Ferroptosis inhibitors-phenoxazine acetamides

Abstract

Provided herein are compounds, including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrates, and stereoisomers thereof, that inhibit ferroptosis activity or modulate or inhibit diseases associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer. The compounds are used in pharmaceutical compositions and methods of making and using, including treating a person in need thereof with an effective amount of a compound or composition, and detecting an improvement in health or condition of the person resulting therefrom.

Description

[0001] Introduction

[0002] Ferroptosis is a type of programmed cell death that is iron-dependent and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis, autophagy, and necrosis. Dysregulated ferroptosis is associated with many diseases, including neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer. SUMMARY OF THE INVENTION

[0004] The present invention provides compounds that modulate or inhibit ferroptosis activity or modulate or inhibit diseases associated with abnormal ferroptosis regulation (such as neuropathy, ischemia-reperfusion injury, acute renal failure and cancer) and their prodrugs, which are generally hydrolyzed in the intestine or blood to produce corresponding compounds / inhibitors.

[0005] In one aspect, the present invention provides a compound of formula I or a salt, hydrate or stereoisomer thereof:

[0006]

[0007] in:

[0008] R1-R8 are independently H, optionally substituted heteroatom or optionally substituted hydrocarbyl; and

[0009] R9 is an optionally substituted alkyl group or an optionally substituted cyclic group which optionally contains a heteroatom.

[0010] In the implementation:

[0011] R1-R7 are independently H, optionally substituted heteroatom or optionally substituted hydrocarbyl;

[0012] R1-R7 are independently H, halogen, optionally substituted OH or NH2 or optionally substituted alkyl;

[0013] R1-R7 are independently H or optionally F-substituted lower alkyl;

[0014] R8 is H, an optionally substituted heteroatom or an optionally substituted hydrocarbyl;

[0015] R8 is H, optionally substituted OH or optionally substituted alkyl;

[0016] R8 is H or OH;

[0017] R9 is an optionally substituted alkyl group or an optionally substituted cyclic group optionally containing a heteroatom;

[0018] R9 is a substituted methyl group;

[0019] R9 is a methyl group substituted by an optionally substituted cyclic group which may contain a heteroatom;

[0020] 1, 2, 3, 4 or 5 of R3-R7 are H; or

[0021] Any combination of the foregoing substituents.

[0022] In one aspect, the present invention provides a compound disclosed herein, or a salt, hydrate or stereoisomer thereof.

[0023] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I (supra) and one or more pharmaceutically acceptable excipients in a predetermined unit dosage form.

[0024] In one aspect, the present invention provides the use of a compound or composition disclosed herein in the preparation of a medicament for inhibiting ferroptosis activity or modulating or inhibiting diseases associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer, in a human in need thereof.

[0025] In one aspect, the invention provides a compound or composition disclosed herein for use in inhibiting ferroptosis activity or modulating or inhibiting a disease associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer, in a human in need thereof, or for use in the preparation of a medicament thereof for use in a human in need thereof.

[0026] In one aspect, the invention provides a method comprising inhibiting ferroptosis activity or modulating or inhibiting a disease associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer, using a compound or composition disclosed herein in a human in need thereof, and optionally detecting the resulting improvement in the health or condition of the human.

[0027] The invention includes all combinations of specific embodiments listed herein, as if each combination had been exhaustively listed.

[0028] Description of certain embodiments of the invention

[0029] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that those skilled in the art may make various modifications or changes based thereon, and that they should be included within the spirit and scope of the present 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.

[0030] The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups of 1 to 18, 1 to 12, or 1 to 6 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 sec-butyl ("s-Bu"), and 1,1-dimethylethyl or tert-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.

[0031] Lower alkyl refers to 1-8, preferably 1-6, more preferably 1-4 carbon atoms; lower alkenyl or alkynyl refers to 2-8, 2-6 or 2-4 carbon atoms.

[0032] The term "alkenyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2-18 or 2-12 or 2-6 carbon atoms. Examples of alkenyl groups may be selected from ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.

[0033] The term "alkynyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and 2-18 or 2-12 or 2-6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0034] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, the cycloalkyl group can have 3-12 or 3-8 or 3-6 carbon atoms. Even further, for example, the cycloalkyl group can be a monocyclic group of 3-12 or 3-8 or 3-6 carbon atoms. The example of monocyclic cycloalkyl includes 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. Examples of bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or arranged as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, as aromatic is defined herein.

[0035] The term "aryl" refers herein to a group selected from: 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, selected from, for example, naphthalene, indane and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0036] For example, the aryl group is selected from a 5- and 6-membered carbocyclic aromatic ring fused to a 5-7-membered cycloalkyl or heterocyclic ring (optionally containing at least one heteroatom selected from N, O and S), provided that when the carbocyclic aromatic ring is fused to the heterocyclic ring, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the cycloalkyl, the point of attachment may be at the carbocyclic aromatic ring or at the cycloalkyl. Divalent groups formed from substituted benzene derivatives and having free valences at ring atoms are named substituted phenylene groups. Divalent groups derived from monovalent polycyclic hydrocarbon groups (whose names end with "-yl") by removing one hydrogen atom from a carbon atom having a free valence are named by adding "-idene" to the name of the corresponding monovalent group, for example, naphthyl with two points of attachment is called naphthylene.

[0037] The term "halogen" or "halo" refers to F, Cl, Br or I.

[0038] The term "heteroalkyl" refers to an alkyl group containing at least one heteroatom.

[0039] The term "heteroaryl" refers to a group selected from:

[0040] 5-7 membered aromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon;

[0041] 8-12 membered bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in said aromatic ring; and

[0042] An 11-14 membered tricyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in said aromatic ring.

[0043] For example, heteroaryl includes a 5-7 membered heterocyclic aromatic ring fused to a 5-7 membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems where only one ring contains at least one heteroatom, the point of attachment can be at the heteroaromatic ring or at the cycloalkyl ring.

[0044] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1.

[0045] Examples of heteroaryl groups include, but are not limited to (numbered from the attachment position designated as priority 1), pyridyl (such as 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, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3 ,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0046] The term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a ring selected from 4-12 membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings, which contains 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 5-7 membered heterocycle containing at least one heteroatom selected from N, O and S fused to a 5-, 6- and / or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that when the heterocycle is fused to the carbocyclic aromatic or heteroaromatic ring, the point of attachment is at the heterocycle, and when the heterocycle is fused to the cycloalkyl, the point of attachment can be at the cycloalkyl or heterocycle.

[0047] "Heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O and S, provided that the point of attachment is at the heterocycle. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle may be oxo-substituted. The point of attachment may be a carbon or heteroatom in the heterocycle. The heterocycle is not a heteroaryl as defined herein.

[0048] Examples of heterocycles include, but are not limited to (numbered from the attachment position designated as priority 1) 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, oxirane, aziridine, thiirane, azetidinyl, oxetanyl, thietanyl , 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathianyl, 1,4-oxaazepanyl, 1,4-dithianyl 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithiacyclohexane, 1,4-azathiacyclohexane, oxazepine, diazepine, thiazepine, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indole, 1-oxo-1-thiomorpholinyl, 1,1-di ...

[0049] The term "fused ring" refers herein to a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, in which the two rings share only two ring atoms and one common bond. Examples of fused rings may include: fused bicyclic cycloalkyl rings, such as those having 7-12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems as described above; fused bicyclic aryl rings such as 7-12 membered bicyclic aryl ring systems as described above, fused tricyclic aryl rings such as 10-15 membered tricyclic aryl ring systems as described above; fused bicyclic heteroaryl rings such as 8-12 membered bicyclic heteroaryl rings as described above, fused tricyclic heteroaryl rings such as 11-14 membered tricyclic heteroaryl rings as described above; and fused bicyclic or tricyclic heterocyclyl rings as described above.

[0050] In an embodiment, the substituents are selected from optionally substituted heteroatoms and optionally substituted, optionally heteroatom-containing, optionally cyclic C1-C18 hydrocarbon groups, in particular wherein the optionally substituted, optionally heteroatom-containing, optionally cyclic C1-C18 hydrocarbon group is an optionally substituted, optionally heteroatom-containing, optionally cyclic alkyl, alkenyl or alkynyl group, or an optionally substituted, optionally heteroatom-containing aryl group; and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxy (such as alkoxy, aryloxy), optionally substituted acyl (such as formyl, alkanoyl, carbamoyl, carboxyl, acylamino), optionally substituted amino (such as amino, alkylamino, dialkylamino, acylamino, sulfonylamino), optionally substituted thiol (such as mercapto, alkylthiol, arylthio) thiol)), optionally substituted sulfinyl or sulfonyl (such as alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl), nitro or cyano.

[0051] In an embodiment, the substituents are selected from halogen, -R', -OR', =O, =NR', =N-OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR'-SO2NR"', -NR"CO2R ', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, the number is 0 to 3, those groups with 0, 1 or 2 substituents are particularly preferred. R', R" and R"' each independently refers to hydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, (C1-C8)alkyl and heteroalkyl substituted by 1-3 halogens, unsubstituted aryl, aryl substituted by 1-3 halogens, unsubstituted alkyl, alkoxy or alkylthio, or aryl-(C1-C4)alkyl. When R' and R" are attached to the same nitrogen atom, they 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 aryl is 1,2,3,4-tetrahydronaphthalene, it can be substituted with a substituted or unsubstituted (C3-C7)spirocyclic hydrocarbon group. The (C3-C7)spirocyclic hydrocarbon group can be substituted in the same manner as defined herein for "cycloalkyl".

[0052] Preferred substituents are selected from halogen, -R', -OR', =O, -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR"CO2R', -NR'-SO2NR"R"', -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R" are as defined above.

[0053] Preferred substituents are disclosed herein and exemplified in the tables, structures, examples and claims, and may be applicable to different compounds of the invention, ie, substituents of any given compound may be used in combination with other compounds.

[0054] In certain embodiments, suitable substituents are independently substituted or unsubstituted heteroatoms, substituted or unsubstituted C1-C6 alkyl groups containing 0-3 heteroatoms, substituted or unsubstituted C2-C6 alkenyl groups containing 0-3 heteroatoms, substituted or unsubstituted C2-C6 alkynyl groups containing 0-3 heteroatoms, or substituted or unsubstituted C6-C14 aryl groups containing 0-3 heteroatoms, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.

[0055] In more specific embodiments, suitable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamido, carboxyl, cyano, ester, halogen, haloformyl, peroxyhydroxy, hydroxy, imine, isocyanide, isocyanate, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphonyl, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluoromethyl ether (OCF3).

[0056] The compound may contain an asymmetric center and may therefore exist as an enantiomer. In the case where the compound has two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a wider class of stereoisomers. It is intended to include all such possible stereoisomers, which are substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. It is intended to include all stereoisomers of the compound and / or its pharmaceutically acceptable salt. Unless otherwise specifically mentioned, reference to an isomer is applicable to any possible isomer. Whenever isomer composition is not specified, all possible isomers are included.

[0057] The term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, even further such as no more than 20% of any other stereoisomer. In certain embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, for example no more than 5%, such as no more than 1% of any other stereoisomer.

[0058] When compounds contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0059] Some compounds may have different points of hydrogen attachment, known as tautomers. For example, a compound containing a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Individual keto and enol forms as well as mixtures thereof are also intended to be included, if applicable.

[0060] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to a desired degree of homogeneity by techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve 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 and apparatus; small-scale analytical chromatography; simulated moving bed ("SMB") chromatography and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0061] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture 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 (e.g., hydrolyzing) each diastereomer to the corresponding pure enantiomer. Enantiomers can also be separated by using a chiral HPLC column.

