The reaction mixture was stirred at 120° C. for 1.0 h. Water was added and the mixture was extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethylisoxazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (4.7 mg, 9.5%) as a white solid. LC-MS (m / z) 486.4 (M+H + ).

[0509] 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.4 Hz, 1H), 7.15 - 7.05 (m, 2H), 7.01 - 6.94 (m, 2H), 5.28 - 5.18 (m, 1H), 3.79 - 3.48 (m, 8H), 3.35 - 3.30 (m, 1H), 2.66 - 2.58 (m, 1H), 2.45 (d, J = 2.4 Hz, 3H), 2.28 (d, J = 1.2 Hz, 3H).

[0510] Compound 109: (S)-1-(2-(4-(5-(3-cyanophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000153.jpg28159

[0511] The title compound 109 was prepared in a similar manner to the preparation of compound 103 from (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (20 mg, 0.08 mmol) and 1-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide (30 mg, crude) in 13.2% yield as a white solid. LC-MS (m / z) 489.4 (M+H + )

[0512] 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 0.8 Hz, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 0.8 Hz, 1H), 7.86 (brs, 1H), 7.73 - 7.67 (m, 1H), 7.61 (dt, J = 8.0, 1.6 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.32 (brs, 1H), 7.10-7.08 (m, 1H), 5.31 - 5.22 (m, 1H), 3.85 - 3.50 (m, 8H), 3.45 - 3.36 (m, 1H), 2.70 - 2.62 (m, 1H).

[0513] Compound 110: (S)-1-(5-fluoro-2-(4-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000154.jpg33159

[0514] The title compound 110 was prepared in a similar manner to the preparation of compound 103 from (S)-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (20 mg, 0.08 mmol) and 1-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide (30 mg, crude) in 5.2% yield as a white solid. LC-MS (m / z) 482.4 (M+H + )

[0515] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (m, 1H), 8.65 (dd, J = 4.0, 0.8 Hz, 1H), 8.21 (d, J = 0.8 Hz, 1H), 7.88 (brs, 1H), 7.41 - 7.30 (m, 2H), 7.14 - 7.02 (m, 4H), 5.29 - 5.22 (m, 1H), 3.87 - 3.51 (m, 8H), 3.42 - 3.35 (m, 1H), 2.68 - 2.58 (m, 1H).

[0516] Compound 111: (S)-1-(5-fluoro-2-(4-(5-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide JPEG0007760530000155.jpg34159

[0517] The title compound 111 was prepared in a similar manner to the preparation of compound 103 from (S)-(1H-imidazol-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone (20 mg, 0.08 mmol) and 1-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide (30 mg, crude) in 2.4% yield as a white solid. LC-MS (m / z) 464.4 (M+H + )

[0518] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 0.8 Hz, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 0.8 Hz, 1H), 7.86 (brs, 1H), 7.35 - 7.28 (m, 3H), 7.26 - 7.19 (m, 3H), 7.09 - 7.03 (m, 1H), 5.23 (dd, J = 11.6, 9.6 Hz, 1H), 3.87 - 3.47 (m, 8H), 3.41 - 3.35 (m, 1H), 2.59 (ddd, J = 18.4, 9.6, 1.6 Hz, 1H).

[0519] Compound 112: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1H-imidazol-2-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000156.jpg71159

[0520] The title compound 112 was prepared in a similar manner to the preparation of compound 7 from 2-chloro-5-fluoro-4-(1H-imidazol-2-yl)pyrimidine (30 mg, 0.15 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (40 mg, 0.13 mmol), DIEA (100 mg, 0.77 mmol), and DMF (3 mL) in a 23.7% yield as a white solid. LC-MS (m / z) 464.4 (M+H) + )

[0521] 1H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.63 (m, 1H), 8.50-8.47 (m, 1H), 7.93-7.89 (m, 1H), 7.77 - 7.72 (m, 1H), 7.67-7.61 (m, 1H), 7.56 - 7.49 (m, 1H), 7.21-7.15 (m, 1H), 7.14-7.09 (m, 1H), 5.29 (t, J = 10.8 Hz, 1H), 3.86 - 3.51 (m, 8H), 3.41 - 3.35 (m, 1H), 2.77 - 2.65 (m, 1H).

[0522] Compound 113: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone JPEG0007760530000157.jpg75159

[0523] Step 1: To a solution of 2,6-dichloro-3-fluoropyridine (168 mg, 1.00 mmol) in dioxane (20 mL) and HO (5 mL) was added 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (222 mg, 1.00 mmol), Pd(PPh) (115 mg, 0.10 mmol), and KCO (256 mg, 2.00 mmol) under argon at 30 °C. The reaction was stirred at 70 °C for 2.0 h. The solvent was removed in vacuo, and the crude product was purified by silica gel chromatography to give 6-chloro-2-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoropyridine (50 mg, 22.0%) as a white solid. LC-MS (m / z) 226.5 (M+H + ).

[0524] Step 2: To a solution of 6-chloro-2-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoropyridine (40 mg, 0.17 mmol) in dioxane (10 mL) was added (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (52 mg, 0.17 mmol), Pd(dba) (16 mg, 0.02 mmol), Xphos (16 mg, 0.04 mmol), and t-BuONa (28 mg, 0.30 mmol) under argon at 30° C. The reaction mixture was stirred at 100° C. for 2.0 h. The solvent was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone (4.3 mg, 5.0%) as a white solid. LC-MS (m / z) 484.5 (M+H + ).

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (t, J = 9.2 Hz, 1H), 7.34 (s, 1H), 7.16 - 7.08 (m, 2H), 7.05 - 6.98 (m, 3H), 5.26 (t, J = 10.8 Hz, 1H), 3.77 (s, 3H), 3.75 - 3.43 (m, 8H), 3.41 - 3.35 (m, 1H), 2.77 - 2.65 (m, 1H),1.96 (d, J = 2.0 Hz, 3H).

[0526] Compound 114: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone JPEG0007760530000158.jpg70159

[0527] Step 1: To a solution of 2,4-dichloro-5-fluoropyridine (210 mg, 1.00 mmol) in dioxane (20 mL) and HO (5 mL) was added 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (222 mg, 1.00 mmol), Pd(PPh) (115 mg, 0.10 mmol), and KCO (256 mg, 2.00 mmol) under argon at 30 °C. The reaction was stirred at 70 °C for 3.0 h. The solvent was removed in vacuo, and the crude product was purified by silica gel chromatography to give 2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridine (50 mg, 22.0%) as a white solid. LC-MS (m / z) 226.5 (M+H + ).

[0528] Step 2: To a solution of 2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridine (50 mg, 0.22 mmol) in dioxane (2 mL) was added tert-butyl piperazine-1-carboxylate (60 mg, 0.32 mmol), Pd(dba) (40 mg, 0.04 mmol), Xphos (40 mg, 0.08 mmol), and t-BuONa (40 mg, 0.41 mmol) under argon at 30° C. The reaction was stirred at 100° C. for 1.0 h. The solvent was removed in vacuo, and the crude product was purified by silica gel chromatography to afford tert-butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazine-1-carboxylate (40 mg, 48.7%) as a yellow oil. LC-MS (m / z) 376.4 (M+H + ).

[0529] Step 3: To a solution of tert-butyl 4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazine-1-carboxylate (40 mg, 0.10 mmol) in DCM (5 mL) was added TFA (2 mL) at 30° C. The reaction was stirred at 30° C. for 0.5 h. The solvent was removed under vacuum and the crude product (60 mg, crude) as a yellow oil was used in the next step reaction. LC-MS (m / z) 276.4 (M+H + ).

[0530] Step 4: Preparation of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone To a solution of 2,2,2-trifluoroacetaldehyde and 1-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazine (1:1) (60 mg, crude) in THF (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (32 mg, 0.28 mmol), (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (40 mg, 0.14 mmol) at 30° C. The solvent was removed under vacuum, and the reaction mixture was left at 70° C. for 3.0 hours. The crude product was purified by silica gel chromatography to give (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone (8 mg, 11.5%) as a white solid. LC-MS (m / z) 484.5 (M+H + ).

[0531] 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.39 (s, 1H), 7.16 - 7.06 (m, 2H), 7.03 - 6.96 (m, 2H), 6.89 (d, J = 4.8 Hz, 1H), 5.25 (dd, J = 11.6, 10.0 Hz, 1H), 3.69 (s, 3H), 3.59-3.43 (m, 8H), 3.40 - 3.35 (m, 1H), 2.66-2.60 (m, 1H), 1.94 (s, 3H).

[0532] Compound 115: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(6-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone JPEG0007760530000159.jpg50159

[0533] The title compound 115 was prepared in a similar manner to the preparation of 114 from 1-(6-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazine (1:1) (60 mg, crude), (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (50 mg, 0.18 mmol), and 1,4-diazabicyclo[2.2.2]octane (100 mg, 0.89 mmol) in 3.0% yield as a white solid. LC-MS (m / z) 484.5 (M+H) + ).

[0534] 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 1.6 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.01 - 6.94 (m, 2H), 6.87 (d, J = 4.8 Hz, 1H), 6.26 (s, 1H), 5.23 (dd, J = 11.6, 10.0 Hz, 1H), 3.69 (d, J = 1.2 Hz, 3H), 3.67 - 3.41 (m, 8H), 3.38 - 3.32 (m, 1H), 2.66 - 2.58 (m, 1H), 2.16 (s, 3H).

[0535] Compound 116: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazin-1-yl)methanone JPEG0007760530000160.jpg48159

[0536] The title compound 116 was prepared in a similar manner to the preparation of 114 from 2,2,2-trifluoroacetaldehyde compound, 1-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-2-yl)piperazine (1:1) (110 mg, crude), (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (100 mg, 0.36 mmol), and 1,4-diazabicyclo[2,2.2]octane (200 mg, 1.78 mmol) in a 22.9% yield as a white solid. LC-MS (m / z) 484.5 (M+H + ).

[0537] 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J = 9.6 Hz, 1H), 7.10 (d, J = 9.2 Hz, 2H), 7.02-6.90 (m, 3H), 6.44-6.39 (m, 1H), 5.25 (t, J = 10.8 Hz, 1H), 3.99 (d, J = 2.8 Hz, 3H), 3.75 - 3.44 (m, 8H), 3.38 - 3.32 (m, 1H), 2.64 (dd, J = 18.4, 9.2 Hz, 1H), 2.18 (s, 3H).

[0538] Compound 117: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000161.jpg96159

[0539] Steps 1-4: (4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoro-2-(piperazin-1-yl)pyrimidine (300 mg, crude) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (116 mg, 0.41 mmol), 1,4-diazabicyclo[2.2.2]octane (300 mg (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone was prepared in a similar manner to the preparation of 114 from 1,2,67 mmol) as a white solid in 52.0% yield. LC-MS (m / z) 484.5 (M+H + )

[0540] Step 5: To a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (30 mg, 0.06 mmol) in DMF (3 mL) was added NaH (10 mg, 60% in mineral oil), iodoethane (50 mg, 0.32 mmol) at 30° C. The solvent was removed under vacuum and the reaction mixture was left at 30° C. for 1.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum. The crude product was purified by silica gel chromatography to give (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (9.0 mg, 29.0%) as a white solid. LC-MS (m / z) 513.4 (M+H + ).

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.4 Hz, 1H), 7.16 - 7.08 (m, 2H), 7.06 - 6.97 (m, 2H), 5.31 - 5.21 (m, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.80 - 3.61 (m, 8H), 3.56-3.51 (m, 1H), 2.71 - 2.59 (m, 1H), 2.29 (d, J = 1.8 Hz, 3H), 2.18 (d, J = 1.8 Hz, 3H), 1.32 (t, J = 7.2Hz, 3H).

[0542] Compound 118: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000162.jpg29159

[0543] The title compound 118 was prepared in a similar manner to the preparation of compound 59 from (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (80 mg, 0.16 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (54 mg, 0.22 mmol) as a white solid in 11.0% yield. LC-MS (m / z) 529.6 (M+H + )

[0544] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.4 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.03 - 6.98 (m, 2H), 5.31 - 5.22 (m, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.81 - 3.50 (m, 8H) ,3.57 - 3.49 (m, 2H), 3.42-3.30 (m, 1H), 2.68 - 2.59 (m, 1H), 2.30 (d, J = 2.0 Hz, 3H), 2.19 (d, J = 1.6 Hz, 3H).

[0545] Compound 119: (S)-2-(4-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetamide JPEG0007760530000163.jpg31159

[0546] The title compound 119 was prepared in a similar manner to the preparation of compound 59 from (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (80 mg, 0.16 mmol), 2-bromoacetamide (50 mg, 0.36 mmol), CsCO (105 mg, 0.32 mmol), and DMF (5 mL) in a 13.0% yield as a white solid. LC-MS (m / z) 542.6 (M+H) + )

[0547] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.4 Hz, 1H), 7.61 (brs, 1H), 7.29 (brs, 1H), 7.15 - 7.08 (m, 2H), 7.04 - 6.97 (m, 2H), 5.26 (dd, J = 11.6, 10.0 Hz, 1H), 4.72 (s, 2H), 3.82 - 3.49 (m, 8H), 3.42 - 3.36 (m, 1H), 2.71 - 2.59 (m, 1H), 2.24 (d, J = 2.0 Hz, 3H), 2.18 (d, J = 1.6 Hz, 3H).

