Azetidine cyclic ureas

Abstract

Azetidine 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, are provided. The compounds of the invention are used in pharmaceutical compositions and methods of use and manufacturing, including treating a person in need thereof with an effective amount of a compound or composition of the invention and detecting a resulting improvement in the person's health or condition.

Description

[Background technology]

[0001] This application claims priority to International Patent Application No. PCT / CN2020 / 091416, 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 various pathological conditions, including ischemic brain injury, neurodegenerative diseases, and viral infections. Dunai et al., Dec 2011, Pathol. Oncol. Res: POR 17 (4): 791-800. Necrostatin-1 (Nec-1), a small molecule inhibitor of RIP1 kinase activity, can block necroptosis. Degterev et al., Nat Chem Biol 2005; 1: 112-119.

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

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

[0007] <Summary of the Invention>

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

[0009] In one aspect, the present invention provides a compound of formula I, or a salt, hydrate, or stereoisomer thereof: JPEG0007764398000001.jpg90127

[0010] (In the formula, R1 is a 1-F substituted C6 aryl containing 0, 1 or 2 N heteroatoms; and R2 is a C5 aryl containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.

[0011] In embodiments:

[0012] R2 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] R1 includes N2, N4, or N2 / N4 (unless otherwise specified, " / " means "and");

[0014] R2 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 or N2 / N3 / N4; or Any combination of the above substituents.

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

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

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

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

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

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

[0021] Description of Specific Embodiments of the Invention

[0022] It is understood that the examples and embodiments described herein are merely illustrative of the present invention, and that various modifications or variations will be suggested to those skilled in the art based on these examples and embodiments, and that such modifications or variations 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.

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

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

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

[0026] The term "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, 2 to 12, 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.

[0027] 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, or 3 to 4 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, and groups having 7 to 12 ring atoms arranged 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 or 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.

[0028] As used herein, the term "aryl" refers to groups selected from five- and six-membered carbocyclic aromatic rings (e.g., phenyl, etc.); bicyclic systems (e.g., 7- to 12-membered bicyclic systems) in which at least one ring is carbocyclic aromatic (e.g., bicyclic systems selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline); and tricyclic systems (e.g., 10- to 15-membered tricyclic systems) in which at least one ring is carbocyclic aromatic (e.g., fluorene, etc.). A five- or six-membered "aryl" may contain zero, one, two, or three heteroatoms selected from the group consisting of N, S, or O.

[0029] For example, an aryl group may be selected from a 5- or 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring or heterocycle, optionally containing at least one heteroatom selected from N, O, and S. When the carbocyclic aromatic ring is fused to a heterocycle, the point of attachment is on the carbocyclic aromatic ring; when the carbocyclic aromatic ring is fused to a cycloalkyl group, the point of attachment may be on either the carbocyclic aromatic ring or the cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are called substituted phenylene radicals. In monovalent polycyclic hydrocarbon radicals whose names end in "yl," divalent radicals derived by removing one hydrogen atom from the carbon atom having the free valence are named by adding "idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two points of attachment is called naphthylidene.

[0030] The term "halogen" or "halo" refers to F, Cl, Br, or I.

[0031] The term "heteroalkyl" refers to an alkyl that includes at least one heteroatom.

[0032] The term "heteroaryl" refers to a group selected from:

[0033] 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;

[0034] 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

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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 the heterocycle.

[0040] 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.

[0041] Examples of heterocyclic rings (numbered starting from the bonding position) include 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, and oxetanyl. , thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4- Examples include, but are not limited to, thiazepanyl, 1,4-diazepane, 1,4-dithianyl, 1,4-azathiyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0042] 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 groups having 7 to 12 ring atoms arranged as a bicyclic group selected from the aforementioned [4,4] ring system, [4,5] ring system, [5,5] ring system, [5,6] ring system, and [6,6] ring system; fused bicyclic aryl rings, such as the aforementioned 7- to 12-membered bicyclic aryl ring system; fused tricyclic aryl rings, such as the aforementioned 10- to 15-membered tricyclic aryl ring system; fused bicyclic heteroaryl rings, such as the aforementioned 8- to 12-membered bicyclic heteroaryl ring; fused tricyclic heteroaryl rings, such as the aforementioned 11- to 14-membered tricyclic heteroaryl ring; and the aforementioned fused bicyclic heterocyclyl rings and fused tricyclic heterocyclyl rings.

[0043] 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 hydrocarbyls are optionally substituted, heteroatom-containing, and cyclic alkyl, alkenyl, or alkynyl, or optionally substituted, heteroatom-containing, and cyclic aryl, and / or the optionally substituted heteroatoms are 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.

[0044] 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."

[0045] 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.

[0046] Preferred substituents are disclosed herein, specific examples of which are illustrated 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.

[0047] In certain embodiments, applicable substituents are each independently a substituted or unsubstituted heteroatom, a substituted or unsubstituted C1-C6 alkyl, C1-C3 alkyl, or C1-C2 alkyl having 0 to 3 heteroatoms, a substituted or unsubstituted C2-C6 alkenyl having 0 to 3 heteroatoms, a substituted or unsubstituted C2-C6 alkynyl having 0 to 3 heteroatoms, or a substituted or unsubstituted C6-C14 aryl or C5-C6 aryl having 0 to 3 heteroatoms, and each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0048] 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). It should be noted that when used in the context of a substituent, terms such as aldehyde, aldimine, amine, azo, ester, imine, isocyanide, isocyanate, nitrate, nitrite, phosphate, sulfide or trifluoromethyl ether are equivalent to an aldehyde group, an aldimine group, an amino group, an azo group, an ester group, an imino group, an isocyanide group, an isocyanate group, a nitrate group, a nitrite group, a phosphate group, a sulfide group or a trifluoromethyl ether group, respectively.

[0049] Combinations of substituents disclosed herein are those that result in the formation of stable or chemically feasible compounds. If, by omission or convention, a hydrogen atom bonded to an atom (e.g., a carbon atom C or a nitrogen atom N) is not specifically designated in a chemical structure, formula, or representation, the hydrogen atom is deemed to be present to the extent that the valence of that atom (e.g., C or N) is satisfied.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] Some compounds of the present invention may have different points of attachment of hydrogen, and such compounds are called tautomers. For example, a compound having a carbonyl group (-CHC(O)-) (keto form) may form a hydroxyl group (-CH=C(OH)-) (enol form) through tautomerism. Where applicable, both the keto and enol forms are intended to be included, both individually and as mixtures of the keto and enol forms.

[0054] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products from each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a single solvent or a mixture of solvents, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase chromatography; size-exclusion chromatography; ion-exchange chromatography; high-, medium-, and low-pressure liquid chromatography methods and devices; small-volume analytical chromatography; simulated moving bed ("SMB") chromatography; preparative thin-layer chromatography; preparative thick-layer chromatography; and small-volume thin-layer and flash chromatography techniques. One skilled in the art will be able to apply the technique most likely to achieve the desired separation.

[0055] Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomeric mixtures can be converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting each resulting diastereomer into its corresponding pure enantiomer (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0056] Single stereoisomers (e.g., substantially pure enantiomers) may be obtained by resolving a racemic mixture, such as by forming diastereomers using an optically active resolving agent. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by suitable methods, including, for example, (1) forming ionic diastereomeric salts with chiral compounds and separating them by methods such as fractional crystallization, (2) forming diastereomeric compounds with chiral derivatizing reagents, separating the diastereomers, and converting them to pure stereoisomers, and (3) directly isolating substantially pure or enriched stereoisomers under chiral conditions.

[0057] 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.

[0058] Furthermore, if a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) may be prepared by dissolving the free base in a suitable organic solvent and treating the resulting solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be aware of the various synthetic methods available for preparing pharmaceutically acceptable, non-toxic addition salts without undue experimentation.

[0059] "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.

[0060] An "effective amount" refers to an amount of at least one compound, and / or at least one stereoisomer 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.

[0061] 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:

[0062] The subject compounds, their stereoisomers, hydrates, and pharmaceutically acceptable salts thereof may be used alone to provide therapy, or may be used in combination with at least one other therapeutic agent to provide therapy. In some embodiments, the compounds of the present invention, their stereoisomers, hydrates, 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.

[0063] Additionally, compositions comprising the subject compounds, their stereoisomers, their hydrates, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier are provided.

[0064] Compositions containing the subject compounds, their stereoisomers, hydrates, and pharmaceutically acceptable salts thereof can be administered by a variety of known methods, including oral, topical, rectal, parenteral, 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.

[0065] The subject compounds, their stereoisomers, and pharmaceutically acceptable salts thereof can be administered orally in solid dosage forms such as capsules, tablets, lozenges, dragees, granules, powders, and the like, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The subject compounds disclosed herein, their stereoisomers, and pharmaceutically acceptable salts thereof can also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions, and solutions. The subject compounds disclosed herein, their stereoisomers, and pharmaceutically acceptable salts thereof can also be administered using other dosage forms, such as ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions (i.e., eye drops) for ophthalmic administration; aerosol spray or powder compositions for inhalation or intranasal administration; and creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0066] 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.

[0067] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring agents and flavoring agents to facilitate patient administration.

[0068] In general, examples of suitable carriers for parenteral solutions include water, suitable oils, saline, aqueous dextrose (glucose), related sugar solutions, and glycols (such as propylene glycol or polyethylene glycol). Solutions for parenteral administration may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Examples of suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, which may be used alone or in combination. Examples of suitable stabilizers include citric acid and its salts and sodium EDTA. Furthermore, parenteral solutions may contain at least one preservative, such as benzalkonium chloride, methylparaben, propylparaben, and chlorobutanol.

[0069] 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 improve 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.

[0070] When administered by inhalation, the subject compounds, their stereoisomers, and pharmaceutically acceptable salts thereof may be conveniently delivered in the form of an aerosol spray from a pressurized container or inhaler. The subject compounds, their stereoisomers, and pharmaceutically acceptable salts thereof may also be delivered as powders, which may be formulated, 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 pharmaceutically acceptable salts thereof in at least one suitable propellant, such as fluorocarbons and hydrocarbons.

[0071] For ocular administration, the ophthalmic formulation may be formulated as a suspension or solution containing the subject compound, its stereoisomers, hydrates thereof, and pharmaceutically acceptable salts thereof in an appropriate weight percentage in a suitable ophthalmic solvent, thereby maintaining contact of the subject compound, its stereoisomers, hydrates thereof, and 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 interior regions of the eye.

[0072] Pharmaceutical dosage forms useful for administering the subject compounds disclosed herein, their stereoisomers, hydrates thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, hard gelatin capsules, soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

[0073] 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.

[0074] In some embodiments, for example, a number of unit capsules can be prepared by filling a standard two-piece hard gelatin capsule with 100 mg of a powdered subject compound disclosed herein, its stereoisomers, hydrates thereof, and pharmaceutically acceptable salts thereof, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

[0075] 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, 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.

[0076] In some embodiments, bulk tablets can be prepared by conventional procedures so that, for example, a dosage unit contains 100 mg of the compound of the present invention, its stereoisomers, and pharmaceutically acceptable salts 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.

[0077] 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.

[0078] In some embodiments, an aqueous suspension for oral administration can be prepared. For example, 5 mL of an aqueous suspension containing 100 mg of a micronized compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP), and 0.025 mL of vanillin can be used.

[0079] When the compound of the present invention, its stereoisomers, and 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.

[0080] The compounds disclosed herein, their stereoisomers, hydrates, and 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.

[0081] The subject compounds, their stereoisomers, hydrates, and / or pharmaceutically acceptable salts are incorporated into pharmaceutical compositions or formulations. These compositions will contain pharmaceutically acceptable diluents and / or carriers, i.e., diluents or carriers that are physiologically compatible and substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing administrable compositions will be 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 are administered in the morning / midday with a rest period at night.

[0082] The target compound may be used as it is, or may be used in the form of a pharmaceutically acceptable salt such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compound of the present invention has a relatively acidic functionality, a salt can be obtained by adding a desired base in a solvent-free or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salt, potassium salt, calcium salt, ammonium salt, organic amino salt, magnesium salt, etc. When the compound of the present invention has a relatively basic functionality, a salt can be obtained by adding a desired acid in a solvent-free or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen 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).

[0083] The neutral compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds may differ from the various salt forms in physical properties such as solubility in polar solvents, but for purposes of the present invention, the salts are otherwise equivalent to the parent forms of the compounds.

[0084] In addition to salt forms, the present invention provides compounds in prodrug forms. Prodrugs of the compounds described herein are compounds that are readily chemically altered under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. In some situations, prodrugs are often useful because they are easier to administer than the parent drug. For example, prodrugs may have better oral bioavailability than the parent drug. Prodrugs may also have improved solubility in pharmacological compositions compared to the parent drug. Various prodrug derivatives are known in the art, including, for example, prodrugs that utilize hydrolysis or oxidative activation. Examples of prodrugs include, but are not limited to, compounds of the present invention that are administered as an ester (the "prodrug") and then metabolically hydrolyzed to the active carboxylic acid.

[0085] 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.

[0086] Some of the subject compounds possess asymmetric carbon atoms (optical centers) or double bonds; all of the racemates, diastereomers, geometric isomers and individual isomers thereof are intended to be encompassed within the scope of the present invention.

[0087] The compounds of the present invention may contain isotopes such as deuterium at one or more of the constituent atoms of the compound in proportions not found in nature, for example, -CD3, CD2H, or CDH2 in place of methyl. For example, the compounds of the present invention may contain isotopes such as tritium ( 3 H), iodine-125( 125 I), carbon-14 ( 14 The compounds of the present invention may be radiolabeled with a radioisotope such as C. All compounds of the present invention that contain isotopes, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present invention.

[0088] Compounds are typically administered in a "therapeutically effective amount," i.e., an amount of the compound of interest that will induce in a tissue, system, animal, or human the biological or medical response desired by a researcher, veterinarian, physician, or other clinician. The term "therapeutically effective amount" encompasses an amount of compound sufficient, when administered, to prevent the development of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0089] Contacting is typically achieved by administering to the subject an effective amount of one or more compounds having general formula I (see above), including the various embodiments described above. Generally, administration is adjusted to provide a therapeutic dose of about 0.1 to 50 mg / kg, preferably 0.5 to 10 mg / kg, and more preferably 1 to 10 mg / kg, although the optimal dose is compound-specific and is generally determined empirically for each compound.

[0090] 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 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 at least 6, 9 or 12 sheets of unit dosage forms.

[0091] 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.

[0092] In one embodiment, the compound of the present disclosure is a compound of the following structural formula I, or a salt, hydrate, or stereoisomer thereof: JPEG0007764398000002.jpg93127 (wherein R1 is a 1-F substituted C6 aryl containing 0, 1, or 2 N heteroatoms; and R2 is a C5 aryl containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0093] In one embodiment, the substituents of R2 are independently selected from the group consisting of 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, phospho R1 is N2, N4, or N2 / N4; R2 is 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, or N2 / N3 / N4; or any combination of the foregoing substituents.

[0094] 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): JPEG0007764398000003.jpg99127 (wherein R2 (ring 2) is a C5 aryl (5-membered aryl) containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0095] 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): JPEG0007764398000004.jpg104127 (wherein R2 (ring 2)) is a C5 aryl (5-membered aryl) containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[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(3): JPEG0007764398000005.jpg104127 (wherein R2 (ring 2) is a C5 aryl (5-membered aryl) containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[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(4): JPEG0007764398000006.jpg105127 (wherein R2 (ring 2) is a C5 aryl (5-membered aryl) containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[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(5): JPEG0007764398000007.jpg101127 (wherein R2 (ring 2)) is a C5 aryl (5-membered aryl) containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom, and substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0099] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R2 is substituted with 0-3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl. JPEG0007764398000008.jpg71159, 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 III(1): JPEG0007764398000009.jpg101127 (wherein R1 (ring 1) is a 1-F substituted C6 aryl (6-membered aryl) containing 0, 1, or 2 N heteroatoms; and wherein R2 (ring 2) is a C5 aryl represented by structural formula III(1) substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[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 III(2): JPEG0007764398000010.jpg101127 (wherein R1 (ring 1) is a 1-F substituted C6 aryl (6-membered aryl) containing 0, 1, or 2 N heteroatoms; and wherein R2 (ring 2) is a C5 aryl represented by structural formula III(2) substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0102] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has the following structural formula III(3): JPEG0007764398000011.jpg106127 (wherein R1 (ring 1) is a 1-F substituted C6 aryl (6-membered aryl) containing 0, 1, or 2 N heteroatoms; and wherein R2 (ring 2) is a C5 aryl as shown in structural formula III(3) substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0103] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has any of the following structural formulas IV(1)-IV(5): JPEG0007764398000012.jpg82159 (wherein R2 is a C5 aryl represented by structural formulas IV(1) to IV(5) substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0104] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has any of the following structural formulas IV(6)-IV(10): JPEG0007764398000013.jpg42159JPEG0007764398000014.jpg43159 (In the formula, R2 is a C5 aryl represented by structural formulas IV(6) to IV(10) substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0105] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has any of the following structural formulas IV(11)-IV(15): JPEG0007764398000015.jpg85159 (wherein R2 is a C5 aryl represented by structural formulas IV(11) to IV(15) substituted with 0 to 3 substituents selected from halide, optionally substituted N, S, or O, and optionally substituted hydrocarbyl.)

[0106] In one embodiment, the disclosure provides a compound, salt, hydrate, or stereoisomer thereof, wherein R2 is 0 to 3 R a where R a 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 、 -ORs , -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 a The 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; where: R p , R q , R r , and R sis, for each occurrence, independently selected from hydrogen, OH, NH, C-C alkyl, C-C cycloalkyl, and 3-6 membered heterocyclyl; where: R p , R q , R r , and R s Any one of the C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 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)(3-6 membered heterocyclyl), -C(=O)(C3-C6 cycloalkyl), C3-C6 cycloalkyl, phenyl, and 3-6 membered heterocyclyl; where: w is an integer selected from 0, 1, and 2; 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, salt, hydrate, or stereoisomer thereof, wherein R2 is selected from 1 to 3 R a where R a is, for each occurrence independently, one of the following: halogen; cyano; 4- to 6-membered heterocyclyl optionally substituted with oxo; -C(=O)(C1-C6 alkyl); -C(=O)(C3-C6 cycloalkyl); -C(=O)(4- to 6-membered heterocyclyl); 3- to 4-membered cycloalkyl; -C(=O)OR s , where R s is H or C1-C3 alkyl; C1-C3 alkyl, which may be substituted with OH, NH2, cyano, halogen, C1-C3 alkoxyl, 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, OH, CN, 4- to 6-membered heterocyclyl, C1-C3 alkyl optionally substituted with OH, and 3- to 4-membered cycloalkyl optionally substituted with OH; -NR p R q , where R p and R q are each independently selected from H, OH, —C(═O)CH3, and C1-C3 alkyl optionally substituted with OH, 3- to 4-membered cycloalkyl, or 6-membered heterocyclyl; -NR p C(=O)NR q R r , where R p , R q and R r 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, R s is selected from C1-C3 alkyl and 3-4 membered cycloalkyl; -S(=O) w R s , where R s is selected from phenyl or C1-C3 alkyl optionally substituted with NH2, and w is 0 or 2; and -S(=O) w NR p R q , where R p and R q are each independently selected from H, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, and C1-C3 alkyl optionally substituted with OH, C1-C3 alkoxyl, or phenyl, and w is 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, salt, hydrate, or stereoisomer thereof, wherein R2 is selected from 1 to 3 R a where R a is, for each occurrence independently, one of the following: methyl, ethyl, -NH2, -CN, -OCH3, -O(CH2)2N(CH3)2, -NHCH3, -O(CH2)2OCH3, -N(CH3)2, -NH(CH2)OCH3, -NHC(=O)CH3, -NHC(=O)CH2CH3, -NHC(=O)CH(CH3)2, -NHC(=O)CH2CH(CH3)2, -NHCH2C(=O)NHCH3, -NHCH2C(=O)NHCH3, JPEG0007764398000016.jpg239159JPEG0007764398000017.jpg100159-CH2C(=O)OH, -C(CH3)2C(=O)OH, and -C(CH3)2C(=O)NH2 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, salt, hydrate, or stereoisomer thereof, wherein R2 is selected from 1 to 3 R a where R a is, for each occurrence independently, one of the following: methyl, ethyl, -NH2, -NHCH3, -CN, -CH2CH2OH, JPEG0007764398000018.jpg179159 -C(=O)NHCH2CH2OH and -CH2CN 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, salt, hydrate, or stereoisomer thereof, wherein R2 is selected from 1 to 3 R a where R a is, for each occurrence independently, one of the following: methyl, ethyl, -NH2, -C(=O)NH2, -NHCH3, -CN, -CH2CN, -NHCH2OH, -CH2NH2, -SCH3, CONHCH3, -SO2CH3, -CH2OH, -Cl, -N(CH3)2, -NHCH(CH3)2, -NHCH2CH2OCH3, -CH2CH2OH, -C(=O)OCH2CH3, -C(=O)OCH3, -C(=O)OH, -S(=O)2NH2, -CH2C(=O)NH2, -C(=O)NHCH2CH2OH, JPEG0007764398000019.jpg25159, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0111] In one embodiment, the disclosure provides a compound, a salt, a hydrate, or a stereoisomer thereof, wherein the compound has one of the structural formulas in Table 1 and Table 3.

[0112] Table 1: Active compounds 1-116: Structure [Table 1-1]

[0113] [Table 1-2]

[0114] [Table 1-3]

[0115] [Table 1-4]

[0116] Table 1-5

[0117] Table 1-6

[0118] Table 1-7

[0119] Table 2: Cell activity (EC) of compounds 1-116 50 ) Table 2-1

[0120] Table 2-2

[0121] Table 3: Structure of active compounds 117-281 Table 3-1

[0122] Table 3-2

[0123] Table 3-3

[0124] Table 3-4

[0125] Table 3-5

[0126] [Table 3-6]

[0127] [Table 3-7]

[0128] [Table 3-8]

[0129] [Table 3-9]

[0130] [Table 3-10]

[0131] [Table 3-11]

[0132] [Table 3-12]

[0133] Table 4: Cellular activity (EC 50 ) [Table 4-1]

[0134] [Table 4-2] [Example]

[0135] Preparation of compounds

[0136] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (1) JPEG0007764398000043.jpg89159

[0137] Step 1: tert-Butyl 3-hydroxyazetidine-1-carboxylate (1.5 g, 8.66 mmol) was dissolved in 15 mL of DCM, trifluoroacetic acid (1.5 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Concentration gave the desired product 1-01, which was used in the next step without further purification.

[0138] Step 2: 1-01 (633 mg, 8.66 mmol), 1-02 (2.39 g, 8.66 mmol), and TEA (1 mL) were dissolved in THF (15 mL) and stirred at 25 °C for 6 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave intermediate 1-03 (2.1 g, 87.5%). MS (m / z): 282.3 [M+H] + .

[0139] Step 3: 6-Chloro-3-fluoropyridin-2-ol (200 mg, 1.36 mmol) was dissolved in 3 mL of dry THF. DEAD (328 mg mL, 1.63 mmol), compound 1-03 (400 mg, 1.423 mmol), and PPh3 (540 mg, 2.04 mmol) were added to the above solution at room temperature. The mixture was stirred at 25 °C for 12 hours. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded compound 1-04 (300 mg, 51%) as a white solid. Mass (m / z) 411.2 [M+H] + .

[0140] Step 4: 1-04 (200 mg, 0.49 mmol), x-phos (46.3 mg, 0.098 mmol), bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (534 mg, 2 mmol), KOAc (150 mg, 1.5 mmol), and Pd2(dba)3 (44.5 mg, 0.098 mmol) were placed in dioxane (3 mL). The mixture was stirred at 100 °C under N2 for 2 h. The mixture was extracted with DCM, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded intermediate 1-05 as a white solid. Mass (m / z): 503.2 [M+H] + .

[0141] Step 5: 1-05 (100 mg, 0.24 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (101 mg, 0.48 mmol), X-Phos (11.42 mg, 0.028 mmol), KOAc (70.56 mg, 0.96 mmol), Pd(dba) (21.9 mg, 0.024 mmol), and KPO (5N, 1 mL) were added to dioxane (3 mL). The mixture was stirred at 100 °C under N for 2 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 1 (20 mg, 20.3%) as a white solid. Mass (m / z) 457.2 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 0.0 Hz, 2H), 7.20 (dd, J = 8.2, 2.8 Hz, 1H), 6.86 - 6.61 (m, 4H), 6.55 - 6.45 (m, 1H), 5.57 - 5.35 (m, 1H), 5.27 (dd, J = 12.3, 6.5 Hz, 1H), 4.70 -4.45(m, 2H), 4.31 (dd, J = 30.8, 9.7 Hz, 2H), 4.16 (s, 3H), 3.34 (dd, J = 18.6, 12.2 Hz, 1H), 2.69 (dd, J = 18.6, 6.4 Hz, 1H).

[0142] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (2) JPEG0007764398000044.jpg68159

[0143] Step 1: To a solution of CsCO (19.5 g, 59.9 mmol) in DMF (100 mL), 2,4-dichloro-5-fluoropyrimidine (5 g, 29.9 mmol) was added, followed by tert-butyl 3-hydroxyazetidine-1-carboxylate (5.7 g, 32.9 mmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was then extracted three times with EtOAc / HO (50 mL / 50 mL). The organic layers were combined, washed with brine, dried over NaSO, concentrated, and further purified by silica gel column chromatography (PE / EA = 5 / 1) to give 3.9 g of tert-butyl 3-((2-chloro-5-fluoropyrimidin-4-yl)oxy)azetidine-1-carboxylate (2-01) as a colorless oil (43%). Mass (m / z) 304.1 [M+H] +

[0144] Step 2: To a solution of 2-01 (3.9 g, 12.9 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 0.5 h, and then the solvent was evaporated in vacuo to give 5.2 g of 4-(azetidin-3-yloxy)-2-chloro-5-fluoropyrimidine (2-02) (crude) as a colorless oil. Mass (m / z) 204.1 [M+H] +

[0145] Step 3: (S)-(5-(3,5-Difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (1-02) (3.23 g, 11.7 mmol) was added to a solution of TEA (3.55 g, 35.1 mmol) and 4-(azetidin-3-yloxy)-2-chloro-5-fluoropyrimidine (2-02) in 1,4-dioxane (30 mL). The reaction mixture was stirred at room temperature overnight. The solvent was then evaporated in vacuo. The oil residue was purified by silica gel column chromatography (PE / EA=1 / 1) to give 4.35 g of (S)-(3-((2-chloro-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone as a yellow oil (2-03) (90%). Mass (ESI) m / z [M+H] + :412.1.

[0146] Step 4: Following the procedure outlined for compound 1, the title compound 2 was prepared from 2-03 in 59.2% yield. Mass (m / z) 458.2 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.79 (t, J = 1.7 Hz, 1H), 6.77 - 6.74 (m, 2H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 5.53 (tt, J = 6.6, 4.2 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 4.69 - 4.58 (m, 2H), 4.37 (dd, J = 10.7, 4.1 Hz, 1H), 4.30 (s, 4H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0147] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (3) JPEG0007764398000045.jpg82159

[0148] Step 1: Under a nitrogen atmosphere, at -72°C, to a stirred solution of 2-chloro-5-fluoropyridine (25.0 g, 190 mmol) in tetrahydrofuran (250 mL) is added LDA (124 mL, 2 M in tetrahydrofuran) dropwise over 30 minutes. The reaction mixture is stirred at -72°C for 2 hours. Then, a solution of trimethyl borate (39 g, 375 mmol) is added dropwise over 20 minutes. After the addition, the reaction mixture is stirred at room temperature for an additional 2 hours. The reaction mixture is cooled to 0°C and acetic acid (32.5 mL) is added. The reaction mixture is stirred at 0°C for 30 minutes. Hydrogen peroxide (58 mL, 30% solution) is added dropwise at 0°C. The reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched with saturated aqueous NaSO. HCl (4 M in dioxane) is added to the reaction mixture until the pH is <7. After extraction with EA (300 mL × 3), the combined organic phase was washed with water and brine, dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The crude was stirred with DCM and filtered. The mother liquor was recrystallized twice with DCM to give 15.2 g of a white solid as intermediate 3-01 (yield: 54%).

[0149] Step 2: PPh3 (1.43 g, 5.4 mmol) in 50 mL of dry THF was added to DIAD (1.1 g, 5.4 mmol) at room temperature under nitrogen protection. After 5 minutes, 3-01 (670 mg, 4.5 mmol) was added to the above solution at room temperature. The mixture was stirred at room temperature for 30 minutes. Next, tert-butyl 3-hydroxyazetidine-1-carboxylate (944 mg, 5.4 mmol) was added. The mixture was heated to reflux for 3 hours. HO was added to the resulting solution, which was then extracted with EA. The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1.3 g of intermediate 3-02 (yield: 95%) as a white solid.

[0150] Steps 3 and 4: Intermediate 3-04 was prepared from 3-02 following the procedure for 2-03.

[0151] Step 5: Following the procedure for 1, the title compound 3 was prepared from 3-04.

[0152] Mass (m / z) 457.2 [M+H] + 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 6.5 Hz, 1H), 6.80 (s, 1H), 6.78, 6.66 (m, 3H), 6.47 (d, J = 2.0 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.13- 5.04 (m, 1H), 4.67- 4.52 (m, 2H), 4.32 (dd, J = 29.1, 10.4 Hz, 2H), 4.17 (s, 3H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0153] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1-ethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (4) JPEG0007764398000046.jpg4464

[0154] Following the procedure outlined for compound 3, the title compound 4 was prepared in 80.1% yield. Mass (m / z) 471.2 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.42 (dd, J = 2.8, 0.6 Hz, 1H), 7.51 (dd, J = 2.0, 0.6 Hz, 1H), 6.85 (d, J = 6.5 Hz, 1H), 6.80 - 6.66 (m, 4H), 6.44 (dd, J = 2.0, 0.6 Hz, 1H), 5.29 - 5.20 (m, 1H), 5.12-5.04 (m, 1H), 4.59 (q, J = 7.2 Hz, 4H), 4.39 - 4.15 (m, 2H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.7, 6.5, 1.7 Hz, 1H), 1.41 (t, J = 7.2, 3H).

[0155] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (5) JPEG0007764398000047.jpg4164

[0156] Following the procedure outlined for compound 1, the title compound 5 was prepared in 18.6% yield. Mass (m / z) 457.2 [M+H] + ; 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (dd, J = 8.1, 3.0 Hz, 1H), 7.64 (td, J = 8.8, 2.8 Hz, 1H), 7.55 (s, 1H), 7.28 - 7.14 (d, 1H), 6.87 - 6.63 (m, 4H), 5.47-5.36 (m, 1H), 5.28 - 5.21 (m, 1H), 4.66-4.51 (m, 2H), 4.44 - 4.21 (m, 2H), 4.14 (s, 3H), 3.47 - 3.29 (m, 1H), 2.80 - 2.56 (m, 1H).

[0157] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(1-methyl-1H-imidazol-5-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (6) JPEG0007764398000048.jpg4164

[0158] Following the procedure outlined for compound 1, the title compound 6 was prepared from 1-05 in 18.7% yield. Mass (m / z) 457.3 [M+H] + ; 1 H NMR (400 MHz, Chloroform-d) δ 7.41 - 6.70 (m, 4H), 6.70 - 5.98 (m, 4H), 4.89 (d, J = 16.0 Hz, 2H), 4.44-4.05 (m, 2H), 3.92 (d, J = 37.8 Hz, 2H), 3.54 (s, 3H), 3.11 - 2.85(m, 1H), 2.43 - 2.18 (m, 1H).

[0159] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-imidazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (7) JPEG0007764398000049.jpg3864

[0160] Following the procedure outlined for compound 3, the title compound 7 was prepared from 3-04 in 24.1% yield. Mass (m / z): 457.2 [M+H]+, 1H NMR (400 MHz, Chloroform-d) δ 8.36 (dd, J = 2.9, 1.0 Hz, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 6.91 - 6.65 (m, 5H), 5.28 - 5.22 (m, 1H), 5.09 - 5.07 (m, 1H), 4.67 -4.51 (s, 2H), 4.36 -4.26 (dd, J = 27.7, 9.7 Hz, 2H), 3.95 (s, 3H), 3.43 - 3.29 (m, 1H), 2.78 - 2.65 (m, 1H).

[0161] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (8) JPEG0007764398000050.jpg3964

[0162] Following the procedure outlined for compound 2, the title compound 8 was prepared from 3-04 in 65.5% yield. Mass (m / z) 458.3 [M+H] + ; 1 H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 7.98 (s, 1H), 6.89 - 6.59 (m, 4H), 5.51 (s, 1H), 5.29 (dd, J = 12.3, 6.2 Hz, 1H), 4.64 (d, J = 25.7 Hz, 2H), 4.42 - 4.12 (m, 5H), 3.37 (dd, J = 18.7, 12.1 Hz, 1H), 2.72 (dd, J = 18.6, 6.4 Hz, 1H).

[0163] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-methylthiazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (9) JPEG0007764398000051.jpg53159

[0164] Step 1: 5-Bromo-4-methylthiazole (89 mg, 0.5 mmol), B2pin2 (254 mg, 1.0 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), KOAc (147 mg, 1.5 mmol) in 1,4-dioxane (2 mL) under N2, and the reaction mixture was stirred at 100 °C for 3 h. Concentration gave intermediate 9-01, which was used in the next step without further purification. Mass (m / z): 226.2 [M+H] + .