[0062] By resolving the racemic mixture using methods such as the use of an optically active resolving agent to form diastereoisomers, a single stereoisomer, such as a substantially pure enantiomer, can be obtained. The racemic mixture of the chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods, (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereoisomers and converting to pure stereoisomers, and (3) separating the substantially pure or enriched stereoisomers directly under chiral conditions.

[0063] "Pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids selected from, for example, hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates and nitrates; and salts formed with organic acids selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoates such as acetate, and salts formed with HOOC-(CH2)n-COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium.

[0064] Additionally, if the compound is obtained as an acid addition salt, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0065] "Treatment" refers to the administration of at least one compound and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof to a subject deemed to be in need thereof.

[0066] "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, which is effective to "treat" a disease or disorder in a subject and which will elicit the biological or medical response of the tissue, system, animal or human being sought to some significant degree, such as sufficient to prevent the development of one or more symptoms of the condition or disorder being treated or to alleviate the symptoms to some extent when administered. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0067] The term "at least one substituent" includes, for example, 1-4, such as 1-3, further 1 or 2 substituents. For example, "at least one substituent R 16 " herein includes 1-4, such as 1-3, further 1 or 2 selected from R described herein 16 List of substituents.

[0068] The subject compound and its stereoisomer and pharmaceutically acceptable salt thereof can be used alone or in combination with at least one other therapeutic agent for treatment. In certain embodiments, the compound, its stereoisomer and pharmaceutically acceptable salt thereof can be used in combination with at least one other therapeutic agent. The compound disclosed herein and / or a pharmaceutically acceptable salt can be administered in a single dosage form or as a separate dosage form with at least one other therapeutic agent. When administered as a separate dosage form, at least one other therapeutic agent can be administered before, simultaneously or after the administration of the compound disclosed herein and / or a pharmaceutically acceptable salt.

[0069] Also provided is a composition comprising the subject compound and stereoisomers thereof and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier.

[0070] Compositions comprising subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation spray or via implanted reservoirs, although the most appropriate approach in any given case will depend on the nature and severity of the illness for which the active ingredient is administered to the particular host. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Compositions disclosed herein can conveniently be present in unit dosage form and prepared by any method well known in the art.

[0071] The subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof can be orally administered in the following dosage forms: solid dosage forms, such as capsules, tablets, lozenges, dragees, granules and powders, or liquid dosage forms, such as elixirs, syrups, emulsions, dispersants and suspensions. The subject compounds disclosed herein and stereoisomers thereof and pharmaceutically acceptable salts thereof can also be administered parenterally in sterile liquid dosage forms such as dispersants, suspensions or solutions. Other dosage forms that can also be used to administer the subject compounds disclosed herein and stereoisomers thereof and pharmaceutically acceptable salts thereof include ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspension preparations for ocular administration, i.e., eye drops, aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.

[0072] Gelatin capsules containing a compound disclosed herein and / or at least one pharmaceutically acceptable salt thereof and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. can also be used. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be made into sustained release products to provide continuous release of the drug over a period of time. Compressed tablets can be coated with sugar or film to mask any unpleasant taste and protect the tablet from atmospheric influences, or can be enteric coated to selectively disintegrate in the gastrointestinal tract.

[0073] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring agents and flavoring agents to increase patient acceptance.

[0074] In general, water, suitable oil, saline, dextrose (glucose) aqueous solution and relevant sugar solution and glycols such as propylene glycol or polyethylene glycol can be examples of suitable carriers of parenteral solutions. The solution for parenteral administration can include a water-soluble salt of at least one compound as described herein, at least one suitable stabilizer and at least one buffer substance if necessary. An antioxidant such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, can be an example of a suitable stabilizer. Citric acid and its salts and sodium EDTA can also be used as examples of suitable stabilizers. In addition, parenteral solutions can further include at least one preservative, which is selected from, for example, benzalkonium chloride, methyl parahydroxybenzoate and propyl parahydroxybenzoate and chlorobutanol.

[0075] Pharmaceutically acceptable carriers are, for example, selected from carriers that are compatible with the active ingredient of the composition (and, in certain embodiments, capable of stabilizing the active ingredient) and harmless to the subject to be treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with at least one compound disclosed herein and / or at least one pharmaceutically acceptable salt) can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other 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 art.

[0076] For administration by inhalation, the subject compound and its stereoisomer and its pharmaceutically acceptable salt can be conveniently delivered in an aerosol spray delivery form from a pressurized bag or atomizer. The subject compound and its stereoisomer and its pharmaceutically acceptable salt can also be delivered as a powder, which can be prepared and can be inhaled by means of an insufflation powder inhaler device. An exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated into a suspension or solution of the subject compound disclosed herein and its stereoisomer and its pharmaceutically acceptable salt in at least one suitable propellant, the propellant being selected from, for example, fluorocarbons and hydrocarbons.

[0077] For ocular administration, ophthalmic preparations can be formulated with appropriate weight percentages of a solution or suspension of the subject compound, stereoisomers thereof, and pharmaceutically acceptable salts thereof in an appropriate ophthalmic vehicle such that the subject compound, stereoisomers thereof, and at least one pharmaceutically acceptable salt thereof remain in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and the inner regions of the eye.

[0078] Useful pharmaceutical dosage forms for administering the subject compounds disclosed herein and stereoisomers thereof and pharmaceutically acceptable salts thereof include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections and oral suspensions.

[0079] The dosage administered will depend on factors such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect. In general, the daily dose of the active ingredient may vary, for example, 0.1-2000 mg per day. For example, 10-500 mg once or more per day may be effective to obtain the desired result.

[0080] In certain embodiments, a large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules with, for example, 100 mg of a powdered form of a subject compound disclosed herein and stereoisomers thereof and pharmaceutically acceptable salts thereof, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

[0081] In certain embodiments, a mixture of the compound, its stereoisomers and pharmaceutically acceptable salts thereof, a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected into gelatin with the aid of a positive displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried.

[0082] In certain embodiments, a large number of tablets can be prepared by conventional procedures so that the dosage unit contains, for example, 100 mg of the compound, 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 increase palatability or delay absorption.

[0083] In certain embodiments, a parenteral composition suitable for administration by injection can be prepared as follows: 1.5% by weight of a compound disclosed herein and / or at least an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof is stirred in 10% by volume propylene glycol. The solution is made up to the desired volume with water for injection and sterilized.

[0084] In certain embodiments, an aqueous suspension may be prepared for oral administration. For example, an aqueous suspension containing 100 mg of finely divided compound, its stereoisomers and pharmaceutically acceptable salts thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP) and 0.025 ml of vanillin per 5 ml may be used.

[0085] When the compound, its stereoisomers and pharmaceutically acceptable salts thereof are administered in steps or in combination with at least one other therapeutic agent, the same dosage form can generally be used. When the drugs are administered in physical combination, the dosage form and administration route should be selected based on the compatibility of the combined drugs. Therefore, the term co-administration should be understood to include simultaneous or sequential administration of at least two medicaments, or alternatively as a fixed dose combination of at least two active ingredients.

[0086] The compounds disclosed herein, their stereoisomers, and pharmaceutically acceptable salts thereof can be administered as the sole active ingredient or in combination with at least one second active ingredient.

[0087] The subject compound is incorporated into a pharmaceutical composition or formulation. The composition will contain a pharmaceutically acceptable diluent and / or carrier, i.e., a diluent or carrier that is physiologically compatible and substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing compositions that can be administered are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991). The composition can also be in the form of controlled release or sustained release compositions known in the art. For many applications, the subject compound is administered in the morning / daytime and discontinued at night.

[0088] The subject compound can be used per se, or in the form of a pharmaceutically acceptable salt thereof such as a hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compound contains a relatively acidic functional group, a salt can be obtained by adding a desired base in pure or suitable inert solvents. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, etc. When the compound contains a relatively basic functional group, a salt can be obtained by adding a desired acid in pure or suitable inert solvents. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and those derived from relatively nontoxic 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are amino acid salts such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0089] By contacting the salt with a base or acid and isolating the parent compound in a conventional manner, the neutral form of the compound can be regenerated. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but for purposes of the present invention, the salt is equivalent to the parent form of the compound in other respects.

[0090] In addition to salt forms, the present invention provides compounds in the form of prodrugs. Prodrugs of compounds described herein are those compounds that are easily subjected to chemical changes under physiological conditions to provide compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, prodrugs can be slowly converted into compounds of the present invention. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, their bioavailability by oral administration may be higher than that of 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, such as those that rely on hydrolytic cleavage or oxidative activation of prodrugs. A non-limiting example of a prodrug is a compound of the present invention that is administered as an ester ("prodrug") but then metabolically hydrolyzed into a carboxylic acid active entity.

[0091] Some compounds of the present invention may exist in unsolvated form and solvated form (including hydrated form). Generally speaking, the solvated form is equivalent to the unsolvated form, and is intended to be included within the scope of the present invention. Some compounds of the present invention may exist in multiple crystalline forms or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes encompassed by the present invention, and are intended to be within the scope of the present invention.

[0092] Certain of the subject compounds possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and various isomers are intended to be encompassed within the scope of the present invention.

[0093] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more atoms constituting such compounds, such as deuterium (e.g., -CD3, CD2H or CDH2) in place of a methyl group. For example, the compounds may be substituted with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0094] The compounds are typically administered in a "therapeutically effective amount," i.e., an amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human being that is being sought by the researcher, veterinarian, physician or other clinician. The term "therapeutically effective amount" includes an amount of the compound that, when administered, is sufficient to prevent the development of or alleviate to some extent one or more symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0095] Contact is usually achieved by administering to the subject an effective amount of one or more compounds of Formula I (supra) (including the various embodiments described above). Administration is usually adjusted to achieve a therapeutic dose of about 0.1-50, preferably 0.5-10, more preferably 1-10 mg / kg, but the optimal dose is compound-specific and is usually determined empirically for each compound.

[0096] The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, lozenges, etc. in the case of solid compositions. In such compositions, the simulant is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the remainder is various vehicles or carriers and processing aids that help form the desired form of administration. The unit dose formulation is preferably about 5, 10, 25, 50, 100, 250, 500 or 1,000 mg per unit. In a specific embodiment, the unit dosage form is packaged in a multi-pack suitable for sequential use, such as a blister pack containing at least 6, 9 or 12 sheets of unit dosage forms.

[0097] The subject compositions may also be co-formulated and / or co-administered with different compounds to treat applicable indications, inhibit ferroptosis activity, or modulate or inhibit diseases associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer. In embodiments, applicable indications include cancer, neuropathy and neurodegenerative diseases of the central or peripheral nervous system, muscular dystrophy, ischemia and ischemia-reperfusion injury, kidney disease and failure, degenerative arthritis, retinal necrosis, heart disease, liver, gastrointestinal or pancreatic disease, avascular necrosis, diabetes, cancer-chemo / radiotherapy-induced cell death and poisoning.