[0548] Compound 120: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(5-fluoro-4-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000164.jpg31159

[0549] The title compound 120 was prepared as a white solid in 13.7% yield from (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (30 mg, 0.06 mmol) and 1-bromo-2-methoxyethane (50 mg, 0.35 mmol), NaH (10 mg, 60% in mineral oil), DMF (3 mL) following the procedure outlined for compound 59. LC-MS (m / z) 543.6 (M+H + )

[0550] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.4 Hz, 1H), 7.17 - 7.07 (m, 2H), 7.05 - 6.96 (m, 2H), 5.26 (dd, J = 11.6, 10.0 Hz, 1H), 4.18 (t, J = 5.2 Hz, 2H), 3.82 - 3.49 (m, 8H), 3.41 - 3.35 (m, 1H), 3.24 (s, 3H), 2.71 - 2.59 (m, 1H), 2.28 (d, J = 2.0 Hz, 3H), 2.19 (d, J = 1.6Hz, 3H).

[0551] Compound 121: (S)-(4-(4-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000165.jpg30159

[0552] The title compound 121 was prepared as a white solid in 8.1% yield from (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (30 mg, 0.06 mmol) and (bromomethyl)cyclopropane (50 mg, 0.37 mmol), CsCO (108 mg, 0.32 mmol), KI (16 mg, 0.10 mmol) and DMF (3 mL) following the procedure outlined for compound 59. LC-MS (m / z) 539.4 (M+H) + )

[0553] Compound 122: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000166.jpg29159

[0554] The title compound 227 was prepared as a white solid in 12.6% yield from (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone (30 mg, 0.06 mmol) and 4-(bromomethyl)tetrahydro-2H-pyran (50 mg, 0.28 mmol), CsCO (108 mg, 0.32 mmol), KI (16 mg, 0.10 mmol) and DMF (3 mL) following the procedure outlined for compound 59. LC-MS (m / z) 583.6 (M+H) + )

[0555] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.4 Hz, 1H), 7.17 - 7.07 (m, 2H), 7.05 - 6.96 (m, 2H), 5.28 (d, J = 10.8 Hz, 1H), 3.92 (d, J = 7.2 Hz, 2H), 3.88 - 3.49 (m, 12H), 3.41 - 3.35 (m, 1H), 2.71 - 2.59 (m, 1H), 2.29 (d, J = 2.0 Hz, 3H), 2.19 (d, J = 1.6 Hz, 3H), 2.10-2.06 (m, 1H), 1.48-1.39 (m, 1H), 1.30-1.22 (m, 1H), 1.16-1.13 (m, 2H).

[0556] Compound 123: (S)-2-(4-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetamide JPEG0007760530000167.jpg36159

[0557] The title compound 123 was prepared as a white solid in 35.0% yield from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (70 mg, 0.14 mmol) and 2-bromoacetamide (40 mg, 0.28 mmol), CsCO (92 mg, 0.28 mmol), DMF (3 mL) following the procedure outlined for compound 59. LC-MS (m / z) 549.6 (M+H) + )

[0558] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.4 Hz, 1H), 7.78-7.70 (m, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.60 (brs, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.28 (brs, 1H), 7.11 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 4.71 (s, 2H), 3.82 - 3.50 (m, 8H), 3.42 - 3.34 (m, 1H), 2.71 - 2.59 (m, 1H), 2.23 (d, J = 2.0 Hz, 3H), 2.17 (d, J = 1.6 Hz, 3H).

[0559] Compound 124: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000168.jpg37159

[0560] The title compound 124 was prepared as a white solid in 73.1% yield from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (70 mg, 0.14 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (54 mg, 0.22 mmol), CsCO (108 mg, 0.32 mmol), DMF (5 mL) following the procedure outlined for compound 59. LC-MS (m / z) 536.4 (M+H) + )

[0561] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.4 Hz, 1H), 7.76-7.71 (m, 1H), 7.64 (t, J = 1.6 Hz, 1H), 7.52 (dt, J = 9.6, 2.0 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.05 (t, J = 5.6 Hz, 2H), 3.79 - 3.60 (m, 8H), 3.57 - 3.48 (m, 2H), 3.42 - 3.34 (m, 1H), 2.75 - 2.63 (m, 1H), 2.29 (d, J = 2.0 Hz, 3H), 2.18 (d, J = 1.6 Hz, 3H).

[0562] Compound 125: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-1,2,4-triazole-3-carbonitrile JPEG0007760530000169.jpg75159

[0563] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (334 mg, 2.00 mmol) in DMF (5 mL) under argon at 30 °C was added 1H-1,2,4-triazole-5-carbonitrile (188 mg, 2.00 mmol) Cs2CO3 (1.3 g, 4.00 mmol). The reaction was stirred at 80 °C for 10 min. Water was added and extracted with EA, washed with brine, and dried (Na2SO4). The resulting mixture was evaporated in vacuo and the crude product was purified by silica gel chromatography to give 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-1,2,4-triazole-3-carbonitrile (200 mg, 44.4%) as a pale yellow solid. LC-MS (m / z) 225.4 (M+H + ).

[0564] Step 2: To a solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-1,2,4-triazole-3-carbonitrile (60 mg, 0.26 mmol) in DMF (3 mL) was added (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (80 mg, 0.26 mmol), DIEA (100 mg, 0.77 mmol) under argon at 30° C. The reaction was stirred at 100° C. for 20 min. Water was added and extracted with EA, washed with brine, and dried (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give the title compound 5 (28 mg, 21.3%) as a white solid. LC-MS (m / z) 490.4 (M+H + ).

[0565] 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 3.6 Hz, 1H), 7.76 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.54 (dt, J = 9.6, 2.0 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 5.30 (dd, J = 11.6, 10.0 Hz, 1H), 3.89 - 3.51 (m, 8H), 3.44 - 3.35 (m, 1H), 2.78 - 2.66 (m, 1H).

[0566] Compound 126: (S)-3-(1-(4-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000170.jpg74159

[0567] The title compound 126 was prepared as a white solid in 53.1% yield from 2-chloro-4-(3-chloro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine (62 mg, 0.26 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (80 mg, 0.26 mmol), DIEA (100 mg, 0.77 mmol), DMF (3 mL) following the procedure outlined for compound 125. LC-MS (m / z) 499.6 (M+H + )

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.83 (d, J = 3.2 Hz, 1H), 7.76 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.17 - 7.11 (m, 1H), 5.30 (t, J = 10.8 Hz, 1H), 3.92 - 3.53 (m, 8H), 3.42 - 3.36 (m, 1H), 2.78 - 2.66 (m, 1H).

[0569] Compound 127: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carbonitrile JPEG0007760530000171.jpg74159

[0570] The title compound 127 was prepared as a white solid in 47.4% yield from 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carbonitrile (60 mg, 0.27 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (80 mg, 0.26 mmol), DIEA (100 mg, 0.77 mmol), DMF (3 mL) following the procedure outlined for compound 125. LC-MS (m / z) 489.4 (M+H + )

[0571] 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.49 (s, 1H), 7.80 - 7.72 (m, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.13 (d, J = 1.6 Hz, 1H), 5.30 (dd, J = 11.6, 10.0 Hz, 1H), 3.90 - 3.51 (m, 8H), 3.43 - 3.36 (m, 1H), 2.78 - 2.66 (m, 1H).

[0572] Compound 128: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-pyrazole-3-carbonitrile JPEG0007760530000172.jpg77159

[0573] The title compound 128 was prepared as a white solid in 57.4% yield from 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazole-3-carbonitrile (60 mg, 0.27 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (80 mg, 0.26 mmol), DIEA (100 mg, 0.77 mmol), DMF (3 mL) following the procedure outlined for compound 125. LC-MS (m / z) 489.4 (M+H) + )

[0574] 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 2.8 Hz, 1H), 8.75 (d, J = 3.6 Hz, 1H), 7.76 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 5.30 (dd, J = 11.6, 10.0 Hz, 1H), 3.88 - 3.52 (m, 8H), 3.42 - 3.34 (m, 1H), 2.78 - 2.66 (m, 1H).

[0575] Compound 129: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-1,2,4-triazole-3-carboxylate ethyl JPEG0007760530000173.jpg82159

[0576] The title compound 129 was prepared in a similar manner to the preparation of 125 from ethyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (30 mg, 0.10 mmol), (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (40 mg, 0.13 mmol), DIEA (100 mg, 0.77 mmol), and DMF (3 mL) in 35.0% yield as a white solid. LC-MS (m / z) 551.6 (M+H + )

[0577] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.8 Hz, 1H), 7.74 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.64 (t, J = 1.6 Hz, 1H), 7.52 (dt, J = 9.6, 2.0 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.82 - 3.52 (m, 8H), 3.42 - 3.35 (m, 1H), 2.75 - 2.66 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H).

[0578] Compound 130: (S)-3-(1-(4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000174.jpg72159

[0579] The title compound 130 was prepared in a similar manner to the preparation of 125 from 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-1,3,5-triazine (50 mg, crude) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (50 mg, 0.16 mmol), DIEA (60 mg, 0.46 mmol), and DMF (4 mL) in 11.2% yield as a yellow solid. LC-MS (m / z) 476.4 (M+H) + )

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.80 - 7.72 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.55 (dt, J = 9.6, 2.0 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 5.30 (t, J = 10.8 Hz, 1H), 3.97 - 3.52 (m, 8H), 3.42 - 3.35 (m, 1H), 2.75 (s, 3H), 2.74 - 2.66 (m, 1H), 2.29 (s, 3H).

[0581] Compound 131: (S)-3-(1-(4-(4-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000175.jpg69159

[0582] Step 1: To a solution of 2,4-dichloro-5-fluoropyrimidine (334 mg, 2.00 mmol) in DMF (5 mL) was added 3,5-dimethyl-4-nitro-1H-pyrazole (280 mg, 2.00 mmol) and DIEA (516 mg, 4.00 mmol) at 30° C. The reaction was stirred at 120° C. for 1.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give 2-chloro-4-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)-5-fluoropyrimidine (250 mg, 44.4%) as a yellow solid. LC-MS (m / z) 272.6 (M+H + ).

[0583] Step 2: To a solution of 2-chloro-4-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)-5-fluoropyrimidine (100 mg, 0.37 mmol) in DMF (4 mL) was added (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (110 mg, 0.36 mmol), DIEA (190 mg, 1.47 mmol) at 30° C. The reaction was stirred at 80° C. for 1.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-3-(1-(4-(4-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (150 mg, 76.2%) as a yellow solid. LC-MS (m / z) 537.6 (M+H + ).

[0584] Step 3: To a solution of (S)-3-(1-(4-(4-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (120 mg, 0.22 mmol) in EtOH (6 mL) and HO (2 mL) was added NHCl (53 mg, 1.00 mmol), Fe (112 mg, 2.00 mmol) at 30° C. The reaction was stirred at 80° C. for 0.5 h. Water was added and extracted with EA, washed with brine, and dried over (NaSO). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)-3-(1-(4-(4-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (62 mg, 54.8%) as a pale yellow solid. LC-MS (m / z) 507.4 (M+H + ).

[0585] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 4.0 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.29 (t, J = 10.8 Hz, 1H), 4.03( brs, 1H), 3.77 - 3.52 (m, 8H), 3.41 - 3.34 (m, 1H), 2.76 - 2.65 (m, 1H), 2.38 (s, 3H), 2.10 (s, 3H).

[0586] Compound 132: 3-((5S)-1-(4-(4-(3,5-dimethyl-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000176.jpg33159

[0587] The title compound 132 was prepared in a 31.4% yield from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), 3-(bromomethyl)tetrahydrofuran (50 mg, 0.30 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL) in a manner similar to that used to prepare compound 59. LC-MS (m / z) 576.4 (M+H) + )

[0588] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 4.07 - 3.93 (m, 2H), 3.83 - 3.46 (m, 12H), 3.47 - 3.39 (m, 1H), 3.31 (s, 2H), 2.75 - 2.65 (m, 2H), 2.29 (d, J = 2.0 Hz, 3H), 2.18 (d, J = 1.6 Hz, 3H), 2.01 - 1.87 (m, 1H), 1.67-1.60 (m, 1H).