[0165] Step 2: Compound 2-03 (82 mg, 0.20 mmol), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole 9-01 (90 mg, 0.40 mmol), Pd(dba) (18 mg, 0.02 mmol), and X-phos (19 mg, 0.04 mmol) were added to a solution of KPO (5N, 0.2 mL, 1.0 mmol) in 1,4-dioxane (2 mL) under N, and the whole reaction mixture was stirred at 110 °C for 2 h. The mixture was concentrated and then further purified by prep-HPLC to give the final compound 9 (9 mg, 9.5%) as a white solid. Mass (m / z) 475.2 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.40 (d, J = 2.3 Hz, 1H), 6.85 - 6.64 (m, 4H), 5.53 (s, 1H), 5.30 (d, J = 0.4 Hz, 1H), 4.66 (s, 2H), 4.46 - 4.25 (m, 2H), 3.37 (dd, J = 18.6, 11.5 Hz, 1H), 2.91 (s, 3H), 2.72 (dd, J = 18.4, 5.3 Hz, 1H).

[0166] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(4-methylthiazol-5-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (10) JPEG0007764398000052.jpg4264

[0167] The title compound 10 was prepared from 1-05 following the procedure outlined for compound 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (dd, J = 8.7, 4.2 Hz, 1H), 7.48-7.34 (m, 1H), 7.20-7.07 (m, 1H), 6.84 - 6.56 (m, 4H), 5.50-5.35 (m, 1H), 5.30-5.20 (m, 1H), 4.77 - 4.48 (m, 2H), 4.43 - 4.17 (m, 2H), 3.44 - 3.16 (m, 1H), 2.68 (dd, J = 8.8, 4.2 Hz, 3H), 2.13 - 1.91 (m, 1H). Mass (m / z): 474.2 [M+H] + .

[0168] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-methylthiazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (11) JPEG0007764398000053.jpg4164

[0169] Following the procedure outlined for compound 3, the title compound 11 was prepared from 3-04 in 42.2% yield. Mass (m / z) 474.2 [M+H] + ; 1 H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.43 (dd, J = 3.0, 1.7 Hz, 1H), 6.99 - 6.63 (m, 5H), 5.34 - 5.23 (m, 1H), 5.13 (s, 1H), 4.62 (s, 2H), 4.35 (dd, J = 35.1, 10.3 Hz, 2H), 3.38 (dd, J = 18.7, 12.1 Hz, 1H), 2.73 (s, 4H).

[0170] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(5-methylthiazol-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (12) JPEG0007764398000054.jpg3864

[0171] Following the procedure outlined for compound 2, the title compound 12 was prepared from 2-03 in 6.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.51 (s, 1H), 6.75 (dd, J = 23.2, 16.4 Hz, 4H), 5.76 (s, 1H), 5.37 - 5.24 (m, 1H), 4.65 (s, Mass (m / z) 475.2 [M+H] + .

[0172] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(5-methylthiazol-4-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (13) JPEG0007764398000055.jpg4364

[0173] Following the procedure outlined for compound 1, the title compound 13 was prepared from 1-05 in 17.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.78 (dd, J = 8.3, 3.1 Hz, 1H), 7.45 (dd, J = 9.8, 8.3 Hz, 1H), 6.83 - 6.66 (m, 4H), 5.52 (tt, J = 6.6, 4.2 Hz, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.59 (d, J = 8.2 Hz, 2H), 4.32 (dd, J = 38.5, 10.5 Hz, 2H), 3.35 (ddd, J = 18.5, 12.2, 1.7 Hz, 1H), 2.84 (s, 3H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H). Mass (m / z) 474.2 [M+H] + .

[0174] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(5-methylthiazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (14) JPEG0007764398000056.jpg4364

[0175] Following the procedure outlined for compound 3, the title compound 14 was prepared from 3-04 in 30.3% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 6.80 - 6.63 (m, 4H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 5.15 (td, J = 6.5, 3.3 Hz, 1H), 4.63 (s, 2H), 4.32 (dd, J = 27.0, 10.6 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.86 (s, 3H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H). Mass (m / z) 474.2 [M+H]+.

[0176] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-methylisothiazol-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (15) JPEG0007764398000057.jpg3964

[0177] Following the procedure outlined for compound 2, the title compound 15 was prepared from 2-03 in 19.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 6.86 - 6.65 (m, 4H), 5.56 (s, 1H), 5.30 (dd, J = 11.9, 6.3 Hz, 1H), 4.66 (s, 2H), 4.46 - 4.25 (m, 2H), 3.40 - 3.29 (m, 1H), 2.85 (s, 3H), 2.72 (dd, J = 18.7, 5.8 Hz, 1H). Mass (m / z) 475.2 [M+H]+.

[0178] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(3-methylisothiazol-4-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (16) JPEG0007764398000058.jpg4064

[0179] Following the procedure outlined for compound 1, the title compound 16 was prepared from 1-05 in 39.6% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (q, J = 0.9 Hz, 1H), 7.77 (dd, J = 8.2, 3.2 Hz, 1H), 7.47 (dd, J = 9.8, 8.2 Hz, 1H), 6.80 - 6.64 (m, 4H), 5.51 (tt, J = 6.6, 4.1 Hz, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.59 (d, J = 9.0 Hz, 2H), 4.31 (dd, J = 36.4, 10.0 Hz, 2H), 3.34 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 2.69 (ddd, J = 18.5, 6.6, 1.7 Hz, 1H), 2.60 (d, J = 0.9 Hz, 3H). Mass (m / z) 474.2 [M+H]+.

[0180] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-methylisothiazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (17) JPEG0007764398000059.jpg4064

[0181] Following the procedure outlined for compound 3, the title compound 17 was prepared from 3-04 in 30.3% yield. 1 H NMR (300 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.44 (d, J = 3.0 Hz, 1H), 6.90 - 6.52 (m, 5H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 5.10 (s, 1H), 4.60 (q, J = 9.2, 8.8 Hz, 2H), 4.33 (dd, J = 24.1, 8.3 Hz, 2H), 3.42 - 3.30 (m, 1H), 2.79 - 2.56 (m, 4H). Mass (m / z) 474.2 [M+H] + .

[0182] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-methylisothiazol-3-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (18) JPEG0007764398000060.jpg4164

[0183] Following the procedure outlined for compound 2, the title compound 18 was prepared from 2-03 in 0.6% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.42 (s, 1H), 6.83 (s, 1H), 6.77 - 6.51 (m, 3H), 5.65 (s, 1H), 5.32 (dt, J = 12.2, 5.7 Hz, 1H), 4.67 (s, 2H), 4.38 (d, J = 30.1 Hz, 2H), 3.38 (dd, J = 18.6, 12.1 Hz, 1H), 2.81 - 2.66 (m, 1H), 2.62 (s, 3H).

[0184] Mass (m / z) 475.2 [M+H] + .

[0185] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(2,4-dimethylthiazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (19) JPEG0007764398000061.jpg4064

[0186] Following the procedure outlined for compound 2, the title compound 19 was prepared from 2-03 in 21.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (dd, J = 2.5, 0.4 Hz, 1H), 6.83 - 6.67 (m, 4H), 5.54 - 5.48 (m, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.64 (q, J = 10.7 Hz, 2H), 4.41 - 4.24 (m, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.80 (s, 3H), 2.75 - 2.66 (m, 4H). Mass (m / z) 489.2 [M+H] + .

[0187] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethylisoxazol-4-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (20) JPEG0007764398000062.jpg4064

[0188] Following the procedure outlined for compound 2, the title compound 20 was prepared from 2-03 in 33.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 2.5 Hz, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.78 - 6.73 (m, 2H), 6.70 (tt, J = 8.8, 2.3 Hz, 1H), 5.53 (tt, J = 6.6, 4.0 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 4.62 (q, J = 11.3, 9.6 Hz, 2H), 4.38 (d, J = 10.8 Hz, 1H), 4.29 (d, J = 10.1 Hz, 1H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.74 (s, 3H), 2.73 - 2.67 (m, 1H), 2.56 (s, 3H). Mass (m / z) 473.2 [M+H] + .

[0189] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(5-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (21) JPEG0007764398000063.jpg4164

[0190] Following the procedure outlined for compound 2, the title compound 21 was prepared from 2-03 in 9.8% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 6.83 - 6.66 (m, 4H), 5.56 - 5.49 (m, 1H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 4.65 (d, J = 18.1 Hz, 2H), 4.33 (dd, J = 33.0, 10.9 Hz, 2H), 3.36 (ddd, J = 18.5, 12.3, 1.6 Hz, 1H), 2.81 (s, 3H), 2.71 (ddd, J = 18.5, 6.4, 1.7 Hz, 1H). Mass (m / z) 459.2 [M+H] + .

[0191] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-methylisoxazol-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (22) JPEG0007764398000064.jpg4164

[0192] Following the procedure outlined for compound 2, the title compound 22 was prepared from 2-03 in 14.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 1H), 8.37 (dd, J = 2.4, 0.8 Hz, 1H), 6.82 - 6.65 (m, 4H), 5.52 (qd, J = 6.6, 4.1 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 4.63 (d, J = 18.1 Hz, 2H), 4.33 (dd, J = 33.3, 10.8 Hz, 2H), 3.36 (dd, J = 18.6, 12.2 Hz, 1H), 2.71 (dd, J = 18.8, 6.5 Hz, 1H), 2.63 (s, 3H). Mass (m / z) 459.2 [M+H] + .

[0193] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(4-methylisothiazol-3-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (23) JPEG0007764398000065.jpg4164

[0194] Following the procedure outlined for compound 1, the title compound 23 was prepared from 1-05 in 42.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 0.6 Hz, 1H), 7.43 (dd, J = 9.7, 8.1 Hz, 1H), 7.13 (dd, J = 8.1, 2.8 Hz, 1H), 6.81 - 6.64 (m, 4H), 5.47 (tt, J = 6.6, 4.2 Hz, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.60 (dd, J = 17.7, 10.9 Hz, 2H), 4.38 - 4.23 (m, 2H), 3.34 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 2.76 - 2.63 (m, 4H). Mass (m / z) 474.2 [M+H] + .

[0195] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (24) JPEG0007764398000066.jpg4264

[0196] Following the procedure outlined for compound 1, the title compound 24 was prepared from 1-05 in 4.7% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.94 (dd, J = 8.2, 3.1 Hz, 1H), 7.51 (dd, J = 9.4, 8.2 Hz, 1H), 6.80 - 6.66 (m, 4H), 5.43 (ddd, J = 11.2, 6.7, 4.4 Hz, 1H), 5.32 - 5.22 (m, 1H), 4.64 (d, J = 10.3 Hz, 2H), 4.43 - 4.11 (m, 2H), 3.46 - 3.20 (m, 1H), 2.81 (s, 3H), 2.75 - 2.60 (m, 1H). Mass (m / z) 475.1 [M+H] +

[0197] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2-methylthiazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (25) JPEG0007764398000067.jpg4264

[0198] Following the procedure outlined for compound 2, the title compound 25 was prepared from 2-03 in 23.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 2.5 Hz, 1H), 8.28 (s, 1H), 6.80 - 6.66 (m, 4H), 5.52 (tt, J = 6.7, 4.3 Hz, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.65 (dt, J = 18.3, 8.4 Hz, 2H), 4.32 (ddd, J = 32.0, 10.7, 4.4 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.76 (s, 3H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H). Mass (m / z) 475.2 [M+H] + .

[0199] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (26) JPEG0007764398000068.jpg4164

[0200] Following the procedure outlined for compound 3, the title compound 26 was prepared from 3-04 in 17.1% yield. 1 H NMR (300 MHz, Chloroform-d) δ 8.33 (d, J = 3.0 Hz, 1H), 7.92 (s, 1H), 6.89 (d, J = 6.4 Hz, 1H), 6.85 - 6.61 (m, 4H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.12 (ddd, J = 10.6, 6.5, 4.0 Hz, 1H), 4.62 (q, J = 9.3, 8.8 Hz, 2H), 4.32 (ddd, J = 24.0, 10.5, 4.0 Hz, 2H), 3.41 - 3.30 (m, 1H), 2.79 - 2.63 (m, 4H). Mass (m / z) 474.2 [M+H] + .

[0201] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (27) JPEG0007764398000069.jpg4364

[0202] Following the procedure outlined for compound 1, the title compound 27 was prepared from 1-05 in 4.5% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.82 (dd, J = 8.2, 3.0 Hz, 1H), 7.55 - 7.48 (m, 1H), 6.81 - 6.64 (m, 4H), 5.61-5.49 (m, 3.3 Hz, 1H), 5.29 (dd, Mass (m / z) 459.2 [M+H]+

[0203] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((3-fluoro-6-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)oxy)azetidin-1-yl)methanone (28) JPEG0007764398000070.jpg3964

[0204] Following the procedure outlined for compound 1, the title compound 28 was prepared from 1-05 in 23.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.84 (m, 2H), 7.53 (dd, J = 9.5, 8.2 Hz, 1H), 6.81 - 6.64 (m, 4H), 5.51 - 5.43 (m, 1H), 5.29 - 5.22 (m, 1H), 4.64 - 4.54 (d, J = 9.7 Hz, 2H), 4.44 - 4.30 (m, 2H), 4.29(s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H). Mass (m / z) 458.2 [M+H] +

[0205] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (29) JPEG0007764398000071.jpg62159

[0206] Step 1: Under N, compound 3-02 (1.04 g, 3.44 mmol), SnMe (1.7 g, 1.5 mmol), 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (112 mg, 0.17 mmol) were dissolved in 1,4-dioxane (15 mL), and the entire reaction mixture was stirred at 120 °C for 3 h. The black suspension was filtered through a plug of Celite and washed with EA (100 mL). Concentration gave 29-01 (1.47 g, 99.3%) as a brown oil.

[0207] Step 2: Under N2, 29-01 (320 mg, 0.74 mmol), 5-bromo-1-methyl-1H-1,2,4-triazole (61 mg, 0.38 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) in PhMe (5 mL) was stirred at 120 °C for 15 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 29-02 (110 mg) as a yellow solid.

[0208] Step 3: The title compound 29 was prepared from 29-02 in 19.4% yield following the procedure outlined for compound 2-03. Mass (m / z): 458.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J = 6.5 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 6.77 - 6.73 (m, 2H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.19 (s, 1H), 4.67 (s, 2H), 4.35 (s, 3H), 4.29 (d, J = 13.5 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0209] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (30) JPEG0007764398000072.jpg74159

[0210] Step 1: To a solution of 5-bromo-1-methyl-1H-1,2,4-triazole (81 mg, 0.5 mmol) in THF (5 mL) was added n-BuLi (1.6 M, 0.38 mL, 0.6 mmol) at −78 °C under Ar. The reaction was stirred at −78 °C for 1 h. ZnCl (1 M in THF, 0.6 mL, 0.6 mmol) was then added to the reaction and stirred at −78 °C for an additional 0.5 h. The reaction mixture was allowed to warm to room temperature over 1 h, at which point 2-01 (152 mg, 0.5 mmol) and Pd(PPh) (115 mg, 0.1 mmol) in THF were added. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over NaSO. The solvent was removed under vacuum and the crude product 30-01 was used directly in the next step.

[0211] Step 2: To a solution of 30-01 (98 mg, 0.28 mmol) in DCM (5 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo. To the resulting residue in THF (5 mL) was added TEA (3 mL) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone 1-02 (76 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by pre-TLC to give the desired product 30 (27 mg, 20.9%) as a white solid. Mass (m / z): 459.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.01 (s, 1H), 6.84 - 6.65 (m, 4H), 5.69 (s, 1H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 4.66 (s, 2H), 4.32 (s, 5H), 3.45 - 3.22 (m, 2H), 2.70 (dd, J = 18.5, 6.0 Hz, 1H).

[0212] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (31) JPEG0007764398000073.jpg4064

[0213] The title compound 31 was prepared from 1-05 following the procedure outlined for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.92 - 7.86 (m, 2H), 7.55 (dd, J = 9.5, 8.2 Hz, 1H), 6.85 - 6.65 (m, 4H), 5.53- 5.42(m, 1H), 5.31 - 5.25 (m, 1H), 4.63- 4.54 (d, J = 9.7 Hz, 2H), 4.46 - 4.33 (m, 2H), 4.29(s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.72 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H). Mass (m / z) 458.2 [M+H] +

[0214] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (32) JPEG0007764398000074.jpg4664

[0215] Following the procedure outlined for compound 29, the title compound 32 was prepared from 29-01 in 42.9% yield. Mass (m / z): 458.2[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 2.9 Hz, 1H), 8.20 (s, 1H), 7.30 (d, J = 6.7 Hz, 1H), 6.82 (t, J = 1.7 Hz, 1H), 6.80 - 6.68 (m, 3H), 5.36 - 5.26 (m, 1H), 5.19 (dt, J = 6.5, 2.7 Hz, 1H), 4.68 (d, J = 7.8 Hz, 2H), 4.36 (dd, J = 32.6, 9.5 Hz, 2H), 4.27 (s, 3H), 3.39 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.74 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H).

[0216] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (33) JPEG0007764398000075.jpg4564

[0217] Following the procedure outlined for compound 29, the title compound 33 was prepared from 29-01 in 38.2% yield. Mass (m / z): 458.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.67 (d, J = 3.8 Hz, 1H), 8.56 (s, 1H), 7.74 (d, J = 7.0 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.79 - 6.65 (m, 3H), 5.35 - 5.24 (m, 2H), 4.73 (s, 2H), 4.38 (dd, J = 19.7, 10.8 Hz, 2H), 4.22 (s, 3H), 3.38 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.73 (ddd, J = 18.6, 6.2, 1.7 Hz, 1H).

[0218] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (34) JPEG0007764398000076.jpg4264

[0219] Following the procedure outlined for compound 30, the title compound 34 was prepared from 1-methyl-1H-1,2,3-triazole and 3-02 as a white solid in 26.2% yield. Mass (m / z): 458.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 8.02 (s, 1H), 6.98 (d, J = 6.3 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.78 - 6.66 (m, 3H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.16 (s, 1H), 4.64 (s, 2H), 4.37 (s, 3H), 4.35 - 4.23 (m, 2H), 3.46 - 3.30 (m, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.6 Hz, 1H).

[0220] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (35) JPEG0007764398000077.jpg4764

[0221] Following the procedure outlined for compound 2, the title compound 35 was prepared from 2-03 in 63.6% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 2.4 Hz, 1H), 6.81 - 6.66 (m, 5H), 5.52 (tt, J = 6.7, 4.2 Hz, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.69 - 4.55 (m, 2H), 4.44 - 4.31 (m, 1H), 4.28 (s, 4H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.34 (s, 3H). Mass (m / z) 472.3 [M+H] + .

[0222] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (36) JPEG0007764398000078.jpg4364

[0223] The title compound 36 was prepared from 3-04 following the procedure outlined for compound 3. Mass (m / z): 471.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.43-8.40 (m, 1H), 6.86 - 6.65 (m, 5H), 6.28 - 6.22 (m, 1H), 5.32 - 5.24 (m, 1H), 5.12-5.04 (m, 1H), 4.67-4.54 (m, 2H), 4.41 - 4.32 (m, 1H), 4.31-4.23 (m, 1H), 4.11 - 4.06 (m, 3H), 3.42-3.31 (m, 1H), 2.77-2.67 (m, 1H), 2.33 - 2.27 (m, 3H).

[0224] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (37) JPEG0007764398000079.jpg4064

[0225] Following the procedure outlined for compound 2, the title compound 37 was prepared from 2-03 in 15.9% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 2.7 Hz, 1H), 7.96 (s, 1H), 6.86 - 6.61 (m, 4H), 5.60 - 5.45 (m, 1H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 4.70 - 4.54 (m, 2H), 4.33 (dd, J = 36.9, 10.4 Hz, 2H), 3.89 (s, 3H), 3.36 (dd, J = 18.6, 12.1 Hz, 1H), 2.77 - 2.65 (m, 1H), 2.58 (s, 3H). Mass (m / z) 472.3 [M+H] + .

[0226] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (38) JPEG0007764398000080.jpg4564

[0227] Following the procedure outlined for compound 3, the title compound 38 was prepared from 3-04 in 32% yield. Mass (m / z): 471.2[M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.35-8.32 (m, 1H), 7.74 (s, 1H), 6.82 - 6.65 (m, 5H), 5.27 (dd, J = 12.3, 6.4 Hz, 1H), 5.11-5.04 (m, 1H), 4.65-4.52 (m, 2H), 4.41-4.33 (m, 1H), 4.32-4.23 (m, 1H), 3.87 (s, 3H), 3.42 - 3.31 (m, 1H), 2.76 - 2.66 (m, 1H), 2.47 (s, 3H).

[0228] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (39) JPEG0007764398000081.jpg4164

[0229] Following the procedure outlined for compound 2, the title compound 39 was prepared from 3-04 in 47.4% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.79 (t, J = 1.7 Hz, 1H), 6.78 - 6.71 (m, 2H), 6.69 (ddd, J = 8.9, 6.5, 2.3 Hz, 1H), 5.61 (tt, J = 6.7, 4.3 Hz, 1H), 5.29 (dd, J = 12.2, 6.4 Hz, 1H), 4.66 (t, J = 10.0 Hz, 2H), 4.37 (d, J = 9.9 Hz, Mass (m / z) 458.2 [M+H] + .

[0230] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-imidazol-2-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (40) JPEG0007764398000082.jpg3964

[0231] The title compound 40 was prepared from 3-04 following the procedure outlined for compound 3. Mass (m / z): 471.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 2.7 Hz, 1H), 7.57-7.49 (m, 1H), 6.81 - 6.73 (m, 3H), 6.72 - 6.65 (m, 2H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.21-5.15 (m, 1H), 4.70-4.57 (m, 2H), 4.36-4.22 (m, 2H), 4.01 (s, 3H), 3.34 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.26 (s, 3H).

[0232] (S)-(3-((2-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (41) JPEG0007764398000083.jpg4164

[0233] The title compound 41 was prepared from 29-01 and 5-bromo-1-methyl-1H-pyrazol-3-amine following the procedure outlined for compound 29. Mass (m / z): 472.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 2.9 Hz, 1H), 6.84 - 6.65 (m, 5H), 5.82 (s, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.12 - 5.02 (m, 1H), 4.66-4.51 (m, 2H), 4.40-4.22 (m, 2H), 3.97 (s, 3H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0234] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (42) JPEG0007764398000084.jpg4164

[0235] Following the procedure outlined for compound 2, the title compound 42 was prepared in 9.8% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 2.4 Hz, 1H), 7.40 (s, 1H), 6.81 - 6.67 (m, 4H), 5.56 - 5.50 (m, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 4.63 (d, J = 17.2 Hz, 2H), 4.33 (dd, J = 33.8, 10.8 Hz, 2H), 4.21 (s, 3H), 3.36 (ddd, J = 18.7, 12.1, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7Hz, 1H), 2.33 (s, 3H). Mass (m / z) 472.3 [M+H] + .

[0236] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (43) JPEG0007764398000085.jpg4164

[0237] The title compound 43 was prepared from 3-02 following the procedure outlined for compound 3. Mass (m / z): 471.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.52 - 8.47 (m, 1H), 7.36 (s, 1H), 6.83 - 6.65 (m, 5H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.10-5.03 (m, 1H), 4.66 - 4.52 (m, 2H), 4.44-4.33 (m, 1H), 4.33-4.24 (m, 1H),3.96 (s, 3H), 3.43 - 3.30 (m, 1H), 2.76-2.67 (m, 1H), 2.12 (s, 3H).

[0238] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((6-(1,4-dimethyl-1H-imidazol-5-yl)-3-fluoropyridin-2-yl)oxy)azetidin-1-yl)methanone (44) JPEG0007764398000086.jpg4264

[0239] Following the procedure outlined for compound 1, the title compound 44 was prepared from 1-05 in 16.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 9.01 (s, 1H), 7.94 (t, J = 8.6 Hz, 1H), 7.47 - 7.35 (m, 1H), 7.22 - 6.99 (m, 4H), 5.80-5.72 (m, 1H), 5.67 - 5.61 (m, 1H), 5.01 - 4.88 (m, 2H), 4.69 (dd, J = 25.3, 10.4 Hz, 2H), 4.28 (s, 3H), 3.74 (dd, J = 18.4, 12.4 Hz, 1H), 3.08 (dd, J = 18.6, 6.4 Hz, 1H), 2.84 (s, 3H). Mass (m / z) 471.2 [M+H] +

[0240] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-imidazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (45) JPEG0007764398000087.jpg4064

[0241] The title compound 45 was prepared from 3-04 following the procedure outlined for compound 3. LC-Mass (m / z): 471.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 3.0 Hz, 1H), 7.50-7.42 (m, 1H), 6.82 - 6.66 (m, 5H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.10-5.03 (m, 1H), 4.65-4.51 (s, 2H), 4.41-4.24 (m, 2H), 3.77 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.35 (s, 3H).

[0242] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (46) JPEG0007764398000088.jpg3964

[0243] Following the procedure outlined for compound 30, the title compound 46 was prepared from 2-01 and 1,4-dimethyl-1H-1,2,3-triazole as a white solid in 45.1% yield. Mass (m / z): 473.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 2.3 Hz, 1H), 6.84 - 6.60 (m, 4H), 5.54 (tt, J = 6.6, 4.0 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.62 (dt, J = 16.6, 9.0 Hz, 2H), 4.37 (s, 4H), 4.29 (dd, J = 10.3, 3.6 Hz, 1H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7Hz, 1H), 2.64 (s, 3H).

[0244] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (47) JPEG0007764398000089.jpg4064

[0245] Following the procedure outlined for compound 30, the title compound 47 was prepared from 3-02 and 1,4-dimethyl-1H-1,2,3-triazole as a white solid in 30.8% yield. Mass (m / z): 472.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, J = 2.9 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.79 - 6.66 (m, 4H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 5.09 (s, 1H), 4.60 (s, 2H), 4.37 (d, J = 10.3 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.18 (s, 3H), 3.37 (dd, J = 18.6, 12.1 Hz, 1H), 2.76 - 2.67 (m, 1H), 2.45 (s, 3H).

[0246] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-4-carbonitrile (48) JPEG0007764398000090.jpg67159

[0247] Step 1: A mixture of compound 2-01 (1 g, 3.3 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (820 mg, 3.96 mmol), Pd(dba) (310 mg, 0.33 mmol), X-Phos (320 mg, 0.66 mmol), and KPO (3.5 g, 16.5 mmol) in dioxane (10 mL) and water (3 mL) was stirred at 110 °C for 2 h under Ar. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over NaSO. The solvent was removed under vacuum, and the crude product 48-01 was used directly in the next step.

[0248] Step 2: To a solution of 48-01 (1.3 g, 3.7 mmol) in AcOH (20 mL) was added NIS (1 g, 4.5 mmol). The reaction was stirred at 75 °C for 2 h. The reaction was quenched with water and extracted with EA. The combined organic extracts were washed with saturated aqueous NaHCO and brine, dried over NaSO, and concentrated to give crude product 48-02, which was used directly in the next step.

[0249] Step 3: A mixture of compound 48-02 (480 mg, 1.26 mmol) and CuCN (340 mg, 3.78 mmol) in DMF (10 mL) was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo, and the crude product 48-03 was used directly in the next step.

[0250] Step 4: To a solution of tert-butyl 3-((2-(4-cyano-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidine-1-carboxylate 48-03 (200 mg, 0.53 mmol) in DCM (5 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo. To the resulting residue in THF (5 mL) was added TEA (3 mL) and (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (133 mg, 0.48 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was cooled to room temperature and concentrated. The crude product was purified by Pre-TLC to give the desired product 48 (50 mg, 21.4%) as a white solid. MS (m / z): 483.3 [M+H] + . 1H NMR (300 MHz, Chloroform-d) δ 8.49 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 6.80 - 6.73 (m, 3H), 6.69 (tt, J = 8.8, 2.2 Hz, 1H), 5.76 (tt, J = 6.7, 3.6 Hz, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 4.73 (s, 2H), 4.34 (s, 3H), 4.32 - 4.20 (m, 2H), 3.35 (ddd, J = 18.5, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.5, 6.4, 1.7 Hz, 1H).

[0251] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carbonitrile (49) JPEG0007764398000091.jpg3464

[0252] Following the procedure for 48, the title compound 49 was prepared from 3-02 as a white solid in 62% yield (200 mg, 0.42 mmol). Mass (m / z): 482.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 2.7 Hz, 1H), 7.82 (s, 1H), 7.30 (d, J = 6.4 Hz, 1H), 6.81 - 6.73 (m, 3H), 6.69 (tt, J = 8.9, 2.4 Hz, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.16-5.09 (m, 1H), 4.74-4.60 (m, 2H), 4.40 - 4.26 (m, 2H), 4.19 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H).

[0253] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-methoxy-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (50) JPEG0007764398000092.jpg69159

[0254] Step 1: To a solution of 50-01 (1 g, 2.1 mmol) in THF (5 mL) was added i-PrMgCl (2 M, 5.2 mL, 10.5 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h, and then DMF (3 mL) was added. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl and extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo, and the crude product 50-02 was used directly in the next step.

[0255] Step 2: A mixture of 50-02 (800 mg, 2.1 mmol), TfOH (32 mg, 0.21 mmol), and m-CPBA (732 mg, 4.2 mmol) in DCM (20 mL) was stirred at room temperature for 6 h. The reaction mixture was diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo, and the crude product 50-03 was used directly in the next step.

[0256] Step 3: A mixture of 50-03 (300 mg, 0.83 mmol) and K2CO3 (344 mg, 3.5 mmol) in MeOH (20 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated to give crude product 50-04, which was used directly in the next step.

[0257] Step 4: To a solution of 50-04 (80 mg, 0.22 mmol) in THF (5 mL) was added NaH (17 mg, 0.43 mmol) at 0 °C. The reaction was stirred at room temperature for 1 h, and then MeI (63 mg, 0.43 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl and extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo, and the crude product 50-05 was used directly in the next step.

[0258] Step 5: To a solution of 50-05 (40 mg, 0.1 mmol) in DCM (5 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo. To the resulting residue in THF (5 mL) was added TEA (3 mL) and 1-02 (26 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by pre-TLC to give the desired product 50 (14 mg, 27.4%) as a white solid. Mass (m / z): 487.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 2.9 Hz, 1H), 7.30 (s, 1H), 7.27-7.25 (m, 1H), 6.82 - 6.79 (m, 1H), 6.78 - 6.66 (m, 3H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.08 (ddd, J = 10.5, 6.5, 4.1 Hz, 1H), 4.60 (d, J = 7.9 Hz, 2H), 4.33 (dd, J = 37.0, 10.8 Hz, 2H), 4.17 (s, 3H), 3.87 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0259] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(4-(2-(dimethylamino)ethoxy)-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (51) JPEG0007764398000093.jpg4077

[0260] Following the procedure outlined for compound 50, the title compound 51 was prepared from 50-04 and 2-bromo-N,N-dimethylethan-1-amine as a white solid in 17.6% yield. Mass (m / z): 544.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 2.8 Hz, 1H), 7.28 (s, 1H), 7.04 (d, J = 6.5 Hz, 1H), 6.84 (s, 1H), 6.73 - 6.58 (m, 3H), 5.19 (dd, J = 11.6, 6.1 Hz, 2H), 4.57 (s, 2H), 4.46 (s, 2H), 4.21 (s, 2H), 3.99 (s, 3H), 3.40 - 3.26 (m, 3H), 2.78 (s, 6H), 2.66 (dd, J = 18.5, 6.0 Hz, 1H).

[0261] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(2-methoxyethoxy)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (52) JPEG0007764398000094.jpg3777

[0262] Following the procedure outlined for compound 50, the title compound 52 was prepared from 50-04 and 1-bromo-2-methoxyethane as a white solid in 11.1% yield. Mass (m / z): 531.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 7.43 (d, J = 6.3 Hz, 1H), 7.35 (s, 1H), 6.80 (s, 1H), 6.77 - 6.66 (m, 3H), 5.35 - 5.25 (m, 1H), 5.10 (s, 1H), 4.64 (s, 2H), 4.33 (d, J = 26.2 Hz, 2H), 4.23 - 4.13 (m, 5H), 3.73 (s, 2H), 3.40 (s, 3H), 3.38 - 3.32 (m, 1H), 2.71 (dd, J = 18.5, 5.7 Hz, 1H).

[0263] (S)-(3-((2-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (53) JPEG0007764398000095.jpg78159

[0264] Step 1: A mixture of tert-butyl 3-((5-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidine-1-carboxylate 50-01 (500 mg, 1.05 mmol), (1R,2R)-cyclohexane-1,2-diamine (240 mg, 2.1 mmol), NHBoc (182 mg, 1.58 mmol), CuI (19 mg, 0.105 mmol), and KPO (445 mg, 2.1 mmol) in dioxane (10 mL) was stirred at 120 °C for 8 h under Ar. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over NaSO. The solvent was removed under vacuum, and the crude product 53-01 was used directly in the next step.

[0265] Step 2: The title compound 53 was prepared from 53-01 as a white solid in 57.3% yield following the procedure outlined for compound 50 from 50-05. Mass (m / z): 472.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 2.8 Hz, 1H), 7.27 (s, 1H), 7.06 (d, J = 6.4 Hz, 1H), 6.79 (s, 1H), 6.69 (t, J = 6.9 Hz, 3H), 5.14 (s, 2H), 4.72 (d, J = 8.0 Hz, 1H), 4.63 (s, 1H), 4.38 (s, 1H), 4.25 (s, 1H), 3.99 (s, 3H), 3.34 (dd, J = 18.6, 12.0 Hz, 1H), 2.67 (dd, J = 18.4, 6.4 Hz, 1H).