[0098] Table: Active compounds: Structure

[0099]

[0100]

[0101]

[0102]

[0103] Active compounds were confirmed to inhibit ferroptosis:

[0104] Table: Biological activity (RSL3-induced ferroptosis in HT-1080 cells (10% FBS):

[0105] # # # # 1 1-100nM 2 1-100nM 3 1-100nM 4 1-100nM 5 1-100nM 6 1-100nM 7 1-100nM 8 1-100nM 9 1-100nM 10 1-100nM 11 1-100nM 12 1-100nM 13 1-100nM 14 1-100nM 15 1-100nM 16 1-100nM 17 1-100nM 18 1-100nM 19 1-100nM 20 1-100nM 21 1-100nM 22 1-100nM 23 1-100nM 24 1-100nM 25 1-100nM 26 1-100nM 27 1-100nM 28 1-100nM 29 1-100nM 30 1-100nM 31 1-100nM 32 1-100nM 33 1-100nM 34 1-100nM 35 1-100nM 36 1-100nM 37 1-100nM 38 1-100nM 39 1-100nM 40 1-100nM 41 1-100nM 42 1-100nM 43 1-100nM 44 1-100nM 45 1-100nM 46 1-100nM 47 1-100nM 48 1-100nM 49 1-100nM 50 1-100nM 51 1-100nM 52 1-100nM 53 1-100nM 54 1-100nM 55 1-100nM 56 1-100nM 57 1-100nM 58 1-100nM 59 1-100nM 60 1-100nM 61 1-100nM 62 1-100nM 63 1-100nM

[0106] Active compounds: Representative syntheses

[0107] N-Hydroxy-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)hexanamide (1)

[0108]

[0109] Step 1. A mixture solution of 2-bromo-5-(trifluoromethyl)phenol (20 g, 82.99 mmol), 3-fluoro-4-nitrobenzaldehyde (15.44 g, 91.28 mmol), K2CO3 (34.41 g, 248.96 mmol) in DMF (500 mL) was stirred at 60° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with PE:EA=10:1 to 1:1, to give the desired product (12 g, 37.5%) as a yellow solid.

[0110] Step 2. To a solution of 3-(2-bromo-5-(trifluoromethyl)phenoxy)-4-nitrobenzaldehyde (12 g, 30.76 mmol) in EA (300 mL) was added SnCl2 (34.99 g, 184.56 mmol), and the mixture was stirred at 65 °C for 8 h. NaHCO3 (saturated) (300 mL) was added to the mixture, and the mixture was filtered, and the filter cake was washed with EA (100 mL x 3). The combined organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography, eluting with PE:EA = 10:1 to 1:1, to give the product as a yellow solid (9.4 g, 84.8%). Mass (m / z): 359.6 [M+H] + .

[0111] Step 3. A mixture of 4-amino-3-(2-bromo-5-(trifluoromethyl)phenoxy)benzaldehyde (8 g, 22.21 mmol), Pd2(dba)3 (2.03 g, 2.22 mmol), Xantphos (2.56 g, 4.44 mmol), Cs2CO3 (21.82 g, 66.6 mmol) and Tol (1200 mL) was stirred at 90° C. for 8 h under N2 atmosphere. The mixture was concentrated and purified by flash chromatography, eluting with PE:EA=1:0 to 1:1, to give the desired product (3.2 g, 51.6%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.42 (s, 1H), 7.35 (dd, J = 8.0, 1.7 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.92 (s, 1H), 6.59 (dd, J = 8.0, 5.2 Hz, 2H). Mass (m / z): 279.8 [M+H] + .

[0112] Step 4. To a solution of 7-(trifluoromethyl)-10H-phenoxazine-3-carbaldehyde (600 mg, 2.150 mmol) in EtOH (15 mL), THF (6 mL) and water (3 mL) was added hydroxylamine hydrochloride (224 mg, 3.226 mmol). The reaction was then stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The crude material was used directly in the next step (100%). Mass (m / z): 295.1 [M+H] + .

[0113] Step 5. To a solution of E)-7-(trifluoromethyl)-10H-phenoxazine-3-carbaldehyde oxime (700 mg, 2.381 mmol) in MeOH (15 mL) was added NaBH4 (225 mg, 3.572 mmol). Then 10% HCl (5 mL) was added dropwise at 0°C. The solution was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (MeOH:DCM=1:10) to provide the target product (543 mg, 77.0%) as a yellow solid. Mass (m / z): 264.1 [M-32] + .

[0114] Step 6. To a solution of N-((7-(trifluoromethyl)-10H-phenoxazine-3-yl)methyl)hydroxylamine (30 mg, 0.101 mmol) and hexanoyl chloride (16 mg, 0.122 mmol) in THF / H2O (2 mL / 2 mL) was added NaHCO3 (25 mg, 0.303 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4 and concentrated to give a crude product, which was purified by TLC (MeOH / DCM=15:1) to give the desired product (2.1 mg, 5.3%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 6.96 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.59 (s, 2H), 2.26 (t, J = 7.6 Hz, 2H), 1.65-1.55 (m, 4H), 1.28 (s, 2H), 0.91 (s, 3H). Mass (m / z): 392.9 [MH] + .

[0115] N-Hydroxy-2-(2-methoxyethoxy)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (2)

[0116]

[0117] Step 1. To a solution of N-((7-(trifluoromethyl)-10H-phenoxazine-3-yl)methyl)hydroxylamine (30 mg, 0.101 mmol) and 2-(2-methoxyethoxy)acetic acid (18 mg, 0.132 mmol) in DMF (3 mL) was added DMT-MM (39 mg, 0.132 mmol) and DIPEA (17 mg, 0.132 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4 and concentrated to give a crude product, which was purified by TLC (MeOH / DCM=10:1) to give the desired product (6.2 mg, 14.8%) as a white solid. 1 HNMR (400MHz, methanol-d4) δ 6.97 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.72-6.68 (m, 1H), 6.58 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.64-4.51 (m, 4H), 4.36 (s, 2H), 3.71-3.68 (m, 2H), 3.60-3.57 (m, 2H), 3.37 (s, 3H). Mass (m / z): 413.2 [M+H] + .

[0118] 1-Ethyl-5-oxo-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)pyrrolidine-3-carboxamide (3)

[0119]

[0120] The title compound 3 (28.2 mg) was prepared as a yellow solid in 51.7% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (44 mg, 0.15 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (24 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol) and HATU (57 mg, 0.15 mmol) according to the procedure for 1. 1 H NMR (400 MHz, methanol-d4) δ 6.96 (d, J = 6.9 Hz, 1H), 6.74 (s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.54 (s, 1H), 6.45 (d, J = 8.2 Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 4.16 (s, 2H), 3.68-3.52 (m, 2H), 3.39-3.31 (m, 2H), 3.24-3.15 (m, 1H), 2.60 (d, J = 8.4 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H). Mass (m / z): 420.2 [M+H] + .

[0121] 4-(Dimethylamino)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)butanamide (4)

[0122]

[0123] Step 1. To a solution of 7-(trifluoromethyl)-10H-phenoxazine-3-carbaldehyde (1.4 g, 5 mmol) in EtOH (40 mL) was added hydroxylamine hydrochloride (690 mg). The reaction was then stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The crude material was used directly in the next step (100%). Mass (m / z): 295.1 [M+H] + .

[0124] Step 2. To a solution of (E)-7-(trifluoromethyl)-10H-phenoxazine-3-carbaldehyde oxime (1.0 g, 3.4 mmol) in EtOH (20 mL) was added 10% Pd / C (36 mg, 0.034 ml) and AcOH (0.5 mL). The reaction was then stirred at room temperature overnight under a hydrogen atmosphere. The Pd / C was filtered off. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4 and concentrated to give the desired product as a yellow solid. (450 mg, 47.4%). 264.1 [M-NH2]+ .

[0125] Step 3. To a solution of (7-(trifluoromethyl)-10H-phenoxazine-3-yl)methanamine (28 mg, 0.1 mmol) and 4-(dimethylamino)butyric acid hydrochloride (16.7 mg, 0.1 mmol) in DMF (2 ml) was added DIEA (38.7 mg, 0.3 mmol). HATU (41.8 mg, 0.11 mmol) was subsequently added and the reaction mixture was stirred at room temperature for 2 hours. 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (MeOH / DCM=1 / 10) to give the desired product (10.0 mg, 25.4%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 6.99-6.94 (m, 1H), 6.76-6.71 (m, 1H), 6.67 (dd, J = 8.0, 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.50-6.45 (m, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.13-3.04 (m, 2H), 2.84 (s, 6H), 2.40 (t, J = 7.0 Hz, 2H), 2.02-1.94 (m, 2H). Mass (m / z): 394.2 [M+H] + .

[0126] 2-(4-Methylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (5)

[0127]

[0128] According to the procedure for compound 4, the title compound 5 (15 mg) was prepared as a white solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (15.8 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) in an overall yield of 35.7%. 1H NMR (400MHz, methanol-d4) δ6.99-6.95(m,1H),6.74(dd,J=2.0,0.6Hz,1H),6.69(dd,J=8.0,2.0Hz,1H),6.57(d,J=2. 0Hz, 1H), 6.47 (dd, J = 8.2, 0.8Hz, 1H), 6.39 (d, J = 8.0Hz, 1H), 4.21 (s, 2H), 3.29-3.09 (m, 6H), 2.97-2.60 (m, 7H). Mass(m / z):421.2[M+H] + .

[0129] N-((10H-phenoxazin-3-yl)methyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (6)

[0130]

[0131] Step 1. To a solution of 10H-phenoxazine (1.83 g, 10 mmol) and AcOH (20 mL) was added hexamethylenetetramine (1.4 g, 10 mmol). The mixture was then stirred at 90 °C for several minutes. After cooling to room temperature, 30 ml of water was added. The mixture was then extracted with DCM (30 mL x 3). The combined organic layers were washed with water (30 mL x 3), dried over Na2SO4 and concentrated under vacuum to provide the crude desired product (1.05 g, 49.5%) as a yellow solid. Mass (m / z): 212.2 [M+H] + .

[0132] Step 2. To a solution of 10H-phenoxazine-3-carbaldehyde (1.05 g, 5 mmol) in THF / EtOH / H2O solution (2 / 5 / 1, 32 mL) was added hydroxylamine hydrochloride (690 mg, 10 mmol). The reaction was then stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give the crude product as a yellow solid. The crude was used directly in the next step (100%). Mass (m / z): 227.1 [M+H] + .

[0133] Step 3. To a solution of (E)-10H-phenoxazine-3-carbaldehyde oxime (110 mg, 0.5 mmol) in EtOH (15 mL) was added borane-pyridine (93 mg, 1.0 mmol). Then 10% HCl (5 mL) was added dropwise at 0°C. The solution was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC MeOH / DCM (0-1 / 20) to provide the target product (70 mg, 63.6%) as a yellow solid. Mass (m / z): 229.1 [M+H] + .

[0134] Step 4. To a solution of N-((10H-phenoxazine-3-yl)methyl)hydroxylamine (30 mg, 0.13 mmol), 2-(4-methylpiperazine-1-yl)acetic acid (20.7 mg, 0.13 mmol) and DIEA (50.3 mg, 0.39 mmol) in DMF (1 ml) was added DMT-MM (39.5 mg, 0.14 mmol), and the reaction mixture was stirred at room temperature for 3 hours. 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (MeOH / DCM=1 / 20) to give the desired product (5.0 mg, 10.4%) as a yellow solid. 1HNMR (400MHz, methanol-d4) δ 6.75-6.65 (m, 2H), 6.60-6.48 (m, 3H), 6.44-6.33 (m, 2H), 4.53 (s, 2H), 3.63 (s, 2H), 3.34-3.28 (m, 4H), 2.87 (s, 7H). Mass (m / z): 369.2 [M+H] + . N-((10H-phenoxazin-3-yl)methyl)-4-(dimethylamino)-N-hydroxybutyramide (7)

[0135]

[0136] According to the procedure for compound 6, the title compound 7 (4.0 mg) was prepared as a yellow solid from N-((10H-phenoxazin-3-yl)methyl)hydroxylamine (36 mg, 0.16 mmol), 4-(dimethylamino)butyric acid hydrochloride (26 mg, 0.16 mmol), DIEA (62 mg, 0.48 mmol) and DMT-MM (49 mg, 0.18 mmol) in an overall yield of 7.3%. 1HNMR (400MHz, methanol-d4) δ 6.71-6.66 (m, 2H), 6.60-6.51 (m, 3H), 6.43-6.35 (m, 2H), 4.54 (s, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.80 (s, 6H), 2.64 (t, J = 6.8 Hz, 2H), 2.03-1.94 (m, 2H). Mass (m / z): 342.2 [M+H] + .