[0589] Compound 133: 3-((S)-1-(4-(4-(3,5-dimethyl-1-(((R)-oxiran-2-yl)methyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000177.jpg29159

[0590] The title compound 133 was prepared in a similar manner to the preparation of 59 as a white solid in 22.6% yield from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), (S)-2-(bromomethyl)oxirane (5 mg, 0.36 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL). LC-MS (m / z) 548.6 (M+H) + )

[0591] 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.54 (dt, J = 9.6, 2.0 Hz, 1H), 7.15 - 7.09 (m, 1H), 5.29 (t, J = 10.8 Hz, 1H), 4.38 (dd, J = 15.2, 3.6 Hz, 1H), 4.12 (dd, J = 15.2, 6.0 Hz, 1H), 3.81 - 3.50 (m, 8H), 3.43 - 3.34 (m, 1H), 3.32-3.30 (m, 1H), 2.81 (dd, J = 5.2, 4.0 Hz, 1H), 2.76 - 2.64 (m, 1H), 2.59 (dd, J = 5.2, 2.4 Hz, 1H), 2.29 (d, J = 2.0 Hz, 3H), 2.20 (d, J = 1.6 Hz, 3H).

[0592] Compound 134: 3-((S)-1-(4-(4-(3,5-dimethyl-1-(((S)-oxiran-2-yl)methyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000178.jpg30159

[0593] The title compound 134 was prepared in a similar manner to the preparation of 59 from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), (R)-2-(bromomethyl)oxirane (50 mg, 0.36 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL) in 29.1% yield as a white solid. LC-MS (m / z) 548.6 (M+H) + )

[0594] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.4 Hz, 1H), 7.74 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.52 (dt, J = 10.0, 2.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 4.36 (dd, J = 15.2, 3.6 Hz, 1H), 4.10 (dd, J = 15.2, 6.0 Hz, 1H), 3.80 - 3.48 (m, 8H), 3.42-3.35 (m, 1H), 3.32-3.30 (m, 1H), 2.81 (dd, J = 5.2, 4.0 Hz, 1H), 2.73 - 2.64 (m, 1H), 2.58 (dd, J = 5.2, 2.4 Hz, 1H), 2.28 (dd, J = 5.2, 2.0 Hz, 3H), 2.18 (d, J = 1.6 Hz, 3H).

[0595] Compound 135: (S)-3-(1-(4-(4-(3,5-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000179.jpg29159

[0596] The title compound 135 was prepared in a similar manner to the preparation of 59 from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), 3-(iodomethyl)oxetane (60 mg, 0.30 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL) in 29.1% yield as a white solid. LC-MS (m / z) 562.4 (M+H) + )

[0597] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.15 - 7.09 (m, 1H), 5.29 (t, J = 10.8 Hz, 1H), 4.66 (dd, J = 7.6, 6.0 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 4.33 (d, J = 7.2 Hz, 2H), 3.81 - 3.49 (m, 8H), 3.47 - 3.39 (m, 1H), 3.38-3.34 (m, 1H), 2.76 - 2.67 (m, 1H), 2.30 (d, J = 2.0 Hz, 3H), 2.17 (d, J = 1.6 Hz, 3H).

[0598] Compound 137: 3-((5S)-1-(4-(4-(3,5-dimethyl-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000180.jpg32159

[0599] The title compound 137 was prepared in a similar manner to the preparation of 117 as a white solid in 29.5% yield from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), 2-(bromomethyl)tetrahydro-2H-pyran (50 mg, 0.28 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL). LC-MS (m / z) 590.4 (M+H) + )

[0600] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.4 Hz, 1H), 7.74 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 - 7.63 (m, 1H), 7.52 (dt, J = 9.6, 2.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 4.07 - 3.92 (m, 2H), 3.85 - 3.48 (m, 10H), 3.40 - 3.20 (m, 2H), 2.74 - 2.64 (m, 1H), 2.26 (d, J = 2.0 Hz, 3H), 2.17 (d, J = 1.6 Hz, 3H), 1.82-1.73 (m, 1H), 1.63-1.55 (m, 1H), 1.47-1.37 (m, 3H), 1.28-1.17(m, 1H).

[0601] Compound 138: (S)-3-(1-(4-(4-(3,5-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000181.jpg33159

[0602] The title compound 138 was prepared in a similar manner to the preparation of 59 from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), 4-(2-bromoethyl)tetrahydro-2H-pyran (60 mg, 0.31 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL) in 40.6% yield as a white solid. LC-MS (m / z) 604.4 (M+H) + )

[0603] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.57 - 7.49 (m, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.29 (t, J = 10.8 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.87 - 3.43 (m, 8H), 3.43 - 3.35 (m, 1H), 3.30-3.23 (m, 3H), 2.76 - 2.67 (m, 1H), 2.29 (d, J = 2.0 Hz, 3H), 2.18 (d, J = 1.6 Hz, 3H), 1.70-1.59 (m, 4H), 1.58-1.50 (m, 2H), 1.27-1.14 (m, 2H).

[0604] Compound 136: (S)-3-(1-(4-(4-(1-(cyanomethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000182.jpg31159

[0605] The title compound 136 was prepared in a similar manner to the preparation of 59 from (S)-3-(1-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.20 mmol), 2-bromoacetonitrile (50 mg, 0.42 mmol), CsCO (131 mg, 0.40 mmol), and DMF (5 mL) in 25.7% yield as a brown solid. LC-MS (m / z) 531.6 (M+H) + )

[0606] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.46 (s, 2H), 5.29 (t, J = 10.8 Hz, 1H), 3.81 - 3.50 (m, 8H), 3.43 - 3.35 (m, 1H), 2.76 - 2.64 (m, 1H), 2.35 (d, J = 2.0 Hz, 3H), 2.21 (d, J = 1.6 Hz, 3H).

[0607] Compound 139: (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-1,2,4-triazole-3-carbonitrile JPEG0007760530000183.jpg104159

[0608] Step 1: To a solution of tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (1.2 g, 3.79 mmol) in DMF (20 mL) was added ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (600 mg, 3.87 mmol), CsCO (2.5 g, 7.62 mmol) under argon at 30 °C. The reaction was stirred at 120 °C for 0.5 h. Water was added and extracted with EA, washed with brine, and dried (NaSO). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate. As a yellow oil (1.2 g, 75.0%). LC-MS (m / z) 436.4 (M+H + ).

[0609] Step 2: To a solution of tert-butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (1.1 g, 2.52 mmol) in MeOH (10 mL) was added NH3 (7 M in MeOH) (20 mL) at 30 °C. The reaction was stirred at 90 °C for 3.0 h. The solvent was removed under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-(3-carbamoyl-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (700 mg, 70.0%) as a white solid. LC-MS (m / z) 407.4 (M+H + ).

[0610] Step 3: To a solution of tert-butyl 4-(4-(3-carbamoyl-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.49 mmol) in DCM (5 mL) was added TEA (149 mg, 1.47 mmol), TFAA (206 mg, 0.98 mmol) under argon at 0° C. The reaction was stirred at 0° C. for 1.0 h. Water was added and extracted with EA, washed with brine, and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl 4-(4-(3-cyano-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (140 mg, 73.2%) as a colorless oil. LC-MS (m / z) 389.4 (M+H + ).

[0611] Step 4: To a solution of tert-butyl 4-(4-(3-cyano-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (140 mg, 0.36 mmol) in DCM (5 mL) was added TFA (20 mL) at 30° C. The reaction was stirred at 30° C. for 0.5 h. The solvent was removed under vacuum and the crude product was used in the next step reaction without purification as a brown oil (200 mg, crude). LC-MS (m / z) 289.4 (M+H + ).

[0612] Step 5: To a solution of 1-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-5-methyl-1H-1,2,4-triazole-3-carbonitrile compound and 2,2,2-trifluoro-113-ethan-1-one (1:1) (200 mg, crude) in THF (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (150 mg, 1.34 mmol), (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (60 mg, 0.21 mmol) at 30° C. The solvent was removed under vacuum, and the reaction mixture was heated to 80° C. for 2.0 hours. The crude product was purified by silica gel chromatography to give (S)-1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-5-methyl-1H-1,2,4-triazole-3-carbonitrile (12.0 mg, 4.9%) as a white solid. LC-MS (m / z) 504.4 (M+H + ).

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.6 Hz, 1H), 7.76 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.54 (dt, J = 9.6, 2.0 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 5.29 (dd, J = 11.6, 10.0 Hz, 1H), 3.85 - 3.53 (m, 8H), 3.43 - 3.35 (m, 1H), 2.76 (s, 3H), 2.75 - 2.65 (m, 2H)

[0614] Compound 140: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000184.jpg99159

[0615] The title compound 140 was prepared in a similar manner to the preparation of 139 from (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (70 mg, 0.15 mmol), iodomethane (140 mg, 1.00 mmol), KCO (500 mg, 1.32 mmol), and DMF (8 mL) in 27.1% yield as a white solid. LC-MS (m / z) 495.4 (M+H + )

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 3.81 - 3.49 (m, 8H), 3.40-3.34 (m, 4H), 2.76 - 2.67 (m, 1H).

[0617] Compound 141: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000185.jpg82159

[0618] The title compound 141 was prepared as a pale yellow solid in 12.2% yield from 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one (100 mg, crude) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (50 mg, 0.17 mmol), DIEA (100 mg, 0.77 mmol), DMF (5 mL) following the procedure outlined for compound 125. LC-MS (m / z) 494.4 (M+H + )

[0619] 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (brs, 1H), 8.51 (d, J = 4.0 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.77 (s, 1H), 5.34 - 5.24 (m, 1H), 3.78 - 3.51 (m, 8H), 3.41 - 3.35 (m, 1H), 2.76 - 2.64 (m, 1H), 2.49 (s, 3H).

[0620] Compound 142: (S)—N-(1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide JPEG0007760530000186.jpg31159

[0621] To a solution of (S)-3-(1-(4-(4-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (100 mg, 0.48 mmol) in DCM (5 mL) was added TEA (0.5 mL), acetyl chloride (40 mg, 0.50 mmol) at 30° C. The reaction was stirred at 30° C. for 0.5 h. Water was added and extracted with EA, washed with brine and dried over (Na2SO4). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give (S)—N-(1-(2-(4-(5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide (21.7 mg, 20.1%) as a white solid. LC-MS (m / z) 549.4 (M+H + ).

[0622] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (brs, 1H), 8.59 (d, J = 3.6 Hz, 1H), 7.74 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.64 (t, J = 1.6 Hz, 1H), 7.52 (dt, J = 9.6, 2.0 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 5.28 (t, J = 10.8 Hz, 1H), 3.78 - 3.49 (m, 8H), 3.40 - 3.34 (m, 1H), 2.75 - 2.63 (m, 1H), 2.30 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H).

[0623] Compound 143: (S)-(4-(4-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000187.jpg116159

[0624] Step 1: To a solution of HO (4 mL) in 1,4-dioxane (20 mL) was added 2,4-dichloropyrimidine (1450 mg, 10 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2220 mg, 10 mmol), Pd(PPh) (578 mg, 0.5 mmol), KCO (4150 mg, 30 mmol) under nitrogen, and the whole reaction mixture was stirred at 100 °C for 2 h. The mixture was concentrated, and after further purification by silica gel chromatography, 2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidine (887 mg, 42.4%) was obtained as a clear oil. LC-MS (m / z) 209.1 (M+H) + ).

[0625] Step 2: 2-Chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidine (832 mg, 4 mmol), NBS (784 mg, 4.4 mmol) in CHCN (15 mL) and the whole reaction mixture was stirred at 50° C. for 5 h. The mixture was concentrated and after further purification by silica gel chromatography, 4-(3-bromo-1,4-dimethyl-1H-pyrazol-5-yl)-2-chloropyrimidine (720 mg, 62.7%) was obtained as a white solid. LC-MS (m / z) 287.0 (M+H) + ).

[0626] Step 3: 4-(3-bromo-1,4-dimethyl-1H-pyrazol-5-yl)-2-chloropyrimidine (604 mg, 2.1 mmol), tert-butyl piperazine-1-carboxylate (430 mg, 2.3 mmol), CsCO (1370 mg, 4.2 mmol) in DMF (10 mL) and the whole reaction mixture was stirred at 100° C. for 2 h. The mixture was concentrated and, after further purification by silica gel chromatography, tert-butyl 4-(4-(3-bromo-1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate (930 mg, 99.9%) was obtained as a white solid. LC-MS (m / z) 437.2 (M+H) + ).

[0627] Step 4: To a solution of CsCO (2082 mg, 6.39 mmol) in 1,4-dioxane (15 mL) was added tert-butyl 4-(4-(3-bromo-1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate (930 mg, 2.13 mmol), NHBoc (374 mg, 3.19 mmol), CuI (610 mg, 3.19 mmol), DMEDA (281 mg, 3.19 mmol) under nitrogen, and the whole reaction mixture was stirred at 100° C. for 12 h. The mixture was concentrated and, after further purification by silica gel chromatography, tert-butyl 4-(4-(3-((tert-butoxycarbonyl)amino)-1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate (392 mg, 38.9%) was obtained as a white solid. LC-MS (m / z) 474.4 (M+H + ).