[0266] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-4-(methylamino)-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (54) JPEG0007764398000096.jpg34159

[0267] Following the procedure outlined for compound 50, the title compound 54 was prepared from 50-01 and iodomethane as a white solid in 42.6% yield. Mass (m / z): 486.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 3.0 Hz, 1H), 7.25 (s, 1H), 6.65 (d, J = 6.5 Hz, 1H), 6.82 - 6.79 (m, 1H), 6.77 - 6.65 (m, 3H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.15 - 5.05 (m, 1H), 4.62 (t, J = 8.7 Hz, 2H), 4.32 (dd, J = 35.5, 9.6 Hz, 2H), 4.00 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.83 (s, 3H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0268] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(4-(dimethylamino)-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (55) JPEG0007764398000097.jpg41159

[0269] To a solution of 53 (64 mg, 0.14 mmol) in THF (5 mL) was added NaH (11 mg, 0.27 mmol) at 0 °C. The reaction was stirred at room temperature for 1 h, and then MeI (77 mg, 0.54 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl and extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum. The crude product was purified by pre-TLC to give the desired product 55 (20 mg, 29.5%) as a white solid. Mass (m / z): 500.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.62 (s, 1H), 6.79 (s, 1H), 6.77 - 6.66 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.07 (s, 1H), 4.61 (s, 2H), 4.43 - 4.22 (m, 2H), 4.05 (s, 3H), 3.46 - 3.30 (m, 1H), 2.70 (dd, J = 18.6, 6.4 Hz, 1H), 1.31 - 1.18 (m, 6H).

[0270] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-((2-methoxyethyl)amino)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (56) JPEG0007764398000098.jpg3377

[0271] Following the procedure outlined for compounds 50-04 to 50, the title compound 56 was prepared from 53-01 and 1-bromo-2-methoxyethane as a white solid in 41.6% yield. Mass (m / z): 530.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.6 Hz, 1H), 7.75 (s, 1H), 7.07 (d, J = 6.1 Hz, 1H), 6.82 (s, 1H), 6.78 - 6.65 (m, 4H), 5.29 (dd, J = 12.1, 6.0 Hz, 1H), 5.20 (s, 1H), 4.63 (s, 2H), 4.42 - 4.26 (m, 2H), 4.08 (s, 3H), 3.64 (s, 2H), 3.42 (s, 2H), 3.40 - 3.36 (m, 1H), 3.34 (s, 3H), 2.72 (dd, J = 18.7, 5.9 Hz, 1H).

[0272] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)acetamide (57) JPEG0007764398000099.jpg3364

[0273] Following the procedure outlined for compound 53, the title compound 57 was prepared from 50-01 and acetamide as a white solid in 28.2% yield. Mass (m / z): 514.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 6.87 (d, J = 6.3 Hz, 1H), 6.79 (s, 1H), 6.77 - 6.65 (m, 3H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.08 (s, 1H), 4.60 (s, 2H), 4.32 (dd, J = 31.1, 9.6 Hz, 2H), 4.01 (s, 3H), 3.36 (dd, J = 18.6, 11.9 Hz, 1H), 2.71 (dd, J = 18.6, 6.1 Hz, 1H), 2.14 (s, 3H).

[0274] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)propionamide (58) JPEG0007764398000100.jpg3977

[0275] Following the procedure outlined for compound 53, the title compound 58 was prepared from 50-01 as a white solid in 39.9% yield. Mass (m / z): 528.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.23 (s, 1H), 8.48 (d, J = 3.0 Hz, 1H), 8.21 (s, 1H), 6.87 (d, J = 6.4 Hz, 1H), 6.82 - 6.78 (m, 1H), 6.78 - 6.62 (m, 3H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.09 (d, J = 3.7 Hz, 1H), 4.62 (d, J = 15.9 Hz, 2H), 4.33 (dd, J = 31.3, 9.8 Hz, 2H), 4.04 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.72 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.40 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 4H).

[0276] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)isobutyramide (59) JPEG0007764398000101.jpg3977

[0277] Following the procedure outlined for compound 53, the title compound 59 was prepared from 50-01 as a white solid in 42.2% yield. Mass (m / z): 542.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 9.49 (s, 1H), 8.48 (d, J = 3.0 Hz, 1H), 8.25 (s, 1H), 6.87 (d, J = 6.4 Hz, 1H), 6.83 - 6.79 (m, 1H), 6.79 - 6.65 (m, 3H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.70 - 4.53 (m, 2H), 4.33 (dd, J = 33.2, 9.7 Hz, 2H), 4.05 (s, 3H), 3.37 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.72 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.55 (p, J = 6.9 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H).

[0278] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-3-methylbutanamide (60) JPEG0007764398000102.jpg3977

[0279] Following the procedure outlined for compound 53, the title compound 60 was prepared from 50-01 as a white solid in 26.4% yield. Mass (m / z): 556.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.49 (d, J = 3.0 Hz, 1H), 8.22 (s, 1H), 6.87 (d, J = 6.4 Hz, 1H), 6.82 - 6.78 (m, 1H), 6.78 - 6.65 (m, 3H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.10 (s, 1H), 4.60 (s, 2H), 4.33 (dd, J = 31.4, 10.4 Hz, 2H), 4.04 (s, 3H), 3.37 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.72 (ddd, J = 18.7, 6.4, 1.7 Hz, 1H), 2.25 - 2.16 (m, 3H), 0.99 (d, J = 6.3 Hz, 7H).

[0280] (S)-2-((5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)amino)-N-methylacetamide (61) JPEG0007764398000103.jpg3677

[0281] Following the procedure outlined for compounds 50-04 to 50, the title compound 61 was prepared from 53-01 and 2-bromo-N-methylacetamide as a white solid in 20.4% yield. Mass (m / z): 543.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 2.8 Hz, 1H), 7.67 (s, 1H), 6.98 (d, J = 6.6 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.78 - 6.66 (m, 4H), 5.28 (dd, J = 12.1, 6.2 Hz, 1H), 5.02 (s, 1H), 4.56 (d, J = 32.7 Hz, 2H), 4.32 (dd, J = 23.3, 10.4 Hz, 2H), 4.08 (d, J = 3.7 Hz, 3H), 4.01 - 3.93 (m, 2H), 3.42 - 3.30 (m, 1H), 2.95 (d, J = 5.0 Hz, 3H), 2.74 - 2.66 (m, 1H).

[0282] (S)-2-((5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)amino)-1-morpholinoethan-1-one (62) JPEG0007764398000104.jpg3977

[0283] The title compound 62 was prepared from 53-01 as a white solid in 10.7% yield following the procedure outlined for compounds 50-04 to 50. Mass (m / z): 599.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 2.9 Hz, 1H), 8.23 ​​(s, 1H), 7.66 (s, 1H), 7.37 (d, J = 6.9 Hz, 1H), 6.83 - 6.80 (m, 1H), 6.76 - 6.66 (m, 3H), 5.27 (ddd, J = 12.4, 6.5, 3.2 Hz, 1H), 5.11 (td, J = 6.6, 3.4 Hz, 1H), 4.59 (s, 2H), 4.35 - 4.22 (m, 2H), 4.15 (s, 3H), 3.81 (t, J = 4.9 Hz, 2H), 3.73 (dq, J = 4.9, 3.0, 2.6 Hz, 4H), 3.69 - 3.59 (m, 4H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0284] (S)-2-((5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)amino)-N,N-dimethylacetamide (63) JPEG0007764398000105.jpg3677

[0285] The title compound 63 was prepared from 53-01 as a white solid in 1.7% yield following the procedure outlined for compounds 50-04 to 50. Mass (m / z): 557.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.9 Hz, 1H), 8.26 (d, J = 7.5 Hz, 0H), 7.52 (s, 1H), 6.82 - 6.66 (m, 4H), 5.35 (s, 1H), 5.27 (s, 1H), 5.11 (s, 1H), 4.60 (s, 2H), 4.31 (s, 2H), 4.12 (d, J = 43.2 Hz, 3H), 3.50 (s, 1H), 3.21 (d, J = 6.7 Hz, 1H), 3.10 - 2.99 (m, 3H), 2.71 (s, 1H), 2.28 - 2.15 (m, 1H), 2.02 (d, J = 10.1 Hz, 2H).

[0286] Methyl (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxylate (64) JPEG0007764398000106.jpg64159

[0287] Step 1: Compound 50-01 (3.7 g, crude) was dissolved in 40 mL of CHOH. Pd(OAc) (0.35 g, 1.56 mmol) and EtN (2.37 g, 23.4 mmol) were added to the above solution at room temperature. The reaction was degassed with CO and stirred at 55 °C for 2 h. The resulting solution was filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 2.6 g of a yellow solid. (Yield for two steps: 70%) Mass (m / z): 407.3 [M+H] + .

[0288] Step 2-3: The title compound 64 was prepared from 64-01 in 66% yield following the procedure outlined for compounds 50-05 to 50. Mass (m / z): 515.3[M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.8 Hz, 1H), 7.95 (s, 1H), 7.20 (d, J = 6.7 Hz, 1H), 6.80 - 6.73 (m, 3H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.13-5.05 (m, 1H), 4.66-4.54 (m, 2H), 4.42-4.24 (m, 2H), 3.65 (s, 3H), 3.77 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H).

[0289] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (65) JPEG0007764398000107.jpg34159

[0290] Compound 64 (540 mg, 1.05 mmol) was dissolved in 20 mL of CHOH and 10 mL of THF. Then, NaOH (1 M, 4.2 mL, 4.2 mmol) was added at room temperature. The mixture was stirred at 55 °C for 2 h. The pH of the resulting solution was adjusted to 4-5. Then, HO was added and extracted with EA. The organic layer was concentrated in vacuo. The crude product was purified by silica gel chromatography to give the desired compound 65 (250 mg, yield: 48%) as a pale yellow solid. Mass (m / z): 501.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.8 Hz, 1H), 8.03 (s, 1H), 7.10 (d, J = 6.5 Hz, 1H), 6.82 - 6.65 (m, 4H), 5.27 (dd, J = 12.1, 6.3 Hz, 1H), 5.08-5.00 (m, 1H), 4.66-4.52 (m, 2H), 4.43 - 4.22 (m, 2H), 3.95 (s, 3H), 3.41-3.28 (m, 1H), 2.75 - 2.65 (m, 1H).

[0291] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (66) JPEG0007764398000108.jpg31159

[0292] Step 1: To a solution of 66-01 (200 mg, 0.54 mmol) in MeOH (5 mL) and DMSO (5 mL) was added 15% NaOH (3 mL) and 3% HO (5 mL). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over NaSO. The solvent was removed in vacuo, and the crude product 66-02 was used directly in the next step.

[0293] Step 2: The title compound 66 was prepared from compound 66-02 as a white solid in 31.2% yield following the procedure outlined for compounds 50-05 to 50. Mass (m / z): 500.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.90 (s, 1H), 7.04 (s, 1H), 6.66 (d, J = 1.6 Hz, 1H), 6.79 - 6.73 (m, 2H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H), 5.30 (dd, J = 12.2, 6.3 Hz, 1H), 5.05 (s, 1H), 4.61 (s, 2H), 4.34 (d, J = 35.3 Hz, 2H), 3.65 (s, 3H), 3.43 - 3.30 (m, 1H), 2.71 (ddd, J = 18.7, 6.4, 1.6 Hz, 1H).

[0294] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,1-dimethyl-1H-pyrazole-4-carboxamide (67) JPEG0007764398000109.jpg34159

[0295] Compound 64 (60 mg, 0.12 mmol) in aqueous methylamine solution was stirred at 60 °C for 12 h. EA was added to the resulting solution, which was washed with brine, dried over MgSO and concentrated in vacuo. The crude product was purified by prep-HPLC to give 20 mg (yield: 33%) of a white solid. Mass (m / z): 514.3[M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.52-8.48 (m, 1H), 7.84 (s, 1H), 7.25-7.21 (m, 1H), 6.80 (s, 1H), 6.78 - 6.61 (m, 3H), 5.28 (dd, J = 12.1, 2.88 (d, J = 3.9 Hz, 3H), 2.76 - 2.66 (m, 1H).

[0296] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,N,1-trimethyl-1H-pyrazole-4-carboxamide (68) JPEG0007764398000110.jpg35159

[0297] Compound 65 (50 mg, 0.1 mmol) was dissolved in 10 mL of DMF. HATU (57 mg, 0.15 mmol) and DIEA (39 mg, 0.3 mmol) were added to the above solution at room temperature. The reaction was stirred at room temperature for 15 minutes. Then, dimethylamine in THF was added. The reaction was stirred at room temperature for 1 hour. HO was added to the resulting solution and extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 18.6 mg (yield: 35%) of a white solid. Mass (m / z): 528.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 2.8 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J = 6.7 Hz, 1H), 6.79 - 6.65 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.09-4.99 (m, 1H), 4.75 - 4.57 (m, 2H), 4.26 (t, J = 11.5 Hz, 2H), 4.04 (s, 3H), 3.35 (ddd, J = 18.6, 12.1, 1.7 Hz, 1H), 3.04 (s, 3H), 2.84 (s, 3H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H).

[0298] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-(2-(dimethylamino)ethyl)-1-methyl-1H-pyrazole-4-carboxamide (69) JPEG0007764398000111.jpg3777

[0299] The title compound 69 was prepared from compound 65 (50 mg, 0.1 mmol) as a white solid in 46% yield (26 mg, 0.05 mmol) following the procedure outlined for compound 68. Mass (m / z): 571.4 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 2.9 Hz, 1H), 7.92-7.83 (m, 2H), 6.84-6.81 (m, 1H), 6.78 - 6.66 (m, 3H), 5.26 (dd, J = 12.1, 6.2 Hz, 1H), 5.14-5.07 (m, 1H), 4.69-4.59 (m, 2H), 4.43-4.23 (m, 2H), 3.86 (s, 3H), 3.78-3.63 (m, 2H), 3.37 (ddd, J = 18.6, 12.1, 1.6 Hz, 1H), 3.27 (s, 2H), 2.89 (s, 6H), 2.71 (ddd, J = 18.6, 6.2, 1.8 Hz, 1H).

[0300] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-isobutyl-1-methyl-1H-pyrazole-4-carboxamide (70) JPEG0007764398000112.jpg3777

[0301] The title compound 70 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 27% yield (15.2 mg, 0.03 mmol). Mass (m / z): 556.4 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 7.83 (s, 1H), 7.19 (d, J = 6.6 Hz, 1H), 6.81 - 6.64 (m, 4H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.15-5.07 (m, 1H), 4.69-4.52 (m, 2H), 4.39-4.22 (m, 2H), 3.90 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 3.21 - 3.09 (m, 2H), 2.70 (ddd, J = 18.6, 6.4, 1.8 Hz, 1H), 1.79 - 1.73 (m, 1H), 0.88 (d, J = 6.7 Hz, 6H).

[0302] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-ethyl-1-methyl-1H-pyrazole-4-carboxamide (71) JPEG0007764398000113.jpg3777

[0303] The title compound 71 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 29% yield (15.2 mg, 0.03 mmol). Mass (m / z): 528.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 7.80 (s, 1H), 6.82 - 6.63 (m, 4H), 6.55-6.48 (m, 1H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.15-5.07 (m, 1H), 4.68-4.53 (m, 2H), 4.38-4.22 (m, 2H), 3.91 (s, 3H), 3.43 - 3.27 (m, 3H), 2.69 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 1.14 (t, J = 7.2 Hz, 3H).

[0304] (S)-Azetidin-1-yl(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)methanone (72) JPEG0007764398000114.jpg3677

[0305] The title compound 72 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 21% yield (11.5 mg, 0.02 mmol). Mass (m / z): 540.3[M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.8 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J = 6.8 Hz, 1H), 6.79 - 6.64 (m, 4H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.16-5.08 (m, 1H), 4.70-4.56 (m, 2H), 4.37-4.22 (m, 2H), 4.15 - 4.05 (m, 4H), 3.97 (s, 3H), 3.34 (ddd, J = 18.5, 12.2, 1.7 Hz, 1H), 2.68 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.32-2.19 (m, 2H).

[0306] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(3-hydroxyazetidine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (73) JPEG0007764398000115.jpg3364

[0307] The title compound 73 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 59% yield (33 mg, 0.06 mmol). Mass (m / z): 556.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.6 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J = 6.6 Hz, 1H), 6.81 - 6.64 (m, 4H), 5.25 (dd, J = 12.1, 6.3 Hz, 1H), 5.10 (s, 1H), 4.68-4.48 (m, 3H), 4.38 - 4.16 (m, 4H), 3.96 (s, 3H), 3.92-3.76 (m, 2H), 3.34 (ddd, J = 18.5, 12.2, 1.8 Hz, 1H), 2.68 (ddd, J = 18.6, 6.3, 1.7 Hz, 1H).

[0308] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(3-methoxyazetidine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (74) JPEG0007764398000116.jpg3364

[0309] The title compound 74 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 81% yield (46 mg, 0.08 mmol). Mass (m / z): 570.3[M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 2.8 Hz, 1H), 7.63 (s, 1H), 7.48 (d, J = 6.7 Hz, 1H), 6.81 - 6.64 (m, 4H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 5.14 (s, 1H), 4.70-4.55 (m, 2H), 4.38-4.12 (m, 5H), 3.99 (s, 3H), 3.97 - 3.91 (m, 2H), 3.35 (ddd, J = 18.6, 12.3, 1.6 Hz, 1H), 3.26 (s, 3H), 2.69 (ddd, J = 18.5, 6.5, 1.6 Hz, 1H).

[0310] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (75) JPEG0007764398000117.jpg3464

[0311] The title compound 75 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 78% yield (43 mg, 0.08 mmol). Mass (m / z): 554.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.7 Hz, 1H), 7.61 (s, 1H), 7.46 (d, J = 6.8 Hz, 1H), 6.78 - 6.64 (m, 4H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.11-5.02 (m, 1H), 4.72-4.55 (m, 2H), 4.25 (t, J = 12.9 Hz, 2H), 4.01 (s, 3H), 3.54 (t, J = 6.9 Hz, 2H), 3.34 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 3.25 (t, J = 6.5 Hz, 2H), 2.68 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 1.92 - 1.74 (m, 4H).

[0312] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-4-(piperidine-1-carbonyl)-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (76) JPEG0007764398000118.jpg3464

[0313] The title compound 76 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 75% yield (43 mg, 0.08 mmol). Mass (m / z): 568.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 2.8 Hz, 1H), 7.52 (s, 1H), 7.32 (d, J = 6.7 Hz, 1H), 6.78 - 6.66 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.06-4.97 (m, 1H), 4.74-4.57 (m, 2H), 4.26 (t, J = 12.1 Hz, 2H), 4.05 (s, 3H), 3.65 (s, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.6 Hz, 1H), 3.20 (s, 2H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 1.62-1.50 (m, 4H), 1.32-1.20 (m, 2H).

[0314] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-4-(morpholine-4-carbonyl)-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (77) JPEG0007764398000119.jpg3364

[0315] The title compound 77 was prepared from compound 65 (50 mg, 0.1 mmol) following the procedure for compound 68 as a white solid in 36% yield (20.3 mg, 0.04 mmol). Mass (m / z): 570.3 [M+H] + ; 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 2.8 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J = 6.6 Hz, 1H), 6.79 - 6.65 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.04 (s, 1H), 4.72-4.57 (m, 2H), 4.27 (t, J = 13.5 Hz, 2H), 4.03 (s, 3H), 3.83 - 3.20 (m, 9H), 2.70 (ddd, J = 18.6, 6.4, 1.7Hz, 1H).

[0316] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (78) JPEG0007764398000120.jpg61159

[0317] Step 1: 64-01 (2 g, 4.92 mmol) was dissolved in 20 mL of dry THF, and AlLiH (1 M, 5 mL) was added to the above solution at 0 °C. The mixture was stirred at 0 °C for 10 min. Water was added, extracted with EA, washed with brine, dried (Na SO ), and concentrated to dryness to give intermediate 78-01. MS (m / z): 379.2 [M+H] + .

[0318] Step 2-3: Following the procedure for compounds 50-05 to 50, the title compound 78 was prepared from compound 78-01 (100 mg, 0.27 mmol) as a white solid in 42.9% yield (55 mg). Mass (m / z): 469.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, J = 2.9 Hz, 1H), 7.54 (s, 1H), 7.25 (d, J = 6.7 Hz, 1H), 6.84 - 6.64 (m, 4H), 5.35 - 5.23 (m, 1H), 5.12 (ddd, J = 10.3, 6.5, 3.9 Hz, 1H), 4.70-4.60 (m, 2H), 4.48 (s, 2H), 4.35 (dd, J = 32.1, 10.3 Hz, 2H), 4.08 (s, 3H), 3.38 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.73 (ddd, J = 18.6, 6.4, 1.8 Hz, 1H).

[0319] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (79) JPEG0007764398000121.jpg33159

[0320] Compound 78 (54 mg, 0.11 mmol) was dissolved in 10 mL of dry DCM, TEA (0.1 mL) was added to the above solution at 0° C., and the mixture was stirred for 30 min at 0° C. Then, dimethylamine (5 mg, 0.11 mmol) was added, and the mixture was stirred for 1.5 h, followed by addition of water, extraction with EA, and purification by silica gel chromatography to give the title compound 79 (21 mg, 46.2%) as a white solid. Mass (m / z): 514.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.69 (s, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.84 (d, J = 1.7 Hz, 1H), 6.80 - 6.69 (m, 3H), 5.30 (dd, J = 12.1, 6.3 Hz, 1H), 5.25 - 5.17 (m, 1H), 4.70 - 4.57 (m, 2H), 4.43 - 4.26 (m, 2H), 4.20 (s, 2H), 3.96 (s, 3H), 3.45 - 3.40 (m, 1H), 2.78 (s, 6H), 2.74 - 2.70 (m, 1H).

[0321] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (80) JPEG0007764398000122.jpg37159

[0322] Compound 78 (80 mg, 0.16 mmol) was dissolved in 10 mL of dry THF, and NaH (1 M, 5 mL) was added to the above solution at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, CHCl (1 g, 6.78 mmol) was added, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with EA and purified by silica gel chromatography to give the title compound 80 (50 mg, 60%) as a white solid. Mass (m / z): 501.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.9 Hz, 1H), 7.53 (s, 1H), 7.31 (d, J = 6.8 Hz, 1H), 6.83 - 6.64 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.03 (ddd, J = 10.2, 6.4, 3.9 Hz, 1H), 4.69 - 4.53 (m, 2H), 4.41 - 4.27 (m, 2H), 4.27 (s, 2H), 4.07 (s, 3H), 3.40 (s, 3H), 3.38 - 3.30 (m, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0323] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (81) JPEG0007764398000123.jpg63159

[0324] Step 1: 81-01 (1.1 g, 3.16 mmol) was dissolved in 15 mL of dry MeCN, and Selectfluor (1.18 g, 3.16 mmol) was added to the above solution at 0 °C. The mixture was stirred at 80 °C for 3 h. Water was added, and the mixture was extracted with EA and purified by silica gel chromatography to give compound 81-02 (320 mg, 27.6%). Mass (m / z): 367.2 [M+H]+.

[0325] Step 2-3: Following the procedure for compounds 50-05 to 50, the title compound 81 was prepared from compound 81-02 in 26.9% yield. 1H NMR (300 MHz, Chloroform-d) δ 8.44 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 4.4 Hz, 1H), 6.99 (d, J = 6.6 Hz, 1H), 6.83 - 6.65 (m, 4H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.10 (ddd, J = 10.4, 6.5, 4.0 Hz, 1H), 4.68-4.53 (m, 2H), 4.32 (ddd, J = 24.3, 10.7, 4.0 Hz, 2H), 4.16 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H). Mass (m / z):475.1 [M+H] +

[0326] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (82) JPEG0007764398000124.jpg29159

[0327] Compound 2-03 (82 mg, 0.2 mmol), 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (90 mg, 0.4 mmol), bis(tri-tert-butylphosphine)palladium(0) (21 mg, 0.04 mmol), DIEA (155 mg, 1.2 mmol) in 1,4-dioxane (2 mL) and HO (0.2 mL) under N were stirred at 100° C. for 2 h. The mixture was concentrated and then further purified by prep-HPLC to give the title compound 82 (25 mg, 26.3%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.51 - 7.33 (m, 1H), 6.74 (t, J = 18.9 Hz, 4H), 5.52 (s, 1H), 5.29 (s, 1H), 4.63 (s, 2H), 4.24 (d, J = 31.7 Hz, 5H), 3.35 (t, J = 15.4 Hz, 1H), 2.70 (d, J = 18.4 Hz, 1H). Mass (m / z) 476.2 [M+H]+.

[0328] (S)-(3-((2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (83) JPEG0007764398000125.jpg73159

[0329] Step 1: 81-01 (600 mg, 1.72 mmol) was dissolved in 10 mL of dry DMF, and NCS (230 mg, 1.72 mmol) was added to the above solution at 0 °C. The mixture was stirred at 50 °C for 12 h. Water was added, and the mixture was extracted with EA and purified by silica gel chromatography to give intermediate 83-01 (360 mg, 54%). Mass (m / z): 383.1 [M+H]+.

[0330] Step 2-3: The title compound 83 was prepared from compound 83-01 in 26.6% yield following the procedure for compounds 50-05 to 50. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J = 3.1 Hz, 1H), 7.67 (s, 1H), 7.28 (d, J = 6.8 Hz, 1H), 7.09 (tt, J = 9.3, 2.3 Hz, 1H), 7.01 (s, 1H), 6.92 - 6.86 (m, 2H), 5.31 - 5.17 (m, 2H), 4.60 - 4.45 (m, 2H), 4.14 - 4.00 (m, J = 10.7 Hz, 2H), 3.90 (s, 3H), 3.43 - 3.35 (m, 1H), 2.68 - 2.58 (m, 1H). Mass (m / z) 491.1 [M+H] +

[0331] (S)-(3-((2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (84) JPEG0007764398000126.jpg4264

[0332] Following the procedure outlined for compound 2, the title compound 84 was prepared from 2-03 in 15.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.51 - 8.47 (m, 1H), 7.55 - 7.48 (m, 1H), 6.82 - 6.66 (m, 4H), 5.63 - 5.55 (m, 1H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 4.65 (s, 2H), 4.33 (dd, J = 27.2, 8.7 Hz, 2H), 4.18 (s, 3H), 3.36 (dd, J = 18.6, 12.1 Hz, 1H), 2.70 (dd, J = 18.6, 6.3 Hz, 1H). Mass (m / z) 492.2 [M+H] + .

[0333] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (85) JPEG0007764398000127.jpg3864

[0334] Following the procedure outlined for compound 3, the title compound 85 was prepared from 3-04 in 28.0% yield. 1 H NMR (300 MHz, Chloroform-d) δ 8.36 (d, J = 3.0 Hz, 1H), 7.86 (s, 1H), 6.87 - 6.63 (m, 5H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 5.10 (q, J = 5.3, 4.0 Hz, 1H), 4.60 (q, J = 8.7, 8.2 Hz, 2H), 4.40 - 4.25 (m, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.77 - 2.67 (m, 1H), 2.65 (d, J = 11.5 Hz, 3H). Mass (m / z) 457.3 [M+H] + .

[0335] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (86) JPEG0007764398000128.jpg34159

[0336] Compound 85 (70 mg, 0.15 mmol), 1-bromo-2-methoxyethane (107 mg, 0.75 mmol), and KCO (207 mg, 1.50 mmol) were placed in DMF (3 mL). The mixture was stirred at 90 °C overnight and concentrated. Purification by prep-HPLC afforded the title compound 86 (19 mg, 24.1%) as a white solid. 1 H NMR (300 MHz, Chloroform-d) δ 8.35 (t, J = 3.1 Hz, 1H), 7.77 (d, J = 29.8 Hz, 1H), 6.84 - 6.64 (m, 5H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.08 (dq, J = 6.5, 3.4 Hz, 1H), 4.59 (q, J = 8.1 Hz, 2H), 4.40 - 4.20 (m, 4H), 3.76 (q, J = 5.2 Hz, 2H), 3.42 - 3.29 (m, 4H), 2.71 (ddd, J = 18.6, 6.6, 1.7Hz, 1H), 2.53 (d, J = 29.8 Hz, 3H). Mass (m / z) 515.3 [M+H] + .

[0337] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1H-pyrazol-5-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (87) JPEG0007764398000129.jpg3664

[0338] Following the procedure outlined for compound 2, the title compound 87 was prepared from 2-03 in 13.0% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.87 - 6.56 (m, 4H), 5.57 (tt, J = 6.7, 4.3 Hz, 1H), 5.29 (dd, J = 12.2, 6.5 Hz, 1H), 4.66 (m , 2H), 4.34 (ddd, J = 32.8, 10.7, 4.3 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H). Mass (m / z) 444.2 [M+H] + ,

[0339] (S)-2-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-1H-pyrazol-1-yl)acetamide (88) and (S)-2-(3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-1H-pyrazol-1-yl)acetamide (89) JPEG0007764398000130.jpg56159

[0340] Following the procedure outlined for compound 86, the title compounds 88 and 89 were prepared in yields of 2.9% (1.1 mg) and 10.1% (3.8 mg). 88: 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.78 - 6.67 (m, 3H), 6.03 (s, 1H), 5.82 (s, 1H), 5.58 (s, 1H), 5.48 (s, 2H), 5.30 (dd, J = 12.0, 6.3 Hz, 1H), 4.69 (s, 2H), 4.33 (dd, J = 23.8, 10.6 Hz, 2H), 3.40 - 3.33 (m, 1H), 2.75 - 2.70 (m, 1H). Mass (m / z) 501.3 [M+H] + . 89: 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.57 (s, 1H), 6.96 (s, 1H), 6.81 - 6.67 (m, 4H), 6.23 (s, 1H), 5.60 (ddd, J = 11.8, 7.2, 4.9 Hz, 2H), 5.29 (dd, J = 12.2, 6.5 Hz, 1H), 4.92 (s, 2H), 4.68 (d, J = 17.7 Hz, 2H), 4.35 (dd, J = 35.2, 10.7 Hz, 2H), 3.36 (ddd, J = 18.5, 12.2, 1.6 Hz, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0341] Mass (m / z) 501.3 [M+H] + .

[0342] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(5-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (90) JPEG0007764398000131.jpg4464

[0343] Following the procedure outlined for compound 2, the title compound 90 was prepared from 2-03 in 27% yield (30 mg). 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.6 Hz, 1H), 8.13 (s, 1H), 6.79 (t, J = 1.7 Hz, 1H), 6.77 - 6.57 (m, 3H), 5.58-5.49 (m, 1H), 5.33-5.25 (m, 1H), 4.66 (d, J = 16.6 Hz, 2H), 4.33 (dd, J = 34.3, 10.5 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.7Hz, 1H), 2.64 (s, 3H). Mass (m / z) 458.2 [M+H] + .

[0344] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (91) JPEG0007764398000132.jpg4364

[0345] Following the procedure outlined for compound 2, the title compound 91 was prepared from 2-03 in 34.6% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 2.6 Hz, 1H), 6.78 (t, J = 1.7 Hz, 1H), 6.77 - 6.61 (m, 3H), 5.58-5.50 (m, 1H), 5.30 - 5.25 (m, 1H), 4.61 (q, J = 10.1, 8.8 Hz, 2H), 4.32 (dd, J = 35.8, 10.3 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.61 (s, 6H). Mass (m / z) 472.3 [M+H] + .

[0346] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (92) JPEG0007764398000133.jpg3964

[0347] Following the procedure outlined for compound 3, the title compound 92 was prepared from 3-04 in 31.9% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 3.1 Hz, 1H), 6.83 - 6.67 (m, 4H), 6.62 (d, J = 6.6 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.09 - 5.01 (m, 1H), 4.58 (d, J = 8.2 Hz, 2H), 4.33 (dd, J = 36.9, 10.3 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.41 (s, 6H). Mass (m / z) 471.2 [M+H] + .

[0348] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (93) JPEG0007764398000134.jpg3664

[0349] The title compound 93 was prepared from 92 in 29.6% yield following the procedure outlined for compound 86. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.0 Hz, 1H), 7.12 (tt, J = 9.3, 2.4 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 6.93 (qd, J = 6.6, 3.3 Hz, 2H), 6.84 (d, J = 6.8 Hz, 1H), 5.31 - 5.20 (m, 2H), 4.54 (s, 2H), 4.16 (t, J = 5.4 Hz, 2H), 4.09 (s, 2H), 3.65 (t, J = 5.4 Hz, 2H), 3.44 - 3.37 (m, 1H), 3.23 (s, Mass (m / z) 529.4 [M+H] + .

[0350] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetamide (94) JPEG0007764398000135.jpg75159

[0351] Step 1: 3,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (222 mg, 1.0 mmol), 2-bromoacetamide (276 mg, 2.0 mmol), and NaH (60%, 120 mg, 3.0 mmol) were placed in DMF (5 mL). The mixture was stirred at 25 °C for 45 minutes, and then the reaction solution was poured into water. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by prep-HPLC afforded intermediate compound 94-01 (215 mg, 77.0%) as a white solid.

[0352] Step 2: Following the procedure outlined for compound 3, the title compound 94 was prepared in 36.5% yield (73 mg). 1 H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 3.0 Hz, 1H), 6.83 - 6.65 (m, 4H), 6.59 (d, J = 6.5 Hz, 1H), 6.09 (s, 1H), 5.60 (s, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.05 (td, J = 6.5, 3.3 Hz, 1H), 4.72 (s, 2H), 4.56 (d, J = 14.8 Hz, 2H), 4.33 (dd, J = 34.3, 10.6 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Mass (m / z) 528.3 [M+H] + .

[0353] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N,N-dimethylacetamide (95) JPEG0007764398000136.jpg3964

[0354] The title compound 95 was prepared from compound 92 in 45.6% yield following the procedure outlined for compound 86. 1 H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J = 3.6 Hz, 1H), 6.83 (d, J = 1.7 Hz, 1H), 6.79 - 6.66 (m, 4H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.12 (s, 1H), 5.03 (s, 2H), 4.64 (s, 2H), 4.36 (dd, J = 27.1, 10.5 Hz, 2H), 3.38 (dd, J = 18.6, 12.1 Hz, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 2.77 - 2.68 (m, 1H), 2.31 (s, 6H). Mass (m / z) 556.4 [M+H] + .