[0137] 2-(4-Methylpiperazin-1-yl)-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (8)

[0138]

[0139] Step 1. A mixture of 3-fluoro-4-nitrobenzaldehyde (5 g, 29.6 mmol), 2-bromo-4-(trifluoromethyl)phenol (7.88 g, 32.5 mmol), potassium carbonate (8.18 g, 59.2 mmol) and DMF (20 mL) was stirred at 65 °C for 3 h. The mixture was diluted with EA (400 mL) and washed with water (300 mL x 3). The organic phase was concentrated and purified by flash chromatography, eluting with PE:EA=10:1 to 1:1, to give the desired product (6 g, 46.6%) as a yellow oil.

[0140] Step 2. A solution of 3-(2-bromo-4-(trifluoromethyl)phenoxy)-4-nitrobenzaldehyde (6 g, 15.3 mmol) and SnCl2 (11.7 g, 61.2 mmol) in EA (30 mL) was stirred at 80 °C for 3 h. The mixture was diluted with EA (400 mL) and washed with water (100 x 2). The organic phase was concentrated and purified by flash chromatography, eluting with PE:EA=10:1 to 1:1, to give the desired product (3 g, 49%) as a yellow solid. Mass (m / z): 359.7 [M+H] + .

[0141] Step 3. A mixture of 4-amino-3-(2-bromo-4-(trifluoromethyl)phenoxy)benzaldehyde (3 g, 7.5 mmol), Pd2(dba)3 (686 mg, 0.75 mmol), Xantphos (868 mg, 1.5 mmol), Cs2CO3 (4.89 g, 15 mmol) and Tol (30 mL) was stirred at 110° C. for 10 h under N2 atmosphere. The mixture was concentrated and purified by flash chromatography, eluting with PE:EA=10:1 to 1:1, to give the desired product (864 mg, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.30 (s, 1H), 7.37 (dd, J = 8.0, 1.8 Hz, 1H), 7.05 (d, J = 1.4 Hz, 1H), 7.00 (dd, J = 8.2, 1.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H). Mass (m / z): 280.0 [M+H] + .

[0142] Step 4. To a solution of 8-(trifluoromethyl)-10H-phenoxazine-3-carbaldehyde (419 mg, 1.5 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (155 mg, 2.25 mmol). The reaction was then stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The crude material was used directly in the next step (100%). Mass (m / z): 295.1 [M+H] + .

[0143] Step 5. To a solution of (E)-8-(trifluoromethyl)-10H-phenoxazine-3-carbaldehyde oxime (441 mg, 1.5 mmol) in EtOH (20 mL) was added 10% Pd / C (16 mg, 0.015 ml) and AcOH (0.5 mL). The reaction was then stirred overnight at room temperature under a hydrogen atmosphere. The Pd / C was filtered off. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4 and concentrated to give the desired product as a yellow solid. (320 mg, 76.1%). 264.1 [M-NH2] + .

[0144] Step 6. According to the procedure for compound 4, the title compound 8 (9.5 mg) was prepared as a yellow solid from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (17 mg, 0.11 mmol), DIEA (39 mg, 0.3 mmol) and HATU (42 mg, 0.11 mmol) in an overall yield of 22.6%. 1HNMR (400MHz, methanol-d4) δ 6.85-6.81 (m, 1H), 6.70-6.66 (m, 1H), 6.66-6.62 (m, 1H), 6.59 (dd, J = 15.6, 2.0 Hz, 2H), 6.37 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H), 3.14 (s, 2H), 3.08-2.97 (m, 4H), 2.78-2.68 (m, 4H), 2.65 (s, 3H). Mass (m / z): 421.3 [M+H] + .

[0145] 2-(4-methyl-2-oxopiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (9)

[0146]

[0147] According to the procedure for 4, the title compound 9 (10.5 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(4-methyl-2-oxopiperazin-1-yl)acetic acid hydrochloride (25 mg, 0.12 mmol), DIEA (64.5 mg, 0.3 mmol) and HATU (38 mg, 0.1 mmol) in an overall yield of 24.1%. 1 H NMR (400 MHz, methanol-d4) δ 7.00-6.94 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.69-6.65 (m, 1H), 6.56 (d, J = 1.9 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.38 (dd, J = 7.9, 0.8 Hz, 1H), 4.18 (s, 2H), 4.07 (s, 2H), 3.50-3.43 (m, 2H), 3.18 (s, 2H), 2.84-2.75 (m, 2H), 2.39 (s, 3H). Mass (m / z): 435.2 [M+H] + .

[0148] 2-(4-methyl-3-oxopiperazin-1-yl)-N-((2-methyl-7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (10)

[0149]

[0150] According to the procedure for 4, the title compound 10 (34.2 mg) was prepared as a yellow solid from (2-methyl-7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (44 mg, 0.15 mmol), 2-(4-methyl-3-oxopiperazin-1-yl)acetic acid hydrochloride (37 mg, 0.18 mmol), DIEA (58 mg, 0.45 mmol) and HATU (68 mg, 0.18 mmol) in an overall yield of 48.2%. 1 H NMR (400 MHz, methanol-d4) δ 6.96 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.51 (s, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.26 (s, 1H), 4.21 (s, 2H), 3.40 (d, J = 6.0 Hz, 2H), 3.21 (s, 2H), 3.16 (s, 2H), 2.94 (s, 3H), 2.80 (d, J = 6.0 Hz, 2H), 2.13 (s, 3H). Mass (m / z): 449.3 [M+H] + .

[0151] 1-Methyl-6-oxo-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-3-carboxamide (11)

[0152]

[0153] According to the procedure for 4, the title compound 11 (21.8 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (44 mg, 0.15 mmol), 1-methyl-6-oxopiperidine-3-carboxylic acid (24 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol) and HATU (57 mg, 0.15 mmol) in 34.6% overall yield. 1 HNMR (400MHz, methanol-d4) δ 6.97 (d, J = 8.3 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.43 (dd, J = 30.2, 8.0 Hz, 2H), 4.16 (s, 2H), 3.57-3.37 (m, 2H), 2.94 (s, 3H), 2.84-2.74 (m, 1H), 2.49-2.28 (m, 2H), 2.06-1.91 (m, 2H). Mass (m / z): 420.2 [M+H] + .

[0154] 1-Methyl-2-oxo-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (12)

[0155]

[0156] The title compound 12 (12.5 mg) was prepared as a yellow solid in 29.8% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 1-methyl-2-oxopiperidine-4-carboxylic acid (19 mg, 0.12 mmol), DIEA (39 mg, 0.3 mmol) and HATU (46 mg, 0.12 mmol) according to the procedure for compound 4. 1 H NMR (400 MHz, methanol-d4) δ 6.99-.93 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 7.8, 1.8 Hz, 1H), 6.54 (d, J = 1.8 Hz, 1H), 6.46 (dd, J = 8.2, 1.0 Hz, 1H), 6.38 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 2.8 Hz, 2H), 3.37 (dd, J = 7.8, 4.6 Hz, 2H), 2.92 (s, 3H), 2.80-2.71 (m, 1H), 2.56-2.41 (m, 2H), 2.06-1.88 (m, 2H). Mass (m / z): 420.2 [M+H] + .

[0157] 1-Methyl-5-oxo-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)pyrrolidine-3-carboxamide (13)

[0158]

[0159] The title compound 13 (21.8 mg) was prepared as a yellow solid in 35.9% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 1-methyl-5-oxopyrrolidine-3-carboxylic acid (22 mg, 0.15 mmol), DIEA (39 mg, 0.3 mmol) and HATU (46 mg, 0.12 mmol) according to the procedure for 4. 1HNMR (400MHz, methanol-d4) δ 6.98-6.95 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.67 (dd, J = 8.0, 2.0 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.16 (s, 2H), 3.66-3.53 (m, 2H), 3.24-3.19 (m, 1H), 2.83 (s, 1H), 2.59 (d, J = 8.6 Hz, 2H). Mass (m / z): 406.2 [M+H] + .

[0160] 1-Methyl-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (14)

[0161]

[0162] The title compound 14 (11.7 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 1-methylpiperidine-4-carboxylic acid (14 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4 in an overall yield of 28.9% (11.7 mg). 1 HNMR (400MHz, methanol-d4) δ7.00-6.95 (m, 1H), 6.76-6.72 (m, 1H), 6.69-6.65 (m, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.48-6.45 (m, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.15 (s, 2H), 3.54-3.46 (m, 1H), 3.10-2.99 (m, 2H), 2.85 (s, 3H), 2.59-2.49 (m, 1H), 2.07-1.91 (m, 4H). Mass (m / z): 406.2 [M+H] + .

[0163] 2-Morpholino-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (15)

[0164]

[0165] The title compound 15 (29.7 mg) was prepared as a yellow solid in 72.9% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-morpholinoacetic acid (14.5 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1 H NMR (400 MHz, methanol-d4) δ 7.00-6.95 (m, 1H), 6.75-6.72 (m, 1H), 6.71-6.67 (m, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.49-6.45 (m, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.22 (s, 2H), 3.99-3.89 (m, 6H), 3.37-3.32 (m, 2H). Mass (m / z): 408.2 [M+H] + .

[0166] 4-(4-Methylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)butyramide (16)

[0167]

[0168] According to the procedure for compound 4, the title compound 16 (38.3 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 4-(4-methylpiperazin-1-yl)butanoic acid (18.6 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) in an overall yield of 56.6%. 1 HNMR (400MHz, methanol-d4) δ 6.99-6.95 (m, 2H), 6.74 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.0, 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.48-6.45 (m, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.17 (s, 2H), 3.51-3.33 (m, 8H), 3.06 (t, J = 7.0 Hz, 2H), 2.91 (s, 3H), 2.48-2.41 (m, 2H), 2.02-1.93 (m, 2H). Mass (m / z): 449.3 [M+H] + .

[0169] 2-(Dimethylamino)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (17)

[0170]

[0171] The title compound 17 (11.7 mg) was prepared as a yellow solid in 28.9% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol) and dimethylglycine (10.3 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1 HNMR (400MHz, methanol-d4) δ7.00-6.94 (m, 1H), 6.76-6.71 (m, 1H), 6.71-6.66 (m, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.42-6.37 (m, 1H), 4.21 (s, 2H), 3.47 (d, J = 3.0 Hz, 2H), 2.61 (d, J = 1.8 Hz, 6H). Mass (m / z): 366.2 [M+H] + .