[0628] Step 5: tert-Butyl 4-(4-(3-((tert-butoxycarbonyl)amino)-1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate (310 mg, 0.63 mmol) was dissolved in 10 mL of DCM, trifluoroacetic acid (719 mg, 6.3 mmol) was added, and the mixture was stirred at 25° C. for 1 hour. Concentration gave the desired product, 1,4-dimethyl-5-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazol-3-amine, which was used in the next step without further purification.

[0629] Step 6: 1,4-Dimethyl-5-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazol-3-amine (113 mg, 0.41 mmol), (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (102 mg, 0.37 mmol) and 1,4-diazabicyclo[2.2.2]octane (459 mg, 4.15 mmol) were dissolved in THF (10 mL). Concentrated in vacuo and the whole reaction mixture was stirred at 100° C. for 2 hours. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by preparative HPLC afforded the title compound 143 (58 mg, 32.5%) as a yellow solid.

[0630] 1 H NMR (300 MHz, Chloroform-d) δ 8.40 (dd, J = 5.1, 1.7 Hz, 1H), 6.95 - 6.50 (m, 5H), 5.34 (dd, J = 11.7, 9.9 Hz, 1H), 4.08 - 3.55 (m, 11H), 3.39 - 3.28 (m, 1H), 2.73 - 2.62 (m, 1H), 2.47 (s, 2H), 2.03 (d, J = 1.7 Hz, 3H). LC-MS (m / z) 482.3 (M+H + ).

[0631] Compound 144: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000188.jpg103159

[0632] Step 1: To a solution of tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (2 g, 6.31 mmol) in DMF (15 mL) was added ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (980 mg, 6.31 mmol) and CsCO3 (2.44 g, 12.6 mmol). The reaction mixture was stirred at 100 °C for 2 h. The crude product was purified by column chromatography on silica gel. tert-Butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (2.1 g, 76%) was obtained as a white solid. MS (m / z): 436.1 [M+H] + .

[0633] Step 2: To a solution of tert-butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 459.3 umol) in THF (10 mL) at 0 °C under argon was added LiAlH4 (0.5 mL, 505.2 umol). The reaction mixture was stirred at room temperature for 1 h. The crude product was purified by column chromatography on silica gel. tert-Butyl 4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 55%) was obtained as a white solid. MS (m / z): 394.1 [M+H] + .

[0634] Step 3: To a solution of tert-butyl 4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 254.2 umol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo. The crude was used directly in the next step. MS (m / z): 294.2 [M+H] + .

[0635] Step 4: To a solution of (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (65 mg, 229.5 umol) in THF (5 mL), (1-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-5-methyl-1H-1,2,4-triazol-3-yl)methanol (75 mg, 254.9 umol) and DIPEA (98 mg, 764.9 umol) were added. The reaction mixture was stirred at 70° C. for 12 hours. The crude product was purified by pre-HPLC. Compound 144 (13 mg, 11%) was obtained as a pale yellow solid. MS (m / z): 509.1 [M+H] + .

[0636] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 2.9 Hz, 1H), 7.75 (ddd, J = 8.5, 2.5, 1.3 Hz, 1H), 7.65 (t, J = 1.4 Hz, 1H), 7.53 (ddd, J = 9.8, 2.6, 1.5 Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H), 5.29 (t, J = 10.8 Hz, 1H), 4.46 (s, 2H), 3.87-3.50 (m, 8H), 3.37 (ddd, J = 18.3, 11.6, 1.9 Hz, 1H), 2.74-2.67 (m, 1H), 2.65 (s, 3H).

[0637] Compound 145: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperazin-1-yl)(5-(5-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000189.jpg176159

[0638] Step 1: Synthesis of (E)-3-(5-methylthiazol-2-yl)acrylaldehyde A stirred solution of 5-methylthiazole-2-carbaldehyde (1 g, 7.86 mmol) and 2-(triphenyl-15-phosphaneilidene)acetaldehyde (2.87 g, 9.44 mmol) in THF (15 mL) at room temperature was stirred for an additional 2 hours at 75 °C. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give (E)-3-(5-methylthiazol-2-yl)acrylaldehyde (1.2 g, 99.6%) as a tan oil. MS (m / z): 154.2 [M+H] + .

[0639] Step 2: Synthesis of di-tert-butyl 3-hydroxy-5-(5-methylthiazol-2-yl)pyrazolidine-1,2-dicarboxylate To a stirred solution of (E)-3-(5-methylthiazol-2-yl)acrylaldehyde (1 g, 6.54 mmol) and di-tert-butyl hydrazine-1,2-dicarboxylate (2.3 g, 9.80 mmol) in toluene (20 mL) was added (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (489 mg, 1.50 mmol) at room temperature. The resulting mixture was stirred at room temperature for an additional 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc) (1:1) to afford di-tert-butyl 3-hydroxy-5-(5-methylthiazol-2-yl)pyrazolidine-1,2-dicarboxylate (2.2 g, 87.4%) as a tan solid. MS (m / z): 386.4 [M+H] + .

[0640] Step 3: Synthesis of 2-(4,5-dihydro-1H-pyrazol-5-yl)-5-methylthiazole To a stirred solution of di-tert-butyl 3-hydroxy-5-(5-methylthiazol-2-yl)pyrazolidine-1,2-dicarboxylate (2.2 g, 5.71 mmol) in DCM (8 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 0.5 h. The resulting mixture was concentrated under reduced pressure to give 2-(4,5-dihydro-1H-pyrazol-5-yl)-5-methylthiazole (0.95 g, 99.5%) as a yellow oil. MS (m / z): 168.2 [M+H] + .

[0641] Step 4: Synthesis of (1H-imidazol-1-yl)(5-(5-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone To a stirred solution of 2-(4,5-dihydro-1H-pyrazol-5-yl)-5-methylthiazole (0.95 g, 5.68 mmol) and CDI (4.60 g, 28.40 mmol) in THF (20 mL) was added TEA (1.72 g, 17.06 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 75 °C for an additional 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:2) to give (1H-imidazol-1-yl) (5-(5-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (0.8 g, 53.8%) as a tan oil. MS (m / z): 262.3 [M+H] + .

[0642] Steps 5 and 6: Following the procedure outlined for compound 143, the title compound 145 was prepared in 7.5% yield.

[0643] 1 H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 6.3 Hz, 1H), 7.36 (q, J = 1.2 Hz, 1H), 7.33 (d, J = 0.7 Hz, 1H), 6.91 (t, J = 1.7 Hz, 1H), 5.70 (t, J = 10.4 Hz, 1H), 4.14 (s, 3H), 3.95 - 3.89 (m, 2H), 3.87 - 3.78 (m, 4H), 3.75 - 3.64 (m, 2H), 3.32 (dd, J = 10.5, 1.7 Hz, 2H), 2.42 (d, J = 1.2 Hz, 3H), 2.28 (s, 3H). LC-MS (m / z) 470.3 (M+H + ).

[0644] The following intermediates used in the preparation of compounds 145, 151, 156-162, 212-217, 223-224, 231, 239-242, 291-294, 296, 298-299, and 316-319 were synthesized using a method similar to that described above for the preparation of (1H-imidazol-1-yl)(5-(5-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone. JPEG0007760530000190.jpg138159

[0645] Compound 146: 3-((S)-1-((2S,6R)-4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000191.jpg73159

[0646] Step 1: (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (1 g, 3.53 mmol) and (3R,5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (1.52 g, 7.06 mmol) were dissolved in THF (10 mL), evaporated to dryness, and heated at 120° C. for 3 h. The crude product was purified by column chromatography on silica gel. (3R,5S)-4-((S)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,5-dimethylpiperazine-1-carboxylate (50 mg, 3%) was obtained as an off-white solid. MS (m / z): 430.2 [M+H] + .

[0647] Step 2: To a solution of tert-butyl (3R,5S)-4-((S)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,5-dimethylpiperazine-1-carboxylate (50 mg, 116.4 umol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo. The crude was used directly in the next step. MS (m / z): 330.2 [M+H] + .

[0648] Step 3: To a solution of 3-((S)-1-((2S,6R)-2,6-dimethylpiperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (20 mg, 60.7 umol) in DMF (2 mL), 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidine (14 mg, 60.7 umol) and DIPEA (40 mg, 303.6 umol) were added. The reaction mixture was stirred at 120° C. for 12 hours. The crude product was purified by pre-HPLC. 3-((S)-1-((2S,6R)-4-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (2 mg, 6%) was obtained as a white solid. MS (m / z): 521.2 [M+H] + .

[0649] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 3.1 Hz, 1H), 7.90-7.80 (m, 2H), 7.74-7.71 (m, 1H), 7.32 (d, J = 8.2 Hz, 1H), 5.33 (q, J = 7.8 Hz, 1H), 4.59-4.44 (m, 1H), 4.34-4.27 (m, 1H), 3.73-3.63 (m, 2H), 3.33-3.08 (m, 2H), 2.69 (s, 3H), 2.36 (s, 3H), 1.34 (s, 3H), 1.31 (s, 3H).

[0650] Compound 147: (S)-3-Fluoro-5-(1-(4-(4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000192.jpg31159

[0651] Step 1: To a solution of 2,4-dichloropyrimidine (300 mg, 2.01 mmol) in DMF (5 mL) was added 5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazole (305 mg, 2.01 mmol) and CsCO3 (777 mg, 4.03 mmol). The reaction mixture was stirred at 80 °C for 3 h. The crude product was purified by column chromatography on silica gel. 2-Chloro-4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)pyrimidine (150 mg, 28%) was obtained as a white solid. MS (m / z): 264.0 [M+H] + .

[0652] Step 2: To a solution of (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (100 mg, 331.9 μmol) in DMF (4 mL), 2-chloro-4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)pyrimidine (70 mg, 331.9 μmol) and DIPEA (129 mg, 995.6 μmol) were added. The reaction mixture was stirred at 100° C. for 12 hours. The crude product was purified by pre-HPLC. (S)-3-Fluoro-5-(1-(4-(4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (22 mg, 13%) was obtained as a white solid. MS (m / z): 529.1 [M+H] + .

[0653] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 5.3 Hz, 1H), 7.74 (ddd, J = 8.4, 2.6, 1.3 Hz, 1H), 7.66 (t, J = 1.5 Hz, 1H), 7.54 (ddd, J = 9.7, 2.5, 1.4 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 5.3 Hz, 1H), 5.30 (dd, J = 11.5, 10.1 Hz, 1H), 3.93-3.52 (m, 8H), 3.38 (ddd, J = 18.3, 11.6, 1.9Hz, 1H), 2.91 (s, 3H), 2.71 (ddd, J = 18.3, 10.1, 1.6 Hz, 1H).

[0654] Compound 148: 1-(2-(4-((S)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-2-methyl-1H-imidazole-5-carbonitrile JPEG0007760530000193.jpg65159

[0655] Step 1: Under nitrogen, tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 3.16 mmol), 2-methyl-1H-imidazole-5-carbaldehyde (500 mg, 4.54 mmol), and CsCO (2.0 g, 6.09 mmol) were added to DMF (20 mL), and the entire reaction mixture was stirred at 100° C. for 1.0 h. The mixture was concentrated in vacuo to give tert-butyl 4-(5-fluoro-4-(5-formyl-2-methyl-1H-imidazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 81%) as a yellow oil. MS (m / z): 391.4 [M+H] + .

[0656] Step 2: tert-Butyl 4-(5-fluoro-4-(5-formyl-2-methyl-1H-imidazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.51 mmol) and hydroxylamine (50 mg, 0.81 mmol) were dissolved in EtOH (10 mL) under nitrogen, and the whole reaction mixture was stirred at 80° C. for 1 hour. The mixture was concentrated in vacuo to give tert-butyl (E)-4-(5-fluoro-4-(5-((hydroxyimino)methyl)-2-methyl-1H-imidazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (250 mg, crude) as a yellow solid, which was used in the next step without purification. MS (m / z): 406.4 [M+H] + .

[0657] Step 3: (E)-tert-Butyl 4-(5-fluoro-4-(5-((hydroxyimino)methyl)-2-methyl-1H-imidazol-1-yl)pyrimidin-2-yl)piperazine-1-carboxylate (250 mg, crude), (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (50 mg, 0.17 mmol), and DABCO (300 mg, 2.67 mmol) were dissolved in THF (10 mL) under nitrogen. The solvent was removed in vacuo, and the reaction mixture was left at 80° C. for 2.0 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded compound 148 (57 mg, 46.0%) as a white solid. MS(m / z):503.4[M+H] + .

[0658] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 7.75 (ddd, J = 8.4, 2.4, 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.53 (dt, J = 9.6, 2.0 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.29 (t, J = 10.8 Hz, 1H), 3.82 - 3.51 (m, 8H), 3.43 - 3.36 (m, 1H), 3.34 (s, 3H), 2.76 - 2.67 (m, 1H).