[0355] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-1-morpholinoethan-1-one (96) JPEG0007764398000137.jpg4264

[0356] The title compound 96 was prepared from compound 92 in 35.8% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 3.0 Hz, 1H), 6.82 - 6.58 (m, 5H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.04 (s, 1H), 4.91 (s, 2H), 4.58 (s, 2H), 4.32 (dd, J = 29.2, 9.5 Hz, 2H), 3.71 (d, J = 4.6 Hz, 4H), 3.62 (dd, J = 12.8, 4.9 Hz, 4H), 3.36 (ddd, J = 18.6, 12.2, 1.6 Hz, 1H), 2.71 (ddd, J = 18.7, 6.5, 1.7 Hz, 1H), 2.38 (s, 3H), 2.32 (s, 3H). Mass (m / z) 598.4 [M+H] + .

[0357] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-methylacetamide (97) JPEG0007764398000138.jpg4064

[0358] The title compound 97 was prepared from compound 92 following the procedure outlined for compound 86 in 26.3% yield (30 mg). 1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 3.8 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 6.82 - 6.66 (m, 4H), 6.48 (d, J = 5.1 Hz, 1H), 5.30 (dd, J = 12.1, 6.3 Hz, 1H), 5.19 (tt, J = 6.5, 3.8 Hz, 1H), 4.82 (s, 2H), 4.66 (s, 2H), 4.39 (dd, J = 30.1, 10.5 Hz, 2H), 3.40 (ddd, J = 18.7, 12.1, 1.7 Hz, 1H), 2.83 (d, J = 4.7 Hz, 3H), 2.76 (ddd, J = 18.7, 6.3, 1.8 Hz, 1H), 2.32 (d, J = 8.6 Hz, 6H). Mass (m / z) 542.3 [M+H] + .

[0359] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-methylacetamide (98) JPEG0007764398000139.jpg4064

[0360] The title compound 98 was prepared from compound 91 in 6.1% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.5 Hz, 1H), 6.77 - 6.59 (m, 4H), 6.08 (s, 1H), 5.45 (td, J = 6.5, 3.2 Hz, 1H), 5.21 (dd, J = 12.2, 6.4 Hz, 1H), 4.70 (s, 2H), 4.55 (s, 2H), 4.26 (dd, J = 31.8, 10.4 Hz, 2H), 3.36 - 3.22 (m, 1H), 2.74 (d, J = 4.8 Hz, 3H), 2.64 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.51 (d, J = 20.5 Hz, 6H). Mass (m / z) 543.3 [M+H] + .

[0361] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetamide (99) JPEG0007764398000140.jpg3864

[0362] The title compound 99 was prepared from compound 91 in 22.5% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.42 (dd, J = 2.6, 1.1 Hz, 1H), 6.87 - 6.68 (m, 4H), 6.35 (s, 1H), 5.81 (s, 1H), 5.55 (s, 1H), 5.31 (dd, J = 12.2, 6.3 Hz, 1H), 4.86 (s, 2H), 4.65 (s, 2H), 4.37 (d, J = 32.3 Hz, 2H), 3.39 (dd, J = 18.7, 12.2 Hz, 1H), 2.74 (dd, J = 18.8, 6.3 Hz, 1H), 2.62 (dt, J = 33.5, 2.0 Hz, 6H). Mass (m / z) 529.3 [M+H] + .

[0363] (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N,N-dimethylacetamide (100) JPEG0007764398000141.jpg3964

[0364] The title compound 100 was prepared from compound 91 in 8.5% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 2.6 Hz, 1H), 6.73 - 6.65 (m, 3H), 6.61 (tt, J = 8.8, 2.3 Hz, 1H), 5.44 (td, J = 6.6, 3.4 Hz, 1H), 5.19 (dd, J = 12.2, 6.5 Hz, 1H), 4.86 (s, 2H), 4.52 (d, J = 8.9 Hz, 2H), 4.23 (dd, J = 30.7, 10.8 Hz, 2H), 3.27 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 3.03 (s, 3H), 2.91 (s, 3H), 2.62 (ddd, J = 18.5, 6.5, 1.7 Hz, 1H), 2.48 (d, J = 21.3 Hz, 6H). Mass (m / z) 557.4 [M+H] + .

[0365] (S)-(3-((2-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (101) JPEG0007764398000142.jpg72159

[0366] Step 1: Compound 3-02 (2.0 g, 6.62 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.2 g, 9.93 mmol), Pd(dba) (605 mg, 0.66 mmol), XPhos (314 mg, 0.66 mmol), and 5N KPO (4 mL, 19.9 mmol) were dissolved in dioxane (30 mL) under a N atmosphere. The mixture was stirred at 100 °C for 15 h. Concentration and purification by flash chromatography (PE / EA = 1 / 1) afforded 1.1 g of a yellow oil. Yield: 45.8%.

[0367] Step 2: Intermediate 101-01 (800 mg, 2.21 mmol) was dissolved in AcOH (5 mL) and DMF (2 mL). Then, NIS (994 mg, 4.42 mmol) was added. The mixture was stirred at 80 °C for 4 h. EA (50 mL) was added. It was washed with HO (20 mL) and NaHCO (20 mL). It was then purified by flash chromatography (PE / EA = 1 / 1) to give 300 mg of 101-02 as a brown oil. Yield: 27.8%.

[0368] Step 3: 101-02 (360 mg, 0.74 mmol), tert-butyl carbamate (173 mg, 1.48 mmol), CuI (141 mg, 0.74 mmol), cyclohexanediamine (253 mg, 2.22 mmol), and KPO (471 mg, 22.2 mmol) were dissolved in dioxane (15 mL) under N(g) atmosphere. The mixture was stirred at 100 °C for 15 h. Concentration and purification by TLC-chromatography (DCM / MeOH = 30 / 1) afforded 70 mg of 101-03 as a yellow solid. Yield: 18.6%.

[0369] Step 4-5: The title compound 101 was prepared from compound 101-03 (20 mg, 0.04 mmol) following the procedure outlined for compounds 50-05 to 50. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.9 Hz, 1H), 6.84 - 6.79 (m, 1H), 6.78 - 6.56 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.11 - 5.01 (m, 1H), 4.61 (d, J = 16.4 Hz, 2H), 4.32 (dd, J = 31.4, 10.7 Hz, 2H), 3.78 (s, 3H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 1.95 (s, 3H). Mass (m / z) 486.2 [M+H] + .

[0370] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2-methyl-1H-pyrrol-1-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (102) JPEG0007764398000143.jpg3764

[0371] Compound 2-03 (60 mg, 0.144 mmol), 2-methyl-1H-pyrrole (24 mg, 0.29 mmol), NaOtBu (18 mg, 0.18 mmol), Pd(dba) (12 mg, 0.012 mmol), and X-Phos (6 mg, 0.012 mmol) were added to DMF (3 mL) under a N atmosphere. The mixture was stirred at 90 °C overnight. The mixture was concentrated and purified by TLC (PE / EA = 2 / 1) to give 17 mg of a white solid. Yield: 21.9%. 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 3.3, 1.9 Hz, 1H), 6.82 - 6.73 (m, 3H), 6.73-6.66 (m, 1H), 6.16 (t, J = 3.3 Hz, 1H), 6.03-5.99(m, 1H), 5.53-5.46 (m, 1H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 4.69-4.56(m, 2H), 4.41-4.23 (m, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Mass (m / z) 457.3 [M+H] + .

[0372] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)methanone (103) JPEG0007764398000144.jpg3864

[0373] The title compound 103 was prepared from 2-03 in 1.0% yield following the procedure outlined for compound 102. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 6.82 (t, J = 2.0 Hz, 1H), 6.77 - 6.56 (m, 4H), 5.62-5.52 (m, 1H), 5.29 (dd, J = 12.2, 6.2 Hz, 1H), 4.72-4.57 (m, 2H), 4.36 (dd, J = 27.7, 11.0 Hz, 2H), 3.38 (ddd, J = 18.6, 12.1, 1.7 Hz, 1H), 2.91 (s, 3H), 2.73 (ddd, J = 18.6, 6.1, 1.7Hz, 3H), 2.57-2.41 (m, 3H). Mass (m / z) 473.3[M+H] + .

[0374] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (104) JPEG0007764398000145.jpg4364

[0375] Following the procedure outlined for compound 102, the title compound 104 was prepared from 3-04 in 48.1% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 6.1 Hz, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.78 - 6.58 (m, 3H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.19-5.10 (m, 1H), 4.71-4.59 (m, 2H), 4.32 (dd, J = 31.3, 10.0 Hz, 2H), 3.36 (ddd, J = 18.7, 12.2, 1.8 Hz, 1H), 2.84 (s, 3H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.43 (s, 3H). Mass (m / z) 472.2 [M+H] + .

[0376] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (105) JPEG0007764398000146.jpg3764

[0377] Following the procedure outlined for compound 102, the title compound 105 was prepared from 2-03 in 18.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 1.7 Hz, 1H), 7.89 (s, 1H), 7.37 (s, 1H), 6.83 - 6.78 (m, 1H), 6.78 - 6.62 (m, 3H), 5.55-5.49 (m, 1H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 4.66 (dd, J = 19.8, 11.1 Hz, 2H), 4.35 (dd, J = 22.3, 10.7 Hz, 2H), 3.37 (ddd, J = 18.6, 12.1, 1.7 Hz, 1H), 3.08 (s, 3H), 2.72 (ddd, J = 18.6, 6.3, 1.7 Hz, 1H). Mass (m / z) 458.2 [M+H] + .

[0378] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-1H-pyrrole-2-carbonitrile (106) JPEG0007764398000147.jpg3764

[0379] Following the procedure outlined for compound 102, the title compound 106 was prepared from 2-03 in 29.8% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 3.1, 1.7 Hz, 1H), 7.06 (dd, J = 3.7, 1.7 Hz, 1H), 6.86 - 6.73 (m, 3H), 6.72-6.65 (m, 1H), 6.36 (dd, J = 3.7, 3.2 Hz, 1H), 5.77-5.70 (m, 1H), 5.28 (dd, J = 12.2, 6.3 Hz, 1H), 4.82-4.67 (m, 2H), 4.30 (t, J = 13.0 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.6, 6.3, 1.7 Hz, 1H). Mass (m / z) 468.3 [M+H] + .

[0380] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-1H-pyrrole-2-carboxamide (107) JPEG0007764398000148.jpg3564

[0381] The title compound 107 was prepared from compound 106 in 10.3% yield following the procedure outlined for compound 66-02. 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.55 (s, 1H), 6.91 - 6.62 (m, 5H), 6.27 (t, J = 3.3 Hz, 1H), 5.50-5.49 (m, 1H), 5.33-5.23 (m, Mass (m / z) 486.2 [M+H] + .

[0382] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (108) JPEG0007764398000149.jpg72159

[0383] Step 1: To a mixture of tert-butyl 3-((2-chloro-5-fluoropyridin-4-yl)oxy)azetidine-1-carboxylate 3-02 (300 mg, 0.99 mmol), 3,5-dimethyl-4-nitro-1H-pyrazole (280 mg, 1.98 mmol), and (1S,2S)-cyclohexane-1,2-diamine (338 mg, 2.97 mmol), anhydrous DMF (4.0 mL) was added. The mixture was purged with argon for 5 minutes, and copper(I) iodide (56 mg, 0.297 mmol) and KPO (629 mg, 2.97 mmol) were added. The reaction mixture was heated at 140 °C for 24 hours and then purified by column chromatography to give compound 108-01 as a yellow oil (yield: 28.3%, 210 mg).

[0384] Step 2-3: The title compound 108 was prepared from compound 108-01 following the procedure outlined for compounds 50-05 to 50. 1H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 6.1 Hz, 1H), 6.85 - 6.78 (m, 1H), 6.78 - 6.58 (m, 3H), 5.34 - 5.22 (m, 1H), 5.19-5.12 (m, 1H), 4.71-4.57 (m, 2H), 4.33 (dd, J = 33.7, 10.0 Hz, 2H), 3.37 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.97 (s, 3H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.58 (s, 3H). Mass (m / z) 516.2 [M+H] + .

[0385] (S)-(3-((2-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (109) JPEG0007764398000150.jpg41159

[0386] Compound 108 (45 mg, 0.087 mmol), Fe (24 mg, 0.44 mmol), and NH4Cl (24 mg, 0.44 mmol) were dissolved in EtOH (2 mL) and HO (2 mL). The mixture was stirred at 80 °C for 2 h. The mixture was decompressed and purified by prep-TLC to give the title compound 109 as a white solid. 42 mg, yield: 89.4%. 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 2.5 Hz, 1H), 7.17 (d, J = 6.2 Hz, 1H), 6.78 (t, J = 1.7 Hz, 1H), 6.77 - 6.41 (m, 3H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.19 - 5.05 (m, 1H), 4.69-4.56(m, 2H), 4.31 (dd, J = 31.0, 10.4 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.52 (s, 3H), 2.25 (s, 3H). Mass (m / z) 486.2[M+H] + .

[0387] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (110) JPEG0007764398000151.jpg72159

[0388] Step 1: 3-04 (2 g, 4.87 mmol), ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (900 mg, 5.36 mmol), CuI (4.3 g, 9.74 mmol), and KPO (3.1 g, 14.61 mmol), (1S,2S)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (1.38 g, 9.74 mmol) was placed in dioxane (50 mL). The mixture was stirred under N2 at 120 °C for 12 hours. The mixture was extracted with DCM, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave intermediate compound 110-01 (800 mg, 30.2%) as a white solid. Mass (m / z): 453.2 [M+H] + .

[0389] Step 2: Compound 110-01 (700 mg, 1.55 mmol) and KOH (200 mg, 3.57 mmol) were placed in EtOH (3 mL) and HO (3 mL). The mixture was stirred at 55 °C for 12 h, then the pH was adjusted to 7, extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography gave compound 110-02 (compound 233) (520 mg, 65%) as a white solid. Mass (m / z): 515.2 [M+H] + .

[0390] Step 3: 110-02 (250 mg, 0.48 mmol), DMF (0.01 mL) were placed in THF (5 mL). Then, oxalyl chloride (0.2 mL) was added to the mixture. The mixture was stirred at 25 °C for 30 min, and then NH4OH (10 mL, 30%) was added and stirred at 25 °C for 30 min. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound 110 (18 mg, 24.2%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.10 (d, J = 6.1 Hz, 1H), 6.75 - 6.59 (m, 4H), 5.56 (s, 2H), 5.21 (dd, J = 12.2, 6.4 Hz, 1H), 5.11-5.05 (m, 1H), 4.64 - 4.47 (m, 2H), 4.25 (dd, J = 33.0, 10.6 Hz, 2H), 3.29 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.75 (s, 3H),) δ 2.64 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.41 (s, 3H). Mass (m / z): 515.2 [M+H] +

[0391] 5-(6-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carbonitrile (111) JPEG0007764398000152.jpg3664

[0392] Following the procedure outlined for compound 1, the title compound 111 was prepared from 1-05 in 11.1% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.85 - 7.77 (m, 1H), 7.60 - 7.43 (m, 2H), 6.80-6.62 (m, 4H), 5.49-5.39 (m, 1H), 5.32 - 5.21 (m, 1H), 4.67-4.49 (m, 2H), 4.4.-4.20 (m, 2H), 4.08 (s, 3H), 3.40-3.27(m, 1H), 2.75-2.61 (m, 1H). Mass (m / z) 482.2[M+H] +

[0393] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorophenoxy)azetidin-1-yl)methanone (112) JPEG0007764398000153.jpg68159

[0394] Step 1: 5-Bromo-2-fluorophenol (0.96 g, 5.0 mmol), 6-tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (1.3 g, 5.25 mmol), and CsCO (2.4 g, 7.5 mmol) were placed in DMF (20 mL). The mixture was stirred at 100° C. for 2 hours, water was added, extracted with EA, washed with brine, dried (NaSO), and concentrated to dryness to give intermediate 112-01 (1.4 g, 82.5%) as a white solid. Mass (m / z): 290.1 ​​[M-56+H] + .

[0395] Step 2: Following the procedure outlined for compounds 50-5 to 50, intermediate compound 112-02 was prepared from 112-01 in 86.1% yield. Mass (m / z): 246.0 [M+H] + .

[0396] Step 3: Following the procedure outlined for compound 3, the title compound 112 was prepared from 112-02 in 41.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (s, 1H), 7.21 (dd, J = 11.0, 8.3 Hz, 1H), 6.89 (ddd, J = 8.3, 4.3, 2.0 Hz, 1H), 6.80 - 6.73 (m, 3H), 6.69 (tt, J = 8.9, 2.4 Hz, 1H), 6.62 (dd, J = 7.9, 2.0 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.97 (td, J = 6.3, 3.2 Hz, 1H), 4.54 (d, J = 6.6 Hz, 2H), 4.30 (dd, J = Mass (m / z): 470.3 [M+H] + .

[0397] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluorophenoxy)azetidin-1-yl)methanone (113) JPEG0007764398000154.jpg4064

[0398] Following the procedure outlined for compound 3, the title compound 113 was prepared from 112-02 in 35.1% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.13 (dd, J = 11.2, 8.4 Hz, 1H), 6.85 - 6.64 (m, 5H), 6.58 (dd, J = 8.0, 2.1 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.97 (td, J = 6.4, 3.2 Hz, 1H), 4.60 - 4.47 (m, 2H), 4.31 (dd, J = 31.5, 10.1 Hz, 2H), 3.38 - 3.29 (m, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.26 (s, 6H). Mass (m / z): 470.3 [M+H] + .

[0399] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (117) JPEG0007764398000155.jpg31159

[0400] Compound 92 (99 mg, 0.21 mmol), 2-bromoethan-1-ol (250 mg, 0.42 mmol), and CsCO (342 mg, 1.05 mmol) were placed in CHCN (5 mL). The mixture was stirred at 65 °C for 4.5 days, and then the reaction solution was poured into water. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by prep-HPLC afforded the title compound 117 (29 mg, 26.8%) as a white solid. Mass (m / z) 515.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J = 3.8 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.79 - 6.63 (m, 4H), 5.28 (dd, J = 12.1, 6.2 Hz, 1H), 5.16 (s, 1H), 4.76 - 4.55 (m, 2H), 4.50 - 4.20 (m, 4H), 3.99 (d, J = 8.7 Hz, 2H), 3.38 (ddd, J = 18.7, 12.1, 1.6 Hz, 1H), 2.73 (ddd, J = 18.7, 6.3, 1.8Hz, 1H), 2.33 (dd, J = 22.7, 9.5 Hz, 6H).

[0401] Methyl (S)-2-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetate (118) JPEG0007764398000156.jpg3764

[0402] The title compound 118 was prepared from compound 92 in 34.6% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 3.2 Hz, 1H), 7.01 - 6.64 (m, 5H), 5.16 (d, J = 7.8 Hz, 1H), 4.88 (s, 2H), 4.81 (d, J = 7.8 Hz, 1H), 4.46 (t, J = 7.8 Hz, 2H), 4.20 (d, J = 9.1 Hz, 2H), 3.80 (s, 3H), 3.04 (dd, J = 16.8, 6.1 Hz, 1H), 2.91 (dd, J = 16.8, 5.2 Hz, 1H), 2.32 (d, J = 4.6 Hz, 6H). Mass (m / z) 543.3 [M+H] + .

[0403] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(4-((2-(dimethylamino)ethyl)amino)-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (119) JPEG0007764398000157.jpg3677

[0404] The title compound 119 was prepared from compound 53 in 16.8% yield following the procedure outlined for compound 50. Mass (m / z) 543.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 2.9 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J = 6.5 Hz, 1H), 6.79 (s, 1H), 6.76 - 6.65 (m, 3H), 5.51 (s, 1H), 5.25 (dd, J = 12.2, 6.4 Hz, 1H), 4.63 (s, 2H), 4.35 - 4.21 (m, 2H), 3.97 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 3.34 (dd, J = 18.6, 12.3 Hz, 1H), 3.26 (s, 2H), 2.84 (s, 6H), 2.71 - 2.65 (m, 1H).

[0405] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-4-((2-morpholinoethyl)amino)-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (120) JPEG0007764398000158.jpg3677

[0406] Following the procedure outlined for compound 50, the title compound 120 was prepared from compound 53 in 19.8% yield. Mass (m / z) 585.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.9 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J = 6.5 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.78 - 6.66 (m, 3H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.10 (s, 1H), 4.60 (s, 2H), 4.32 (dd, J = 33.6, 10.4 Hz, 2H), 4.00 (s, 3H), 3.70 (s, 4H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 3.17 (s, 2H), 2.76 - 2.62 (m, 3H), 2.52 (s, 4H).

[0407] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-methoxyacetamide (121) JPEG0007764398000159.jpg33159

[0408] Compound 53 (200 mg, 0.42 mmol), 2-methoxyacetic acid (76 mg, 0.84 mmol), DIPEA (110 mg, 0.84 mmol), and HATU (160 mg, 0.42 mmol) were dissolved in DMF (5 mL) and stirred at 25 °C for 10 min. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by prep-HPLC afforded the title compound 121 (54 mg, 23.5%) as a white solid. Mass (m / z) 544.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 9.77 (s, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.20 (s, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.79 - 6.69 (m, 3H), 5.30 (dd, J = 12.2, 6.4 Hz, 1H), 5.10 (td, J = 6.5, 3.3 Hz, 1H), 4.70 - 4.55 (m, 2H), 4.35 (dd, J = 30.2, 10.3 Hz, 2H), 4.07 (s, 3H), 4.05 (s, 2H), 3.51 (s, 3H), 3.39 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.74 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0409] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(dimethylamino)acetamide (122) JPEG0007764398000160.jpg3577

[0410] The title compound 122 was prepared from compound 53 in 25.8% yield following the procedure outlined for compound 121. Mass (m / z) 557.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.01 (s, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.81 (d, J = 1.7 Hz, 1H), 6.78 - 6.66 (m, 3H), 5.30 - 5.23 (m, 1H), 5.17 (s, 1H), 4.59 (s, 2H), 4.32 (dd, J = 31.6, 10.5 Hz, 2H), 3.98 (s, 5H), 3.46 - 3.29 (m, 1H), 2.97 (s, 6H), 2.70 (ddd, J = 18.5, 6.3, 1.7 Hz, 1H).

[0411] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (123) JPEG0007764398000161.jpg3977

[0412] The title compound 123 was prepared from compound 53 in 24.3% yield following the procedure outlined for compound 121. Mass (m / z) 612.3 [M+H + ]. 1H NMR (400 MHz, Chloroform-d) δ 9.92 (s, 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.13 (s, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.88 - 6.81 (m, 1H), 6.79 - 6.65 (m, 3H), 5.27 (dd, J = 12.1, 6.3 Hz, 1H), 5.12 (q, J = 6.0, 4.9 Hz, 1H), 4.62 (d, J = 9.9 Hz, 2H), 4.33 (dd, J = 29.8, 10.6 Hz, 2H), 4.02 (s, 3H), 3.58 (s, 2H), 3.43 - 3.32 (m, 3H), 3.04 (s, 6H), 2.86 (s, 3H), 2.73 (ddd, J = 18.7, 6.3, 1.8 Hz, 1H).

[0413] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3-ethyl-5-methyl-1H-pyrazole-4-carbonitrile (124) JPEG0007764398000162.jpg4464

[0414] Following the procedure outlined for compound 110, the title compound 124 was prepared in 23.1% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 2.3 Hz, 1H), 7.23 (s, 1H), 6.81 - 6.65 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.14 (dt, J = 6.4, 2.7 Hz, 1H), 4.62 (d, J = 6.5 Hz, 2H), 4.31 (dd, J = 36.7, 10.6 Hz, 2H), 3.35 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.80 - 2.67 (m, 6H), 1.33 (t, J = 7.6 Hz, 3H). Mass (m / z) 510.1 [M+H] + .

[0415] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-3-(methylamino)-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (125) JPEG0007764398000163.jpg4364

[0416] The title compound 125 was prepared from compound 101-03 following the procedure outlined for compound 56. Mass (m / z) 500.2 [M+H] + .

[0417] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (126) JPEG0007764398000164.jpg4164

[0418] The title compound 126 was prepared from 29-01 in 1.2% yield following the procedure outlined for compound 29. Mass (m / z) 456.4 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.8 Hz, 1H), 7.56 (s, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.17 - 7.08 (m, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.97 - 6.90 (m, 2H), 5.30 - 5.21 (m, 2H), 4.59 - 4.51 (m, 2H), 4.15 - 4.05 (m, 2H), 3.41 - 3.35 (m, 1H), 2.70 - 2.65 - 2.56 (m, 1H), 2.31 (s, 3H).

[0419] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethylisothiazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (127) JPEG0007764398000165.jpg4164

[0420] Following the procedure outlined for compound 29, the title compound 127 was prepared from 29-01 in 4.7% yield. Mass (m / z) 488.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 3.1 Hz, 1H), 6.81 (d, J = 1.7 Hz, 1H), 6.79 - 6.66 (m, 3H), 6.62 (d, J = 6.5 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.08 (s, 1H), 4.59 (s, 2H), 4.34 (dd, J = 27.8, 10.3 Hz, 2H), 3.37 (dd, J = 18.7, 12.2 Hz, 1H), 2.72 (dd, J = 18.7, 6.3 Hz, 2H), 2.47 (s, 3H), 2.41 (s, 3H).

[0421] Ethyl (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (128) JPEG0007764398000166.jpg4477

[0422] The title compound 128 was prepared from compound 3-04 in 12.0% yield following the procedure outlined for compound 108. Mass (m / z) 542.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 2.7 Hz, 1H), 6.75 - 6.56 (m, 4H), 6.44 (d, J = 6.0 Hz, 1H), 5.84 (s, 1H), 5.20 (dd, J = 12.2, 6.4 Hz, 1H), 4.93 (td, J = 6.4, 3.3 Hz, 1H), 4.47 (s, 2H), 4.22 (dd, J = 25.3, 10.2 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.29 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 2.73 - 2.39 (m, 2H), 2.28 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H).

[0423] Methyl (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (129) JPEG0007764398000167.jpg4264

[0424] The title compound 129 was prepared from compound 3-04 in 11.5% yield following the procedure outlined for compound 108. Mass (m / z) 528.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.7 Hz, 1H), 6.78 - 6.51 (m, 4H), 6.45 (d, J = 6.0 Hz, 1H), 6.27 (d, J = 1.1 Hz, 1H), 5.20 (ddd, J = 12.2, 6.5, 3.0 Hz, 1H), 5.00 - 4.84 (m, 1H), 4.59 - 4.40 (m, 2H), 4.33 - 4.13 (m, 2H), 3.74 (s, 3H), 3.30 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 2.70 - 2.58 (m, 1H), 2.28 (s, 3H), 1.97 (d, J = 1.0 Hz, 3H).

[0425] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (130) JPEG0007764398000168.jpg34159

[0426] Compound 92 (94 mg, 0.2 mmol), 3-bromooxetane (55 mg, 0.4 mmol), and CsCO (261 mg, 0.8 mmol) were placed in DMF (4 mL). The mixture was stirred at 50 °C for 3 h, and then the reaction solution was poured into water. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by prep-HPLC afforded the title compound 130 (20 mg, 19.0%) as a white solid.

[0427] 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 3.1 Hz, 1H), 6.82 - 6.65 (m, 4H), 6.59 (d, J = 6.6 Hz, 1H), 5.40 (p, J = 7.1 Hz, 1H), 5.25 (dt, J = 22.5, 6.4 Hz, 3H), 5.05 (s, 1H), 4.97 (dd, J = 7.6, 6.4 Hz, 2H), 4.58 (s, 2H), 4.33 (dd, J = 35.0, 10.4 Hz, 2H), 3.36 (ddd, J = 18.7, 12.2, 1.7Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.35 (d, J = 13.0 Hz, 6H). Mass (m / z) 527.3 [M+H] + .

[0428] (S)-(3-((2-(1-(azetidin-3-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (131) JPEG0007764398000169.jpg4164

[0429] The title compound 131 was prepared from compound 92 in 57.1% yield following the procedure outlined for compound 130. 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 3.2 Hz, 1H), 6.85 - 6.58 (m, 5H), 5.41 - 5.22 (m, 2H), 5.09 (tt, J = 6.6, 3.8 Hz, 1H), 4.74 - 4.21 (m, 8H), 3.36 (ddd, J = 18.7, 12.1, 1.6 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.40 - 2.21 (m, 6H). Mass (m / z) 526.3 [M+H] + .

[0430] (S)-(3-((2-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (132) JPEG0007764398000170.jpg5064

[0431] The title compound 132 was prepared from compound 92 in 29.5% yield following the procedure outlined for compound 130. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 3.0 Hz, 1H), 6.83 - 6.65 (m, 4H), 6.59 (d, J = 6.6 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.04 (td, J = 6.5, 3.3 Hz, 1H), 4.59 (t, J = 9.4 Hz, 2H), 4.32 (dd, J = 35.0, 10.2 Hz, 2H), 3.92 (d, J = 6.8 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, 0.63 - 0.53 (m, 2H), 0.38 (dt, J = 6.2, 4.8 Hz, 2H). Mass (m / z) 525.3 [M+H] + .

[0432] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-isopropyl-1-methyl-1H-pyrazole-4-carboxamide (133) JPEG0007764398000171.jpg3977

[0433] The title compound 133 was prepared from compound 65 in 68% yield following the procedure outlined for compound 68. Mass (m / z) 542.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 7.79 (s, 1H), 7.23 (d, J = 6.7 Hz, 1H), 6.80 - 6.64 (m, 4H), 6.38 (d, J = 7.7 Hz, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.15-5.07 (m, 1H), 4.69-4.54 (m, 2H), 4.38-4.24 (m, 2H), 4.17 - 4.04 (m, 1H), 3.91 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.8 Hz, 1H), 1.15 (d, J = 6.6 Hz, 6H).

[0434] (S)-N-Cyclopropyl-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (134) JPEG0007764398000172.jpg3464

[0435] The title compound 134 was prepared from compound 65 in 69% yield following the procedure outlined for compound 68. Mass (m / z) 540.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 7.78 (s, 1H), 7.24 (d, J = 6.7 Hz, 1H), 6.88 - 6.61 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.20 - 5.07 (m, 1H), 4.70-4.53 (m, 2H), 4.41 - 4.25 (m, 2H), 3.90 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.77 (dq, J = 7.2, 3.5 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 0.84 - 0.74 (m, 2H), 0.57 - 0.44 (m, 2H).

[0436] S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-3-yl)acetamide (135) JPEG0007764398000173.jpg48159

[0437] Compound 41 (57 mg, 0.12 mmol), acetyl chloride, and pyridine were placed in DCM (5 mL). The mixture was stirred at room temperature for 1 hour. H2O and DCM were added, and the combined organic layer was washed with saturated NaHCO3 solution and 1N HCl solution. Concentration in vacuo and purification on a silica gel plate afforded the title compound 135 (5 mg, 8%) as a white solid. Mass (m / z) 514.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 2.7 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.82 - 6.65 (m, 4H), 5.28 (dd, J = 12.2, 6.5 Hz, 1H), 5.12-5.04 (m, 1H), 4.66-4.53 (m, 2H), 4.37-4.23 (m, 2H), 4.06 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.17 (s, 3H).

[0438] (S)-N-acetyl-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-3-yl)acetamide (136) JPEG0007764398000174.jpg4864

[0439] The title compound 136 was prepared from compound 41 as a white solid in 10% yield following the procedure outlined for compound 135. Mass (m / z) 556.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 6.4 Hz, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.78 - 6.64 (m, 3H), 6.39 (s, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.10-5.02 (m, 1H), 4.68-4.52 (m, 2H), 4.40 - 4.23 (m, 2H), 4.16 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.7, 6.5, 1.8 Hz, 1H), 2.36 (s, 6H).

[0440] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-3-yl)cyclopropanecarboxamide (137) JPEG0007764398000175.jpg4264

[0441] The title compound 137 was prepared from compound 41 as a white solid in 14% yield following the procedure outlined for compound 135. Mass (m / z) 540.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 2.7 Hz, 1H), 8.26 (s, 1H), 6.93 (s, 1H), 6.88 (d, J = 6.4 Hz, 1H), 6.82 - 6.65 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.08-4.98 (m, 1H), 4.71 - 4.52 (m, 2H), 4.35-4.21 (m, 2H), 4.07 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 1.57-1.47(m, 1H), 1.14 - 1.06 (m, 2H), 0.91-0.83 (m, 2H).

[0442] (S)-N-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (138) JPEG0007764398000176.jpg4864

[0443] The title compound 138 was prepared from compound 109 as a white solid in 19.5% yield following the procedure outlined for compound 135. Mass (m / z) 598.4 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 6.2 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.78 - 6.74 (m, 2H), 6.73 - 6.67 (m, 1H), 5.32 - 5.25 (m, 1H), 5.14 (d, J = 6.3 Hz, 1H), 4.69 - 4.52 (m, 2H), 4.41 - 4.22 (m, 4H), 4.09 (dd, J = 11.0, 7.4 Hz, 2H), 3.49 (td, J = 11.3, 3.2 Hz, 2H), 3.44 - 3.27 (m, 2H), 2.76 - 2.66 (m, 1H), 2.64 - 2.52 (m, 1H), 2.46 (s, 3H), 2.18 (s, 3H), 2.08 - 1.84 (m, 4H).