[0172] 2-(Pyrrolidin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (18)

[0173]

[0174] The title compound 18 (12.8 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(pyrrolidin-1-yl)acetic acid (12.9 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4 in an overall yield of 12.8%. 1 HNMR (400MHz, methanol-d4) δ7.00-6.94 (m, 1H), 6.75-6.73 (m, 1H), 6.71-6.67 (m, 1H), 6.58 (d, J = 2.0 Hz, 1H), 6.49-6.45 (m, 4H), 6.40 (d, J = 8.0 Hz, 1H), 4.21 (s, 2H), 3.79 (s, 2H), 3.21-3.15 (m, 4H), 2.03-1.99 (m, 4H). Mass (m / z): 392.2 [M+H] + .

[0175] 2-(1-Methylpiperidin-4-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (19)

[0176]

[0177] The title compound 19 (9.1 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(1-methylpiperidin-4-yl)acetic acid (15.7 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4 in an overall yield of 22.0%. 1 H NMR (400 MHz, methanol-d4) δ 7.00-6.95 (m, 1H), 6.76-6.73 (m, 1H), 6.69-6.65 (m, 1H), 6.55 (d, J = 1.8 Hz, 1H), 6.48-6.45 (m, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.15 (s, 2H), 3.51-3.39 (m, 2H), 3.06-2.94 (m, 2H), 2.83 (s, 3H), 2.23 (d, J = 7.0 Hz, 2H), 2.10-1.92 (m, 3H), 1.60-1.46 (m, 2H). Mass (m / z): 420.3 [M+H] + .

[0178] N-((7-(Trifluoromethyl)-10H-phenoxazin-3-yl)methyl)quinuclidine-4-carboxamide (20)

[0179]

[0180] The title compound 20 (4.9 mg) was prepared as a yellow solid in 9.2% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(1-methylpiperidin-4-yl)acetic acid (15.7 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for 4. 1H NMR (400 MHz, methanol-d4) δ 6.99-6.95 (m, 1H), 6.75-6.72 (m, 1H), 6.69-6.64 (m, 1H), 6.53 (d, J = 2.0 Hz, 1H), 6.48-6.45 (m, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.18 (s, 2H), 3.42-3.38 (m, 6H), 2.14-2.10 (m, 6H). Mass (m / z): 418.2 [M+H] + .

[0181] 3-(4-Methylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acrylamide (21)

[0182]

[0183] The title compound 21 (22.7 mg) was prepared as a yellow solid in 34.3% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(pyrrolidin-1-yl)acetic acid (17.2 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1 HNMR (400MHz, methanol-d4) δ7.02-6.92 (m, 1H), 6.79-6.64 (m, 2H), 6.61-6.55 (m, 1H), 6.50-6.35 (m, 2H), 4.17 (s, 2H), 3.42-3.32 (m, 4H), 3.18-3.01 (m, 6H), 2.88 (s, 3H), 2.56 (t, J = 6.8 Hz, 2H). 435.3 [M+H] + .

[0184] 5-(Dimethylamino)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)pentanamide (22)

[0185]

[0186] The title compound 22 (3.7 mg) was prepared as a yellow solid in 9.1% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 5-(dimethylamino)pentanoic acid (14.5 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1H NMR (400MHz, methanol-d4) δ6.99-6.95(m,1H),6.75(d,J=2.0Hz,1H),6.68(dd,J=7.8,2.0Hz,1H),6.56(d,J=2.0Hz,1H),6.48-6 .45(m,1H),6.39(d,J=7.8Hz,1H),4.15(s,2H),3.08(t,J=7.2Hz,2H),2.83(s,6H),2.34-2.28(m,2H),1.76-1.65(m,4H). 408.2[M+H] + .

[0187] 4-Oxo-4-(((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)amino)butanoic acid (23)

[0188]

[0189] To a solution of (7-(trifluoromethyl)-10H-phenoxazine-3-yl)methanamine (28 mg, 0.1 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (2 ml) was added dihydrofuran-2,5-dione (12 mg, 0.12 mmol) at 0°C. The reaction was then stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by preparative TLC (MeOH / DCM=1 / 10) to give the desired product (12.2 mg, 32.1%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 6.96 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.45 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 2.61 (t, J = 6.8 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H). Mass (m / z): 381.1 [M+H] + .

[0190] 1-Methyl-2-oxo-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)-1,2-dihydropyridine-4-carboxamide (24)

[0191]

[0192] The title compound 24 (28.2 mg) was prepared as a yellow solid in 45.3% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (44 mg, 0.15 mmol), 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (23 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol) and HATU (57 mg, 0.15 mmol) according to the procedure for 4. 1 H NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 7.0 Hz, 1H), 6.98-6.94 (m, 1H), 6.89 (dd, J = 2.0, 0.7 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 6.67 (dd, J = 7.0, 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.47-6.44 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.31 (s, 2H), 3.58 (s, 3H). Mass (m / z): 416.2 [M+H] + .

[0193] N-Hydroxy-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)pivalamide (25)

[0194]

[0195] The title compound 25 (24.2 mg) was prepared as a white solid in 62.8% overall yield from N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)hydroxylamine (30 mg, 0.101 mmol) and pivaloyl chloride (17 mg, 0.122 mmol) according to the procedure for compound 1. 1 H NMR (400 MHz, methanol-d4) δ 6.95 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.70-6.63 (m, 1H), 6.55 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 6.38 (d, J = 7.8 Hz, 1H), 4.53 (s, 2H), 1.27 (s, 9H). Mass (m / z): 378.9 [MH] + .

[0196] N-Hydroxy-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)cyclohexanecarboxamide (26)

[0197]

[0198] The title compound 26 (11.5 mg) was prepared as a white solid from N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)hydroxylamine (30 mg, 0.101 mmol) and cyclohexanecarbonyl chloride (18 mg, 0.122 mmol) according to the procedure for compound 1 in an overall yield of 28.0%. 1 H NMR (400 MHz, methanol-d4) δ 7.00-6.93 (m, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 7.8, 1.8 Hz, 1H), 6.55 (d, J = 1.8 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.53 (s, 2H), 1.84-1.72 (m, 4H), 1.45-1.28 (m, 6H). Mass (m / z): 404.9 [MH] + .

[0199] N-Hydroxy-2-(4-methylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (27)

[0200]

[0201] The title compound 27 (27.8 mg) was prepared as a white solid from N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)hydroxylamine (30 mg, 0.101 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (21 mg, 0.132 mmol) according to the procedure for compound 2 in an overall yield of 62.9%. 1 H NMR (400 MHz, methanol-d4) δ 6.96 (ddd, J = 8.2, 2.0, 1.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.0, 1.8 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.51-6.45 (m, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.53 (s, 2H), 3.47 (s, 2H), 2.80 (m, 8H), 2.52 (s, 3H). Mass (m / z): 437.2 [M+H] + .

[0202] 1-Ethyl-5-oxo-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)pyrrolidine-3-carboxamide (28)

[0203]

[0204] The title compound 28 (26.6 mg) was prepared as a white solid in 59.1% overall yield from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (30 mg, 0.107 mmol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (17 mg, 0.107 mmol) according to the procedure for 4. 1 H NMR (400 MHz, methanol-d4) δ 6.81 (dd, J = 8.4, 2.1 Hz, 1H), 6.70-6.59 (m, 3H), 6.53 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.65 (dd, J = 9.8, 8.8 Hz, 1H), 3.54 (dd, J = 9.8, 6.0 Hz, 1H), 3.33 (d, J = 8.0 Hz, 1H), 3.30 (s, 1H), 3.23 (qd, J = 8.4, 6.0 Hz, 1H), 2.60 (d, J = 8.4 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). Mass (m / z): 420.3 [M+H] + .

[0205] 1-Methyl-6-oxo-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-3-carboxamide (29)

[0206]

[0207] The title compound 29 (20.7 mg) was prepared as a white solid in 43.4% overall yield from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (30 mg, 0.107 mmol) and 1-methyl-6-oxopiperidine-3-carboxylic acid (17 mg, 0.107 mmol) according to the procedure for 4. 1 H NMR (400 MHz, methanol-d4) δ 6.82 (ddd, J = 8.4, 2.2, 0.8 Hz, 1H), 6.70-6.59 (m, 3H), 6.54 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.15 (d, J = 1.2 Hz, 2H), 3.53 (dd, J = 12.4, 9.6 Hz, 1H), 3.42 (ddd, J = 12.4, 5.6, 1.2 Hz, 1H), 2.93 (s, 3H), 2.81 (tdd, J = 9.6, 5.6, 4.0 Hz, 1H), 2.38 (qt, J = 11.4, 5.6 Hz, 2H), 2.05-1.93 (m, 2H). Mass (m / z): 420.3 [M+H] + .

[0208] N-((7-(Trifluoromethyl)-10H-phenoxazin-3-yl)methyl)quinuclidine-3-carboxamide (30)

[0209]

[0210] The title compound 30 (17.1 mg) was prepared as a yellow solid in 32.2% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), quinuclidine-3-carboxylic acid (15.5 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 8.70 (s, 1H), 8.51 (t, J = 5.8Hz, 1H), 7.08-7.00 ( m,1H),6.84(d,J=2.0Hz,1H),6.64(dd,J=7.8,1.8Hz,1H),6.54-6.50(m,2H),6.41(d, J=7.8Hz,1H),4.14-4.03(m,2H),3.60-3.52(m,1H),3.27(t,J=11.4Hz,1H),3.23-3.12(m,4H),2.91-2.84(m,1H),2.27-2.21(m,1H),1.87-1.76(m,2H),1.70-1.61(m,2H). Mass (m / z):418.2[M+H] + .

[0211] 1-Methyl-2-oxo-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)-1,2-dihydropyridine-4-carboxamide (31)

[0212]

[0213] The title compound 31 (42.2 mg) was prepared as a white solid in 93.8% overall yield from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (30 mg, 0.107 mmol) and 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (17 mg, 0.107 mmol) according to the procedure for 4. 1HNMR(400MHz,DMSO-d6)δ9.03(t,J=6.0Hz,1H),8.48(s,1H),7.76(d,J=7.0Hz,1 H),6.85(ddt,J=8.2,2.0,0.8Hz,1H),6.80(d,J=2.0Hz,1H),6.74-6.67(m,2H), 6.63(d,J=2.2Hz,1H),6.57(d,J=2.0Hz,1H),6.51(dd,J=7.0,2.0Hz,1H),6.40( dd,J=7.8,1.2Hz,1H),5.73(d,J=0.4Hz,1H),4.19(d,J=5.8Hz,2H),3.42(s,3H). Mass (m / z): 416.3 [M+H] + .

[0214] 4-Methyl-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperazine-1-carboxamide (32)

[0215]

[0216] To a solution of (7-(trifluoromethyl)-10H-phenoxazine-3-yl)methylamine (28 mg, 0.1 mmol) in DCM (2 mL) was added triphosgene (29.6 mg, 0.11 mmol). The reaction mixture was then stirred for 1 hour. DIEA (39 mg, 0.3 mmol) and 1-methylpiperazine (11 mg, 0.11 mmol) were added and the reaction mixture was stirred for 3 hours. The reaction solution was washed with water (3x5 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (MeOH / DCM=1 / 10) to give the desired product (18.3 mg, 45.1%) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ6.99-6.94(m,4H),6.74(d,J=2.0Hz,1H),6.67(dd,J=8.0,2.0Hz,1H),6.56(d,J=1.8Hz,1H),6. 46(dd,J=8.2,0.8Hz,1H),6.37(d,J=7.8Hz,1H),4.14(s,2H),3.63-3.50(m,4H),2.86(t,J=4.6Hz,4H),2.62(s,3H). Mass(m / z):407.2[M+H] + .