[0659] Compound 149: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)piperazin-1-yl)methanone JPEG0007760530000194.jpg71159

[0660] Step 1: 2-Chloro-5-fluoro-4-iodopyridine (1.84 g, 7.16 mmol), 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 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] + .

[0661] Steps 2, 3 and 4: The title compound 149 was prepared following the procedure outlined for compound 143 as a white solid in 24.3% yield.

[0662] 1 H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 0.6 Hz, 1H), 6.91 - 6.76 (m, 4H), 6.70 (tt, J = 8.9, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, 9.7 Hz, 1H), 3.93 (s, 3H), 3.88 (ddd, J = 13.4, 7.1, 3.2 Hz, 2H), 3.74 (ddd, J = 13.3, 6.6, 3.2 Hz, 2H), 3.44 - 3.36 (m, 2H), 3.36 - 3.25 (m, 3H), 2.70 (ddd, J = 18.3, 9.7, 1.6 Hz, 1H), 2.11 (s, 3H). Mass (m / z): 484.3[M+H] + .

[0663] Compound 150: (S)-3-Fluoro-5-(1-(4-(5-methoxy-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000195.jpg127159

[0664] Step 1: To a solution of 5-bromo-1-methyl-1H-1,2,4-triazole (1.13 g, 6.98 mmol) in THF (80 mL) was added n-BuLi (3.4 mL, 8.38 mmol) under argon at −78°C. The reaction mixture was stirred at −78°C for 0.5 h. Then, ZnCl (7.7 mL, 7.68 mmol) was added to the reaction mixture at −78°C. The reaction mixture was stirred at −78°C for 0.5 h. 2,4-Dichloro-5-methoxypyrimidine (1 g, 5.59 mmol) and Pd(PPh) (807 mg, 6.98 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 70°C for 16 h. The crude product was purified by column chromatography on silica gel. 2-Chloro-5-methoxy-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine (600 mg, 48%) was obtained as a white solid. MS (m / z): 226.0 [M+H] + .

[0665] Step 2: To a solution of (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (80 mg, 265.5 umol) in DMF (3 mL), 2-chloro-5-methoxy-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine (60 mg, 265.5 umol) and DIPEA (172 mg, 1.33 mmol) were added. The reaction mixture was stirred at 100° C. for 12 hours. The crude product was purified by pre-HPLC. (S)-3-Fluoro-5-(1-(4-(5-methoxy-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (9 mg, 7%) was obtained as a white solid. MS (m / z): 491.1 [M+H] + .

[0666] Compound 151: (S)-5-(5-fluoro-2-(4-(5-(5-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)pyrimidin-4-yl)-1-methyl-1H-1,2,4-triazole-3-carbonitrile JPEG0007760530000196.jpg154159

[0667] Step 1: tert-Butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (2.8 g, 12.96 mmol), CuI (4.0 g, 21.05 mmol), methyl 1-methyl-1H-1,2,4-triazole-3-carboxylate (2.0 g, 14.08 mmol), Pd(PPh)Cl (3.0 g, 4.28 mmol), KPO (6.0 g, 28.30 mmol) were dissolved in dioxane (200 mL) under nitrogen, and the whole reaction mixture was stirred at 100° C. for 15 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded 4-(5-fluoro-4-(3-(methoxycarbonyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl (600 mg, 16.2%) as a yellow solid. MS (m / z): 422.2 [M+H] + .

[0668] Step 2: tert-butyl 4-(5-fluoro-4-(3-(methoxycarbonyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 1.42 mmol) was dissolved in NH in MeOH (10 mL, 7 M) under nitrogen and the whole reaction mixture was stirred at 100° C. for 4 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded tert-butyl 4-(4-(3-carbamoyl-1-methyl-1H-1,2,4-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (500 mg, 86.0%) as a yellow solid. MS (m / z): 407.2 [M+H] + .

[0669] Step 3: tert-Butyl 4-(4-(3-carbamoyl-1-methyl-1H-1,2,4-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 0.71 mmol), TFAA (310 mg, 1.47 mmol), TEA (223 mg, 2.20 mmol) were dissolved in DCM (10 mL) under nitrogen, and the whole reaction mixture was stirred at 0° C. for 0.5 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded tert-butyl 4-(4-(3-cyano-1-methyl-1H-1,2,4-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 70.0%) as a yellow oil. MS(m / z):389.2[M+H] + .

[0670] Step 4: tert-Butyl 4-(4-(3-cyano-1-methyl-1H-1,2,4-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.51 mmol), TFA (2 mL) were added to DCM (5 mL) under nitrogen, and the whole reaction mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to give 5-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1-methyl-1H-1,2,4-triazole-3-carbonitrile (300 mg, crude) as a brown oil, which was used in the next step without purification. MS (m / z): 289.2 [M+H] + .

[0671] Step 5: 5-(5-Fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1-methyl-1H-1,2,4-triazole-3-carbonitrile (300 mg, crude), (S)-(1H-imidazol-1-yl)(5-(5-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (30 mg, 0.11 mmol), and DABCO (200 mg, 1.78 mmol) were in THF (10 mL) under nitrogen. The solvent was removed in vacuo, and the reaction mixture was placed at 90° C. for 3.0 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded compound 151 (5.0 mg, 9.0%) as a white solid. MS(m / z):482.2[M+H] + .

[0672] 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 2.0 Hz, 1H), 7.37 (s, 1H), 6.90 (d, J = 1.6 Hz, 1H), 5.71 (t, J = 10.4 Hz, 1H), 4.29 (s, 3H), 3.95 - 3.62 (m, 8H), 3.33 (d, J = 10.4 Hz, 2H), 2.43 (s, 3H).

[0673] Compound 152: (S)-3-(1-(4-(4-(5-acetyl-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000197.jpg183163

[0674] Step 1: Synthesis of 1-methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 1-Methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (0.487 g, 3.063 mmol), triphenylmethyl chloride (0.974 g, 3.493 mmol), and TEA (0.3 mL) were mixed in 5 mL of DCM. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA=1 / 1) to give 540 mg of a white solid. Yield: 48.2%. LC-MS (m / z): 366.4 [M+H] + .

[0675] Step 2: Synthesis of tert-butyl 4-(5-fluoro-4-(1-methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate 1-Methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (560 mg, 1.53 mmol) was dissolved in 15 mL of THF. n-BuLi (0.765 mL, 1.836 mmol) was added dropwise to the solution at −78° C. It was stirred at −78° C. for 30 minutes. Then, ZnCl solution (1.68 mL, 1.68 mmol) was slowly added to the solution at −78° C. It was stirred at −78° C. for 30 minutes. Then, it was stirred at room temperature for 1 hour. tert-Butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (386.8 mg, 1.22 mmol) and Pd(PPh3)4 (176.8 mg, 0.153 mmol) in 5 mL of THF were added. It was stirred at 70°C for 16 hours. The solvent was evaporated to dryness and purified by column chromatography (PE / EA=3 / 1) to give 250 mg of a pale yellow solid. Yield: 31.7%. LC-MS (m / z): 404.4 [M+H-Trt] + .

[0676] Step 3: Synthesis of tert-butyl 4-(5-fluoro-4-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(5-fluoro-4-(1-methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (125 mg, 0.193 mmol) was dissolved in 5 mL of DCM. 3 mL of AcOH was added. It was stirred at room temperature for 9 hours. The solution was neutralized with saturated Na2CO3 solution and extracted with DCM (15 mL x 3). It was dried over Na2SO4, filtered, and evaporated to dryness to give 139 mg of crude product as a brown oil. LC-MS (m / z): 404.3 [M+H] + .

[0677] Step 4: Synthesis of tert-butyl 4-(4-(5-acetyl-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate The above oil (139 mg) was dissolved in 3 mL of DCM. 0.3 mL of TEA was added. Acetyl chloride (37.3 mg, 0.379 mmol) was added. It was stirred at room temperature for 3 hours. The solvent was evaporated to dryness and purified by column chromatography (EA) to give 99 mg of a pale yellow oil. Combined yield of steps 3 and 4: quantitative. LC-MS (m / z): 446.4 [M+H] +.

[0678] Step 5: Synthesis of 1-(3-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one tert-Butyl 4-(4-(5-acetyl-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (99 mg, 0.222 mmol) was dissolved in 2 mL of DCM. 2 mL of DCM / TFA (1 / 1) was added slowly to the solution at 0° C. It was stirred at room temperature for 1 hour. The solvent was evaporated to dryness to give 75 mg of crude product as a brown oil, which was used in the next step without further purification. LC-MS (m / z): 346.4 [M+H] + .

[0679] Step 6: Synthesis of (S)-3-(1-(4-(4-(5-acetyl-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile The above oil (75 mg), (S)-3-(1-(1H-imidazole-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (62.8 mg, 0.222 mmol) and DABCO (100 mg, 0.893 mmol) were mixed in 2 mL of THF. It was evaporated to dryness and irradiated under a 125 W incandescent lamp for 1 hour. The mixture was purified by preparative HPLC to give 25 mg of an off-white solid. Yield: 20.1%. LC-MS (m / z): 561.4 [M+H] + .

[0680] 1H NMR (400 MHz, CDCl3) δ 8.22-8.18 (m, 1H), 7.41 (s, 1H), 7.36 (d, J = 11.6 Hz, 1H), 7.29-7.27 (m, 1H), 6.91-6.87 (m, 1H), 5.39 - 5.31 (m, 1H), 5.29 - 5.24 (m, 2H), 4.70 - 4.52 (m, 4H), 3.82 - 3.74 (m, 2H), 3.74 - 3.62 (m, 5H), 3.62-3.54 (m, 2H), 3.35 (ddd, J = 18.4, 11.6, 1.6Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H), 2.16 (s, 3H).

[0681] Compound 153: (S)-3-(1-(4-(4-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000198.jpg42159

[0682] Following the procedure outlined for compound 143, the title compound 153 was prepared in 53.2% yield.

[0683] 1 H NMR (300 MHz, Chloroform-d) δ 8.39 (t, J = 1.6 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 4.8 Hz, 2H), 6.90 (d, J = 1.6 Hz, 1H), 5.37 (t, J = LC-MS (m / z) 507.4 (M+H) + ).

[0684] Compound 154: (S)-3-(1-(4-(4-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000199.jpg32159

[0685] Following the procedure outlined for compound 143, the title compound 154 was prepared in 49.3% yield.

[0686] 1 H NMR (300 MHz, Chloroform-d) δ 8.52 (d, J = 4.7 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J = 4.4 Hz, 2H), 6.92 (s, 1H), 6.65 (d, J = 4.8 Hz, 1H), 5.37 (t, J = 10.8 Hz, 1H), 4.11 - 3.60 (m, 13H), 3.37 (ddd, J = 18.3, 11.7, 2.0 Hz, 1H), 2.71 (dd, J = 18.3, 9.9 Hz, 1H), 2.02 (d, J = 2.7 Hz, 3H).LC-MS (m / z) 489.3 (M+H + ).

[0687] Compound 155: (S)-(4-(4-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000200.jpg33159

[0688] Following the procedure outlined for compound 143, the title compound 155 was prepared in 22.6% yield.

[0689] 1H NMR (300 MHz, Chloroform-d) δ 8.31 (d, J = 2.0 Hz, 1H), 7.27 (s, 1H), 6.88 - 6.77 (m, 2H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.33 (dd, J = 11.7, LC-MS (m / z) 500.4 (M+H + ).

[0690] Compound 156: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)piperazin-1-yl)(5-(2-methylthiazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000201.jpg36159

[0691] Following the procedure outlined for compound 143, the title compound 156 was prepared as a white solid in 30.2% yield.

[0692] 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 5.6 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J = 0.5 Hz, 1H), 6.90 (t, J = 1.7 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 5.50 (dd, J = 11.4, 9.9 Hz, 1H), 3.94 (s, 3H), 3.91 - 3.83 (m, 2H), 3.72 (ddd, J = 13.3, 6.6, 3.0 Hz, 2H), 3.41 (d, J = 33.8 Hz, 4H), 3.29 - 3.13 (m, 2H), 2.69 (s, 3H), 2.11 (d, J = 0.6 Hz, 3H). LC-MS (m / z) 469.3 (M+H + ).

[0693] Compound 157: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)piperazin-1-yl)(5-(4-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000202.jpg32159

[0694] Following the procedure outlined for compound 143, the title compound 157 was prepared in 20.5% yield.

[0695] 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 5.5 Hz, 1H), 7.36 (d, J = 0.7 Hz, 1H), 6.90 (t, J = 1.7 Hz, 1H), 6.83 - 6.75 (m, 2H), 5.75 (dd, J = 11.8, 9.2 Hz, 1H), 3.94 (s, 5H), 3.77 (ddd, J = 13.4, 6.7, 3.2 Hz, 2H), 3.51 - 3.32 (m, 5H), 3.24 (ddd, J = 18.4, 9.3, 1.7 Hz, 1H), 2.42 (d, J = 1.0 Hz, 3H), 2.12 (d, J = 0.6 Hz, 3H).LC-MS (m / z) 469.3 (M+H + ).