[0444] (S)-N-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)cyclopropanecarboxamide (139) JPEG0007764398000177.jpg4864

[0445] The title compound 139 was prepared from compound 109 following the procedure outlined for compound 135 as a white solid in 30% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.18 (dd, J = 10.3, 2.4 Hz, 1H), 7.21 (d, J = 6.2 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.80 - 6.76 (m, 2H), 6.73 - 6.68 (m, 1H), 5.34 - 5.26 (m, 1H), 5.22 - 5.3 (m, 1H), 4.70 - 4.60 (m, 2H), 4.34 (d, J = 28.2 Hz, 2H), 3.37 (dd, J = 18.8, 12.3 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.51 (s, 3H), 2.23 (s, 3H), 1.37 - 1.34 (m, 2H), 1.10 (ddd, J = 10.0, 5.9, 3.6 Hz, 2H), 0.89 (dq, J = 7.2, 4.0 Hz, 2H), 0.81 - 0.75 (m, 1H). Mass (m / z) 554.3 [M+H] + .

[0446] (S)-N-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide (140) JPEG0007764398000178.jpg4664

[0447] The title compound 140 was prepared from compound 109 as a white solid in 19.8% yield following the procedure outlined for compound 135. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 6.2 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.75 (dt, J = 6.4, 2.1 Hz, 2H), 6.71 - 6.66 (m, 1H), 5.27 (ddd, J = 12.1, 6.4, 3.2 Hz, 1H), 5.20 - 5.09 (m, 1H), 4.71 - 4.53 (s,2H), 4.40 - 4.24 (m, 2H), 3.42 - 3.30 (m, 1H), 2.74 - 2.65 (m, 1H), 2.48 (s, 3H), 2.20 (s, 6H). Mass (m / z) 528.3 [M+H] + .

[0448] (S)-1-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-3-isopropylurea (141) JPEG0007764398000179.jpg35159

[0449] A mixture of compound 53 (50 mg, 0.11 mmol) and 2-isocyanatopropane (18 mg, 0.22 mmol) in DCM (5 mL) was reacted under N2, and the whole reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated. The crude product was purified by pre-TLC to give the desired product 141 (27 mg, 45.7%) as a white solid. Mass (m / z) 557.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 2.9 Hz, 1H), 7.68 (s, 1H), 7.05 (d, J = 6.5 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 6.76 - 6.66 (m, 3H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.15 (s, 1H), 4.62 (s, 2H), 4.30 (dd, J = 21.6, 10.7 Hz, 2H), 4.05 (s, 3H), 3.93 - 3.84 (m, 1H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 1.09 (d, J = 6.5 Hz, 6H).

[0450] (S)-1-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-3-methylurea (142) JPEG0007764398000180.jpg4477

[0451] The title compound 142 was prepared from compound 53 as a white solid in 37.5% yield following the procedure outlined for compound 141. Mass (m / z) 529.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.8 Hz, 1H), 7.68 (s, 1H), 6.97 (d, J = 6.6 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.77 - 6.64 (m, 3H), 5.26 (dd, J = 12.1, 6.4 Hz, 1H), 5.07 (s, 1H), 4.73 (s, 1H), 4.59 (s, 2H), 4.28 (dd, J = 21.1, 10.4 Hz, 2H), 4.05 (s, 3H), 3.35 (dd, J = 18.6, 12.2 Hz, 1H), 2.78 (s, 3H), 2.75 - 2.64 (m, 1H).

[0452] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-2-methyl-1H-imidazole-5-carbonitrile (143) JPEG0007764398000181.jpg3664

[0453] The title compound 143 was prepared from compound 3-04 as a white solid in 8.6% yield following the procedure outlined for compound 110. Mass (m / z) 482.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.6 Hz, 1H), 7.72 (s, 1H), 6.88 - 6.48 (m, 5H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.10 (d, J = 3.8 Hz, 1H), 4.62 (dd, J = 18.8, 10.9 Hz, 2H), 4.33 (dd, J = 27.3, 10.3 Hz, 2H), 3.37 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.54 (s, 3H).

[0454] (S)-N-(5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazol-3-yl)cyclopropanecarboxamide (144) JPEG0007764398000182.jpg4577

[0455] The title compound 144 was prepared from compound 101 as a brown solid in 12.5% ​​yield following the procedure outlined for compound 135. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.8 Hz, 1H), 6.89 - 6.52 (m, 5H), 5.26 (dd, J = 12.2, 6.5 Hz, 1H), 5.09-4.97 (m, 1H), 4.66 - 4.48 (m, 2H), 4.41 - 4.24 (m, 2H), 3.90 (s, 3H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 3.18-3.08 (m, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.00 (s, 3H), 1.38 (t, J = 7.3 Hz, 2H), 1.13 - 1.06 (m, 2H). Mass (m / z) 554.3 [M+H] + .

[0456] (S)-2-((5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazol-3-yl)amino)acetamide (145) JPEG0007764398000183.jpg4877

[0457] The title compound 145 was prepared from compound 101 as a white solid in 82.1% yield following the procedure outlined for compound 56. 1 H NMR (400 MHz, Chloroform-d) δ 8.59 - 8.44 (m, 1H), 6.80 (t, J = 1.5 Hz, 1H), 6.78 - 6.53 (m, 4H), 5.26 (dd, J = 12.1, 6.4 Hz, 1H), 5.13 - 4.99 (m, 1H), 4.59 (s, 2H), 4.39 - 4.25 (m, 2H), 4.14 - 4.01 (m, 2H), 3.92 - 3.73 (m, 3H), 3.36 (dd, J = 18.6, 12.2 Hz, 1H), 2.71 (ddd, J = 18.7, 6.5, 1.7 Hz, 1H), 2.05 - 1.90 (m, 3H). Mass (m / z) 543.3 [M+H] + .

[0458] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-imidazol-2-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (146) JPEG0007764398000184.jpg3864

[0459] Following the procedure outlined for compound 30, the title compound 146 was prepared from compound 3-02 as a white solid in 34.5% yield. Mass (m / z) 457.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.09 (d, J = 1.1 Hz, 1H), 6.96 (s, 1H), 6.82 - 6.60 (m, 4H), 5.32 - 5.25 (m, 1H), 5.21 - 5.10 (m, 1H), 4.65 (s, 2H), 4.29 (t, J = 12.3 Hz, 2H), 4.08 (s, 3H), 3.34 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.68 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H).

[0460] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (147) JPEG0007764398000185.jpg37159

[0461] Compound 147-01 (100 mg, 0.25 mmol) was dissolved in 3 mL of toluene, hexane-2,5-dione (115 mg, 1 mmol), and 4-methylbenzenesulfonic acid (20 mg, 0.025 mmol), and the mixture was stirred at 120° C. for 12 hours. Concentration and purification by prep-HPLC afforded the title compound 147 (50 mg, 48.2%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 2.7 Hz, 1H), 6.82 (t, J = 1.7 Hz, 1H), 6.78 (dd, J = 4.8, 3.3 Hz, 2H), 6.76 - 6.69 (m, 1H), 6.54 (d, J = 6.0 Hz, 1H), 5.91 (s, 2H), 5.29 (dd, J = 12.2, 6.5 Hz, 1H), 5.03 (td, J = 6.4, 3.2 Hz, 1H), 4.66 - 4.53 (m, 2H), 4.33 (dd, J = 23.3, 10.4Hz, 2H), 3.39 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.74 (ddd, J = 18.7, 6.5, 1.8 Hz, 1H), 2.13 (s, 6H). Mass (m / z) 470.3 [M+H] + .

[0462] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(hydroxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (148) JPEG0007764398000186.jpg72159

[0463] Step 1: Compound 148-01 (500 mg, 1.02 mmol) was dissolved in THF (10 mL), and i-prMgCl (250 uL, 2 M, 2.52 mmol) was added at 0 °C and stirred at 0 °C for 1 h. DMF (1 mL) was added, and the reaction mixture was stirred at room temperature for 12 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave compound 148-02 (96 mg, 25.1%). MS (m / z) 391.2 [M+H] + .

[0464] Step 2: Compound 148-02 (96 mg, 0.25 mmol) was dissolved in MeOH (2 mL), NaBH (20 mg, 0.51 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (Na SO ), and concentrated in vacuo. Purification by silica gel chromatography gave compound 148-03 (76 mg, 79.1%). MS (m / z) 393.3 [M+H] + .

[0465] The title compound 148 was prepared from compound 148-03 as a white solid in 10.2% yield following the procedure outlined for compound 1-03. 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 6.2, 2.6 Hz, 1H), 6.80 - 6.66 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.21 - 5.12 (m, 1H), 4.670 - 4.56 (m, 2H), 4.54 (m, 2H) ,4.31 (dd, J = 30.7, 10.2 Hz, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.76 - 2.67 (m, 1H), 2.61 (s, 3H), 2.34 (s, 3H). Mass (m / z) 501.2 [M+H] + .

[0466] (S)-5-(6-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (149) JPEG0007764398000187.jpg3464

[0467] The title compound 149 was prepared from compound 111 as a pale green solid in 82% yield following the procedure outlined for compound 66. Mass (m / z) 500.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.54-7.48 (m, 1H), 7.30 (dd, J = 8.1, 3.0 Hz, 1H), 6.81 - 6.72 (m, 3H), 6.71-6.64 (m, 1H), 5.44 - 5.34 (m, 1H), 5.26 (dd, J = 12.2, 6.5 Hz, 1H), 4.67 - 4.47 (m, 2H), 4.38 - 4.20 (m, 2H), 3.84 (s, 3H), 3.34 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H).

[0468] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-3-carbonitrile (150) JPEG0007764398000188.jpg32159

[0469] Step 1: Compound 212-01 (500 mg, 1.14 mmol), Zn(CN) (147 mg, 1.25 mmol), Pd(dba) (104 mg, 0.11 mmol), DPPF (61 mg, 0.11 mmol), and Zn (19 mg, 0.29 mmol) were dissolved in DMF (5 mL). The mixture was stirred at 140 °C under N (g) atmosphere for 4 h. Concentration and purification by silica gel chromatography (PE / EA = 2 / 1) afforded compound 150-01 (280 mg, 63.6%) as a yellow oil. Mass (m / z) 388.2 [M+H] + .

[0470] The title compound 150 was prepared from compound 150-01 as a white solid in 96.2% yield following the procedure outlined for compound 1-03. 1 H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 2.9 Hz, 1H), 6.81 (t, J = 1.7 Hz, 1H), 6.78 - 6.58 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.14-5.04 (m, 1H), 4.68 - 4.51 (m, 2H), 4.33 (dd, J = 30.0, 10.5 Hz, 2H), 4.01 (s, 3H), 3.37 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.72 (ddd, J = 18.7, 6.4, 1.7 Hz, 1H), 2.23 (s, 3H). Mass (m / z) 496.3 [M+H] + .

[0471] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carbonitrile (151) JPEG0007764398000189.jpg45159

[0472] Compound 110 (20 mg, 0.04 mmol) was dissolved in 1 mL of THF, and TEA (0.1 mL) and TFAA (0.1 mL) were added at 0° C. The mixture was stirred at 0° C. for 30 min and quenched with ice water. The mixture was concentrated and purified by prep-HPLC to give the title compound 151 (8 mg, 40%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.42 - 8.12 (m, 1H), 7.78 - 7.47 (m, 1H), 6.94 - 6.60 (m, 4H), 5.38 - 5.11 (m, 2H), 4.64 (s, 2H), 4.28 (dd, J Mass (m / z) 496.2 [M+H] + .

[0473] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2,4,5-trimethyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (152) JPEG0007764398000190.jpg53159

[0474] Step 1: Compound 3-04 (960 mg, 2.3 mmol), NHBoc (1.08 g, 9.37 mmol), Pd(dba) (214 mg, 0.23 mmol), CsCO (2.3 g, 7.02 mmol), and X-phos (111 mg, 0.23 mmol) were added to dioxane (10 mL). The mixture was stirred overnight at 100 °C under N. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by column chromatography on silica gel eluted with (PE:EA = 1:2) afforded the title compound 152-01 (500 mg, 43%). Mass (m / z) 492.4 [M+H] + ;

[0475] Step 2: Compound 152-01 (1.3 g, 2.60 mmol) was dissolved in 15 mL of DCM, trifluoroacetic acid (1.5 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Concentration gave the desired product 152-02, which was used in the next step without further purification. Mass (m / z) 392.4 [M+H] + .

[0476] Step 3: Compound 152-02 (50 mg, 0.13 mmol), CHCHO (5.6 mg, 0.13 mmol), AcO (50 mg, 0.13 mmol), and p-toluenesulfonic acid (2 mg, 0.012 mmol) in toluene (coupled with 4A molecular sieves). The mixture was stirred at 120 °C under N for 2 h and concentrated. Purification by prep-HPLC gave the title compound 152 (10 mg, 16%). Mass (m / z) 485.4 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.66 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.4 Hz, 1H), 7.02 (s, 1H), 6.94 - 6.68 (m, 2H), 5.36 - 5.13 (m, 2H), 4.54 (s, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.42 - 3.29 (m, 1H), 2.65 (dd, J = 18.6, 6.3 Hz, 1H), 2.45 (s, 6`H), 1.99 (s, 3H).

[0477] Ethyl (S)-4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (153) JPEG0007764398000191.jpg74159

[0478] Step 1: Compound 153-01 (3 g, 12.195 mmol), BocO (3.19 g, 14.616 mmol), DMAP (0.297 g, 2.43 mmol), and TEA (1 mL) were dissolved in 30 mL of DCM. The mixture was stirred at room temperature for 16 h. The solvent was evaporated to dryness, and the mixture was purified by column chromatography (PE / EA = 10 / 1) to give compound 153-02 (4.2 g, 99.5%) as a colorless oil. Mass (m / z) 347.3 [M+H] + .

[0479] Step 2: Compound 153-02 (212 mg, 0.613 mmol), Pd2(dba)3 (56 mg, 0.061 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (466.8 mg, 1.838 mmol), AcOK (172.4 mg, 1.838 mmol), and P-Cy3 (34.3 mg, 0.123 mmol) were mixed in 4 mL of 1,4-dioxane. The mixture was stirred at 120 °C under N2 for 16 h. The solvent was evaporated to dryness, and the mixture was purified by prep-TLC (PE / EA = 5 / 1) to give compound 153-03 (110 mg, 45.7%) as a pale yellow oil. Mass (m / z) 394.3 [M+H] + .

[0480] Step 3: Compound 3-04 (100 mg, 0.244 mmol), compound 153-03 (110 mg, 0.28 mmol), X-Phos-G3 (20.6 mg, 0.024 mmol), Pd2(dba)3 (22.3 mg, 0.023 mmol), and K3PO4 (517 mg, 2.439 mmol) were placed in 5 mL of 1,4-dioxane / HO (v / v = 4 / 1). The mixture was stirred at 100 °C under N2 for 16 h. The solvent was evaporated to dryness and purified by prep-TLC (PE / EA = 1 / 2) to give 8 mg of a white solid, yield 5.24%. Mass (m / z) 542.4 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.78 (brs, 1H), 8.42 (d, J = 3.2 Hz, 1H), 6.79 (t, J = 1.2 Hz, 1H), 6.77 - 6.73 (m, 2H), 6.72 - 6.66 (m, 1H), 6.56 (d, J = 6.8 Hz, 1H), 5.27 (dd, J = 12.0, 6.4 Hz, 1H), 5.07 - 4.99 (m, 1H), 4.63-4.51 (m, 2H), 4.40 - 4.23 (m, 4H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.71 (ddd, J = 18.4, 6.4, 1.6 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0481] (S)-3-Fluoro-5-(1-(3-((5-fluoro-2-(1-methyl-3-(methylamino)-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidine-1-carbonyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (154) JPEG0007764398000192.jpg4464

[0482] The title compound 154 was prepared from compound 41 as a white solid in 8% yield following the procedure outlined for compound 56. Mass (m / z) 486.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 2.8 Hz, 1H), 6.94 (d, J = 6.3 Hz, 1H), 6.83-6.80 (m, 1H), 6.78 - 6.67 (m, 3H), 5.74 (s, 1H), 5.29 (dd, J = 12.2, 6.4 Hz, 1H), 5.18-5.09 (m, 1H), 4.62 (s, 3H), 4.33 (dd, J = 32.4, 10.5 Hz, 3H), 4.05 (s, 3H), 3.44 - 3.31 (m, 1H), 2.91 (s, 3H), 2.73 (ddd, J = 18.7, 6.3, 1.8 Hz, 1H).

[0483] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(methoxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (155) JPEG0007764398000193.jpg4964

[0484] The title compound 155 was prepared from compound 148 as a white solid in 40% yield following the procedure outlined for compound 50. 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (s, 1H), 6.94 (s, 1H), 6.62 - 6.37 (m, 4H), 5.05 - 4.87 (m, 2H), 4.50 - 4.23(m, 2H), 4.10 - 3.88 (m, Mass (m / z) 515.3 [M+H] + .

[0485] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)methanone (156) JPEG0007764398000194.jpg4064

[0486] The title compound 156 was prepared from compound 91 as a white solid in 8.7% yield following the procedure outlined for compound 86. 1 H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 2.6 Hz, 1H), 6.76 - 6.58 (m, 4H), 5.50 - 5.41 (m, 1H), 5.21 (dd, J = 12.2, 6.4 Hz, 1H), 4.54 (s, 2H), 4.25 (dd, J = 34.6, 10.7 Hz, 2H), 4.12 (t, J = 4.8 Hz, 2H), 3.96 (t, J = 4.8 Hz, 2H), 3.34 - 3.22 (m, 1H), 2.63 (ddd, J = 18.7, 6.5, 1.7 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H). Mass (m / z) 516.3 [M+H] + .

[0487] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (157) JPEG0007764398000195.jpg4364

[0488] The title compound 157 was prepared from compound 92 as a white solid in 21.6% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 6.83 (d, J = 1.7 Hz, 1H), 6.80 - 6.64 (m, 4H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.15 (s, 1H), 4.64 (s, 2H), 4.37 (dd, J = 34.8, 10.1 Hz, 2H), 4.28 - 4.19 (m, 1H), 4.14 (dd, J = 11.7, 4.3 Hz, 2H), 3.54 (t, J = 11.9 Hz, 2H), 3.45 - 3.33 (m, 1H), 2.79 - 2.69 (m, 1H), 2.34 (d, J = 30.9 Hz, 8H), 1.85 (d, J = 12.9 Hz, 2H). Mass (m / z) 555.4 [M+H] + .

[0489] (S)-(3-((2-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (158) JPEG0007764398000196.jpg5064

[0490] The title compound 158 was prepared from compound 91 as a white solid in 24.7% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 2.6 Hz, 1H), 6.83 - 6.65 (m, 4H), 5.53 (s, 1H), 5.29 (s, 1H), 4.61 (s, 2H), 4.33 (d, J = 27.3 Hz, 2H), 3.98 (d, J = 6.8 Hz, 2H), 3.35 (dd, J = 18.6, 12.1 Hz, 1H), 2.77 - 2.49 (m, 7H), 1.26 (s, 1H), 0.58 (dd, J = 7.7, 5.2 Hz, 2H), 0.41 (t, J = 5.0 Hz, 2H). Mass (m / z) 526.3 [M+H] + .

[0491] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (159) JPEG0007764398000197.jpg3964

[0492] Following the procedure outlined for compound 3, the title compound 159 was prepared from compound 3-04 as a white solid in 30.5% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 3.1 Hz, 1H), 6.81 - 6.65 (m, 4H), 6.57 (d, J = 6.6 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.04 (ddd, J = 7.8, 6.4, 3.9 Hz, 1H), 4.58 (t, J = 10.0 Hz, 2H), 4.32 (dd, J = 35.2, 10.2 Hz, 2H), 3.76 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.35 (d, J = 22.7 Hz, 6H). Mass (m / z) 485.3 [M+H] + .

[0493] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-((2-methoxyethyl)amino)-1,4-dimethyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (160) JPEG0007764398000198.jpg4777

[0494] The title compound 160 was prepared from compound 101-03 as a white solid in 36.8% yield following the procedure outlined for compound 56. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 2.9 Hz, 1H), 6.91 - 6.60 (m, 5H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.13-5.05 (m, 1H), 4.71-4.54(m, 2H), 4.33 (dd, J = 23.8, 10.5 Hz, 2H), 3.80 (s, 3H), 3.62 (t, J = 4.6 Hz, 2H), 3.55 (t, J = 4.7 Hz, 2H), 3.40 (s, 3H), 3.39 - 3.31 (m, 1H), 2.72 (dd, J = 18.6, 6.2 Hz, 1H), 1.95 (s, 3H). Mass (m / z) 544.4 [M+H] + .

[0495] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-2-carboxamide (161) JPEG0007764398000199.jpg3464

[0496] Following the procedure outlined for compound 66-02, the title compound 161 was prepared in 19.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 6.77-6.65 (m, 3H), 6.10 (d, J = 2.8Hz, 1H), 6.04 (d, J = 4.0 Hz, 1H), 5.75 (s, 1H), 5.33 - 5.21 (m, 1H), 5.08-5.00 (m, 1H), 4.62-4.49 (m, 2H), 4.42 - 4.19 (m, 2H), 3.41-3.30 (m, 1H), 2.77 - 2.63 (m, 1H), 2.08 (s, 3H). Mass (m / z) 499.3 [M+H] + .

[0497] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-(isopropylamino)-1,4-dimethyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (162) JPEG0007764398000200.jpg4264

[0498] The title compound 162 was prepared from compound 101-03 as a white solid in 42.8% yield following the procedure outlined for compound 56. 1H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 2.8 Hz, 1H), 6.81 (t, J = 1.6 Hz, 1H), 6.78 - 6.55 (m, 4H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.14-5.02 (m, 1H), 4.71-4.52 (m, 2H), 4.32 (dd, J = 21.1, 10.1 Hz, 2H), 3.92 - 3.84 (m, 1H), 3.82 (s, 3H), 3.44 - 3.28 (m, 1H), 2.76-2.67 (m, 1H), 1.99 (s, 3H), 1.43 - 1.18 (m, 6H). Mass (m / z) 528.4 [M+H] + .

[0499] (S)-(3-((2-(3-((cyclopropylmethyl)amino)-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (163) JPEG0007764398000201.jpg32159

[0500] Step 1: Compound 163-01 (150 mg, 0.34 mmol), cyclopropylmethanamine (48.4 mg, 0.68 mmol), Pd(dba) (27 mg, 0.03 mmol), MetBuPhos (16 mg, 0.03 mmol), and NaOtBu (65 mg, 0.68 mmol) were dissolved in DMF (3 mL). The mixture was stirred at 90 °C under a N atmosphere for 2 h. Concentration and purification by prep-TLC afforded compound 163-02 (70 mg, 42.2%) as a yellow oil.

[0501] The title compound 163 was prepared from compound 163-02 as a white solid in 42.1% yield following the procedure outlined for compound 1-03. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.9 Hz, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.78 - 6.57 (m, 4H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 5.09-5.01 (m, 1H), 4.67-4.51(m, 2H), 4.32 (dd, J = 31.8, 10.5 Hz, 2H), 3.77 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 3.13 (d, J = 7.0 Hz, 2H), 2.71 (ddd, J = Mass (m / z) 539.2 [M+H] + .

[0502] (S)-(3-((2-(3-((cyclopropylmethyl)(methyl)amino)-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (164) JPEG0007764398000202.jpg4164

[0503] The title compound 164 was prepared from compound 163 as a white solid in 16.7% yield following the procedure outlined for compound 56. 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 2.7 Hz, 1H), 6.82 (s, 1H), 6.69 (d, J = 25.6 Hz, 4H), 5.30 (s, 1H), 5.07 (s, 1H), 4.63 (d, J = 25.8 Hz, 2H), 4.33 (s, 2H), 3.89 (s, 3H), 3.39 (d, J = 7.1 Hz, 2H), 3.36 - 3.29 (m, 1H), 3.26 (s, 2H), 2.73 (s, 1H), 2.19 (s, 3H), 1.05 (s, 1H), 0.62 (d, J = 7.9 Hz, 2H), 0.35 (s, 2H). Mass (m / z) 554.4 [M+H] + .

[0504] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-3-carboxamide (165) JPEG0007764398000203.jpg4264

[0505] The title compound 165 was prepared from compound 150 as a white solid in 96.1% yield following the procedure outlined for compound 66. 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 2.9 Hz, 1H), 6.87-6.78 (m, 2H), 6.78 - 6.55 (m, 4H), 5.46 (s, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.11-5.04 (m, 1H), 4.60 (dd, J = 19.7, 10.9 Hz, 2H), 4.33 (dd, J = 25.1, 10.3 Hz, 2H), 3.95 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.37 (s, 3H). Mass (m / z) 514.2 [M+H] + .

[0506] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3-(dimethylamino)-1-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (166) JPEG0007764398000204.jpg4064

[0507] The title compound 166 was prepared from compound 41 as a white solid in 48% yield following the procedure outlined for compound 56. Mass (m / z) 500.3 [M+H] + . 1 H NMR (301 MHz, Chloroform-d) δ 8.46-8.39 (m, 1H), 6.90 - 6.62 (m, 5H), 5.95 (s, 1H), 5.28 (dd, J = 12.3, 6.4 Hz, 1H), 5.15-5.04 (m, 1H), 4.69-4.53 (m, 2H), 4.41-4.22 (m, 2H), 4.04 (s, 3H), 3.45-3.29 (m, 1H), 2.98 (s, 6H), 2.79 - 2.64 (m, 1H).

[0508] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(4-(ethylsulfonyl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (167) JPEG0007764398000205.jpg115159

[0509] Step 1: 3-Bromopentane-2,4-dione (1.0 g, 5.65 mmol), ethanethiol (700 mg, 11.29 mmol), TEA (1.1 g, 1.89 mmol) in EtOH (10 mL) under N2. The whole reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give compound 167-01 (1.5 g) as a yellow oil, which was used in the next step reaction without purification. MS (m / z) 161.2 [M+H] + .

[0510] Step 2: Compound 167-01 (1.5 g, crude), N2H4-H2O (5 mL) were placed in dioxane (10 mL) under N2, and the entire reaction mixture was stirred at 80 °C for 2 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave compound 167-02 (100 mg) as a yellow oil. MS (m / z) 157.2 [M+H] + .

[0511] Step 3: Compound 167-02 (100 mg, 0.64 mmol), tert-butyl 3-((2-chloro-5-fluoropyridin-4-yl)oxy)azetidine-1-carboxylate (386 mg, 1.27 mmol), (1R,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (273 mg, 1.92 mmol), CuI (365 mg, 1.92 mmol), and K3PO4 (407 mg, 1.92 mmol) were placed in DMF (10 mL) under N2, and the whole reaction mixture was stirred at 150 °C for 2 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave compound 167-03 (200 mg) as a yellow oil. MS (m / z) 423.5 [M+H] + .

[0512] Step 4: Compound 167-03 (200 mg, 0.47 mmol), m-CPBA (200 mg, 1.16 mmol) were placed in DCM (10 mL) under N2, and the whole reaction mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo to give compound 167-04 (300 mg, crude) as a yellow oil, which was used in the next step reaction without purification. MS (m / z) 455.5 [M+H] + .

[0513] Step 5: Compound 167-04 (300 mg, crude), TFA (2 mL) were dissolved in DCM (5 mL) and stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to give compound 167-05 (400 mg, crude) as a yellow oil, which was used in the next step without purification. MS (m / z): 355.4 [M+H] + .

[0514] Step 6: Compound 167-05 (400 mg, crude), (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (80 mg, 0.28 mmol) and TEA (3 mL) were placed in THF (5 mL) under N, and the whole reaction mixture was stirred at 60 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (NaSO) and concentrated in vacuo. Purification by silica gel chromatography gave compound 167 (2.0 mg, 1.2%) as a gray solid. Mass (m / z): 563.5 [M+H] +

[0515] (S)-(3-((2-(1-(cyclopropylmethyl)-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (168) JPEG0007764398000206.jpg4564

[0516] The title compound 168 was prepared from 169-04 in 2.0% yield following the procedure outlined for compound 169. Mass (m / z): 541.5 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.10 (tt, J = 9.6, 2.4 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.96 - 6.86 (m, 2H), 5.23 (m, 2H), 4.59 - 4.50 (m, 2H), 4.48 - 4.41 (m, 2H), 4.11 - 4.05 (m, 2H), 3.94 (d, J = 6.8 Hz, 2H), 3.39 (dd, J = 18.8, 12.0 Hz, 1H), 2.74 - 2.54 (m, 1H), 2.47 (s, 3H), 1.30 - 1.23 (m, 1H), 0.56 - 0.45 (m, 2H), 0.42 - 0.32 (m, 2H).

[0517] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-(hydroxymethyl)-5-methyl-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (169) JPEG0007764398000207.jpg131159

[0518] Step 1: Compound 29-01 (7.0 g, crude), 1-(tert-butyl) 3-ethyl 4-bromo-5-methyl-1H-pyrazole-1,3-dicarboxylate (5.0 g, 15.06 mmol), Pd(PPh3)4 (1.70 g, 1.47 mmol) were added to PhMe (50 mL) under N2, and the entire reaction mixture was stirred at 120 °C for 15 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 169-01 (1.0 g) as a yellow solid. MS (m / z): 421.4 [M+H] + .

[0519] Step 2: Under N2, 169-01 (600 mg, 1.42 mmol), LAH (7.0 mL, 1 mol / L, 5.00 mmol) were dissolved in THF (5 mL), and the entire reaction mixture was stirred at 0 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 169-02 (300 mg) as a yellow oil. MS (m / z): 379.4 [M+H] + .

[0520] Step 3: 169-02 (300 mg, 0.79 mmol), TFA (3 mL) in DCM (6 mL) under N2, and the whole reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo and used in the next step without purification. MS (m / z): 279.4 [M+H] + .

[0521] Step 4: 169-03 (500 mg, crude), 1-02 (400 mg, 1.45 mmol) and TEA (1 mL) were dissolved in THF (5 mL) under N2, and the entire reaction mixture was stirred at 25 °C for 15 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 169-04 (200 mg) as a yellow oil. MS (m / z): 487.4 [M+H] + .

[0522] Step 5: 169-04 (70 mg, 0.14 mmol), CsCO (100 mg, 0.30 mmol), and 3-(bromomethyl)oxetane (50 mg, 0.33 mmol) were dissolved in DMF (5 mL) and stirred at 25 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded 169 (1.7 mg, 2.0%) as a yellow oil. MS (m / z): 557.5 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 3.2 Hz, 1H), 7.16 - 7.07 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.94 - 6.87 (m, 2H), 5.75 (s, 1H), 5.29 - 5.20 (m, 2H), 4.77 (s, 2H), 4.73 - 4.31 (m, 6H), 4.15 - 4.05 (m, 2H), 3.63 (d, J = 5.6 Hz, 2H), 3.49 - 3.33 (m, 2H), 2.74 - 2.60 (m, 1H), 2.56 (s, 3H).

[0523] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (170) JPEG0007764398000208.jpg4564

[0524] The title compound 170 was prepared from 3-04 in 4.0% yield following the procedure outlined for compound 102. Mass (m / z): 525.4 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 2.8 Hz, 1H), 7.30 (d, J = 6.0 Hz, 1H), 7.10 (tt, J = 9.6, 2.4 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.96 - 6.86 (m, 2H), 6.81 (s, 1H), 5.35 (dd, J = 6.4, 3.2 Hz, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.55 - 4.50 (m, 2H), 4.12 - 4.07 (m, 2H), 3.48 - 3.35 (m, 1H), 2.74 - 2.57 (m, 1H), 2.54 (d, J = 0.8 Hz, 3H).

[0525] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide (171) JPEG0007764398000209.jpg46159

[0526] Following the procedure outlined for compound 2, compound 171-01 was prepared in 34.0% yield.

[0527] Compound 171-01 (100 mg, 0.2 mmol), dimethylamine (16 mg, 0.40 mmol), DIPEA (100 mg), and HATU (188 mg, 0.5 mmol) were dissolved in DMF (5 mL) and stirred at 25 °C for 10 min. The mixture was extracted with EA, washed with brine, dried (Na SO ), and concentrated in vacuo. Purification by prep-HPLC afforded the title compound 171 (20 mg, 19.0%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 2.7 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.86 - 6.68 (m, 4H), 5.30 (dd, J = 12.2, 6.4 Hz, 1H), 5.13-5.05 (m, 1H), 4.72-4.54 (m, 3H), 4.46-4.25(m,2H), 4.21 (s, 3H), 3.43 (s, 3H), 3.41 - 3.32 (m, 1H), 3.15 (s, 3H), 2.73 (dd, J = 18.7, 6.5 Hz, 1H). Mass (m / z) 528.3 (M+H + ).

[0528] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxamide (172) JPEG0007764398000210.jpg52159

[0529] Compound 172-01 (200 mg, 0.4 mmol), NH in MeOH (2 mL) was stirred at 100 °C for 12 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by prep-HPLC afforded the title compound 172 (34 mg, 16.9%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 2.7 Hz, 1H), 6.98 (s, 1H), 6.84 - 6.62 (m, 5H), 5.21 (dd, J = 12.2, 6.4 Hz, 1H), 5.05 - 4.05 (m, Mass (m / z) 500.2 [M+H] + .

[0530] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carbonitrile (173) JPEG0007764398000211.jpg4164

[0531] Following the procedure outlined for compound 3, the title compound 173 was prepared from 3-04 in 16.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 6.94 - 6.66 (m, 6H), 5.29 (dd, J = 12.0, 6.2 Hz, 1H), 5.11 (s, 1H), 4.68 - 4.56 (m, Mass (m / z) 482.7 [M+H] + .

[0532] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (174) JPEG0007764398000212.jpg4764

[0533] Following the procedure outlined for compound 3, the title compound 174 was prepared from 3-04 in 10.2% yield. 1 H NMR (301 MHz, Chloroform-d) δ 8.46 (d, J = 2.7 Hz, 1H), 6.99 - 6.47 (m, 6H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.16-5.02 (m, 1H), 4.70-4.50 Mass (m / z) 487.2 [M+H] + .