[0217] 3-(Dimethylamino)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acrylamide (33)

[0218]

[0219] The title compound 33 (16.3 mg) was prepared as a yellow solid in 43.1% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 3-(dimethylamino)propanoic acid (11.7 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1 HNMR (400MHz, methanol-d4) δ 6.99-6.94 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.70-6.66 (m, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.49-6.43 (m, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.17 (s, 2H), 3.44-3.36 (m, 2H), 2.89 (s, 6H), 2.74 (t, J = 6.6 Hz, 2H). Mass (m / z): 380.2 [M+H] + .

[0220] :4-(Pyrrolidin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazine-3-yl)methyl)butyramide (34)

[0221]

[0222] Step 1. To a solution of (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (2 mL) was added 4-chlorobutyryl chloride (14 mg, 0.1 mmol) dropwise at 0°C. The reaction was then stirred at 0°C for 2 hours. The reaction solution was washed with water (3 x 5 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product as a yellow oil. The crude was used directly in the next step. Mass (m / z): 385.2 [M+H] + .

[0223] Step 2. Pyrrolidine (0.1 ml) was added to a solution of 34-1 (38.4 mg, 0.1 mmol) in ACN (2 ml). The reaction was then stirred at 80 ° C overnight. After cooling to room temperature, 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (15 mL x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (MeOH / DCM=1 / 10) to produce the desired product (15.0 mg, 35.8%) as a yellow solid. 1H NMR (400MHz, methanol-d4) δ 6.99-6.95 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.50-6.45 (m, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.15 (s, 2H), 3.35-3.31 (m, 2H), 3.23-3.17 (m, 2H), 2.39 (d, J = 7.0 Hz, 2H), 2.10-1.99 (m, 6H). Mass (m / z): 420.2 [M+H] + .

[0224] 2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35)

[0225]

[0226] Step 1. According to the procedure for 34-1, the crude title compound 35-1 (2.5 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-chloroacetyl chloride (22.4 mg, 0.2 mmol) and DIEA (39 mg, 0.3 mmol) in 100% overall yield. Mass (m / z): 356.0 [M+H] + .

[0227] Step 2. According to the procedure for compound 34, the title compound 35 (41.6 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (91.5 mg, 0.5 mmol) in 49.2% overall yield. 1HNMR (400MHz, methanol-d4) δ 6.98 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.21 (s, 2H), 3.68-3.58 (m, 3H), 3.30-2.96 (m, 12H), 2.87 (s, 3H), 2.35-2.20 (m, 2H), 1.97-1.81 (m, 2H). Mass (m / z): 504.3 [M+H] + .

[0228] 2-(4-(Pyrrolidin-1-yl)piperidin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (36)

[0229]

[0230] The title compound 36 (3.9 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 4-(pyrrolidin-1-yl)piperidine (77.0 mg, 0.5 mmol) according to the procedure for compound 34 in an overall yield of 8.2%. 1 H NMR (400 MHz, methanol-d4) δ 7.00-6.95 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.0, 1.8 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.50-6.44 (m, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.20 (s, 2H), 3.76-3.38 (m, 3H), 3.23-2.97 (m, 8H), 2.34 (t, J = 12.2 Hz, 2H), 2.16-2.07 (m, 4H), 1.89-1.79 (m, 2H). Mass (m / z): 475.3 [M+H] + .

[0231] 2-(4-(3-(Dimethylamino)propyl)piperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (37)

[0232]

[0233] The title compound 37 (11.6 mg) was prepared as a yellow solid in 23.6% overall yield from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (85.5 mg, 0.5 mmol) according to the procedure for compound 34. 1 H NMR (400 MHz, methanol-d4) δ 7.01-6.95 (m, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.0, 1.8 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 4.21 (s, 2H), 3.45 (s, 2H), 3.26-3.12 (m, 6H), 3.10-2.95 (m, 6H), 2.90 (s, 6H), 2.16-2.05 (m, 2H). Mass (m / z): 492.3 [M+H] + .

[0234] 2-(4-Methyl-1,4-diazepan-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (38)

[0235]

[0236] According to the procedure for compound 34, the title compound 38 (11.3 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 1-methyl-1,4-diazepane (57 mg, 0.5 mmol) in an overall yield of 26.0%. 1 HNMR (400MHz, methanol-d4) δ 6.99-6.95 (m, 2H), 6.75-6.68 (m, 2H), 6.59 (t, J = 1.6 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.39 (dd, J = 8.0, 1.2 Hz, 1H), 4.22 (s, 2H), 3.49-3.39 (m, 2H), 3.36-3.31 (m, 2H), 3.02-2.78 (m, 7H), 2.10-1.95 (m, 2H). Mass (m / z): 435.2 [M+H] + .

[0237] 2-(4-methyl-3-oxopiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (39)

[0238]

[0239] The title compound 39 (12.1 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 1-methylpiperazin-2-one (57 mg, 0.5 mmol) according to the procedure for compound 34 in an overall yield of 27.9%. 1 H NMR (400 MHz, methanol-d4) δ 6.99-6.94 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.70-6.66 (m, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.38 (dd, J = 8.0, 0.8 Hz, 1H), 4.19 (s, 2H), 3.43-3.38 (m, 2H), 3.20 (s, 2H), 3.16 (s, 2H), 2.94 (s, 3H), 2.83-2.76 (m, 2H). Mass (m / z): 435.2 [M+H] + .

[0240] 2-(3-(Dimethylamino)piperidin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (40)

[0241]

[0242] The title compound 40 (6.5 mg) was prepared as a yellow solid in 14.5% overall yield from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and N,N-dimethylpiperidin-3-amine (64 mg, 0.5 mmol) according to the procedure for compound 34. 1 H NMR (400 MHz, methanol-d4) δ 6.99-6.95 (m, 1H), 6.75-6.68 (m, 2H), 6.59 (d, J = 1.8 Hz, 1H), 6.49-6.44 (m, 1H), 6.39 (dd, J = 8.0, 0.8 Hz, 1H), 4.21 (d, J = 2.4 Hz, 2H), 3.37-3.33 (m, 1H), 3.25-3.11 (m, 2H), 2.93-2.86 (m, 7H), 2.80-2.74 (m, 1H), 2.66-2.57 (m, 1H), 2.54-2.46 (m, 1H), 1.93-1.67 (m, 4H). Mass (m / z): 449.3 [M+H] + .

[0243] 2-(4-Acetylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (41)

[0244]

[0245] Step 1. The title compound 41-1 (101 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and tert-butyl piperazine-1-carboxylate (186 mg, 0.5 mmol) in 100% overall yield according to the procedure for 34. Mass (m / z): 507.3 [M+H] + .

[0246] Step 2. To a solution of compound 41-1 (101 mg, 2 mmol) in DCM (5 mL) was added TFA (3 mL). The reaction was then stirred at room temperature for 30 min. The reaction solution was concentrated under vacuum to provide a crude product as a yellow solid. The crude was used directly in the next step (89 mg, 69%). Mass (m / z): 407.2 [M+H] + .

[0247] Step 3. To a solution of 41-2 (89 mg, 0.14 mmol) and DIEA (88.9 mg, 0.69 mmol) in DCM (5 ml) was added acetyl chloride (16.4 mg, 0.21 mmol) at 0°C. The reaction was then stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by preparative TLC (MeOH / DCM=1 / 10) to provide the desired product (22.4 mg, 36.5%) as a yellow solid. 1HNMR (400MHz, methanol-d4) δ 6.99-6.94 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.70-6.67 (m, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.48-6.44 (m, 1H), 6.38 (d, J = 7.8 Hz, 1H), 4.21 (s, 2H), 3.66-3.55 (m, 4H), 3.08 (s, 2H), 2.51 (dt, J = 20.2, 5.2 Hz, 4H), 2.08 (s, 3H). Mass (m / z): 449.3 [M+H]+.

[0248] N-Hydroxy-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)benzamide (42)

[0249]

[0250] The title compound 42 (22.6 mg) was prepared as a white solid from N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)hydroxylamine (30 mg, 0.101 mmol) and benzoyl chloride (17 mg, 0.122 mmol) according to the procedure for compound 1 in an overall yield of 55.8%. 1 H NMR (400MHz, methanol-d4) δ8.13-8.08 (m, 2H), 8.03-7.98 (m, 2H), 7.74-7.65 (m, 1H), 7.58-7.50 (m, 4H), 7.45-7.39 (m, 2H), 5.02 (s, 2H). Mass (m / z): 398.9 [MH] + .

[0251] N-((7-methyl-10H-phenoxazin-3-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide (43)

[0252]

[0253] The title compound 43 (36.2 mg) was prepared as a white solid in 74.5% overall yield from (7-methyl-10H-phenoxazin-3-yl)methanamine (30 mg, 0.133 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (27 mg, 0.173 mmol) according to the procedure for compound 2. 1 HNMR (400MHz, methanol-d4) δ 6.65-6.60 (m, 1H), 6.52 (d, J = 2.0 Hz, 1H), 6.50 (ddd, J = 7.9, 2.0, 0.8 Hz, 1H), 6.38 (dd, J = 2.0, 0.8 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 6.30 (d, J = 7.8 Hz, 1H), 4.18 (s, 2H), 3.12 (s, 2H), 3.00 (m, 4H), 2.71 (m, 4H), 2.63 (s, 3H), 2.11 (s, 3H). Mass (m / z): 367.3 [M+H] + .

[0254] 1-Isopropyl-N-((7-methyl-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (44)

[0255]

[0256] The title compound 44 (37.6 mg) was prepared as a white solid in 75.2% overall yield from (7-methyl-10H-phenoxazin-3-yl)methanamine (30 mg, 0.133 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (36 mg, 0.173 mmol) according to the procedure for compound 2. 1 H NMR (400 MHz, methanol-d4) δ 6.62 (dd, J = 7.8, 2.0 Hz, 1H), 6.52-6.48 (m, 2H), 6.38 (dd, J = 1.8, 0.8 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 6.30 (d, J = 7.8 Hz, 1H), 4.14 (s, 2H), 3.49 (m, 3H), 3.10 (m, 2H), 2.58 (m, 1H), 2.12 (s, 3H), 2.11-1.88 (m, 4H), 1.35 (d, J = 6.8 Hz, 6H). Mass (m / z): 380.3 [M+H] + .

[0257] 1-Isopropyl-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (45)

[0258]

[0259] The title compound 45 (12.3 mg) was prepared as a yellow solid in 28.4% overall yield from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), isopropylpiperidine-4-carboxylic acid hydrochloride (23 mg, 0.11 mmol), DIEA (39 mg, 0.3 mmol) and HATU (42 mg, 0.11 mmol) according to the procedure for compound 4. 1 H NMR (400 MHz, methanol-d4) δ 6.86-6.81 (m, 1H), 6.69-6.60 (m, 3H), 6.54 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 4.15 (s, 2H), 3.53-3.46 (m, 3H), 3.15-2.97 (m, 2H), 2.60-2.51 (m, 1H), 2.14-1.94 (m, 4H), 1.35 (d, J = 6.8, 6H). Mass (m / z): 434.3 [M+H] + .

[0260] 2-(Pyrazin-2-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (46)

[0261]

[0262] The title compound 46 (2.5 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(pyrazin-2-yl)acetic acid (17 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4 in an overall yield of 6.3%. 1 H NMR (400 MHz, methanol-d4) δ 8.61 (d, J = 1.6 Hz, 1H), 8.57 (dd, J = 2.8, 1.6 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H), 6.99-6.92 (m, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 7.8, 1.8 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.38 (d, J = 7.8 Hz, 1H), 4.19 (s, 2H), 3.82 (s, 2H). Mass (m / z): 401.2 [M+H] + .