[0696] Compound 158: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperazin-1-yl)(5-(2-methylthiazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000203.jpg34159

[0697] Following the procedure outlined for compound 143, the title compound 158 was prepared in 17.7% yield.

[0698] 1 H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 6.3 Hz, 1H), 7.33 (s, 1H), 7.07 (s, 1H), 6.90 (t, J = 1.7 Hz, 1H), 5.50 (dd, J = 11.4, 9.9 Hz, 1H), 4.14 (s, 3H), 3.94 - 3.87 (m, 2H), 3.87 - 3.77 (m, 4H), 3.71 - 3.61 (m, 2H), 3.28 - 3.12 (m, 2H), 2.68 (s, 3H), 2.28 (s, 3H). LC-MS (m / z) 470.3 (M+H +).

[0699] Compound 159: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperazin-1-yl)(5-(thiazol-5-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000204.jpg32159

[0700] Following the procedure outlined for compound 143, the title compound 159 was prepared in 13.2% yield.

[0701] 1 H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 0.7 Hz, 1H), 8.18 (d, J = 6.3 Hz, 1H), 7.84 (d, J = 0.7 Hz, 1H), 7.31 (d, J = 0.7 Hz, 1H), 6.91 (t, J = 1.7 Hz, 1H), 5.70 (dd, J = 11.4, 10.0 Hz, 1H), 4.12 (s, 3H), 3.95 - 3.86 (m, 2H), 3.85 - 3.75 (m, 4H), 3.69 - 3.58 (m, 2H), 3.38 (ddd, J = 18.3, 11.5, 1.8 Hz, 1H), 2.88 (ddd, J = 18.2, 10.0, 1.6 Hz, 1H), 2.26 (s, 3H). LC-MS (m / z) 456.3 (M+H + ).

[0702] Compound 160: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperazin-1-yl)(5-(thiazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000205.jpg33159

[0703] Following the procedure outlined for compound 143, the title compound 160 was prepared in 13.2% yield.

[0704] 1 H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 6.4 Hz, 1H), 7.33 (dd, J = 6.6, 1.4 Hz, 2H), 6.92 (t, J = 1.7 Hz, 1H), 5.63 (dd, J = 11.3, 9.7 Hz, 1H), 4.13 (s, 3H), 3.95 - 3.86 (m, 2H), 3.86 - 3.75 (m, 4H), 3.72 - 3.60 (m, 2H), 3.34 - 3.16 (m, 2H), 2.27 (d, J = 0.6 Hz, 3H). LC-MS (m / z) 456.2 (M+H + ).

[0705] Compound 161: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperazin-1-yl)(5-(4-methylthiazol-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000206.jpg34159

[0706] Following the procedure outlined for compound 143, the title compound 161 was prepared in 12.1% yield.

[0707] 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 6.3 Hz, 1H), 7.34 (d, J = 0.8 Hz, 1H), 6.91 (t, J = 1.7 Hz, 1H), 6.82 (q, J = 1.0 Hz, 1H), 5.76 (dd, J = LC-MS (m / z) 470.3 (M+H + ).

[0708] Compound 162: (4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)piperazin-1-yl)(5-(2-methylthiazol-5-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000207.jpg33159

[0709] Following the procedure outlined for compound 143, the title compound 162 was prepared in 25.9% yield.

[0710] 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 6.3 Hz, 1H), 7.57 (s, 1H), 7.34 (s, 1H), 6.93 - 6.87 (m, 1H), 5.62 (t, J = 10.7 Hz, 1H), 4.14 (s, 3H), 3.95 - 3.85 (m, 2H), 3.84 - 3.75 (m, 4H), 3.65 (dd, J = 10.3, 6.8 Hz, 2H), 3.34 (ddd, J = 18.2, 11.5, 1.8 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.65 (s, 3H), 2.29 (s, 3H). LC-MS (m / z) 470.3 (M+H + ).

[0711] Compound 163: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000208.jpg130159

[0712] Step 1: Synthesis of tert-butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (316 mg, 1 mmol), 1-(tert-butyl)3-ethyl 4-bromo-5-methyl-1H-pyrazole-1,3-dicarboxylate (390 mg, 1.175 mmol), cataxium A (72 mg, 0.2 mmol), bis(pinacolato)diboron (380 mg, 3.534 mmol), CsF (789.88 mg, 5.2 mmol), and Pd(AcO) (22.4 mg, 0.1 mmol) were mixed in 15 mL of MeOH / HO (9 / 1) and stirred at 60 °C for 3 h. Then, another portion of cataxium A (36 mg, 0.1 mmol) and Pd(AcO)2 (11 mg, 0.05 mmol) in 2 mL of toluene were added. It was stirred at 80°C for 16 hours. The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 3 / 1) to give 180 mg of a pale yellow oil. Yield: 41.3%. LC-MS (m / z): 435.4 [M+H] + .

[0713] Step 2: Synthesis of tert-butyl 4-(5-fluoro-4-(3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (150 mg, 0.346 mmol) was dissolved in 4 mL of THF. LiAlH (1 M in THF solution, 0.6 mL, 0.6 mmol) was slowly added to the solution at 0 °C. It was stirred at room temperature for 8 h. The reaction was quenched by adding 0.6 mL of HO and 0.6 mL of 1 N NaOH. It was filtered through Celite. The filtrate was evaporated to dryness to give 180 mg of crude product as a brown oil, which was used in the next step without further purification.

[0714] Step 3 and Step 4: Following the procedure outlined for compound 152, the title compound 163 was prepared as a white solid in 3.7% yield. LC-MS (m / z): 508.3 [M+H] + .

[0715] 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.52-7.42 (m, 2H), 7.28 (s, 1H), 6.89 (s, 1H), 5.43-5.26 (m, 2H), 5.18-4.92 (m, 2H), 4.85-4.40 (m, 3H), 3.91-3.81 (m, 2H), 3.76 (s, 3H), 3.68-3.59 (m, 2H), 3.35 (ddd, J = 18.4, 11.6, 1.6 Hz, 1H), 2.69 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H).

[0716] Compound 164: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000209.jpg78159

[0717] Following the procedure outlined for compound 152, the title compound 164 was prepared as a white solid in 40.8% yield. LC-MS (m / z): 505.3 [M+H] + .

[0718] Compound 165: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000210.jpg134159

[0719] Step 1: Synthesis of tert-butyl 4-(4-(3-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(4-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (140 mg, 0.322 mmol) was dissolved in 3 mL of THF. NaH (28 mg, 0.7 mmol) was added portionwise at 0 °C. It was stirred at room temperature for 16 h. Water was added and extracted with EtOAc (15 mL × 3). It was dried over Na2SO4, filtered and evaporated to dryness to give 70 mg of a brown oil. Yield: 48.6%. LC-MS (m / z): 449.4 [M+H] + .

[0720] Step 2, Step 3 and Step 4: Following the procedure outlined for compound 152, the title compound 165 was prepared as a white solid in 6.4% yield. LC-MS (m / z): 522.3 [M+H] + .

[0721] Compound 166: (S)-3-(1-(4-(5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000211.jpg135159

[0722] Step 1: Synthesis of 2,5-dichloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine The synthesis procedure was the same as that of tert-butyl 4-(5-fluoro-4-(1-methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate. 44 mg of a white solid was obtained. Yield: 48.6%. LC-MS (m / z): 231.4 [M+H] + .

[0723] Step 2: Synthesis of (S)-3-(1-(4-(5-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile 2,5-Dichloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidine (44 mg, 0.1932 mmol) and (S)-3-fluoro-5-(1-(piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (56.5 mg, 0.188 mmol) were dissolved in 2 mL of DMF. 0.2 mL of TEA was added. It was stirred at 70 °C for 16 hours. Water was added and extracted with EtOAc (15 mL × 3). It was dried over Na2SO4, filtered, and evaporated to dryness, and purified by column chromatography (PE / EA = 1 / 3) to give 40 mg of a pale yellow solid. Yield: 43%. LC-MS (m / z): 495.4 [M+H] + .

[0724] Compound 167: (S)-3-(1-(4-(4-(1-ethyl-1H-1,2,4-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000212.jpg139159

[0725] Following the procedure outlined for compound 166, the title compound 167 was prepared as a pale yellow solid in 25.6% yield. LC-MS (m / z): 493.3 [M+H] + .

[0726] 1 H NMR (300 MHz, CDCl3) δ 8.43 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 7.77-7.63(m, 1H), 7.57 - 7.40 (m, 2H), 6.90 (s, 1H), 5.45 - 5.30 (m, 1H), 4.63 (q, J = 7.2 Hz, 2H), 4.01 - 3.52 (m, 8H), 3.37 (dd, J = 17.6, 12.4 Hz, 1H), 2.70 (dd, J = 17.6, 10.0 Hz, 1H), 1.53 (t, J = 7.2 Hz, 3H).

[0727] Compound 168: (S)-3-(1-(4-(5-chloro-4-(1-ethyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000213.jpg158157

[0728] Following the procedure outlined for compound 166, the title compound 168 was prepared as a pale yellow solid in 32.4% yield. LC-MS (m / z): 509.4 [M+H] + .

[0729] 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.04 (s, 1H), 7.41 (s, 1H), 7.28 (s, 2H), 6.89 (s, 1H), 5.36 (t, J = 10.8 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.00 - 3.55 (m, 8H), 3.36 (dd, J = 18.3, 11.7 Hz, 1H), 2.69 (dd, J = 18.2, 10.0 Hz, 1H), 1.50 (t, J = 7.2 Hz, 3H).

[0730] Compound 169: (S)-3-fluoro-5-(1-(4-(4-(3-(fluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000214.jpg139159

[0731] Step 1: Synthesis of (5-(2-chloropyrimidin-4-yl)-1-methyl-1H-1,2,4-triazol-3-yl)methanol 4-(3-(((tert-butyldimethylsilyl)oxy)methyl-1-methyl-1H-1,2,4-triazol-5-yl)-2-chloropyrimidine (150 mg, 0.442 mmol) was dissolved in 3 mL of THF. 2 mL of TFA was added. It was stirred at 50° C. for 2 hours. The solvent was evaporated to dryness and used in the next step without further purification. LC-MS (m / z): 226.4 [M+H] + .

[0732] Step 2: Synthesis of tert-butyl 4-(4-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate The residue above, tert-butyl piperazine-1-carboxylate (90.7 mg, 0.487 mmol), and TEA (0.2 mL) were dissolved in 3 mL of DMF. The mixture was stirred at 70° C. for 16 hours. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (EA) to give 120 mg of a pale yellow solid. Total yield: 72.7%. LC-MS (m / z): 376.4 [M+H] + .

[0733] Step 3: Synthesis of tert-butyl 4-(4-(3-(fluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(4-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylate (120 mg, 0.32 mmol) was dissolved in 3 mL of DCM. DAST (101.5 mg, 0.63 mmol) was added at 0° C. It was stirred at room temperature for 2 hours. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA=1 / 5) to give 118 mg of a pale yellow solid. Total yield: 97.8%. LC-MS (m / z): 378.4 [M+H] + .

[0734] Step 4 and Step 5: Following the procedure outlined for compound 152, the title compound 169 was prepared as a pale yellow solid in 22.7% yield. LC-MS (m / z): 493.4 [M+H] + .

[0735] 1 H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 7.42 (s, 2H), 7.28 (s, 2H), 6.90 (s, 1H), 5.52 (s, 1H), 5.45-5.31(m, 2H), 4.37 (s, 3H), 4.11 - 3.54 (m, 8H), 3.37 (dd, J = 17.4, 10.8 Hz, 1H), 2.70 (dd, J = 17.4, 10.2 Hz, 1H)

[0736] Compound 170: (S)-3-fluoro-5-(1-(4-(5-fluoro-4-(3-(fluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000215.jpg88159

[0737] Following the procedure outlined for compound 152, the title compound 170 was prepared as a pale yellow solid in 28.7% yield. LC-MS (m / z): 511.3 [M+H] + .

[0738] 1 H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 2.1 Hz, 1H), 7.42 (s, 1H), 7.33-7.27 (m, 2H), 6.90 (s, 1H), 5.57 (s, 1H), 5.41 (s, 1H), 5.35 (d, J = 10.8 Hz, 1H), 4.23 (s, 3H), 3.96 - 3.74 (m, 6H), 3.71 - 3.63 (m, 2H), 3.37 (ddd, J = 18.3, 11.7, 1.5 Hz, 1H), 2.70 (ddd, J = 18.3, 10.0, 1.2 Hz, 1H).