[0534] (S)-(3-((2-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (175) JPEG0007764398000213.jpg4164

[0535] The title compound 175 was prepared from 3-02 in 47.2% yield following the procedure outlined for compound 101-02. 1 H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J = 2.9 Hz, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.78 - 6.57 (m, 4H), 5.26 (dd, J = 12.1, 6.4 Hz, 1H), 5.06 (td, J = 6.4, 3.2 Hz, 1H), 4.58 (dt, J = 16.3, 8.6 Hz, 2H), 4.41 - 4.22 (m, 2H), 3.89 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.4, 1.8 Hz, 1H), 2.05 (s, 3H). Mass (m / z): 505.2[M+H] + .

[0536] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-3-(methylthio)-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (176) JPEG0007764398000214.jpg4464

[0537] The title compound 176 was prepared following the procedure outlined for compound 163. 1H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.79 - 6.64 (m, 4H), 5.31 - 5.25 (m, 1H), 5.07 (d, J = 3.6 Hz, 1H), 4.60 (s, 2H), 4.34 (dd, J = 29.7, 10.6 Hz, 2H), 3.92 (s, 3H), 3.43 - 3.31 (m, 1H), 2.76 - 2.70 (m, 1H), 2.47 (s, 3H), 2.08 (s, 3H). Mass (m / z): 517.2[M+H] + .

[0538] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-3-(methylsulfonyl)-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (177) and (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-3-(methylsulfinyl)-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (178) JPEG0007764398000215.jpg32159

[0539] Compound 176 (20 mg, 0.04 mmol) and m-CPBA (3.3 mg, 0.02 mmol) were dissolved in DCM (2 mL). The mixture was stirred at room temperature for 90 minutes. Concentration and purification by prep-TLC afforded compound 177 (10 mg) and compound 178 (0.7 mg) as white solids.

[0540] Compound 177: 1H NMR (301 MHz, Chloroform-d) δ 8.53 (d, J = 3.0 Hz, 1H), 8.07 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 6.85 - 6.64 (m, 3H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.13-5.03 (m, 1H), 4.70-5.51 (m, 2H), 4.40 - 4.19 (m, 2H), 3.98 (s, 3H), 3.37 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 3.21 (s, 3H), 2.72 (ddd, J = 18.8, 6.6, 1.8 Hz, 1H), 2.32 (s, 3H). Mass (m / z): 548.3[M+H] +

[0541] Compound 178: Mass (m / z): 533.3[M+H] +

[0542] ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (179) JPEG0007764398000216.jpg36159

[0543] To a solution of compound 179-01 (100 mg, 0.17 mmol) in THF (2 mL) was added isopropylmagnesium chloride lithium chloride complex solution (0.15 mL, 0.20 mmol) at 0 °C. The reaction mixture was stirred for 30 min, then cooled to −78 °C, and N-methoxy-N-methylacetamide (53 mg, 0.51 mmol) was added. The solution was stirred at −78 °C for 1 h, then the cooling bath was removed and allowed to warm to ambient temperature. The solution was diluted with EtOAc and quenched by the addition of 1 N HCl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude residue was taken up in MeOH and cooled to 0 °C before the addition of NaBH (19 mg, 0.51 mmol). The reaction was stirred while warming to ambient temperature and quenched when LCMS indicated the disappearance of the starting material. The solution was then diluted with 1 N HCl and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by pre-HPLC to give the desired product 179 (6 mg, 7%) as a white solid. Mass (m / z) 501.3 [M+H + ]. 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.7 Hz, 1H), 7.58 (s, 1H), 6.88 (d, J = 6.3 Hz, 1H), 6.76 - 6.68 (m, 3H), 6.51 (s, 1H), 5.31 (d, J = 5.2 Hz, 1H), 5.19 - 5.04 (m, 1H), 4.63 (s, 2H), 4.45 - 4.26 (m, 2H), 4.19 (s, 3H), 3.98 (dt, J = 27.4, 6.0 Hz, 1H), 3.02 - 2.93 (m, 3H), 1.29 (dd, J = 6.2, 4.2 Hz, 3H).

[0544] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(2-(hydroxymethyl)-4-methylthiazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (180) JPEG0007764398000217.jpg4664

[0545] Following the procedure outlined for compound 2, the title compound 180 was prepared from 3-04 in 28% yield. Mass (m / z) 504.2 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 8.39 (d, J = 2.8 Hz, 1H), 7.01 - 6.55 (m, 5H), 5.27 (dd, J = 12.1, 6.1 Hz, 1H), 5.10 (s, 1H), 4.93 (s, 2H), 4.61 (s, 2H), 4.34 (d, J = 27.3 Hz, 2H), 3.37 (dd, J = 18.4, 11.8 Hz, 1H), 2.74 (d, J = 5.9 Hz, 1H), 2.66 (d, J = 9.9 Hz, 3H).

[0546] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (181) JPEG0007764398000218.jpg4264

[0547] The title compound 181 was prepared from 92 in 23.6% yield following the procedure outlined for compound 86. 1H NMR (400 MHz, Chloroform-d) δ 9.69 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 6.86 - 6.64 (m, 4H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.14 (s, 1H), 4.98 (s, 1H), 4.63 (s, 2H), 4.37 (d, J = 31.5 Hz, 3H), 3.72 (s, 2H), 3.38 (dd, J = 18.6, 12.2 Hz, 1H), 3.21 (s, 2H), 2.73 (dd, J = 18.7, 6.3 Hz, 1H), 2.30 (d, J = 31.0 Hz, 8H). Mass (m / z) 554.4[M+H] + .

[0548] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(2,5-dimethyl-1H-imidazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (182) JPEG0007764398000219.jpg30159

[0549] Step 1: Compound 147-01 (100 mg, 0.26 mmol) and N,N-dimethylacetamide dimethyl acetal (170 mg, 1.28 mmol) were mixed in toluene, and the reaction mixture was heated to 85° C. with stirring and kept at this temperature overnight. The mixture was cooled to room temperature to give the desired product 182-01 with 90% purity. Mass (m / z) 461.4 [M+H] + .

[0550] Step 2: To compound 182-01 (50 mg, 5.4 mmol) in 50 mL of dry MeCN was added prop-2-yn-1-amine (8 mg, 0.15 mmol) and AcOH (20 mg, 0.33 mmol) until the temperature reached 0 °C. The reaction mixture was stirred at 80 °C overnight and cooled to room temperature. The mixture was concentrated and then further purified by prep-HPLC to give the final compound 182 (20 mg, 40%) as a white solid. Mass (m / z) 470.2 [M+H] + ; 1 H NMR (301 MHz, CDCl3) δ 8.41 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 19.1 Hz, 2H), 6.85 - 6.58 (m, 4H), 5.34 - 5.02 (m, 2H), 4.64 (s, 2H), 4.30 (s, 2H), 3.35 (dd, J = 18.4, 12.0 Hz, 1H), 2.69 (dd, J = 18.5, 5.3 Hz, 1H), 2.53 (s, 3H), 2.07 (d, J = 32.8 Hz, 3H).

[0551] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (183) JPEG0007764398000220.jpg4164

[0552] The title compound 183 was prepared from 110-02 in 14.8% yield following the procedure outlined for compound 68. 1H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.12 (s, 1H), 6.76 - 6.57 (dd, J = 23.8, 17.0 Hz, 4H), 5.21 (dd, J = 12.0, 6.3 Hz, 1H), 5.014-5.02 (m, 1H), 4.64-4.50 (m, 2H), 4.25 (dd, J = 29.1, 9.9 Hz, 2H), 3.75-3.54 (m, 2H), 3.39-3.20 (m, 3H), 2.64 (dd, J = 18.6, 6.2Hz, 1H), 2.51 (s, 3H), 2.21 (s, 3H), 1.56 (s, 6H). Mass (m / z) 582.3 [M+H] + .

[0553] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (184) JPEG0007764398000221.jpg3764

[0554] The title compound 184 was prepared from 110-02 in 14.9% yield following the procedure outlined for compound 68. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.22 (d, J = 6.1 Hz, 1H), 6.85 - 6.69 (m, 4H), 5.30 (dd, J = 12.2, 6.4 Hz, 1H), 5.18 (s, 1H), 4.65 (s, 2H), 4.34 (dd, J = 31.0, 10.5 Hz, 2H), 3.62 (d, J = 94.6 Hz, 8H), 3.38 (dd, J = 18.5, 12.2 Hz, 1H), 2.73 (dd, J = 18.6, 6.5 Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H). Mass (m / z) 584.3 [M+H] + .

[0555] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoropyridin-2-yl)oxy)azetidin-1-yl)methanone (185) JPEG0007764398000222.jpg3964

[0556] Following the procedure outlined for compound 2, the title compound 185 was prepared from 1-04 in 47% yield. Mass (m / z): 471.3[M+H] + . 1H NMR (300 MHz, Chloroform-d) δ 7.52-7.42 (m, 1H), 7.37 (s, 1H), 7.01 (dd, J = 8.1, 2.9 Hz, 1H), 6.85 - 6.73 (m, 3H), 6.68 (tt, J = 8.8, 2.4 Hz, 1H), 5.49-5.36 (m, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.69-4.45 (m, 1H), 4.40-4.21 (m, 2H), 3.96 (s, 3H), 3.34 (ddd, J = 18.6, 12.2, 1.7Hz, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.12 (s, 3H).

[0557] (S)-5-(6-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-3-carbonitrile (186) JPEG0007764398000223.jpg4064

[0558] Following the procedure outlined for compound 150, the title compound 186 was prepared in 51% yield. Mass (m / z): 496.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J = 9.4, 8.0 Hz, 1H), 7.02 (dd, J = 8.0, 2.8 Hz, 1H), 6.81 - 6.72 (m, 3H), 6.69 (tt, J = 8.8, 2.2 Hz, 1H), 5.44-5.35 (m, 1H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 4.68 - 4.49 (m, 2H), 4.38-4.21 (m, 2H), 3.99 (s, 3H), 3.42-3.29 (m, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.23 (s, 3H).

[0559] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (187) JPEG0007764398000224.jpg4464

[0560] The title compound 187 was prepared from compound 92 in 33.2% yield following the procedure outlined for compound 86. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 3.0 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.78 - 6.65 (m, 3H), 6.60 (d, J = 6.5 Hz, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.07 (tt, J = 6.7, 4.0 Hz, 1H), 4.64 - 4.52 (m, 2H), 4.40 - 4.25 (m, 2H), 3.41 - 3.34 (m, 1H), 3.33 (s, 3H), 2.73 - 2.67 (m, 1H), 2.56 (s, 3H), 2.32 (s, 3H). Mass (m / z) 549.3 [M+H]+ .

[0561] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-4-methylthiazole-2-carbonitrile (188) JPEG0007764398000225.jpg4164

[0562] The title compound 188 was prepared from compound 3-02 in 11% yield following the procedure outlined for compound 48. Mass (m / z) 499.1 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 8.42 (d, J = 2.9 Hz, 1H), 6.96 (d, J = 6.2 Hz, 1H), 6.88 - 6.63 (m, 4H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 5.12 (s, 1H), 4.62 (d, J = 8.5 Hz, 2H), 4.35 (dd, J = 27.0, 10.6 Hz, 2H), 3.38 (dd, J = 18.7, 12.2 Hz, 1H), 2.77-2.68 (m, 4H).

[0563] (S)-5-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-4-methylthiazole-2-carboxamide (189) JPEG0007764398000226.jpg4764

[0564] The title compound 189 was prepared from compound 188 in 7.9% yield following the procedure outlined for compound 66. Mass (m / z) 517.2 [M+H] + . 1H NMR (300 MHz, Chloroform-d) δ 8.43 (d, J = 2.9 Hz, 1H), 7.14 (s, 1H), 6.88 (d, J = 6.3 Hz, 1H), 6.84 - 6.64 (m, 4H), 5.77 (s, 1H), 5.28 (dd, J = 12.1, 6.3 Hz, 1H), 5.10 (s, 1H), 4.72 - 4.50 (m, 2H), 4.46 - 4.22 (m, 2H), 3.37 (dd, J = 18.6, 12.1 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.66 (s, 3H).

[0565] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-(methylsulfonyl)-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (190) JPEG0007764398000227.jpg4664

[0566] The title compound 190 was prepared from compound 3-02 in 5.0% yield following the procedure outlined for compound 167. Mass (m / z): 549.5 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 6.0 Hz, 1H), 6.73 (t, J = 1.6 Hz, 1H), 6.71 - 6.75 (m, 2H), 6.63 (tt, J = 8.8, 2.4 Hz, 1H), 5.21 (dd, J = 12.0, 6.4 Hz, 1H), 5.08 (ddd, J = 10.4, 6.4, 4.0 Hz, 1H), 4.60 - 4.55 (m, 2H), 4.29 - 4.23 (m, 2H), 3.30 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 3.01 (s, 3H), 2.78 (s, 3H), 2.64 (ddd, J = 18.4, 6.4, 1.6 Hz, 1H), 2.43 (s, 3H).

[0567] (S)-4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrrole-2-carboxamide (191) JPEG0007764398000228.jpg28159

[0568] Compound 110-02 (50 mg, 0.097 mmol) was dissolved in 2 mL of THF. 0.1 mL of SOCl2 was added. Stirred at room temperature for 1 hour. The solvent was evaporated to dryness. It was used in the next step without further purification. The above residue was dissolved in 2 mL of DCM. It was added dropwise to 2 mL of ammonia solution (0.5 mL) in DCM at 0 °C. It was stirred at 0 °C for 30 minutes. The organic layer was separated, evaporated to dryness, and purified by prep-TLC (PE / EA = 1 / 3) to give compound 191 (5 mg, 10%) as a white solid. Mass (m / z) 513.4 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.85 (brs, 1H), 8.71 (s, 1H), 6.81 (s, 1H), 6.77-6.70 (m, 2H), 6.69-6.60 (m, 2H), 6.00 (brs, 2H), 5.27 (dd, J = 11.6, 6.4 Hz, 1H), 5.17-5.10 (m, 1H), 4.68-4.53 (m, 2H), 4.45-4.26 (m, 2H), 3.37 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.72 (ddd, J = 18.4, 6.4, 1.6Hz, 1H), 2.29 (s, 6H).

[0569] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,N,3,5-tetramethyl-1H-pyrazole-4-carboxamide (192) JPEG0007764398000229.jpg4264

[0570] The title compound 192 was prepared from compound 191 in 16.4% yield following the procedure outlined for compound 68. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 6.1 Hz, 1H), 6.82 (t, J = 1.7 Hz, 1H), 6.78 (dt, J = 6.5, 2.2 Hz, 2H), 6.72 (tt, J = 8.8, 2.3 Hz, 1H), 5.30 (dd, J = 12.2, 6.5 Hz, 1H), 5.17 (td, J = 6.5, 3.2 Hz, 1H), 4.71 - 4.58 (m, 2H), 4.34 (dd, J = 30.3, 10.4 Hz, 2H), 3.38 (ddd, J = Mass (m / z) 542.3 [M+H] + .

[0571] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,3,5-trimethyl-1H-pyrazole-4-carboxamide (193) JPEG0007764398000230.jpg4364

[0572] The title compound 193 was prepared from compound 191 in 15.2% yield following the procedure outlined for compound 68. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.20 (s, 1H), 6.82 - 6.67 (m, 4H), 5.61 (s, 1H), 5.30 (dd, J = 12.2, 6.4 Hz, 1H), 5.19 (s, 1H), 4.65 (s, 2H), 4.35 (d, J = 32.9 Hz, 2H), 3.38 (dd, J = 18.0, 12.4 Hz, 1H), 3.02 (d, J = 3.7 Hz, 3H), 2.79 (s, 2H), 2.73 (dd, J = 17.9, 6.5 Hz, 1H), 2.47 (s, 3H). Mass (m / z) 528.3 [M+H] + .

[0573] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (194) JPEG0007764398000231.jpg4064

[0574] The title compound 194 was prepared from compound 191 in 21.2% yield following the procedure outlined for compound 68. 1 H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.21 (s, 1H), 6.82 (s, 1H), 6.79 - 6.64 (m, 3H), 5.27 (s, 1H), 5.18 (s, 1H), 4.67 (s, 2H), 3.67 (s, 2H), 3.35 (d, J = 18.6 Hz, 3H), 2.78 - 2.67 (m, 2H), 2.57 (s, 4H), 2.32 (s, 3H), 1.97 (d, J = 26.7 Hz, 4H). Mass (m / z) 568.1 [M+H] + .

[0575] (S)-Azetidin-1-yl(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)methanone (195) JPEG0007764398000232.jpg4064

[0576] The title compound 195 was prepared from compound 191 in 2.9% yield following the procedure outlined for compound 68. 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 6.3 Hz, 1H), 6.74 - 6.60 (m, 4H), 5.21 (dd, J = 12.2, 6.4 Hz, 1H), 5.13 - 5.03 (m, 1H), 4.65 - 4.48 (m , 2H), 4.25 (dd, J = 29.0, 10.2 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H), 3.37 - 3.26 (m, 3H), 2.64 (dd, J = 18.8, 6.5 Hz, 2H), 2.51 (s, 3H), 2.24 (s, 3H), 1.97 - 1.84 (m, 2H). Mass (m / z) 554.3 [M+H] + .

[0577] (S)-5-(6-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-3-carboxamide (196) JPEG0007764398000233.jpg4164

[0578] The title compound 196 was prepared from compound 186 in 46% yield following the procedure outlined for compound 66. Mass (m / z): 514.3[M+H]+ . 1 H NMR (400 MHz, Chloroform-d) δ 7.50 (dd, J = 9.5, 8.0 Hz, 1H), 7.02 (dd, J = 8.0, 2.9 Hz, 1H), 6.86 (s, 1H), 6.80 - 6.72 (m, 3H), 6.68 (tt, J = 8.9, 2.3 Hz, 1H), 5.73 (s, 1H), 5.45-5.37 (m, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.66-4.48 (m, 2H), 4.39-4.22 (m, 2H), 3.92 (s, 3H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.36 (s, 3H).

[0579] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorophenoxy)azetidin-1-yl)methanone (197) JPEG0007764398000234.jpg121159

[0580] Step 1: Compound 197-01 (955 mg, 5.0 mmol), compound 197-02 (1320 mg, 5.25 mmol), and CsCO (2445 mg, 7.5 mmol) were added to DMF (20 mL) under N, and the entire reaction mixture was stirred at 100° C. for 2 h. The mixture was concentrated and then further purified by silica gel chromatography to give compound 197-03 (1.43 g, 82.5%) as a white solid.

[0581] Mass (m / z) 290.1 ​​[M+H-56] + .

[0582] Step 2: Compound 197-03 (710 mg, 2.05 mmol) was dissolved in 10 mL of DCM, trifluoroacetic acid (2337 mg, 20.5 mmol) was added, and the mixture was stirred at 25° C. for 1 h. Concentration gave the desired product compound 197-04, which was used in the next step without further purification.

[0583] Step 3: Compound 197-04, compound 1-05 (510 mg, 1.845 mmol), and TEA (5 mL) were dissolved in THF (10 mL) and stirred at 75 °C for 2 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded compound 197-05 (720 mg, 86.1%) as a yellow solid. Mass (m / z) 454.0 [M+H] + .

[0584] Step 4: Compound 197-05 (91 mg, 0.2 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54 mg, 0.24 mmol), Pd(dba) (19 mg, 0.02 mmol), and X-phos (19 mg, 0.04 mmol) were added to a solution of KPO (5N, 0.2 mL, 1.0 mmol) in 1,4-dioxane (2 mL) under N, and the whole reaction mixture was stirred at 110 °C for 2 h. The mixture was concentrated and then further purified by prep-HPLC to give compound 197 (39 mg, 41.5%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 7.37 (s, 1H), 7.21 (dd, J = 11.0, 8.3 Hz, 1H), 6.89 (ddd, J = 8.3, 4.3, 2.0 Hz, 1H), 6.80 - 6.73 (m, 3H), 6.69 (tt, J = 8.9, 2.4 Hz, 1H), 6.62 (dd, J = 7.9, 2.0 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.97 (td, J = 6.3, 3.2 Hz, 1H), 4.54 (d, J = 6.6 Hz, 2H), 4.30 (dd, J = Mass (m / z) 470.3 [M+H] + .

[0585] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-(5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluorophenoxy)azetidin-1-yl)methanone (198) JPEG0007764398000235.jpg4264

[0586] Following the procedure outlined for compound 197, the title compound 198 was prepared from compound 197-05 in 35.1% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.13 (dd, J = 11.2, 8.4 Hz, 1H), 6.85 - 6.64 (m, 5H), 6.58 (dd, J = 8.0, 2.1 Hz, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.97 (td, J = 6.4, 3.2 Hz, 1H), 4.60 - 4.47 (m, 2H), 4.31 (dd, J = 31.5, 10.1 Hz, 2H), 3.38 - 3.29 (m, 1H), 2.69 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.26 (s, 6H). Mass (m / z) 470.3 [M+H] + .

[0587] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-2,5-dimethyl-1H-imidazole-4-carbonitrile (199) JPEG0007764398000236.jpg4364

[0588] The title compound 199 was prepared from compound 182 in 16% yield following the procedure outlined for compound 150. Mass (m / z) 496.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.6 Hz, 1H), 6.75 (s, 1H), 6.71 - 6.53 (m, 4H), 5.20 (dd, J = 12.2, 6.4 Hz, 1H), 5.04 (s, 1H), 4.56 (s, 2H), 4.31 - 4.15 (m, 2H), 3.30 (dd, J = 18.7, 12.3 Hz, 1H), 2.65 (dd, J = 18.7, 6.4 Hz, 1H), 2.25 (s, 3H), 2.19 (s, 3H).

[0589] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-2,5-dimethyl-1H-imidazole-4-carboxamide (200) JPEG0007764398000237.jpg4064

[0590] The title compound 200 was prepared from compound 199 in 62% yield following the procedure outlined for compound 66. Mass (m / z) 514.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.7 Hz, 1H), 6.92 (brs, 1H), 6.74 (t, J = 1.6 Hz, 1H), 6.70 - 6.58 (m, 3H), 6.47 (d, J = 5.9 Hz, 1H), 5.23 - 5.16 (m, 1H), 5.03 - 4.96 (m, 1H), 4.61 - 4.42 (m, 2H), 4.25 (dd, J = 16.9, 10.6 Hz, 2H), 3.30 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.65 (ddd, J = 18.7, 6.4, 1.7 Hz, 1H), 2.35 (s, 3H), 2.18 (s, 3H).

[0591] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-(fluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (201) JPEG0007764398000238.jpg35159

[0592] Step 1: To a solution of compound 202 (100 mg, 0.26 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 0.5 h. The solvent was then evaporated in vacuo to give compound 201 as a colorless oil. Mass (m / z) 280.1 [M+H] + .

[0593] Step 2: Compound 201-01 was added to a solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1H-imidazol-1-yl)methanone (87 mg, 0.31 mmol) and TEA (80 mg, 0.79 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature overnight. Then, the solvent was evaporated in vacuo. The oil residue was purified by prep-HPLC to give compound 201 (20 mg, 15%) as a white solid. Mass (m / z) 490.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 6.7 Hz, 1H), 6.76 - 6.57 (m, 4H), 5.44 (s, 1H), 5.32 (s, 1H), 5.21 (dd, J = 12.2, 6.3 Hz, 1H), 5.10 (td, J = 6.4, 3.3 Hz, 1H), 4.60 (s, 2H), 4.27 (d, J = 0.7 Hz, 3H), 4.22 (d, J = 11.0 Hz, 2H), 3.29 (ddd, J = 18.6, 12.2, 1.6Hz, 1H), 2.64 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H).

[0594] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (202) JPEG0007764398000239.jpg4764

[0595] Following the procedure outlined for compound 30, the title compound 202 was prepared from compound 3-02 in 24.7% yield. Mass (m / z) 488.1 [M+H] + . 1 H NMR (301 MHz, Chloroform-d) δ 8.42 (d, J = 2.6 Hz, 1H), 7.59 (d, J = 6.7 Hz, 1H), 6.83 - 6.64 (m, 4H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.16 (d, J = 4.4 Hz, 1H), 4.78 (s, 2H), 4.66 (s, 2H), 4.30 (s, 5H), 3.45 - 3.27 (m, 1H), 2.79 - 2.62 (m, 1H).

[0596] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-(methylthio)-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (203) JPEG0007764398000240.jpg4064

[0597] The title compound 203 was prepared from compound 3-02 in 32.0% yield following the procedure outlined for compound 167. Mass (m / z) 517.5 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.19 - 8.13 (m, 1H), 7.21 (d, J = 6.0 Hz, 1H), 6.79(t, J = 1.6 Hz, 1H), 6.77 - 6.73 (m, 2H), 6.70 (tt, J = 8.8, 2.4 Hz, 1H), 5.28 (dd, J = 12.0, 6.4 Hz, 1H), 5.15 (td, J = 6.4, 3.2 Hz, 1H), 4.68 - 4.57 (m, 2H), 4.39 - 4.24 (m, 2H), 3.36 (ddd, J = 18.4, 12.0, 1.6Hz, 1H), 2.75 - 2.70 (m, 1H), 2.69 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H).

[0598] ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-4-(methylsulfinyl)-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (204) JPEG0007764398000241.jpg4864

[0599] The title compound 204 was prepared from compound 203 in 32.0% yield following the procedure outlined for compound 167. Mass (m / z) 533.5 [M+H] + .

[0600] 1H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 6.0 Hz, 1H), 6.80 (t, J = 1.6 Hz, 1H), 6.78 - 6.73 (m, 2H), 6.73 - 6.67 (m, 1H), 5.28 (dd, J = 12.0, 6.4 Hz, 1H), 5.15 (ddd, J = 10.4, 6.4, 4.0 Hz, 1H), 4.70 - 4.57 (m, 2H), 4.41 - 4.24 (m, 2H), 3.41 - 3.31 (m, 1H), 2.93 (s, 3H), 2.75 (s, 3H), 2.73 - 2.65 (m, 1H), 2.52 (s, 3H).

[0601] (S)-(3-((2-(5-amino-3-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (205) JPEG0007764398000242.jpg71159

[0602] Step 1: Compound 205-01 (1 g, 5.68 mmol), BocO (4.96 g, 22.75 mmol), DMAP (0.139 g, 1.14 mmol), and TEA (2 mL) were dissolved in 15 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 prep-TLC (PE / EA = 3 / 1) to give compound 205-02 (430 mg, 20.1%) as a white solid. Mass (m / z) 377.3 [M+H] + .

[0603] Step 2: Compound 205-02 (430 mg, 1.144 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (55.7 mg, 0.136 mmol), and Pd(AcO)2 (15.2 mg, 0.068 mmol) were mixed in 8 mL of 1,4-dioxane. TEA (411 mg, 4.07 mmol) was added. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (694 mg, 5.42 mmol) was slowly added to the reaction mixture. It was stirred at 70 °C for 1 h. The solvent was evaporated to dryness and purified by prep-TLC (PE / EA = 3.5 / 1) to give compound 205-03 (210 mg, 43.5%) as a pale yellow oil. Mass (m / z) 424.3 [M+H] + .

[0604] Step 3: Compound 205-03 (190 mg, 0.463 mmol), tert-butyl 5-((tert-butoxycarbonyl)amino)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (210 mg, 0.506 mmol), X-Phos-G3 (39 mg, 0.043 mmol), Pd2(dba)3 (39 mg, 0.043 mmol), and K3PO4 (982 mg, 4.63 mmol) were mixed in 8 mL of 1,4-dioxane / HO (v / v = 4 / 1). The mixture was stirred at 100 °C for 16 h under N2. The solvent was evaporated to dryness and purified by prep-TLC (PE / EA=1 / 3) to give compound 205-04 (40 mg, 12.9%) as a pale yellow solid. Mass (m / z) 673.4 [M+H] + .

[0605] Step 4: Compound 205-04 (40 mg, 0.06 mmol) was dissolved in 2 mL of DCM, and 2 mL of DCM / TFA (1 / 1) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated to dryness, and the mixture was purified by prep-TLC (DCM / MeOH = 12 / 1) to give compound 205 (9.8 mg, 34.6%) as a pale yellow oil. Mass (m / z) 473.4 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 6.80 (t, J = 1.6 Hz, 1H), 6.79 - 6.73 (m, 2H), 6.73 - 6.65 (m, 1H), 6.64 (d, J = 6.4 Hz, 1H), 5.27 (dd, J = 12.0, 6.4 Hz, 1H), 5.11 - 5.01 (m, 1H), 4.65 - 4.51 (m, 2H), 4.42 - 4.33 (m, 1H), 4.30 - 4.23 (m, 1H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.71 (ddd, J = 18.4, 6.4, 1.6 Hz, 1H), 2.49 (s, 3H).

[0606] (S)-(3-((2-(5-amino-1,2,4-trimethyl-1H-pyrrol-3-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (206) JPEG0007764398000243.jpg58159

[0607] Step 1: Compound 110-01 (260 mg, 0.48 mmol) and Cs2CO3 (623.6 mg, 1.92 mmol) were mixed in an 8 mL can. MeI (170.3 mg, 1.2 mmol) was added. The mixture was stirred at 40 °C for 2 h. The solvent was evaporated to dryness and purified by column chromatography (PE / EA = 1 / 3) to give compound 206-01 (190 mg, 71.2%) as a pale yellow oil. Mass (m / z) 556.4 [M+H] + .

[0608] Step 2: Compound 206-01 (190 mg, 0.34 mmol) was dissolved in 5 mL of MeOH. 2 mL of THF was added. 4 mL of 1N NaOH was added. It was stirred at 65 °C for 9 hours. The solvent was evaporated to dryness and acidified with 1N HCl to pH = 6. It was extracted with EA (15 mL x 3). The organic layer was evaporated to dryness and purified by column chromatography (PE / EA = 1 / 3) to give compound 206-02 (60 mg, 34.2%). Mass (m / z) 514.3 [M+H] + .

[0609] Step 3: Compound 206-02 (60 mg, 0.114 mmol) and TEA (11.5 mg, 0.114 mmol) were dissolved in 1 mL of DMF. Diphenylphosphorazidate (282.2 mg, 0.102 mmol) was added to the mixture at 0 °C. It was stirred in the dark at room temperature for 2 h. Then, it was added to 2 mL of t-BuOH solution. It was stirred at 80 °C for 1.5 h. The solvent was evaporated to dryness, and water was added. It was extracted with EA (15 mL × 3). The organic layer was evaporated to dryness and purified by column chromatography (PE / EA=1 / 3) to give 5 mg of tert-butyl (S)-(4-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,3,5-trimethyl-1H-pyrrol-2-yl)carbamate as a pale yellow solid. Yield: 8.2%. Mass (m / z) 599.4 [M+H] + The residue was dissolved in 2 mL of DCM. It was added dropwise to a solution of ammonia solution (0.5 mL) in 2 mL of DCM at 0 °C. It was stirred at 0 °C for 30 min. The organic layer was separated, evaporated to dryness, and purified by prep-TLC (DCM / MeOH = 8 / 1) to give compound 206 (2 mg, 48%) as a white solid. Mass (m / z) 499.4 [M+H] + .

[0610] (S)-(3-((2-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyrimidin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (207) JPEG0007764398000244.jpg4064

[0611] Following the procedure outlined for compound 1-03, the title compound 207 was prepared in 44% yield. Mass (m / z) 487.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.2 Hz, 1H), 6.78 - 6.56 (m, 4H), 5.69 (brs, 2H), 5.43 (ddd, J = 10.5, 6.6, 4.0 Hz, 1H), 5.21 (dd, J = 2.65 (ddd, J = 18.7, 6.3, 1.6 Hz, 1H), 2.09 (s, 3H).

[0612] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluoropyridin-3-yl)oxy)azetidin-1-yl)methanone (208) JPEG0007764398000245.jpg4064

[0613] Following the procedure outlined for compound 197, the title compound 208 was prepared in 26.1% yield. 1H NMR (301 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.44 (s, 1H), 6.97 (d, J = 9.3 Hz, 1H), 6.85 - 6.61 (m, 4H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 5.01 (s, 1H), 4.57 (d, J = 10.5 Hz, 2H), 4.32 (dt, J = 21.5, 6.6 Hz, 2H), 3.80 (s, 3H), 3.37 (ddd, J = 18.6, 12.1, 1.6 Hz, 1H), 2.71 (ddd, J = 18.7, 6.5, 1.7 Hz, 1H), 2.02 (s, 3H). Mass (m / z) 471.3 [M+H] + .

[0614] (S)-(3-((2-(4-amino-1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (209) JPEG0007764398000246.jpg58159

[0615] Step 1: To a solution of compound 3-02 (1 g, 3.3 mmol) in dioxane / HO (4:1, 50 mL), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (807 mg, 3.63 mmol), Pd(PPh) (573 mg, 495.5 mmol), and KCO (1.37 g, 9.91 mmol) were added under Ar. The reaction mixture was stirred at 100 °C for 3 h. The crude mixture was purified by column chromatography on silica gel to give compound 209-01 (0.9 g, 75%) as a white solid. Mass (m / z) 363.3 [M+H] + .

[0616] Step 2: To a solution of compound 209-01 (900 mg, 2.48 mmol) in MeCN (50 mL) was added NBS (884 mg, 4.97 mmol). The reaction mixture was stirred at 70 °C for 4 h. The crude mixture was purified by column chromatography on silica gel to give compound 209-02 (1 g, 91%) as a white solid. Mass (m / z) 442.2 [M+H] + .

[0617] Step 3: To a solution of compound 209-02 (1 g, 2.27 mmol) in DMSO (20 mL), NH3·H2O (950 mg, 6.8 mmol), K2CO3 (375 mg, 2.72 mmol), CuI (648 mg, 3.4 mmol), and L-proline (392 mg, 3.4 mmol) were added under Ar. The reaction mixture was stirred at 90 °C for 12 h. The crude mixture was purified by column chromatography on silica gel to give compound 209-03 (180 mg, 21%) as a pale yellow solid. Mass (m / z) 378.1 [M+H] + .