[0263] 2-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (47)

[0264]

[0265] The title compound 47 (3.6 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid (15.5 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) in an overall yield of 8.6%. 1 HNMR (400MHz, methanol-d4) δ 6.97 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.58 (s, 1H), 6.46 (d, J = 8.0 Hz, 1H), 6.39 (dd, J = 8.0, 1.2 Hz, 1H), 4.82 (s, 2H), 4.19 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H). Mass (m / z): 418.2 [M+H] + .

[0266] N-((7-(Trifluoromethyl)-10H-phenoxazin-3-yl)methyl)oxazole-4-carboxamide (48)

[0267]

[0268] The title compound 48 (6.5 mg) was prepared as a yellow solid in 17.3% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), oxazole-4-carboxylic acid (11.3 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4. 1 HNMR (400 MHz, methanol-d4) δ 8.40 (t, J = 0.8 Hz, 1H), 8.19 (s, 1H), 6.99-6.94 (m, 1H), 6.75-6.71 (m, 2H), 6.60 (d, J = 1.8 Hz, 1H), 6.45 (dd, J = 8.2, 1.0 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.33 (s, 2H). Mass (m / z): 376.1 [M+H]+.

[0269] 2-(1H-pyrrol-2-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (49)

[0270]

[0271] According to the procedure for compound 4, the title compound 49 (15.4 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(1H-pyrrol-2-yl)acetic acid (12.5 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) in an overall yield of 39.8%. 1 HNMR (400MHz, methanol-d4) δ 6.98-6.93 (m, 1H), 6.75-6.70 (m, 1H), 6.68-6.64 (m, 1H), 6.64-6.58 (m, 1H), 6.53-6.42 (m, 2H), 6.36-6.32 (m, 1H), 6.02 (t, J = 3.2 Hz, 1H), 5.97-5.92 (m, 1H), 4.13 (s, 2H), 3.52 (s, 2H). Mass (m / z): 388.2 [M+H] + .

[0272] 1-Methyl-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxamide (50)

[0273]

[0274] The title compound 50 (6.5 mg) was prepared as a yellow solid from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(1H-pyrrol-2-yl)acetic acid (12.7 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) in an overall yield of 16.7%. 1 H NMR (400 MHz, methanol-d4) δ 7.90 (s, 1H), 6.99-6.94 (m, 1H), 6.76-6.72 (m, 2H), 6.63 (d, J = 1.8 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.33 (s, 2H), 4.21 (s, 3H). Mass (m / z): 390.2 [M+H] + .

[0275] 2-(4-ethylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (51)

[0276]

[0277] The title compound 51 (5.3 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 1-ethylpiperazine (114 mg, 1 mmol) according to the procedure for compound 34 in an overall yield of 12.2%. 1 HNMR (400MHz, methanol-d4) δ 6.99-6.94 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.0, 2.0 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 8.2, 0.8 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.21 (s, 2H), 3.58-3.43 (m, 2H), 3.21-2.96 (m, 8H), 2.71-2.51 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H). Mass (m / z): 435.3 [M+H] + .

[0278] 2-(3,4-Dimethylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (52)

[0279]

[0280] The title compound 52 (7.2 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 1,2-dimethylpiperazine (114 mg, 1 mmol) according to the procedure for compound 34 in an overall yield of 16.6%. 1 HNMR (400MHz, methanol-d4) δ7.02-6.98 (m, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.74-6.68 (m, 1H), 6.61-6.55 (m, 1H), 6.49 (d, J = 8.2 Hz, 1H), 6.41 (dd, J = 8.0, 1.0 Hz, 1H), 4.22 (s, 2H), 3.30-3.20 (m, 2H), 3.15 (s, 2H), 3.04-2.87 (m, 4H), 2.71 (s, 3H), 2.62-2.50 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H). Mass (m / z): 435.3 [M+H] + .

[0281] N-((7-(Trifluoromethyl)-10H-phenoxazin-3-yl)methyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)acetamide (53)

[0282]

[0283] The title compound 53 (12.3 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and (2S,6R)-1,2,6-trimethylpiperazine (64 mg, 0.5 mmol) according to the procedure for compound 34 in an overall yield of 27.5%. 1HNMR (400MHz, methanol-d4) δ 6.98 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.69 (dt, J = 8.0, 1.6 Hz, 1H), 6.57 (t, J = 1.6 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.39 (dd, J = 8.0, 1.2 Hz, 1H), 4.20 (s, 2H), 3.11 (s, 2H), 2.99-2.87 (m, 2H), 2.75-2.65 (m, 2H), 2.36-2.20 (m, 2H), 1.27 (d, J = 6.8 Hz, 6H). Mass (m / z): 449.3 [M+H] + .

[0284] 2-(4-Cyclopropylpiperazin-1-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (54)

[0285]

[0286] The title compound 54 (14.0 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol) and 1-cyclopropylpiperazine (63 mg, 0.5 mmol) according to the procedure for compound 34 in an overall yield of 31.4%. 1 HNMR (400MHz, methanol-d4) δ7.00-6.95 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.70-6.67 (m, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.47-6.43 (m, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H), 3.13 (s, 2H), 2.91-2.76 (m, 4H), 2.70-2.54 (m, 4H), 1.93-1.80 (m, 1H), 0.59-0.45 (m, 4H). Mass (m / z): 447.3 [M+H] + .

[0287] 2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (55)

[0288]

[0289] The title compound 55 (3.5 mg) was prepared as a yellow solid from 2-chloro-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)acetamide (35.6 mg, 0.1 mmol), (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (92 mg, 0.5 mmol) and DIEA (65 mg, 0.5 mmol) in 8.1% overall yield. 1 HNMR (400MHz, methanol-d4) δ 6.99-6.57 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.70-6.67 (m, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.21 (s, 2H), 4.13-4.10 (m, 1H), 3.67-3.63 (m, 1H), 3.36-3.31 (m, 4H), 3.00 (s, 2H), 2.90 (s, 3H), 2.20-2.07 (m, 2H). Mass (m / z): 433.3 [M+H] + .

[0290] N-((8-(Trifluoromethyl)-10H-phenoxazin-3-yl)methyl)quinuclidine-4-carboxamide (56)

[0291]

[0292] The title compound 56 (16.9 mg) was prepared as a yellow solid from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 2-(1-methylpiperidin-4-yl)acetic acid (15.7 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 4 in an overall yield of 31.8%. 1H NMR (400MHz, methanol-d4) δ 6.83 (d, J = 7.0 Hz, 1H), 6.65 (t, J = 9.2 Hz, 2H), 6.60 (s, 1H), 6.54 (s, 1H), 6.36 (dt, J = 7.8, 1.0 Hz, 1H), 4.18 (d, J = 5.4 Hz, 2H), 3.44-3.36 (m, 6H), 2.15-2.08 (m, 6H). Mass (m / z): 418.3 [M+H] + .

[0293] 5-(Dimethylamino)-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)pentanamide (57)

[0294]

[0295] The title compound 57 (2.6 mg) was prepared as a yellow solid in 6.6% overall yield from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), 4-(dimethylamino)butyric acid hydrochloride (18 mg, 0.11 mmol), DIEA (39 mg, 0.3 mmol) and HATU (42 mg, 0.11 mmol) according to the procedure for compound 4. 1 HNMR (400MHz, methanol-d4) δ 6.82 (d, J = 8.2 Hz, 1H), 6.71-6.58 (m, 3H), 6.55 (s, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.17-3.11 (m, 2H), 2.88 (s, 6H), 2.39 (t, J = 6.8 Hz, 2H), 2.03-1.95 (m, 2H). Mass (m / z): 394.2 [M+H] + .

[0296] N-((7-Chloro-10H-phenoxazin-3-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide (58)

[0297]

[0298] Step 1. A mixture of 2-bromo-5-chlorophenol (3 g, 0.01 mol), 3-fluoro-4-nitrobenzaldehyde (2 g, 0.012 mol), K2CO3 (2.7 g, 0.02 mol), and DMF (50 mL) was stirred at 60°C for 3 h. The mixture was concentrated and purified by flash chromatography, eluting with PE:EA=10:1 to 5:1, to give the desired product (4.26 g, 42.4%) as a yellow solid. Mass (m / z): 355.1 [M+H] + .

[0299] Step 2. A mixture of 3-(2-bromo-5-chlorophenoxy)-4-nitrobenzaldehyde (3 g, 8.4 mmol), SnCl2 (5.68 g, 25.2 mmol) and EA (30 mL) was stirred at 80 °C for 16 h. The mixture was basified with NaHCO3 to pH = 8, poured into water, and extracted with EA (20 mL x 3). The mixture was concentrated and purified by flash chromatography, eluting with PE:EA = 10:1 to 5:1 to give the desired product (2.2 g, 14.05%) as a yellow solid. Mass (m / z): 326.3 [M+H] + .

[0300] Step 3. A mixture of 4-amino-3-(2-bromo-5-chlorophenoxy)benzaldehyde (1 g, 3.1 mmol), Pd2(dba)3 (283 mg, 0.31 mmol), Xantphos (269 mg, 0.46 mmol), Cs2CO3 (2.02 g, 6.2 mmol) and dioxane (20 mL) was stirred at 100°C for 16 h. The mixture was concentrated and purified by flash chromatography, eluting with PE:EA=5:1 to 1:1, to give the desired product (630 mg, 91.64%) as a yellow solid. Mass (m / z): 246.6 [M+H] + .

[0301] Step 4. A solution of 7-chloro-10H-phenoxazine-3-carbaldehyde (630 mg, 2.56 mmol), NH2OH-HCl (266 mg, 3.84 mmol), DIEA (661 mg, 5.12 mmol) and MeOH (20 mL) was stirred at room temperature for 2 h. The mixture was poured into water, extracted with EA (20 mL x 3), and the organic layer was concentrated to give the desired product (550 mg, 31.26%) as a yellow solid. Mass (m / z): 261.2 [M+H] + .

[0302] Step 5. A solution of (E)-7-chloro-10H-phenoxazine-3-carbaldehyde oxime (550 mg, 2.11 mmol), Zn (690 mg, 10.55 mmol) in THF / CH3COOH=1:1 (20 mL) was stirred at 50°C for 2 h. The mixture was basified to pH=8 with NaHCO3, extracted with DCM / MeOH=10:1, the organic layer was concentrated and purified by flash chromatography, eluting with DCM:MeOH (1% NH3)=60:1 to 15:1 to give the desired product (103.5 mg, 59.7%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ8.29 (s, 2H), 6.77 (s, 2H), 6.69 (s, 1H), 6.65 (s, 2H), 6.44-6.39 (m, 1H), 3.52 (s, 2H). Mass (m / z): 247.2 [M+H] + .

[0303] Step 6. According to the procedure for compound 4, the title compound 58 (9.8 mg) was prepared as a yellow solid from (7-chloro-10H-phenoxazin-3-yl)methanamine (25 mg, 0.1 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (16 mg, 0.1 mmol), DIEA (39 mg, 0.3 mmol) and HATU (38 mg, 0.1 mmol) in an overall yield of 25.4%. 1 HNMR (400MHz, methanol-d4) δ 6.74-6.67 (m, 2H), 6.60-6.54 (m, 2H), 6.40-6.33 (m, 2H), 4.22 (s, 2H), 3.46-3.33 (m, 6H), 3.06-2.88 (m, 7H). Mass (m / z): 387.2 [M+H] + .