[0739] Compound 171: (S)-3-fluoro-5-(1-(4-(4-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000216.jpg81159

[0740] Steps 1 and 2: The synthesis procedure was the same as that of 166. 77 mg of (S)-3-(1-(4-(4-(3-((((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile was obtained as a pale yellow oil. Yield: 54.9%. LC-MS (m / z): 605.4 [M+H] + .

[0741] Step 3: Synthesis of (S)-3-fluoro-5-(1-(4-(4-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (S)-3-(1-(4-(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (77 mg, 0.127 mmol) was dissolved in 2 mL of DCM. 2 mL of DCM / TFA (1 / 1) was added slowly to the solution at 0° C. It was stirred at room temperature for 2 hours. The solvent was evaporated to dryness and purified by preparative TLC (DCM / MeOH=12 / 1) to give 40 mg of a white solid. Yield: 64.3%. LC-MS (m / z): 491.4 [M+H] + .

[0742] 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 4.8 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 5.4 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.91 (s, 1H), 5.44 - 5.32 (m, 1H), 4.80 (s, 2H), 4.35 (s, 3H), 4.03 - 3.62 (m, 8H), 3.37 (ddd, J = 18.3, 11.7, 1.5 Hz, 1H), 2.70 (ddd, J = 18.3, 10.0, 1.2 Hz, 1H).

[0743] Compound 172: (S)-3-fluoro-5-(1-(4-(5-fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000217.jpg85159

[0744] Step 1: tert-Butyl 2-(6-chloro-3-fluoropicolinoyl)hydrazine-1-carboxylate 6-Chloro-3-fluoropicolinic acid (500 mg, 2.841 mmol) was dissolved in 5 mL of THF. DMF (1 drop) was added. SOCl (1 mL) was added. It was stirred at room temperature for 1 hour. The solvent was evaporated to dryness and used in the next step without further purification. The above residue in 4 mL of DCM was slowly added to a solution of tert-butyl hydrazinecarboxylate (412.5 mg, 3.125 mmol) and TEA (574 mg, 5.683 mmol) in 5 mL of DCM at 0° C. It was stirred at room temperature for 16 hours. The solvent was evaporated to dryness and redissolved in DCM and washed with water. It was dried over Na2SO4, filtered and evaporated to dryness and used in the next step without further purification. LC-MS (m / z): 290.4 [M+H] + .

[0745] Step 2: Synthesis of N'-acetyl-6-chloro-3-fluoropicolinohydrazide The residue was dissolved in 4 mL of DCM. 10 mL of HCl / 1,4-dioxane was added. It was stirred at room temperature for 1 hour. The solid was filtered and washed with PE to give 550 mg of 6-chloro-3-fluoropicolinohydrazide as a white solid. Yield for three steps: 84.9%. It was used in the next step without further purification. LC-MS (m / z): 190.4 [M+H] + . 6-Chloro-3-fluoropicolinohydrazide hydrochloride (550 mg) was mixed in 8 mL of DCM. TEA (1 mL) was added. Acetyl chloride (209.2 mg, 2.665 mmol) was added. It was stirred at room temperature for 1.5 hours. The solvent was evaporated to dryness to give 700 mg of crude brown solid, which was used in the next step without further purification. LC-MS (m / z): 232.3 [M+H] + .

[0746] Step 3: Synthesis of 2-(6-chloro-3-fluoropyridin-2-yl)-5-methyl-1,3,4-thiadiazole N'-acetyl-6-chloro-3-fluoropicolinohydrazide (700 mg, crude) and Lawesson's reagent (836.5 mg, 2.068 mmol) were mixed in 10 mL of toluene. The mixture was stirred at 110°C for 16 hours. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 3 / 2) to give 95 mg of a yellow solid. Yield: 20.1%. LC-MS (m / z): 230.3 [M+H] + .

[0747] Step 4: Synthesis of tert-butyl 4-(5-fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)piperazine-1-carboxylate 2-(6-Chloro-3-fluoropyridin-2-yl)-5-methyl-1,3,4-thiadiazole (95 mg, 0.415 mmol), tert-butyl piperazine-1-carboxylate (85 mg, 0.457 mmol), X-phos-G3 (70.2 mg, 0.816 mmol), t-BuONa (50 mg, 0.52 mmol), and Pd2(dba)3 (38 mg, 0.042 mmol) were mixed in 5 mL of 1,4-dioxane. The mixture was stirred at 110 °C for 16 h. The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 2 / 3) to give 35 mg of an orange solid. Yield: 22.2%. LC-MS (m / z): 380.3 [M+H] + .

[0748] Steps 5 and 6: Following the procedure outlined for compound 166, the title compound 172 was prepared as a pale yellow solid in 88.1% yield. LC-MS (m / z): 495.3 [M+H] + .

[0749] 1 H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 9.2 Hz, 1H), 7.43-7.39 (m, 1H), 7.30 - 7.26 (m, 2H), 6.89 (t, J = 1.5 Hz, 1H), 6.76 - 6.71 (m, 1H), 5.37 (dd, J = 11.6, 10.1 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.74-3.61 (m, 4H), 3.57 - 3.47 (m, 2H), 3.36 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.82 (s, 3H), 2.70 (ddd, J = 18.2, 9.9, 1.5 Hz, 1H).

[0750] Compound 173: (S)-(4-(5-fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)piperazin-1-yl)(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000218.jpg34159

[0751] Following the procedure outlined for compound 166, the title compound 173 was prepared as a pale yellow solid in 69.4% yield. LC-MS (m / z): 471.3 [M+H] + .

[0752] 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.38 - 7.31 (m, 1H), 6.91 (t, J = 1.6 Hz, 1H), 6.74 (dd, J = 9.2, 2.8 Hz, 1H), 5.45 - 5.37 (m, 1H), 3.88 - 3.79 (m, 2H), 3.73-3.60 (m, 4H), 3.56 - 3.48 (m, 2H), 3.38 (ddd, J = 18.4, 11.6, 1.6Hz, 1H), 2.82 (s, 3H), 2.77 (ddd, J = 18.4, 10.0, 1.6 Hz, 1H).

[0753] Compound 174: (S)-(4-(5-fluoro-4-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)piperazin-1-yl)(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)methanone JPEG0007760530000219.jpg111159

[0754] Step 1: Synthesis of tert-butyl 4-(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,4-triazol-5-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate The synthesis procedure was the same as that of tert-butyl 4-(5-fluoro-4-(1-methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate. 42 mg of a pale yellow oil was obtained. Yield: 3.5%. LC-MS (m / z): 508.3 [M+H] + .

[0755] Steps 2 and 3: Following the procedure outlined for compound 166, the title compound 174 was prepared as a pale yellow solid in 22.5% yield. LC-MS (m / z): 485.3 [M+H] + .

[0756] 1 H NMR (300 MHz, CDCl3) δ 8.48-8.34 (m, 3H), 7.39 - 7.30 (m, 1H), 6.91 (s, 1H), 5.41 (t, J = 10.8 Hz, 1H), 4.82 (s, 2H), 4.19 (s, 3H), 3.92 - 3.61 (m, 8H), 3.38 (ddd, J = 18.2, 11.8, 1.7 Hz, 1H), 2.75 (ddd, J = 18.3, 10.1, 1.5 Hz, 1H).

[0757] Compound 175: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(3-fluoro-6-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)piperazin-1-yl)methanone JPEG0007760530000220.jpg111159

[0758] Step 1: Synthesis of 6-bromo-5-fluoropicolinamide The synthesis procedure was the same as that of tert-butyl 2-(6-chloro-3-fluoropicolinoyl)hydrazine-1-carboxylate. 650 mg of a pale yellow oil was obtained. Yield: 83.8%. LC-MS (m / z): 220.3 [M+H] + .

[0759] Step 2: Synthesis of 2-bromo-3-fluoro-6-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine 6-Bromo-5-fluoropicolinamide (650 mg, 2.968 mmol) was dissolved in 10 mL of THF. 2 mL of DMFDMA was added. It was stirred at room temperature for 16 hours. The solvent was evaporated to dryness and used in the next step without further purification. The above solid and methylhydrazine sulfate (1.13 g, 7.8 mmol) were mixed in 10 mL of AcOH. It was stirred at 90 °C for 16 h. The mixture was neutralized with K2CO3. It was extracted with EA (20 mL x 3). The solvent was evaporated to dryness and purified by preparative TLC (PE / EA = 1 / 1) to give 330 mg of a white solid. Yield: 54.2%. LC-MS (m / z): 258.3 [M+H] + .

[0760] Steps 3 and 4: Following the procedure outlined for compound 166, the title compound 175 was prepared as a pale yellow solid in 44% yield. LC-MS (m / z): 471.3 [M+H] + .

[0761] 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.81-7.75 (m, 1H), 7.40 (dd, J = 12.4, 8.2 Hz, 1H), 6.87-6.81(m, 3H), 6.73 - 6.66 (m, 1H), 5.35 (dd, J = 11.6, 10.0 Hz, 1H), 4.34 (s, 3H), 3.92-3.86 (m, 2H), 3.76-3.71 (m, 2H), 3.64 - 3.46 (m, 4H), 3.33 (ddd, J = 18.3, 11.8, 1.8 Hz, 1H), 2.70 (ddd, J = 18.3, 9.9, 1.6 Hz, 1H).

[0762] Compound 176: (S)-3-Fluoro-5-(1-(4-(3-fluoro-6-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000221.jpg42159

[0763] Following the procedure outlined for compound 166, the title compound 176 was prepared as a pale yellow solid in 69.4% yield. LC-MS (m / z): 478.3 [M+H] + .

[0764] 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.79 (dd, J = 8.2, 2.9 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.31 - 7.26 (m, 2H), 6.90 (t, J = 1.7 Hz, 1H), 5.38 (dd, J = 11.6, 10.1 Hz, 1H), 4.34 (s, 3H), 3.93 - 3.84 (m, 2H), 3.76-3.71 (m, 2H), 3.64 - 3.48 (m, 4H), 3.37 (ddd, J = 18.3, 11.7, 1.8Hz, 1H), 2.70 (ddd, J = 18.3, 10.0, 1.6 Hz, 1H).

[0765] Compound 177: (S)-3-Fluoro-5-(1-(4-(3-fluoro-6-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile JPEG0007760530000222.jpg115159

[0766] Following the procedure outlined for compound 166, the title compound 177 was prepared as a pale yellow solid in 57.8% yield. LC-MS (m / z): 478.4 [M+H] + .

[0767] 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.61 (dd, J = 8.1, 2.9 Hz, 1H), 7.42 (t, J = 1.4 Hz, 1H), 7.33 (dd, J = 12.6, 8.1 Hz,1H), 7.30 - 7.25 (m, 2H),6.86 (t, J = 1.6 Hz, 1H), 5.40 - 5.31 (m, 1H), 4.00 (s, 3H), 3.91 - 3.80 (m, 2H), 3.75 - 3.54 (m, 6H), 3.34 (ddd, J = 18.2, 11.7, 1.8Hz, 1H), 2.68 (ddd, J = 18.2, 10.2, 1.6 Hz, 1H).

[0768] Compound 178: (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(4-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methanone JPEG0007760530000223.jpg39159

[0769] Following the procedure outlined for compound 166, the title compound 178 was prepared as a yellow solid in 39.5% yield. LC-MS (m / z): 486.4 [M+H] + .

[0770] 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.0 Hz, 1H), 6.87 (t, J = 1.6 Hz, 1H), 6.85 - 6.79 (m, 2H), 6.70 (tt, J = 8.9, 2.3 Hz, 1H), 5.34 (dd, J = 11.7, 9.8 Hz, 1H), 3.93 (s, 3H), 3.91 - 3.85 (m, 2H), 3.84 - 3.74 (m, 4H), 3.69 - 3.61 (m, 2H), 3.34 (ddd, J = 18.4, 11.8, 1.8 Hz, 1H), 2.75 - 2.66 (m, 4H).

[0771] Compound 179: (S)-3-(1-(4-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile JPEG0007760530000224.jpg31159

[0772] Following the procedure outlined for compound 166, the title compound 179 was prepared as a yellow solid in 47.5% yield. LC-MS (m / z): 493.4 [M+H] + .

[0773] 1 H NMR (400 MHz, cdcl3) δ 8.45 (d, J = 2.0 Hz, 1H), 7.41 (t, J = 1.4 Hz, 1H), 7.30 - 7.26 (m, 2H), 6.90 (t, J = 1.6 Hz, 1H), 5.37 (dd, J = 11.6, 10.0 Hz, 1H), 3.97 - 3.85 (m, 5H), 3.83 - 3.73 (m, 4H), 3.72 - 3.61 (m, 2H), 3.37 (ddd, J = 18.3, 11.7, 1.8 Hz, 1H), 2.75 - 2.64 (m, 4H).