[0618] Step 4: To a solution of compound 209-04 (120 mg, 317.95 umol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo. The crude compound 209-04 was used directly in the next step. MS (m / z) 278.1 [M+H] + .

[0619] Step 5: To a solution of compound 209-04 (40 mg, 144.8 umol) in THF (5 mL), compound 1-02 (44 mg, 159.3 umol) and DIPEA (95 mg, 724 umol) were added. The reaction mixture was stirred at 70 °C for 12 hours. The crude mixture was purified by pre-HPLC to give compound 209 (14 mg, 21%) as a white solid. Mass (m / z) 485.1 [M+H] + .

[0620] (S)-(3-((2-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (210) JPEG0007764398000247.jpg3664

[0621] Following the procedure outlined for compound 3, the title compound 210 was prepared from compound 3-04 as a white solid in 41.4% yield. Mass (m / z) 486.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 6.80 (t, J = 1.6 Hz, 1H), 6.79 - 6.64 (m, 4H), 5.27 (dd, J = 12.0, 6.4 Hz, 1H), 5.11 - 5.01 (m, 1H), 4.65 - 4.51 (m, 2H), 4.42 - 4.33 (m, 1H), 4.30 - 4.23 (m, 1H), 3.80 (s, 3H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.71 (ddd, J = 18.4, 6.4, 1.6 Hz, 1H), 2.54 (s, 3H).

[0622] (S)-(3-((2-(3-(aminomethyl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (211) JPEG0007764398000248.jpg3664

[0623] Following the procedure for compound 30, the title compound 211 was prepared as a white solid in 16% yield (13 mg, 0.03 mmol). Mass (m / z) 500.3 [M+H] +. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.9 Hz, 1H), 6.81-6.78 (m, 1H), 6.78 - 6.65 (m, 4H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 5.10-5.02 (m, 1H), 4.67-4.50 (m, 2H), 4.42-4.22 (m, 2H), 3.99-3.77 (m, 5H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.7, 6.4, 1.7Hz, 1H), 2.19-2.10 (m, 2H), 2.08 (s, 3H).

[0624] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-((2-hydroxyethyl)amino)-1,4-dimethyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (212) JPEG0007764398000249.jpg70159

[0625] Step 1: To a solution of compound 101-01 (5 g, 13.8 mmol) in MeCN (50 mL) was added NBS (2.7 g, 15.2 mmol). The reaction mixture was stirred at 70 °C for 12 h. The crude mixture was purified by column chromatography on silica gel to give compound 212-01 (5.2 g, 85% yield) as a white solid. Mass (m / z) 441.1 [M+H] + .

[0626] Step 2: To a solution of compound 212-01 (400 mg, 906.4 umol) in DMSO (10 mL), 2-aminoethan-1-ol (85 mg, 1.36 mmol), K2CO3 (375 mg, 2.72 mmol), CuI (180 mg, 906.4 umol), and L-proline (110 mg, 906.4 umol) were added under Ar. The reaction mixture was stirred at 90 °C for 12 h. The crude mixture was purified by column chromatography on silica gel to give compound 212-02 (100 mg, 26%) as a white solid. Mass (m / z) 422.1 [M+H] + .

[0627] Step 3: To a solution of compound 212-02 (100 mg, 237.3 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 compound 212-03 was used directly in the next step. MS (m / z) 322.1 [M+H] + .

[0628] Step 4: To a solution of compound 212-03 (70 mg, 253.4 μmol) in THF (7 mL), compound 1-02 (82 mg, 253.4 μmol) and DIPEA (165 mg, 1.27 mmol) were added. The reaction mixture was stirred at 70° C. for 12 hours. The crude mixture was purified by pre-HPLC to give compound 212 (33 mg, 24%) as a white solid. MS (m / z) 530.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 3.0 Hz, 1H), 7.17-7.06 (m, 2H), 7.03 (d, J = 1.7 Hz, 1H), 6.96-6.85 (m, 2H), 5.33-5.19 (m, 2H), 4.61 (d, J = 36.7 Hz, 4H), 3.71 (s, 3H), 3.61 (t, J = 5.8 Hz, 2H), 3.40 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 3.27 (t, J = 5.8 Hz, 2H), 2.66 (ddd, J = 18.7, 6.6, 1.8 Hz, 1H), 1.94 (s, 3H).

[0629] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3-(3-hydroxyazetidin-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (213) JPEG0007764398000250.jpg4764

[0630] The title compound 213 was prepared from compound 212-01 in 27.0% yield following the procedure outlined for compound 212. MS (m / z) 542.1 [M+H] + .

[0631] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (214) JPEG0007764398000251.jpg4677

[0632] The title compound 214 was prepared from compound 110-02 in 7.5% yield following the procedure outlined for compound 68. 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.7 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.32 (d, J = 6.3 Hz, 1H), 7.20 (tt, J = 9.4, 2.4 Hz, 1H), 7.13 - 7.09 (m, 1H), 7.05 - 6.98 (m, 2H), 5.45 - 5.38 (m, 1H), 5.33 (dd, J = 12.2, 6.6 Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H), 4.61 (s, 2H), 4.17 (s, 2H), 3.58 (q, J = Mass (m / z) 558.4 [M+H] + .

[0633] (S)-(3-((6-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoropyridin-2-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (215) JPEG0007764398000252.jpg4064

[0634] Following the procedure for 207, the title compound 215 was prepared as a white solid in 47% yield (43 mg, 0.09 mmol). Mass (m / z) 486.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 7.55-7.48 (m, 1H), 7.07 - 7.01 (m, 1H), 6.81 - 6.73 (m, 3H), 6.72-6.65 (m, 1H), 5.43-5.34 (m, 1H), 5.27 (dd, J = 12.1, 6.5 Hz, 1H), 4.67-4.49 (m, 2H), 4.39-4.22 (m, 2H), 3.84 (s, 3H), 3.40-3.28 (m, 1H), 2.74-2.64 (m, 1H), 2.49-2.14 (m, 2H), 1.97 (s, 3H).

[0635] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (216) JPEG0007764398000253.jpg4864

[0636] Following the procedure outlined for compound 214, the title compound 216 was prepared in 7.5% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 6.1 Hz, 1H), 6.82 - 6.79 (m, 1H), 6.75 (dt, J = 6.6, 2.1 Hz, 2H), 6.70 (tt, J = 8.9, 2.3 Hz, 1H), 5.50 (d, J = 7.9 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.15 (td, J = 6.4, 3.3 Hz, 1H), 4.72 - 4.56 (m, 2H), 4.32 (dd, J = 32.7, 9.4 Hz, 2H), 4.20 (dp, J = 11.5, 4.2, 3.7 Hz, 1H), 4.00 (ddd, J = 11.4, 5.4, 2.9 Hz, 2H), 3.54 (td, J = 11.7, 2.2 Hz, 2H), 3.36 (ddd, J = Mass (m / z) 598.4 [M+H] + .

[0637] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-N-(oxetan-3-yl)-1H-pyrazole-4-carboxamide (217) JPEG0007764398000254.jpg4564

[0638] Following the procedure outlined for compound 214, the title compound 217 was prepared in 7.5% yield. 1H NMR (301 MHz, Chloroform-d) δ 8.20 (d, J = 2.5 Hz, 1H), 7.16 (d, J = 6.1 Hz, 1H), 6.85 - 6.62 (m, 4H), 6.09 (d, J = 7.4 Hz, 1H), 5.30 - 5.12 (m, 2H), 5.03 (t, J = 7.0 Hz, 2H), 4.61 (dt, J = 13.0, 7.7 Hz, 4H), 4.45 - 4.21 (m, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.78 (s, 3H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.47 (s, 3H). Mass (m / z) 570.4 [M+H] + .

[0639] (S)-(3-((2-(5-amino-1,4-dimethyl-1H-pyrazol-3-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (218) JPEG0007764398000255.jpg4364

[0640] Following the procedure outlined for compound 209, the title compound 218 was prepared in 9% yield. Mass (m / z) 486.1 [M+H] + .

[0641] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-1H-pyrazol-3-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (219) JPEG0007764398000256.jpg4764

[0642] The title compound 219 was prepared from compound 3-02 in 37% yield following the procedure outlined for compound 101-01. Mass (m / z) 471.1 [M+H] + .

[0643] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide (220) JPEG0007764398000257.jpg94159

[0644] Step 1: Under N, 227-01 (300 mg, 0.62 mmol), DCDMH (300 mg, 1.52 mmol), AcOH (1.4 mL), and HO (0.6 mL) were placed in a 20 mL can and the whole reaction mixture was stirred at 0 °C for 2 h. The mixture was concentrated in vacuo to give 220-01 (500 mg, crude) as a brown oil, which was used in the next step without purification. Mass (m / z) 461.4 [M+H] + .

[0645] Step 2: Under N2, 220-01 (500 mg, crude) and NH3-H2O (3 mL, 30 w%) were placed in ACN (5 mL), and the whole reaction mixture was stirred at 25 °C for 0.16 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 220-02 (150 mg, crude) as a yellow oil. Mass (m / z) 442.4 [M+H] + .

[0646] Step 3: Under N2, 220-02 (150 mg, crude) and TFA (3 mL) were placed in DCM (5 mL), and the whole reaction mixture was stirred at 25 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo to give 220-03 (200 mg, crude) as a brown oil, which was used in the next step reaction without purification. Mass (m / z) 342.4 [M+H] + .

[0647] Step 4: Under N2, 220-03 (200 mg, crude), TEA (3 mL), and 1-02 (50 mg, 0.18 mmol) were placed in THF (20 mL), and the whole reaction mixture was stirred at 60 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded 220 (12.3 mg, 13.5%) as a pale yellow solid. Mass (m / z) 550.4[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.32 (s, 2H), 7.26 (d, J = 6.4 Hz, 1H), 7.12 (tt, J = 9.2, 2.4 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.98 - 6.88 (m, 2H), 5.32 (tt, J = 6.8, 3.6 Hz, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.59 - 4.47 (m, 2H), 4.15 - 4.00 (m, 2H), 3.46 - 3.36 (m, 1H), 2.67 (dd, J = 6.4, 1.8 Hz, 1H), 2.63 (s, 3H), 2.38 (s, 3H).

[0648] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (221) JPEG0007764398000258.jpg3964

[0649] Following the procedure outlined for compound 110, the title compound 221 was prepared in 15.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 2.5 Hz, 1H), 7.22 (d, J = 6.2 Hz, 1H), 6.85 - 6.63 (m, 4H), 5.98 (s, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.20 -5.13 (m, 1H), 4.71 -4.56 (m , 2H), 4.41 - 4.24 (m, 2H), 3.36 (ddd, J = 18.6, 12.1, 1.7 Hz, 1H), 2.70 (ddd, J = 18.7, 6.5, 1.8 Hz, 1H), 2.59 (s, 3H), 2.28 (s, 3H). Mass (m / z) 471.3 [M+H] + .

[0650] (S)-1-(azetidin-1-yl)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)ethan-1-one (222) JPEG0007764398000259.jpg4464

[0651] Following the procedure outlined for compound 68, the title compound 222 was prepared in 41.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 6.1 Hz, 1H), 6.82 - 6.66 (m, 4H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.20 - 5.10 (m, 1H), 4.72- 4.57 (d, J = 9.9 Hz, 2H), 4.31 (dd, J = 26.8, 9.9 Hz, 2H), 4.16 (t, J = 7.6 Hz, 2H), 4.06 (t, J = 7.8 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, Mass (m / z) 568.4 [M+H] + .

[0652] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)acetamide (223) JPEG0007764398000260.jpg3977

[0653] Following the procedure outlined for compound 68, the title compound 223 was prepared in 38.5% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 2.3 Hz, 1H), 7.21 (d, J = 6.1 Hz, 1H), 6.84 - 6.64 (m, 4H), 6.00 (s, 1H), 5.27 (dd, J = 12.2, 6.4 Hz, 1H), 5.19- 5.11 (m, 1H), 4.671- 4.56 (m, 2H), 4.32 (dd, J = 31.4, 10.4 Hz, 2H), 3.68 (dd, J = 5.5, 4.3 Hz, 2H), 3.46 - 3.31 (m, 5H), 2.70 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.55 (s, 3H), 2.24 (s, 3H). Mass (m / z) 572.4 [M+H] + .

[0654] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-morpholinoethan-1-one (224) JPEG0007764398000261.jpg4564

[0655] Following the procedure outlined for compound 68, the title compound 224 was prepared in 42.8% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 6.2 Hz, 1H), 6.82 - 6.65 (m, 4H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.16 (td, J = 6.4, 3.2 Hz, 1H), 4.70 - 4.57 (m, 2H), 4.31 (dd, J = 28.1, 10.3 Hz, 2H), 3.72 - 3.61 (m, 6H), 3.53 (t, J = 4.8 Hz, 2H), 3.45 (s, 2H), 3.36 (ddd, J = Mass (m / z) 598.4 [M+H] + .

[0656] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide (225) JPEG0007764398000262.jpg42159

[0657] Step 1: 225-01 (100 mg, 0.29 mmol) was dissolved in THF (1 mL) and DMF (1 drop). SOCl (0.05 mL) was added to the above solution at 0 °C. The mixture was stirred for 30 min, then NH H O (2 mL) was added dropwise. The mixture was stirred for 10 min and quenched with ice water. Concentration and prep-HPLC purification gave the title compound 225 (41 mg, 41.2%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 6.2 Hz, 1H), 6.81 - 6.67 (m, 4H), 5.54 (s, 1H), 5.36 (s, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.16 (td, J = 6.5, 3.3 Hz, 1H), 4.70 - 4.56 (m, 2H), 4.32 (dd, J = 31.0, 10.3 Hz, 2H), 3.42 - 3.28 (m, 3H), 2.71 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.57 (s, 3H), 2.27 (s, 3H). Mass (m / z) 528.3 [M+H] + .

[0658] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-methylacetamide (226) JPEG0007764398000263.jpg4864

[0659] Following the procedure outlined for compound 225, the title compound 226 was prepared in 21.4% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 6.1 Hz, 1H), 6.81 - 6.79 (m, 1H), 6.75 (dt, J = 6.4, 2.1 Hz, 2H), 6.70 (tt, J = 8.8, 2.3 Hz, 1H), 5.56 (s, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.21 - 5.12 (m, 1H), 4.70-4.57 (m, 2H), 4.32 (dd, J = 30.7, 10.4Hz, 2H), 3.44 - 3.32 (m, 3H), 2.79 (d, J = 4.6 Hz, 3H), 2.71 (ddd, J = 18.7, 6.4, 1.7 Hz, 1H), 2.54 (s, 3H), 2.24 (s, 3H). Mass (m / z) 542.3 [M+H] + .

[0660] (S)-(3-((2-(4-(benzylthio)-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (227) JPEG0007764398000264.jpg98159

[0661] Step 1: Under N2, compound 148-01 (1.8 g, 3.68 mmol), phenylmethanethiol (680 mg, 5.48 mmol), Pd2(dba)3 (675 mg, 0.74 mmol), Xantphos (852 mg, 1.47 mmol), and DIEA (951 mg, 7.37 mmol) were placed in dioxane (30 mL) and the entire reaction mixture was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo. Purification by silica gel chromatography afforded 227-01 (850 mg, 47.0%) as a brown oil. Mass (m / z) 485.6 [M+H] + .

[0662] Step 2: Under N2, 227-01 (80 mg, 0.16 mmol) and TFA (3 mL) were placed in DCM (5 mL), and the whole reaction mixture was stirred at 25 °C for 2 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo to give 227-02 (150 mg, crude) as a yellow oil, which was used in the next step reaction without purification. Mass (m / z) 385.5 [M+H] + .

[0663] Step 3: Under N, 227-02 (150 mg, crude), TEA (1 mL), and 1-02 (45 mg, 0.16 mmol) were placed in THF (5 mL), and the whole reaction mixture was stirred at 60 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by silica gel chromatography afforded 227 (13.0 mg, 13.5%) as a white solid. Mass (m / z) 593.4 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 2.4 Hz, 1H), 7.24 - 7.18 (m, 4H), 7.06 (dt, J = 6.4, 2.2 Hz, 2H), 6.81 - 6.73 (m, 3H), 6.70 (tt, J = 8.8, 2.4 Hz, 1H), 5.28 (dd, J = 12.0, 6.4 Hz, 1H), 5.15 (ddd, J = 10.4, 6.4, 4.0 Hz, 1H), 4.68 - 4.55 (m, 2H), 4.39 - 4.22 (m, 2H), 3.67 (s, 2H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.70 (ddd, J = 18.4, 6.4, 1.6 Hz, 1H), 2.37 (s, 3H), 2.09 (s, 3H).

[0664] (S)-(3-((2-(3-amino-5-methylisoxazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (228) JPEG0007764398000265.jpg70159

[0665] Step 1: Compound 228-01 (1.77 g, 10 mmol), BocO (2.616 g, 12 mmol), DMAP (0.122 g, 1 mmol), and TEA (0.4 mL) were dissolved in 20 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 prep-TLC (PE / EA = 6 / 1) to give compound 228-02 (1.2 g, 43.3%) as a white solid. Mass (m / z) 278.3 [M+H] + .

[0666] Step 2: Compound 228-02 (715 mg, 2.58 mmol) was dissolved in 15 mL of THF. n-BuLi (2.42 mL, 3.87 mmol) was added slowly at −78° C. It was stirred at −78° C. for 30 minutes. Then, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (960 mg, 5.16 mmol) was added. It was stirred at −78° C. for 1 hour. Water was added to quench the reaction. The solvent was evaporated to dryness and used in the next step without further purification.

[0667] Step 3: Compound 228-03 (250 mg, 0.61 mmol), tert-butyl (5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-3-yl)carbamate (750 mg, crude), X-Phos-G3 (101.5 mg, 0.12 mmol), Pd2(dba)3 (109.8 mg, 0.12 mmol), and K3PO4 (1.272 g, 6.1 mmol) were mixed in 12 mL of 1,4-dioxane / HO (v / v = 4 / 1). The mixture was stirred at 120 °C for 45 min under microwave irradiation. The solvent was evaporated to dryness and purified by column chromatography (EA) to give compound 228-04 (80 mg, 22.9%) as a brown oil. Mass (m / z) 573.4 [M+H] + .

[0668] Step 4: Compound 228-04 (80 mg, 0.14 mmol) was dissolved in 3 mL of DCM. 2 mL of DCM / TFA (1 / 1) was added. It was stirred at room temperature for 1 hour. The solvent was evaporated to dryness and purified by prep-HPLC to give compound 228 (40 mg, 60.6%) as a white solid. Mass (m / z) 473.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 6.81 (t, J = 1.2 Hz, 1H), 6.78 - 6.71 (m, 2H), 6.69 (m, 2H), 5.28 (dd, J = 12.0, 6.4 Hz, 1H), 5.13 - 5.02 (m, 1H), 4.66 - 4.51 (m, 2H), 4.43-4.34 (m, 1H), 4.32 - 4.25 (m, 1H), 3.37 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.72 (ddd, J = 18.4, 6.4, 1.6Hz, 1H), 2.54 (s, 3H).

[0669] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide (229) JPEG0007764398000266.jpg4264

[0670] Following the procedure outlined for compound 66, the title compound 229 was prepared as a white solid in 9% yield. MS (m / z) 514.1 [M+H] + .

[0671] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,3,5-trimethyl-1H-pyrazole-4-sulfonamide (230) JPEG0007764398000267.jpg5264

[0672] Following the procedure outlined for compound 220, the title compound 230 was prepared from 220-01 in 19.8% yield. Mass (m / z) 564.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.4 Hz, 1H), 7.36 (q, J = 5.2 Hz, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.12 (tt, J = 9.2, 2.4 Hz, 1H), 7.03 (t, J = 1.6 Hz, 1H), 6.96 - 6.87 (m, 2H), 5.32 (dq, J = 6.4, 3.6 Hz, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.60 - 4.43 (m, 2H), 4.16 - 4.40 (m, 2H), 3.45 - 3.36 (m, 1H), 2.67 (dd, J = 6.4, 1.6 Hz, 1H), 2.63 (s, 3H), 2.44 (d, J = 5.2 Hz, 3H), 2.37 (s, 3H).

[0673] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-ethyl-3,5-dimethyl-1H-pyrazole-4-carboxamide (231) JPEG0007764398000268.jpg4064

[0674] Following the procedure outlined for compound 225, the title compound 231 was prepared in 32.4% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.4 Hz, 1H), 7.34 (t, J = 1.5 Hz, 1H), 7.29-7.24 (m, 1H) ,7.20 (dt, J = 9.2, 2.0 Hz, 1H), 7.16 (d, J = 6.1 Hz, 1H), 6.83 (t, J = 1.7 Hz, 1H), 5.56 (s, 1H), 5.31 (dd, J = 12.2, 6.7 Hz, 1H), 5.15 (td, J = 6.5, 3.4 Hz, 1H), 4.63 (s, 2H), 4.33 (d, J = 29.5 Hz, Mass (m / z) 542.3 [M+H] + .

[0675] (S)-N-Cyclopropyl-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (232) JPEG0007764398000269.jpg39159

[0676] The title compound 232 was prepared following the procedure outlined for compound 225. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.5 Hz, 1H), 7.34 (t, J = 1.5 Hz, 1H), 7.3 - 7.23 (m, 1H), 7.2 - 7.19 (m, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.8 6- 6.78 (m, 1H), 5.73 (s, 1H), 5.31 (dd, J = 12.2, 6.7 Hz, 1H), 5.15 (td, J = 6.4, 3.3 Hz, 1H), 4.70 - 4.54 (m, 2H), 4.33 (d, J = 31.4 Hz, 2H), 3.40 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.87 (dd, J = 7.2, 3.9 Hz, 1H), 2.75 (s, 3H), 2.75 - 2.63 (m, 1H), 2.41 (s, 3H), 0.89 (q, J = 6.3 Hz, 2H), 0.64 - 0.56 (m, 2H). Mass (m / z) 554.4 [M+H] + .

[0677] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (233) JPEG0007764398000270.jpg107159

[0678] Step 1: 3-02 (8.5 g, 28.15 mmol) and 233-01 (2.76 g, 42.23 mmol) were dissolved in 200 mL of dry dioxane. CuI (10.7 g, 56.3 mmol), KPO (12 g, 56.3 mmol), and (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (7.9 g, 56.3 mmol) were added to the above solution, and the mixture was stirred at 120 °C for 12 h. Water was added, and the reaction mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The concentrate was purified by silica gel chromatography to give compound 233-02 (6 g, 58.8%). Mass (m / z) 363.2 [M+H] + .

[0679] Step 2: 233-02 (6 g, 16.57 mmol) was dissolved in 60 mL of acetic acid, NIS (3.7 g, 16.57 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, and the reaction mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The concentrate was purified by silica gel chromatography to give compound 233-03 (3.85 g, 47.6%). Mass (m / z) 489.2 [M+H] + .

[0680] Step 3: 233-03 (3.8 g, 7.89 mmol) and Pd(OAc) (176 mg, 0.789 mmol) were dissolved in MeOH (150 mL), and the reaction mixture was stirred under CO (1 atm) at 25 °C for 12 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo to give compound 233-04 (2.9 g, crude). Mass (m / z) 388.1 [M+H] + .

[0681] Step 4: 233-04 (1.2 g, 3.9 mmol) was dissolved in EtOH (10 mL), KOH (5 mL, 2 M) was added, and the reaction mixture was stirred at 65 °C for 12 h. Water was added, and the reaction mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The concentrate was purified by silica gel chromatography to give compound 233-05 (800 mg, 69.6%).

[0682] Step 5: 233-05 (800 mg, 1.97 mmol) was dissolved in 10 mL of DCM, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the desired product 233-06, which was used in the next step without further purification.

[0683] Step 6: 233-06 (crude), 1-02 (545 mg, 1.97 mmol), and TEA (1 mL) were dissolved in THF (30 mL) and DMF (5 mL) and stirred at 65 °C for 6 h. The mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. The concentrate was purified by silica gel chromatography to give the title compound. 1 H NMR (400 MHz, Chloroform-d) δ 8.23 ​​(d, J = 2.4 Hz, 1H), 7.18 (d, J = 6.1 Hz, 1H), 6.83 - 6.68 (m, 4H), 5.28 (dd, J = 12.1, 6.5 Hz, 1H), 5.16 (s, 1H), 4.64 (s, 2H), 4.33 (dd, J = 31.2, 10.5 Hz, 2H), 3.36 (dd, J = 18.4, 12.0 Hz, 1H), 2.88 (s, 3H), 2.71 (dd, J = 18.7, 6.9 Hz, 1H), 2.51 (s, 3H).

[0684] 1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (234) JPEG0007764398000271.jpg4364

[0685] Following the procedure outlined for compound 110, the title compound 234 was prepared in 63.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.23 ​​(d, J = 2.4 Hz, 1H), 7.18 (d, J = 6.1 Hz, 1H), 6.81 - 6.79 (m, 1H), 6.77 - 6.74 (m, 2H), 6.70 (ddd, J = 8.8, 6.5, 2.3 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.19 - 5.13 (m, 1H), 4.70 - 4.56 (m, 2H), 4.39 - 4.29 (m, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7Hz, 2H), 2.88 (s, 3H), 2.71 (ddd, J = 18.6, 6.4, 1.7 Hz, 2H), 2.51 (s, 3H). Mass (m / z) 514.3 [M+H] + .

[0686] (S)-N-Cyclobutyl-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide (235) JPEG0007764398000272.jpg5964

[0687] The title compound 235 was prepared from 220-01 in 3.4% yield following the procedure outlined for compound 220. Mass (m / z) 604.3 [M+H]+ .

[0688] (S)-(3-((2-(4-(benzylsulfonyl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (236) JPEG0007764398000273.jpg100159

[0689] Step 1: Under N2, 227-01 (100 mg, 0.20 mmol), oxone (300 mg, 0.49 mmol) were placed in MeOH (5 mL) and HO (3 mL), and the whole reaction mixture was stirred at 25 °C for 3 h. The mixture was concentrated in vacuo. Purification by silica gel chromatography gave 236-01 (70 mg, 66.0%) as a gray solid. Mass (m / z) 517.3 [M+H] + .

[0690] Step 2: Under N2, 236-01 (70 mg, 0.14 mmol) and TFA (3 mL) were placed in DCM (5 mL), and the whole reaction mixture was stirred at 25 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo to give 236-02 (100 mg, crude) as a yellow oil, which was used in the next step reaction without purification. Mass (m / z) 417.4 [M+H] + .

[0691] Step 3: Under N2, 236-02 (100 mg, crude), TEA (1 mL), and 1-02 (30 mg, 0.16 mmol) were placed in THF (5 mL), and the whole reaction mixture was stirred at 60 °C for 1 h. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded 236 (20.0 mg, 29.8%) as a white solid. Mass (m / z) 625.4 [M+H] + .

[0692] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-5-carbonitrile (237) JPEG0007764398000274.jpg81159

[0693] Step 1: To a solution of compound 237-01 (360 mg, 815.8 umol) in DMF (4 mL), Zn (160 mg, 2.54 umol), Zn(CN) (192 mg, 1.63 mmol), and Pd(dppf)Cl (60 mg, 81.6 umol) were added under Ar. The reaction mixture was stirred at 150 °C for 3 h. The crude mixture was purified by column chromatography on silica gel to give compound 237-02 (80 mg, 25%) as a white solid. Mass (m / z) 388.1 [M+H] + .

[0694] Step 2: To a solution of compound 237-02 (80 mg, 206.5 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 compound 237-03 was used directly in the next step. Mass (m / z) 288.1 [M+H] + .

[0695] Step 3: To a solution of compound 237-03 (50 mg, 181 μmol) in THF (4 mL), compound 1-02 (52 mg, 181 μmol) and DIPEA (94 mg, 724.0 μmol) were added. The reaction mixture was stirred at 70° C. for 12 hours. The crude mixture was purified by pre-HPLC to give compound 237 (68 mg, 76%) as a white solid. Mass (m / z) 496.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.8 Hz, 1H), 7.28-7.26 (m, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.77-6.67 (m, 2H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.13 (td, J = 6.4, 3.3 Hz, 1H), 4.71-4.54 (m, 2H), 4.43-4.21 (m, 2H), 4.04 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.51 (s, 3H).

[0696] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1,3-dihydro-2H-imidazol-2-one (238) JPEG0007764398000275.jpg3964

[0697] The title compound 238 was prepared from compound 3-02 in 18.0% yield following the procedure outlined for compound 167-03. Mass (m / z) 487.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 6.2 Hz, 1H), 6.82 - 6.65 (m, 4H), 6.04 (d, J = 1.4 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.11 (td, J = 6.4, 3.2 Hz, 1H), 4.62 (s, 2H), 4.31 (t, J = 14.9 Hz, 2H), 3.44 - 3.30 (m, 1H), 3.27 (s, 3H), 2.69 (ddd, J = 18.6, 6.4, 1.8 Hz, 1H), 2.20 (d, J = 1.4 Hz, 3H).

[0698] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-N,N-dimethylacetamide (239) JPEG0007764398000276.jpg52159

[0699] Following the procedure outlined for compound 225, the title compound 239 was prepared in 10.6% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.19 (d, J = 6.1 Hz, 1H), 6.80 (s, 1H), 6.77 - 6.73 (m, 2H), 6.73 - 6.66 (m, 1H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 5.15 (s, 1H), 4.6 - 4.55 (s, 2H), 4.31 (dd, J = 26.0, 10.4 Hz, 2H), 3.46 (s, 2H), 3.36 (dd, J = 18.4, 12.3 Hz, 1H), 3.10 (s, 3H), 2.99 (s, 3H), 2.70 (dd, J=19.3, 7.2 Hz, 1H), 2.51 (s, 3H), 2.24 (s, 3H). Mass (m / z) 556.4 [M+H] + .

[0700] (S)-N-Cyclobutyl-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide (240) JPEG0007764398000277.jpg6264

[0701] Following the procedure outlined for compound 220, the title compound 240 was prepared from 220-01 in 14.3% yield. Mass (m / z) 606.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 6.4 Hz, 1H), 7.28 (d, J = 6.0 Hz, 1H), 7.12 (tt, J = 9.2, 2.4 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.96 - 6.89 (m, 2H), 5.36 - 5.29 (m, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.60 - 4.46 (m, 4H), 4.39 - 4.29 (m, 3H), 4.13 - 4.02 (m, 2H), 3.43 - 3.36 (m, 1H), 2.70 - 2.65 (m, 1H), 2.63 (s, 3H), 2.37 (s, 3H).

[0702] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-sulfonamide (241) JPEG0007764398000278.jpg6364

[0703] Following the procedure outlined for compound 220, the title compound 241 was prepared from 220-01 in 19.0% yield. Mass (m / z) 634.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 7.16 - 7.07 (m, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.96 - 6.89 (m, 2H), 5.36 - 5.30 (m, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.61 - 4.40 (m, 2H), 4.19 - 3.97 (m, 2H), 3.75 (d, J = 11.6 Hz, 2H), 3.46 - 3.36 (m, 1H), 3.31 - 3.22 (m, 2H), 3.18 (d, J = 6.4 Hz, 1H), 2.66 (s, 3H), 2.65 - 2.61 (m, 1H), 2.38 (s, 3H), 1.57 (d, J = 12.0 Hz, 2H), 1.48 - 1.34 (m, 2H).

[0704] (S)-N-Cyclohexyl-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide (242) JPEG0007764398000279.jpg6264

[0705] Following the procedure outlined for compound 220, the title compound 242 was prepared from 220-01 in 12.6% yield. Mass (m / z) 632.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.17 - 7.06 (m, 1H), 7.05 - 7.00 (m, 1H), 6.96 - 6.89 (m, 2H), 5.37 - 5.29 (m, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.60 - 4.44 (m, 2H), 4.16 - 3.99 (m, 2H), 3.44 - 3.37 (m, 1H), 2.98 - 2.86 (m, 1H), 2.69 - 2.66 (m, 1H), 2.65 (s, 3H), 2.37 (s, 3H), 1.66 - 1.55 (m, 4H), 1.50 - 1.42 (m, 1H), 1.20 - 1.11 (m, 4H), 1.07 - 1.02 (m, 1H).

[0706] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-N-phenyl-1H-pyrazole-4-sulfonamide (243) JPEG0007764398000280.jpg6564

[0707] Following the procedure outlined for compound 220, the title compound 243 was prepared from 220-01 in 16.1% yield. Mass (m / z) 626.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.23 (brs, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.31 - 7.20 (m, 3H), 7.15 - 7.00 (m, 5H), 6.94 - 6.88 (m, 2H), 5.32 - 5.26 (m, 1H), 5.23 (dd, J = 12.0, 6.4 Hz, 1H), 4.60 - 4.44 (m, 2H), 4.16 - 3.99 (m, 2H), 3.44 - 3.35 (m, 1H), 2.68 - 2.58 (m, 1H), 2.55 (s, 3H), 2.28 (s, 3H).

[0708] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide (244) JPEG0007764398000281.jpg6664

[0709] Following the procedure outlined for compound 220, the title compound 244 was prepared from 220-01 in 14.6% yield. Mass (m / z) 594.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.53 (t, J = 6.0 Hz, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.12 (tt, J = 9.2, 2.4 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.97 - 6.89 (m, 2H), 5.32 (dd, J = 6.4, 3.2 Hz, 1H), 5.24 (dd, J = 12.0, 6.4 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.61 - 4.45 (m, 2H), 4.14 - 4.00 (m, 2H), 3.46 - 3.36 (m, 3H), 2.83 (q, J = 6.4 Hz, 2H), 2.69 - 2.66 (m, 1H), 2.63 (s, 3H), 2.37 (s, 3H).

[0710] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-5-carboxylic acid (245) JPEG0007764398000282.jpg28166

[0711] Step 1: To a solution of compound 237-02 (1.2 g, 3.1 mmol) in THF (20 mL) was added 1N KOH (20 mL). The reaction mixture was stirred at 150 °C for 3 h. The crude mixture was purified by column chromatography on silica gel to give compound 245-01 (400 mg, 32%) as a white solid. Mass (m / z) 407.1 [M+H] + .