[0304] N-((9-Chloro-10H-phenoxazin-3-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide (59)

[0305]

[0306] Step 1. A mixture of 3-fluoro-4-nitrobenzaldehyde (3 g, 17.7 mmol), 2-bromo-3-chlorophenol (4 g, 19.5 mmol), potassium carbonate (4.9 g, 35.4 mmol) and DMF (15 mL) was stirred at 65 °C for 3 h. The mixture was diluted with EA (300 mL) and washed with water (300 mL x 3). The organic phase was concentrated and purified by flash chromatography, eluting with PE:EA = 10:1 to 1:1, to give the desired product (2.7 g, 38.4%) as a yellow solid.

[0307] Step 2. A solution of 3-(2-bromo-3-chlorophenoxy)-4-nitrobenzaldehyde (2.7 g, 7.6 mmol) and SnCl2 (6.8 g, 30.4 mmol) in EA (30 mL) was stirred at 80 °C for 3 h. The mixture was diluted with EA (300 mL) and washed with water (150 x 2). The organic phase was concentrated and purified by flash chromatography, eluting with PE:EA=10:1 to 1:1, to give the desired product (2 g, 72%) as a yellow solid. Mass (m / z): 326.0 [M+H] + .

[0308] Step 3. A mixture of 4-amino-3-(2-bromo-3-chlorophenoxy)benzaldehyde (1.9 g, 10 mmol), Pd2(dba)3 (915 mg, 1 mmol), Xantphos (1.16 g, 2 mmol), Cs2CO3 (6.5 g, 20 mmol) and Tol (30 mL) was stirred at 100°C for 10 h under N2 atmosphere. The mixture was concentrated and purified by flash chromatography, eluting with PE:EA=10:1 to 1:1, to give the desired product (700 mg, 26%) as a yellow solid. Mass (m / z): 246.0 [M+H] + .

[0309] Step 4. A solution of 9-chloro-10H-phenoxazine-3-carbaldehyde (500 mg, 2.8 mmol), hydroxylamine hydrochloride (396 mg, 5.7 mmol) and DIPEA (1.4 g, 11.4 mmol) in DMSO (5 mL) was stirred at 25°C for 1 h. The mixture was diluted with water (100 mL) and filtered, and the solid was collected and dried to give the desired product as a yellow solid (600 mg, 72.7%). Mass (m / z): 260.9 [M+H] + .

[0310] Step 5. A solution of (Z)-9-chloro-10H-phenoxazine-3-carbaldehyde oxime (500 mg, 1.92 mmol) and Zn (1.2 g, 19.2 mmol) in aqueous NH4Cl solution (saturated, 10 mL) and THF (2 mL) was stirred at 80 ° C for 3 h. The mixture was filtered and extracted with THF (50 mL x 2). The organic phase was concentrated and purified by flash chromatography, eluting with DCM: MeOH (1% NH3) = 100: 1 to 10: 1 to produce the desired product (90.8 mg, 17.3%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.84 (s, 1H), 6.86 (dd, J = 7.1, 2.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.70 (dd, J = 8.0, 1.6 Hz, 1H), 6.65 (s, 1H), 6.60-6.55 (m, 2H), 3.51 (s, 2H). Mass (m / z): 230.1 [M-NH2] + .

[0311] Step 6. According to the procedure for compound 2, the title compound 59 (29.4 mg) was prepared as a white solid in 62.3% overall yield from (9-chloro-10H-phenoxazin-3-yl)methanamine (30 mg, 0.122 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (25 mg, 0.159 mmol).1 H NMR (400 MHz, methanol-d4) δ 6.87-6.746.76 (m, 1H), 6.69-6.65 (m, 1H), 6.61 (dd, J = 7.8, 0.8 Hz, 1H), 6.55 (dd, J = 1.8, 0.8 Hz, 1H), 6.52 (dd, J = 8.0, 0.8 Hz, 1H), 6.50-6.46 (m, 1H), 4.20 (s, 2H), 3.11 (s, 2H), 2.89 (s, 4H), 2.67 (s, 4H), 2.55 (s, 3H). Mass (m / z): 387.2 [M+H] + .

[0312] 1-Isopropyl-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (60)

[0313]

[0314] The title compound 60 (5.9 mg) was prepared as a yellow solid in 13.3% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (28 mg, 0.1 mmol), isopropylpiperidine-4-carboxylic acid hydrochloride (22.8 mg, 0.11 mmol), DIEA (39 mg, 0.3 mmol) and HATU (45.6 mg, 0.12 mmol) according to the procedure for compound 4. 1 HNMR (400MHz, methanol-d4) δ 6.99-6.96 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.67 (dd, J = 8.0, 2.0 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.53-3.46 (m, 3H), 3.12-2.99 (m, 2H), 2.61-2.51 (m, 1H), 2.12-1.99 (m, 4H), 1.35 (d, J = 6.8 Hz, 6H). Mass (m / z): 434.3 [M+H] + .

[0315] 1-Cyclopropyl-N-((7-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (61)

[0316]

[0317] The title compound 61 (7.1 mg) was prepared as a yellow solid in 23.1% overall yield from (7-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (20 mg, 0.07 mmol), 1-cyclopropylpiperidine-4-carboxylic acid (13 mg, 0.08 mmol), DIEA (28 mg, 0.21 mmol) and HATU (33 mg, 0.09 mmol) according to the procedure for compound 4. 1 HNMR (400MHz, methanol-d4) δ7.00-6.95 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.69-6.65 (m, 1H), 6.54 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 8.2, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.69-3.60 (m, 2H), 3.26-3.11 (m, 2H), 2.83-2.72 (m, 1H), 2.61-2.51 (m, 1H), 2.10-1.88 (m, 4H), 1.00-0.92 (m, 4H). Mass (m / z): 432.3 [M+H] + .

[0318] 1-Methyl-2-oxo-N-((8-(trifluoromethyl)-10H-phenoxazin-3-yl)methyl)piperidine-4-carboxamide (62)

[0319]

[0320] The title compound 62 (21.0 mg) was prepared as a white solid in 46.7% overall yield from (8-(trifluoromethyl)-10H-phenoxazin-3-yl)methanamine (30 mg, 0.107 mmol) and 1-methyl-2-oxopiperidine-4-carboxylic acid (17 mg, 0.107 mmol) according to the procedure for 4. 1 H NMR (400 MHz, methanol-d4) δ 6.81 (ddt, J = 8.2, 2.0, 0.8 Hz, 1H), 6.68-6.59 (m, 3H), 6.53 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.14 (d, J = 2.8 Hz, 2H), 3.40-3.34 (m, 2H), 2.92 (s, 3H), 2.78 (dtd, J = 10.6, 5.8, 3.0 Hz, 1H), 2.59-2.43 (m, 2H), 2.08-2.01 (m, 1H), 1.92 (dddd, J = 13.4, 10.4, 9.0, 6.4 Hz, 1H). Mass (m / z): 420.3 [M+H] + .

[0321] N-((10H-phenothiazin-3-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide (63)

[0322]

[0323] Preparation of 10H-phenothiazine-3-carboxaldehyde:

[0324] Step 1. Preparation of 10H-phenothiazine-3-carboxaldehyde:

[0325] A mixture of 10H-phenothiazine (5 g, 25.09 mmol), (1s, 3s, 5s)-1,3,5,7-tetraazaadamantane (10.55 g, 75.27 mmol), AcOH (120 mL) and H2O (60 mL) was stirred at 120° C. for 2 h. The mixture was concentrated and purified by flash chromatography, eluting with PE:EA=3:1 to 1:1, to give the desired product (2.5 g, 43.8%) as a yellow solid.

[0326] Step 2. Preparation of (E)-10H-phenothiazine-3-carbaldehyde oxime:

[0327] To a solution of 10H-phenothiazine-3-carbaldehyde (2.5 g, 11.00 mmol) in EtOH (50 mL) was added NH2-OH-HCl (1.53 g, 22.00 mmol) and DIPEA (4.26 g, 33.00 mmol), then the mixture was stirred at 25 °C for 3 h and water (50 mL) was added to the mixture, then filtered to afford the product. Mass (m / z): 242.9 [M+H] + .

[0328] Step 3. Preparation of (10H-phenothiazin-3-yl)methanamine (63-3):

[0329] A mixture of (E)-10H-phenothiazine-3-carbaldehyde oxime (400 mg, 1.65 mmol) and THF (5 mL) was added to LiAlH4 (187.9 mg, 4.95 mmol) and stirred for 2 h at 25° C. The mixture was quenched with water and 15% NaOH, filtered and dried over Na2SO4, concentrated, and purified by flash chromatography, eluting with DCM:MeOH=1:0 to 5:1, to give the desired product (30 mg, 7.96%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.49 (s, 1H), 6.98-6.78 (m, 4H), 6.74-6.56 (m, 3H), 3.56 (s, 2H). Mass (m / z): 212.1 [M-NH2] + .

[0330] Step 4. The title compound 63 (9.3 mg) was prepared as a white solid from (10H-phenothiazin-3-yl)methanamine (30 mg, 0.132 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (27 mg, 0.171 mmol) in 19.2% overall yield. 1 H NMR (400 MHz, methanol-d4) δ 6.97-6.93 (m, 1H), 6.91 (dd, J = 5.4, 1.8 Hz, 1H), 6.87 (dd, J = 10.8, 1.8 Hz, 1H), 6.84 (t, J = 1.3 Hz, 1H), 6.73 (td, J = 7.6, 1.4 Hz, 1H), 6.61 (dd, J = 7.8, 1.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.23 (s, 2H), 3.14 (s, 3H), 3.05 (m, 4H), 2.72 (m, 4H), 2.67 (s, 3H). Mass (m / z): 369.3 [M+H] + .

Claims

1. A compound of formula I or a salt, hydrate or stereoisomer thereof: in: R1-R8 are independently H, optionally substituted heteroatom or optionally substituted hydrocarbyl; and R9 is an optionally substituted alkyl group or an optionally substituted cyclic group optionally containing a heteroatom.

2. The compound of claim 1, wherein: R1-R7 are independently H, optionally substituted heteroatom or optionally substituted hydrocarbyl; R1-R7 are independently H, halogen, optionally substituted OH or NH2 or optionally substituted alkyl; R1-R7 are independently H or optionally F-substituted lower alkyl; R8 is H, an optionally substituted heteroatom or an optionally substituted hydrocarbyl; R8 is H, optionally substituted OH or optionally substituted alkyl; R8 is H or OH; R9 is an optionally substituted alkyl group or an optionally substituted cyclic group optionally containing a heteroatom; R9 is a substituted methyl group; R9 is a methyl group substituted by an optionally substituted cyclic group which may contain a heteroatom; 1, 2, 3, 4 or 5 of R3-R7 are H; or Any combination of the aforementioned substituents.

3. The compound of claim 1 having a structure disclosed herein.

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

5. Use of a compound or composition according to any one of claims herein in the preparation of a medicament for inhibiting ferroptosis activity or modulating or inhibiting diseases associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer, in a human in need thereof.

6. A compound or composition according to any one of claims herein for use in inhibiting ferroptosis activity or modulating or inhibiting diseases associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure and cancer, in a human in need thereof, or for use in the preparation of a medicament thereof for use in a human in need thereof.

7. A method of using a compound or composition as claimed in any one of claims 1 to inhibit ferroptosis activity or to modulate or inhibit diseases associated with dysregulation of ferroptosis, such as neuropathy, ischemia-reperfusion injury, acute renal failure and cancer, and optionally detecting the resulting improvement in human health or condition.

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