[0774] Compound 180: (S)-2-(2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-4-ethyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one JPEG0007760530000225.jpg111159

[0775] Step 1: 4-Ethyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one Ethanamine hydrochloride (2.0 g, 10 mmol) was dissolved in anhydrous EtOH (200 mL), to which a suspension of sodium ethoxide (1.33 g, 19.5 mmol) in anhydrous EtOH (70 mL) was added, and the reaction was stirred at room temperature for 5 minutes. A solution of (E)-ethyl 2-(1-ethoxyethylidene)hydrazinecarboxylate (1.6 g, 19.5 mmol) in anhydrous EtOH (50 mL) was added dropwise, and the reaction was refluxed for 4 hours. The reaction was then cooled to room temperature and filtered through a Celite pad. The eluate was dried under reduced pressure, and the resulting residue was recrystallized from EtOAc (via hot filtration) to give the pure product. Isolated yield: 183 mg (10%); white crystals (recrystallized from EtOAc); LCMS (ES, m / z): 128.1 [M+H]. + .

[0776] Step 2: tert-butyl 4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate To tert-butyl 4-(4-chloro-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 0.95 mmol) in DMF (20 mL) was added 4-ethyl-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (128 mg, 1.42 mmol) and CsCO (462 mg, 1.42 mmol). The reaction was stirred at 120 °C for 3 h. Water was added and the mixture was extracted with EA, washed with brine, and dried over (NaSO). The resulting mixture was removed under vacuum and the crude product was purified by silica gel chromatography to give 300 mg of tert-butyl 4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate as a yellow solid. Yield: 77%. LC-MS (m / z) 408.2 (M+H + ).

[0777] Step 3: 4-ethyl-2-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one tert-Butyl 4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (300 mg, 0.73 mmol) was dissolved in 5 mL of DCM. 1 mL of TFA / DCM (1 / 5) was added to the solution at 0° C. It 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): 308.2 [M+H] + .

[0778] Step 4: (S)-3-(1-(4-(4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile The residue, 4-ethyl-2-(5-fluoro-2-(pipe...

Claims

1. A compound of formula Ia, or a salt, hydrate or stereoisomer thereof: During the ceremony, R1 is a 6-membered aryl, a 6-membered heteroaryl containing one N heteroatom, or a 5-membered heteroaryl containing one or two N heteroatoms and an O or S heteroatom, wherein said 6-membered aryl, 6-membered heteroaryl, or 5-membered heteroaryl is unsubstituted or substituted with halogen, CN, or C1-C3 alkyl; R2 is a 6-membered aryl, a 6-membered heteroaryl containing 1 or 2 N or 3 N heteroatoms, or a 5-membered heteroaryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein said 6-membered aryl, 6-membered heteroaryl, or 5-membered heteroaryl is unsubstituted or substituted with halogen, CN, C1-C3 alkoxy, C1-C3 alkyl, or OH-substituted C1-C3 alkyl; R3 contains 1, 2, 3 or 4 N heteroatoms, or 1 or 2 N heteroatoms and O or S heteroatoms, and is selected from the group consisting of 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′-SO 2NR'", -NR"COR', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SOR', -SONR'R", -NR"SOR, -CN, -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; R', R" and R'" each independently represent 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 bound to the same nitrogen atom, R' and R" can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.

2. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(1): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0, 1, or 2.

3. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(2): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0, 1, or 2.

4. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(3): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0, 1, or 2.

5. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(4): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0, 1, or 2.

6. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(5): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0 or 1.

7. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(6): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0 or 1.

8. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(7): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0, 1, or 2.

9. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula II(8): In the formula, R ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl unsubstituted or substituted with OH, where m is 0, 1, or 2.

10. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(1): In the formula, R ａ is selected from halogen, CN, and C1-C3 alkyl, where n is 0, 1, 2, or 3.

11. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(2): In the formula, R ａ is selected from halogen, CN, and C1-C3 alkyl, where n is 0, 1, 2, or 3.

12. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(3): In the formula, R ａ is selected from halogen, CN, and C1-C3 alkyl, where n is 0, 1, 2, or 3.

13. 2. The compound, salt, hydrate or stereoisomer of claim 1, wherein the compound has the following structural formula III(4): In the formula, X １ is S and X ２ is C and X ３ is N, or X １ is S and X ２ is N and X ３ is C, or X １ is N and X ２ is O and X ３ is C, or X １ is N and X ２ is S and X ３ is C; where R ａ is selected from halogen, CN, and C1-C3 alkyl; where n is 0, 1, or 2.

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 ａ is selected from halogen, CN, and C1-C3 alkyl, and n is 0, 1, 2, or 3; ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl that is unsubstituted or substituted with OH; and m 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, X ４ is N and X ５ is C, or X ４ is C and X ５ is N; where R ａ is selected from halogen, CN, and C1-C3 alkyl, and n is 0, 1, 2, or 3; ｄ is selected from halogen, CN, C1-C3 alkoxy, and C1-C3 alkyl that is unsubstituted or substituted with OH; and m 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, X １ is S and X ２ is C and X ３ is N, or X １ is S and X ２ is N and X ３ is C, or X １ is N and X ２ is O and X ３ is C, or X １ is N and X ２ is S and X ３ is C; where R ａ is selected from halogen, CN, and C1-C3 alkyl, and n is 0, 1, 2, or 3; ｄ is halogen, CN, C1-C3 alkoxy, and unsubstituted or substituted with OH. １ ~C ３ alkyl; and m is 0, 1, or 2.

17. R3 is halogen, —R′, —OR′, ═O, ═NR′, ═N-OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —C02R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′″, —NR′-SO2NR′″, —NR″CO2R′ , -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S02R', -S02NR'R'', -NR''S02R, -CN, -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl; And, 17. The compound, salt, hydrate, or stereoisomer according to any one of claims 1 to 16, wherein R', R'', and R''' each independently represent 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, unsubstituted C1-C8 thioalkoxy, or C6-C14 aryl-(C1-C4)alkyl; and when R' and R'' are bound to the same nitrogen atom, R' and R'' can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

18. R3 is, 18. The compound, salt, hydrate or stereoisomer according to any one of claims 1 to 17, wherein:

19. A compound of formula Ia, or a salt, hydrate, or stereoisomer thereof: During the ceremony, R1 is a 6-membered aryl, a 6-membered heteroaryl containing one N heteroatom, or a 5-membered heteroaryl containing one or two N heteroatoms and an O or S heteroatom, wherein said 6-membered aryl, 6-membered heteroaryl, or 5-membered heteroaryl is unsubstituted or substituted with halogen, CN, or C1-C3 alkyl; R2 is a 6-membered aryl, a 6-membered heteroaryl containing 1 or 2 N or 3 N heteroatoms, or a 5-membered heteroaryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein said 6-membered aryl, 6-membered heteroaryl, or 5-membered heteroaryl is unsubstituted or substituted with halogen, CN, C1-C3 alkoxy, C1-C3 alkyl, or OH-substituted C1-C3 alkyl; R3 is a 5- to 8-membered heteroaryl containing 1, 2, 3, or 4 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and said R3 is selected from the group consisting of 0 to 3 R ｅ and R ｅ is, for each occurrence, a compound, salt, hydrate or stereoisomer independently selected from: Halogen, cyano, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocyclyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, —C(═O)(C １ ~C ６ alkyl), -C(=O)(C ３ ~C ６ cycloalkyl), —C(═O)(3- to 6-membered heterocyclyl), ═O, —NO ２ , -C(=O)OR ｓ , —C(═O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (= O) ｗ R ｓ 、 -OR ｓ , —OC(═O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , and -S(=O) ｗ NR ｐ R ｑ where: R ｅ C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocyclyl, C ２ ~C ６ Alkenyl and C １ ~C ６ Alkoxy, —C(═O)(C １ ~C ６ C of alkyl) １ ~C ６ Alkyl, —C(═O)(C ３ ~C ６ Cycloalkyl) C ３ ~C ６ Cycloalkyl and the 3- to 6-membered heterocyclyl of —C(═O)(3- to 6-membered heterocyclyl) are each unsubstituted or substituted with halogen, cyano, ═O, —C(═O)R ｓ , -C(=O)OR ｓ , —C(═O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (= O) ｗ R ｓ , -OR ｓ , —OC(═O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ NR ｐ R ｑ , C ３ ~C ６ substituted with 1 to 3 groups selected from cycloalkyl, and 3- to 6-membered heterocyclyl; The R ｐ , R ｑ , R ｒ , and R ｓ is, for each occurrence, independently hydrogen, OH, NH ２ , C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R ｐ , R ｑ , R ｒ , and R ｓ One of the C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl and 3- to 6-membered heterocyclyl are unsubstituted or substituted with halogen, cyano, —OH, C １ ~C ６ Alkyl, —O(C １ ~C ６ alkyl), -C(=O)N(C １ ~C ６ alkyl) (C １ ~C ６ alkyl), -C(=O)NH(C １ ~C ６ alkyl), —C(═O)(3- to 6-membered heterocyclyl), —C(═O)(C ３ ~C ６ cycloalkyl), C ３ ~C ６ substituted with 1 to 3 groups selected from cycloalkyl, phenyl, and 3- to 6-membered heterocyclyl; The w is an integer selected from 0, 1, and 2.

20. 20. The compound, salt, hydrate or stereoisomer of claim 19, wherein R3 is 0 to 3 R ｅ where R ｅ is, for each occurrence, a compound, salt, hydrate or stereoisomer independently selected from: Halogen; Cyano; =O; -NO ２ 4-6 membered heterocyclyl unsubstituted or substituted by oxo; -C(=O)(C １ ~C ３ -C(=O)(4- to 6-membered heterocyclyl); -C(=O)OR ｓ , where R ｓ is H or C １ ~C ３ is alkyl; -OR ｓ , where R ｓ is H or C １ ~C ３ alkyl; １ ~C ３ Alkyl is unsubstituted or substituted with OH, NH ２ , cyano, halogen, C １ ~C ３ Alkoxy, 3- to 4-membered cycloalkyl, 4- to 6-membered heterocyclyl, —C(═O)OH, —C(═O)(4- to 6-membered heterocyclyl), —C(═O)NH(CH ２ ) ２ OH, or -C(=O)NH ２ is replaced by; -C(=O)NR ｐ R ｑ , where R ｐ and R ｑ are each independently H and C １ ~C ３ selected from alkyl; -NR ｐ R ｑ , where R ｐ and R ｑ are each independently H and C １ ~C ３ selected from alkyl; -NR ｐ C(=O)R ｓ , where R ｐ is H and C １ ~C ３ alkyl, and R ｓ is a 3- to 4-membered cycloalkyl, and unsubstituted or substituted with a 3- to 4-membered cycloalkyl C １ ~C ３ selected from alkyl; -NR ｐ S (= O) ｗ R ｓ , where R ｐ is selected from H and C1-C3 alkyl, and R ｓ is C １ ~C ３ alkyl, where w is 2; -S(=O) ｗ R ｓ , where R ｓ is C １ ~C ３ alkyl, where w is 0 or 2.

21. 20. The compound, salt, hydrate or stereoisomer of claim 19, wherein R3 is one to three R ｅ where R ｅ is, for each occurrence, a compound, salt, hydrate or stereoisomer independently selected from:

22. 20. The compound, salt, hydrate or stereoisomer of claim 19, wherein R3 is one to three R ｅ where R ｅ is, for each occurrence, independently selected from Cl, CN, methyl, -CF ３ , -CH ２ OH, -CH ２ C(=O)NH ２ , -C(=O)OCH ３ , —C(═O)NH ２ and —C(═O)OH.

23. 20. The compound, salt, hydrate or stereoisomer of claim 19, wherein R3 is one to three R ｅ where R ｅ is, for each occurrence, independently selected from CN, methyl, Cl, and —C(═O)NH ２ A compound, salt, hydrate or stereoisomer selected from:

24. R1 is a 6-membered aryl, a 6-membered heteroaryl containing one N heteroatom, or a 5-membered heteroaryl containing one or two N heteroatoms and an O or S heteroatom, wherein the 6-membered aryl, 6-membered heteroaryl, or 5-membered heteroaryl is unsubstituted or substituted with F, Cl, Br, CN, or methyl; R2 is a 6-membered aryl, a 6-membered heteroaryl containing 1 or 2 N or 3 N heteroatoms, or a 5-membered heteroaryl containing 1 or 2 N heteroatoms and an O or S heteroatom, wherein the 6-membered aryl, 6-membered heteroaryl, or 5-membered heteroaryl is unsubstituted or substituted with F, Cl, CN, —OCH3, or —CH2OH; 20. The compound, salt, hydrate or stereoisomer of claim 19.

25. A compound having a structure selected from the following:

26. 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 16 and 19 to 25 and one or more pharmaceutically acceptable excipients.

27. 26. Use of a compound according to any one of claims 1 to 16 and 19 to 25 in the manufacture of a medicament for inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof.

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

29. 26. A compound according to any one of claims 1 to 16 and 19 to 25 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.

30. The composition of claim 26 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.

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