[0712] Step 2: To a solution of compound 245-01 (400 mg, 984.2 umol) in DCM (6 mL) was added TFA (6 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo. The crude compound 245-02 was used directly in the next step. Mass (m / z) 307.1 [M+H] + .

[0713] Step 3: To a solution of compound 245-02 (235 mg, 848.9 umol) in THF (5 mL), compound 1-02 (260 mg, 848.9 umol) and EtN (430 mg, 4.24 mmol) were added. The reaction mixture was stirred at 70 °C for 12 h. The crude mixture was purified by pre-HPLC to give compound 245 (220 mg, 50%) as a white solid. Mass (m / z) 515.1 [M+H] + .

[0714] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N,1,4-trimethyl-1H-pyrazole-5-carboxamide (246) JPEG0007764398000283.jpg4164

[0715] The title compound 246 was prepared from 245 in 54% yield following the procedure outlined for compound 68. Mass (m / z) 528.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.8 Hz, 1H), 7.28-7.26 (m, 1H), 6.80 (t, J = 1.7 Hz, 1H), 6.77-6.67 (m, 2H), 5.24-5.19 (m, 2H), 4.59-4.51 (m, 2H), 4.20-4.05 (m, 2H), 3.90 (s, 3H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.71 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.82 (s, 3H), 2.35 (s, 3H).

[0716] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide (247) JPEG0007764398000284.jpg5277

[0717] The title compound 247 was prepared from 245 in 27% yield following the procedure outlined for compound 68. Mass (m / z) 598.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 2.8 Hz, 1H), 7.31-7.18 (m, 1H), 6.83-6.62 (m, 4H), 5.82-5.80 (m, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.14 (td, J = 6.5, 3.4 Hz, 1H), 4.66-4.58 (m, 2H), 4.42-4.31 (m, 1H), 4.31-4.14 (m, 3H), 4.08 (s, 3H), 4.01 (dt, J = 11.9, 3.5 Hz, 2H), 3.55 (td, J = 11.7, 2.2 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.75-2.66 (m, 1H), 2.51 (s, 3H), 2.13-1.97 (m, 2H), 1.70-1.53 ​​(m, 2H).

[0718] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-methoxy-3,5-dimethyl-1H-pyrazole-4-sulfonamide (248) JPEG0007764398000285.jpg5964

[0719] Following the procedure outlined for compound 220, the title compound 248 was prepared from 220-01 in 10.4% yield. Mass (m / z) 580.4 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.23 ​​(d, J = 2.4 Hz, 1H), 7.17 (d, J = 6.0 Hz, 1H), 7.00 (s, 1H), 6.80 (t, J = 1.6 Hz, 1H), 6.78 - 6.65 (m, 3H), 5.28 (dd, J = 12.0, 6.4 Hz, 1H), 5.15 (ddd, J = 10.4, 6.4, 4.0 Hz, 1H), 4.70 - 4.56(m, 2H), 4.40 - 4.23 (m, 2H), 3.81 (s, 3H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.83 (s, 3H), 2.79 - 2.65 (m, 1H), 2.47 (s, 3H).

[0720] (S)-N-Cyclobutyl-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (249) JPEG0007764398000286.jpg5364

[0721] The title compound 249 was prepared from 245 in 39.2% yield following the procedure outlined for compound 68. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.81 - 6.78 (m, 1H), 6.75 (dt, J = 6.5, 2.1 Hz, 2H), 6.70 (tt, J = 8.8, 2.3 Hz, 1H), 5.71 (d, J = 7.9 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.14 (dd, J = 8.8, 5.0 Hz, 1H), 4.70 - 4.51 (m, 3H), 4.32 (dd, J = 32.7, 10.3 Hz, 2H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.76 (s, 3H), 2.71 (ddd, J = 18.7, 6.5, 1.8 Hz, 1H), 2.44 (s, 3H), 2.50 - 2.40 (m, 2H),1.92 (dt, J = 11.0, 8.8 Hz, 2H), 1.84 - 1.71 (m, 2H). Mass (m / z) 568.4 [M+H] + .

[0722] (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (250) JPEG0007764398000287.jpg4264

[0723] Following the procedure outlined for compound 3, the title compound 250 was prepared. 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 2.9 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 6.4 Hz, 1H), 6.81 (t, J = 1.7 Hz, 1H), 6.75 (dt, J = 6.4, 2.1 Hz, 2H), 6.70 (tt, J = 8.8, 2.3 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.015 - 5.04 (m, 1H), 4.66 - 4.53 (m, 2H), 4.41 - 4.25 (m, 2H), 4.17 (s, 3H), 3.37 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.72 (ddd, J = 18.6, 6.4, 1.8 Hz, 1H). Mass (m / z) 457.2 [M+H] + .

[0724] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (251) JPEG0007764398000288.jpg3964

[0725] The title compound 251 was prepared from 3-04 in 10.2% yield following the procedure outlined for compound 167-03. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 6.2 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 6.75 (dt, J = 6.5, 2.0 Hz, 2H), 6.70 (td, J = 8.9, 4.4 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.15 (td, J = 6.4, 3.3 Hz, 1H), 4.69 - 4.55 (m, 2H), 4.31 (dd, J = 30.7, 10.5 Hz, 2H), 3.35 (ddd, J Mass (m / z) 485.3 [M+H] + .

[0726] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-hydroxy-3,5-dimethyl-1H-pyrazole-4-carboxamide (252) JPEG0007764398000289.jpg4964

[0727] Following the procedure outlined for compound 225, the title compound 252 was prepared in 15% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 6.1 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.77 - 6.74 (m, 2H), 6.73 - 6.67 (m, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.20 - 5.09 (m, 2H), 4.71 - 4.53 (m, 3H), 4.32 (dd, J = 32.1, 10.4 Hz, 3H), 3.42 - 3.32 (m, 1H), 2.79 (s, 3H), 2.78 - 2.68 (m, 1H), 2.44 (s, 3H). Mass (m / z) 530.2 [M+H] + .

[0728] (S)-N-cyano-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (253) JPEG0007764398000290.jpg5064

[0729] Following the procedure outlined for compound 225, the title compound 253 was prepared in 10.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 2.4 Hz, 1H), 7.37 (s, 1H) 7.15 (d, J = 6.1 Hz, 1H), 6.81 (t, J = 1.7 Hz, 1H), 6.78 - 6.74 (m, 2H), 6.74 - 6.68 (m, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.18- 5.09(d, J = 4.1 Hz, 2H), 4.69 - 4.56 (s, 2H), 4.40 - 4.23 (m, 2H), 3.37 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.82 (s, 3H), 2.76 - 2.68 (m, 1H), 2.49 (s, 3H). Mass (m / z) 539.3 [M+H] + .

[0730] 1-(4-((1-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxycyclobutyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (254) JPEG0007764398000291.jpg5264

[0731] Following the procedure outlined for compound 225, the title compound 254 was prepared in 37.8% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.81 - 6.79 (m, 1H), 6.77 - 6.73 (m, 2H), 6.73 - 6.66 (m, 1H), 5.72 (d, J = 7.6 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.14 (td, J = 6.5, 3.4 Hz, 1H), 4.63 (s, 2H), 4.32 (dd, J = 33.4, 9.1 Hz, 2H), 4.15 (dq, J = 14.8, 7.8, 7.3 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.91 (dtd, J = 9.8, 6.9, 3.0 Hz, 2H), 2.76 (s, 2H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 2H), 2.44 (s, 3H), 1.98 - 1.86 (m, 2H). Mass (m / z) 584.4 [M+H] + .

[0732] 1-(4-((1-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-((1r,3r)-3-hydroxycyclobutyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (255) JPEG0007764398000292.jpg5364

[0733] Following the procedure outlined for compound 225, the title compound 255 was prepared in 54.3% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.81 - 6.79 (m, 1H), 6.78 - 6.73 (m, 2H), 6.70 (tt, J = 8.8, 2.4 Hz, 1H), 5.73 (d, J = 6.5 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.15 (ddd, J = 10.3, 6.5, 4.0 Hz, 1H), 4.69 - 4.55 (m, 4H), 4.32 (dd, J = 33.4, 10.2 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 2H), 2.76 (s, 2H), 2.71 (ddd, J = 18.6, 6.4, 1.8 Hz, 2H), 2.53 - 2.45 (m, 2H), 2.44 (s, 3H), 2.38 - 2.30 (m, 2H). Mass (m / z) 584.4 [M+H] + .

[0734] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-(2-(dimethylamino)ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (256) JPEG0007764398000293.jpg6064

[0735] Following the procedure outlined for compound 225, the title compound 256 was prepared in 16% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.11 (d, J = 6.1 Hz, 1H), 6.79 (t, J = 1.7 Hz, 1H), 6.75 (dt, J = 6.4, 2.1 Hz, 2H), 6.70 (tt, J = 8.8, 2.3 Hz, 1H), 5.28 (dd, J = 12.2, 6.3 Hz, 1H), 5.14 (dq, J = 6.7, 4.0, 3.4 Hz, 1H), 4.72 - 4.53 (m, 2H), 4.32 (dd, J = 26.5, 10.7 Mass (m / z) 585.4 [M+H] + .

[0736] 1-(4-((1-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-N-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide (257) JPEG0007764398000294.jpg5364

[0737] Following the procedure outlined for compound 225, the title compound 257 was prepared in 39.8% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.83 - 6.66 (m, 4H), 5.78 (d, J = 7.6 Hz, 1H), 5.28 (dd, J = 12.1, 6.4 Hz, 1H), 5.14 (td, J = 6.5, 3.3 Hz, 1H), 4.78 - 4.56 (m, 3H), 4.32 (dd, J = 32.6, 10.6 Hz, 2H), 4.07 - 3.74 (m, 4H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Mass (m / z) 584.4 [M+H] + .

[0738] 1-(4-((1-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-N-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide (258) JPEG0007764398000295.jpg5264

[0739] Following the procedure outlined for compound 225, the title compound 258 was prepared in 45.4% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.86 - 6.66 (m, 4H), 5.81 (d, J = 7.5 Hz, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.15 (tt, J = 6.4, 4.0 Hz, 1H), 4.81 - 4.54 (m, 3H), 4.32 (dd, J = 32.2, 10.3 Hz, 2H), 4.07 - 3.72 (m, 4H), 3.36 (ddd, J = 18.7, 12.2, 1.7 Hz, 1H), 2.76 (s, 3H), 2.71 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.43 (s, 3H), 2.36 (ddt, J = 13.2, 8.6, 7.1 Hz, 1H), 1.91 (dddd, J = 13.2, 8.0, 5.4, 3.1 Hz, 1H). Mass (m / z) 584.4 [M+H] + .

[0740] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(4-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-1-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (259) JPEG0007764398000296.jpg4964

[0741] Following the procedure outlined for compound 202, the title compound 259 was prepared in 28.9% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 6.2 Hz, 1H), 6.81 - 6.64 (m, 4H), 5.32 - 5.25 (m, 1H), 5.15 (td, J = 6.5, 3.3 Hz, 1H), 4.71 - 4.56 (m, 3H), 4.31 (dd, J = 31.4, 10.3 Hz, 2H), 3.72 (t, J = 6.7 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.76 - 2.66 (m, 3H), 2.55 (s, 3H), 2.27 (s, 2H). Mass (m / z) 514.30 [M+H] +

[0742] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (260) JPEG0007764398000297.jpg4564

[0743] The title compound 260 was prepared from compound 233. Mass (m / z) 537.2 [M+H] +

[0744] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((5-fluoro-2-(1H-pyrazol-5-yl)pyridin-4-yl)oxy)azetidin-1-yl)methanone (261) JPEG0007764398000298.jpg5064

[0745] Following the procedure outlined for compound 3, the title compound 261 was prepared from 3-04 in 3.4% yield. Mass (m / z) 443.4 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 13.06 (brs, 1H), 8.47 (s, 1H), 7.82 (s, 1H), 7.39 (d, J = 0.8 Hz, 1H), 7.14-7.08 (m, 1H), 7.03 (t, J = 1.6 Hz, 1H), 6.98 - 6.86 (m, 2H), 6.78 (s, 1H), 5.37-5.27 (m, 1H), 5.25 (dd, J = 12.0, 6.4 Hz, 1H), 4.68 - 4.43 (m, 2H), 4.17-3.97 (m, 2H), 3.39 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.64 (ddd, J = 18.4, 6.4, 1.6 Hz, 1H).

[0746] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-N-(oxetan-3-yl)-1H-pyrazole-5-carboxamide (262) JPEG0007764398000299.jpg4877

[0747] The title compound 262 was prepared from 245 in 30% yield following the procedure outlined for compound 68. Mass (m / z) 570.1 [M+H] + .

[0748] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-(3-hydroxycyclobutyl)-1,4-dimethyl-1H-pyrazole-5-carboxamide (263) JPEG0007764398000300.jpg5077

[0749] The title compound 263 was prepared from 245 in 31% yield following the procedure outlined for compound 68. Mass (m / z) 584.1 [M+H] + .

[0750] (S)-N-Cyclobutyl-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide (264) JPEG0007764398000301.jpg4677

[0751] The title compound 264 was prepared from 245 in 29% yield following the procedure outlined for compound 68. Mass (m / z) 568.1 [M+H] + .

[0752] (S)-3-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-N-(2-hydroxyethyl)-1,4-dimethyl-1H-pyrazole-5-carboxamide (265) JPEG0007764398000302.jpg4477

[0753] The title compound 265 was prepared from 245 in 22% yield following the procedure outlined for compound 68. Mass (m / z) 558.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H), 6.86-6.59 (m, 4H), 6.40 (m, 1H), 5.28 (dd, J = 12.2, 6.4 Hz, 1H), 5.14 (td, J = 6.4, 3.3 Hz, 1H), 4.62 (d, J = 9.7 Hz, 2H), 4.32 (dd, J = 32.8, 10.3 Hz, 2H), 4.10 (s, 3H), 3.91-3.80 (m, 2H), 3.65 (q, J = 5.3 Hz, 2H), 3.36 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.5, 1.8 Hz, 1H), 2.54 (s, 3H).

[0754] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(5-(4,5-dihydro-1H-imidazol-2-yl)-1,4-dimethyl-1H-pyrazol-3-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (266) JPEG0007764398000303.jpg41159

[0755] To a solution of compound 237 (30 mg, 60.6 μmol) in ethane-1,2-diamine (2 mL) was added TsOH (105 mg, 605.5 μmol). The reaction mixture was stirred at 120° C. for 12 hours. The crude mixture was purified by pre-HPLC to give compound 266 (4 mg, 12%) as a white solid. MS (m / z) 539.1 [M+H] + .

[0756] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(1,4-dimethyl-5-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazol-3-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (267) JPEG0007764398000304.jpg4877

[0757] The title compound 267 was prepared from 237 in 8% yield following the procedure outlined for compound 266. Mass (m / z) 553.1 [M+H] + .

[0758] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(3,5-dimethylisoxazol-4-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (268) JPEG0007764398000305.jpg3964

[0759] Following the procedure outlined for compound 3, the title compound 268 was prepared from 3-02 in 20.2% yield. MS (m / z) 472.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 3.0 Hz, 1H), 7.08 (tt, J = 9.3, 2.4 Hz, 1H), 7.01 - 6.98 (m, 2H), 6.91 - 6.86 (m, 2H), 5.28 - 5.17 (m, 2H), 4.52 (s, 2H), 4.07 (d, J = 14.5 Hz, 2H), 3.36 (ddd, J = 18.4, 12.0, 1.6 Hz, 1H), 2.62 (ddd, J = 18.7, 6.6, 1.7 Hz, 1H), 2.50 (s, 3H), 2.31 (s, 3H).

[0760] (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((2-(4-((dimethylamino)methyl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluoropyridin-4-yl)oxy)azetidin-1-yl)methanone (269) JPEG0007764398000306.jpg4064

[0761] Following the procedure outlined for compound 110, the title compound 269 was prepared in 16.8% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.7 Hz, 1H), 7.25 (d, J = 6.3 Hz, 1H), 7.10 (tt, J = 9.3, 2.4 Hz, 1H), 7.02 (d, J = 1.7 Hz, 1H), 6.96 - 6.88 (m, 2H), 5.32 (tt, J = 6.5, 3.6 Hz, 1H), 5.25 (dd, J = 12.1, 6.6 Hz, 1H), 4.52 (s, 2H), 4.08 (s, 2H), 3.39 (ddd, J = 18.7, 12.1, 1.8 Hz, 1H), 3.18 (s, Mass (m / z) 528.2 [M+H] + .

[0762] (S)-1-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrrolidin-2-one (270) JPEG0007764398000307.jpg5377

[0763] Following the procedure outlined for compound 110, the title compound 270 was prepared in 20.1% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.6 Hz, 1H), 7.25 (d, J = 6.3 Hz, 1H), 7.10 (tt, J = 9.2, 2.3 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 6.93 (qd, J = 6.6, 3.3 Hz, 2H), 5.34 (tt, J = 6.6, 3.6 Hz, 1H), 5.25 (dd, J = 12.1, 6.6 Hz, 1H), 4.53 (s, 2H), 4.09 (s, 2H), 3.59 (t, J = 6.9 Hz, 2H), 3.39 (ddd, J = Mass (m / z) 554.2 [M+H] + .

[0764] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)acetonitrile (271) JPEG0007764398000308.jpg5364

[0765] Following the procedure outlined for compound 110, the title compound 271 was prepared in 35.4% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 6.1 Hz, 1H), 6.82 - 6.63 (m, 4H), 5.30 - 5.23 (m, 1H), 5.15 (s, 1H), 4.62 (s, 2H), 4.31 (dd, J = 31.6, 10.2 Hz, 2H), 3.47 (s, 2H), 3.41 - 3.30 (m, 1H), 2.74 - 2.66 (m, 1H), 2.59 (s, 3H), 2.31 (s, 3H). Mass (m / z) 510.3 [M+H] +

[0766] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxamide (272) JPEG0007764398000309.jpg4977

[0767] Following the procedure outlined for compound 110, the title compound 272 was prepared in 73.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 6.1 Hz, 1H), 6.85 - 6.63 (m, 4H), 5.63 (s, 2H), 5.27 (dd, J = 12.1, 6.4 Hz, 1H), 5.20-5.22 (m, 1H), 4.72 - 4.58 (m, 2H), 4.32 (dd, J = 30.4, 9.4 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.70 (ddd, J = 18.6, 6.4, 1.7 Hz, 1H), 2.55 (s, 3H). Mass (m / z) 500.30 [M+H] + .

[0768] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxamide (273) JPEG0007764398000310.jpg3964

[0769] Following the procedure outlined for compound 110, the title compound 273 was prepared in 21.2% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.23 ​​(d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.17 (d, J = 6.1 Hz, 1H), 6.82 - 6.65 (m, 4H), 5.61 (m, 2H), 5.27 (dd, J = 12.6, 6.8 Hz, 1H), 5.18 - 5.08 (m, 1H), 4.62 (m, 2H), 4.31 (dd, J = 28.8, 10.4 Hz, 2H), 3.35 (ddd, J = 18.6, 12.1, 1.7 Hz, 1H), 2.89 (s, 3H), 2.70 (ddd, J = 18.7, 6.4, 1.7 Hz, 1H). Mass (m / z) 500.30 [M+H] +

[0770] (S)-1-((1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)pyrrolidin-2-one (274) JPEG0007764398000311.jpg4264

[0771] Following the procedure outlined for compound 110, the title compound 274 was prepared in 28.1% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 6.2 Hz, 1H), 6.82 - 6.62 (m, 4H), 5.31 - 5.23 (m, 1H), 5.148-5.10(m, 1H), 4.69-4.54 (m, 2H), 4.39-4.22 (m, 2H), 4.32 (s, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 3.23 (t, J = 7.1 Hz, 2H), 2.69 (ddd, J = 18.6, 6.4, 1.7 Hz, Mass (m / z) 568.40 [M+H] +

[0772] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (275) JPEG0007764398000312.jpg4677

[0773] Following the procedure outlined for compound 110, the title compound 275 was prepared in 58.2% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J = 9.1, 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.7 Hz, 1H), 6.79 - 6.74 (m, 3H), 6.72-6.65 (m, 1H), 5.69 (s, 2H), 5.40-5.34 (m, 1H), 5.27 (dd, J = 12.2, 6.5 Hz, 1H), 4.65 - 4.52 (m, 2H), 4.38 - 4.22 (m, 2H), 3.34 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2.77 (s, 3H), 2.69 (ddd, J = 18.6, 6.5, 1.7 Hz, 1H), 2.48 (s, 3H). Mass (m / z) 514.3 [M+H] +

[0774] (S)-1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyrimidin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (276) JPEG0007764398000313.jpg5077

[0775] Following the procedure outlined for compound 110, the title compound 276 was prepared in 82.3% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 6.84 - 6.64 (m, 4H), 5.62 (s, 2H), 5.52 (tt, J = 6.6, 4.0 Hz, 1H), 5.26 (dd, J = 12.2, 6.4 Hz, 1H), 4.70 - 4.55 (m, 2H), 4.31 (dd, J = 28.4, 10.5 Hz, 2H), 3.35 (ddd, J = 18.6, 12.2, 1.7 Hz, 1H), 2. 2.84 (s, 3H), 2.70 (ddd, J = 18.6, 6.5, 1.7Hz, 1H), 2.52 (s, 3H). Mass (m / z) 515.4 [M+H] + .

[0776] 1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl-5-d)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide (277) JPEG0007764398000314.jpg4677

[0777] Following the procedure outlined for compound 110, the title compound 277 was prepared in 26% yield. Mass (m / z) 515.1 [M+H] + .

[0778] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (278) JPEG0007764398000315.jpg80159

[0779] Step 1: Pentane-2,4-dione (10 g, 100 mmol) was dissolved in 100 mL of dry THF, and NaH (3.6 g, 150 mmol) was added to the above solution at 0 °C, and the mixture was stirred for 1 h. Then, 2-bromoethyl acetate (16.7 g, 100 mmol) was added to the above solution, and the mixture was stirred for 3 h. Water was added to the mixture, and the mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave compound 278-01 (15 g, 80.6%) as a yellow oil. Mass (m / z) 186.2 [M+H] + .

[0780] Step 2: 278-01 (15 g, 80.6 mmol) and N2H4·H2O (4 g, 120 mmol) were added to MeOH (200 mL). The mixture was stirred at room temperature for 3 hours, water was added, extracted with DCM, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound 278-02 (10 g, 79.4%) as a yellow oil. Mass (m / z) 183.2 [M+H] + .

[0781] Step 3: 278-02 (10 g, 33.1 mmol) and 3-02 (10 g, 54 mmol) were dissolved in 200 mL of dry dioxane. CuI (10.7 g, 56.3 mmol), KPO (12 g, 56.3 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (7.9 g, 56.3 mmol) were added to the above solution, and the mixture was stirred at 120 °C for 12 h. Water was added, and the mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave compound 278-03 (6 g, 40.5%). Mass (m / z) 449.2 [M+H] + .

[0782] Step 4: 278-03 (1 g, 2.23 mmol) was dissolved in 10 mL of DCM, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 30 min. Concentration gave the desired product 278-04, which was used in the next step without further purification.

[0783] Step 5: 278-04 (crude), 1-02 (616 mg, 2.23 mmol), and TEA (1 mL) were dissolved in THF (30 mL) and DMF (5 mL) and stirred at 65 °C for 6 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 278-05 (600 mg, 49.5%). Mass (m / z) 556.4 [M+H] + .

[0784] Step 6: 278-05 (600 mg, 1.08 mmol) was dissolved in EtOH (10 mL), KOH (5 mL, 2 M) was added, and the mixture was stirred at 65 °C for 12 h. Water was added, and the mixture was extracted with EA, washed with brine, dried (NaSO), and concentrated in vacuo. Purification by prep-HPLC afforded the title compound 278 (300 mg, 52.6%). 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.6 Hz, 1H), 7.19 (d, J = 6.3 Hz, 1H), 7.08 (tt, J = 9.3, 2.4 Hz, 1H), 7.00 - 6.99 (m, 1H), 6.92 - 6.87 (m, 2H), 5.29 (tt, J = 6.5, 3.5 Hz, 1H), 5.21 (dd, J = 12.1, 6.6 Hz, 1H), 4.49 (s, 2H), 4.05 (s, 2H), 3.42-3.35 (m, 1H),3.33 (s, 2H),2.66 - 2.57 (m, 1H), 2.42 (s, 3H), 2.12 (s, 3H). Mass (m / z) 528.4 [M+H] + .

[0785] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-2-methylpropanoic acid (279) JPEG0007764398000316.jpg4164

[0786] Following the procedure outlined for compound 110, the title compound 279 was prepared in 15.8% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.7 Hz, 1H), 7.15 (d, J = 6.3 Hz, 1H), 7.08 (tt, J = 9.3, 2.4 Hz, 1H), 7.01 - 6.99 (m, 1H), 6.93 - 6.83 (m, 2H), 5.28 (dq, J = 6.4, 3.3, 2.9 Hz, 1H), 5.21 (dd, J = 12.1, 6.6 Hz, 1H), 4.48 (s, 2H), 4.04 (s, 2H), 3.35-3.20 (m, 1H), 2.65 - 2.58 (m, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 1.45 (s, 6H). Mass (m / z) 557.4 [M+H] +

[0787] (S)-2-(1-(4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin-3-yl)oxy)-5-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-2-methylpropanamide (280) JPEG0007764398000317.jpg4777

[0788] Following the procedure outlined for compound 68, the titl...

Claims

1. A compound of formula I or a salt, hydrate or stereoisomer thereof: (In the formula, R1 is a 1-F substituted 6-membered aryl or heteroaryl containing 0, 1, or 2 N heteroatoms; and R2 is a 5-membered heteroaryl containing 1, 2, or 3 N heteroatoms, or 1 or 2 N heteroatoms and an O or S heteroatom; the 5-membered heteroaryl of R2 is substituted by 0 to 3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

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

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

4. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has the following structural formula II(3):

5. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has the following structural formula II(4):

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

7. The method of claim 1, wherein R2 is substituted with 0 to 3 substituents independently selected from halogen, -R', -OR', =O, -NR'R'', -SR', -OC(O)R', -C(O)R', -C0R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR'-S0NR''', -NR''C0R', -S(O)R', -S0R', -S0NR'R'', -NR''S0R, -CN, -NO, -CH(Ph), perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl. And, wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and 7. The compound, salt, hydrate, or stereoisomer of any one of claims 1 to 6, wherein when R' and R'' are attached to the same nitrogen atom, they are optionally joined to the nitrogen atom to form a 5-, 6-, or 7-membered ring.

8. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has the following structural formula III(1): (In the formula, R1 is a 1-F substituted 6-membered aryl or heteroaryl containing 0, 1 or 2 N heteroatoms; and R2 is a 5-membered heteroaryl of formula III(1) substituted with 0 to 3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

9. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has the following structural formula III(2): (In the formula, R1 is a 1-F substituted 6-membered aryl or heteroaryl containing 0, 1 or 2 N heteroatoms; and R2 is a 5-membered heteroaryl of formula III(2) substituted with 0 to 3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

10. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has the following structural formula III(3): (In the formula, R1 is a 1-F substituted 6-membered aryl containing 0, 1 or 2 N heteroatoms; and R2 is a 5-membered heteroaryl of formula III(3) substituted with 0 to 3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

11. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has any of the following structural formulas IV(1) to IV(5): (In the formula, R2 is a 5-membered heteroaryl of any of structural formulas IV(1)-IV(5), substituted with 0-3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

12. 2. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has any of the following structural formulas IV(6) to IV(10): (In the formula, R2 is a 5-membered heteroaryl of any of structural formulas IV(6)-IV(10), substituted with 0-3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

13. 2. The compound, salt, hydrate, or stereoisomer of claim 1, wherein the compound has any of the following structural formulas IV(11) to IV(15): (In the formula, R2 is a 5-membered heteroaryl of any of structural formulas IV(11)-IV(15), substituted with 0-3 substituents independently selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —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′, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; wherein R', R'', and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with 1-3 halogens, C1-C8 heteroalkyl substituted with 1-3 halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with 1-3 halogens, or unsubstituted aryl-(C1-C4)alkyl; and When R' and R'' are attached to the same nitrogen atom, they can optionally be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.

14. A compound of formula I or a salt, hydrate, or stereoisomer thereof: (In the formula, R1 is a 1-F substituted 6-membered aryl or heteroaryl containing 0, 1 or 2 N heteroatoms; and R2 contains 1, 2 or 3 N heteroatoms, or 1 or 2 N heteroatoms and O or S heteroatoms, and said R2 is selected from 0 to 3 R ａ is replaced by The R ａ For each occurrence, independently: 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 Selected from: The R ａ 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 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 optionally 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; The 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 exemplified by 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 optionally 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.

15. The compound according to claim 1, wherein R2 is substituted with 0 to 3 R a .

15. The compound, salt, hydrate or stereoisomer of claim 14, wherein:

16. R2 is 1 to 3 R ａ where R ａ 15. The compound, salt, hydrate or stereoisomer of claim 14, wherein, for each occurrence, is independently selected from the following: Halogen; cyano; 4- to 6-membered heterocyclyl optionally substituted by oxo; —C(═O)(C １ ~C ６ alkyl); -C(=O)(C ３ ~C ６ -C(=O)(4- to 6-membered heterocyclyl); 3- to 4-membered cycloalkyl; -C(=O)OR ｓ , where R ｓ is H or C １ ~C ３ is alkyl; C １ ~C ３ Alkyl, which is OH, NH ２ , cyano, halogen, C １ ~C ３ Alkoxyl, 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 optionally substituted with; -C(=O)NR ｐ R ｑ , where R ｐ and R ｑ are each independently H, OH, CN, 4- to 6-membered heterocyclyl, C optionally substituted with OH １ ~C ３ alkyl, and 3-4 membered cycloalkyl optionally substituted with OH; -NR ｐ R ｑ , where R ｐ and R ｑ are each independently H, OH, or —C(═O)CH ３ and C optionally substituted with OH, 3- to 4-membered cycloalkyl or 6-membered heterocyclyl １ ~C ３ selected from alkyl; -NR ｐ C(=O)NR ｑ R ｒ , where R ｐ , R ｑ and R ｒ 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 C １ ~C ３ selected from alkyl and 3-4 membered cycloalkyl; -S(=O) ｗ R ｓ , where R ｓ is phenyl or NH ２ C optionally substituted with １ ~C ３ alkyl and w is 0 or 2; and -S(=O) ｗ NR ｐ R ｑ , where R ｐ and R ｑ are each independently H, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, and OH, C １ ~C ３ C optionally substituted with alkoxyl or phenyl １ ~C ３ alkyl, and w is 2.

17. R2 is 1 to 3 R ａ where R ａ is, for each occurrence, independently selected from methyl, ethyl, -NH ２ , -CN, -OCH ３ , -O(CH ２ ) ２ N (CH ３ ) ２ , -NHCH ３ , -O(CH ２ ) ２ OCH ３ , -N(CH ３ ) ２ , -NH(CH ２ ) OCH ３ , -NHC(=O)CH ３ , -NHC(=O)CH ２ CH ３ , -NHC(=O)CH(CH ３ ) ２ , -NHC(=O)CH ２ CH (CH ３ ) ２ , -NHCH ２ C(=O)NHCH ３ , -NHCH ２ C(=O)NHCH ３ , -CH ２ C(=O)OH, -C(CH ３ ) ２ C(=O)OH and -C(CH ３ ) ２ C(=O)NH ２ 15. The compound, salt, hydrate or stereoisomer of claim 14 selected from:

18. R2 is 1 to 3 R ａ where R ａ is, for each occurrence, independently selected from methyl, ethyl, -NH ２ , -NHCH ３ , -CN, -CH ２ CH ２ OH, -C(=O)NHCH ２ CH ２ OH, and -CH ２ 15. The compound of claim 14, wherein the compound is selected from: CN.

19. R2 is 1 to 3 R ａ where R ａ is, for each occurrence, independently selected from methyl, ethyl, -NH ２ , —C(═O)NH ２ , -NHCH ３ , -CN, -CH ２ CN, -NHCH ２ OH, -CH ２ NH ２ , -SCH ３ , CONHCH ３ , -SO ２ CH ３ , -CH ２ OH, -Cl, -N(CH ３ ) ２ , -NHCH(CH ３ ) ２ , -NHCH ２ CH ２ OCH ３ , -CH ２ CH ２ OH, -C(=O)OCH ２ CH ３ , -C(=O)OCH ３ , -C(=O)OH, -S(=O) ２ NH ２ , -CH ２ C(=O)NH ２ , -C(=O)NHCH ２ CH ２ OH, 15. The compound, salt, hydrate, or stereoisomer of claim 14, selected from:

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

21. 21. A pharmaceutical composition in a predetermined unit dosage form comprising a therapeutically effective amount of a compound, salt, hydrate, or stereoisomer according to any one of claims 1 to 6 and 8 to 20, and one or more pharmaceutically acceptable excipients.

22. 21. Use of a compound, salt, hydrate or stereoisomer according to any one of claims 1 to 6 and 8 to 20 in the manufacture of a medicament for inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof.

23. Use of the composition of claim 21 in the manufacture of a medicament for inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or a related indication in a person in need thereof.

24. 21. The compound, salt, hydrate, or stereoisomer of any one of claims 1 to 6 and 8 to 20 for use in inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or related indications thereof in a person in need thereof, or for use in the manufacture of a medicament in a person in need thereof.

25. The composition of claim 21 for use in inhibiting necrosis, necroptosis, ferroptosis, human RIP1, or related indications thereof in a person in need thereof, or for use in the manufacture of a medicament in a person in need thereof.

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