Coumarin compounds and their uses

Abstract

The present invention discloses a series of coumarin compounds and their uses, which have the formula (I): TIFF2025503187000038.tif2478(I) Specifically disclosed are compounds of the formula: and pharma- ceutically acceptable salts thereof.

Description

[Technical field]

[0001] This application claims priority to CN202210093816.8, filed on January 26, 2022, and CN202210405730.4, filed on April 18, 2022.

[0002] The present disclosure discloses a series of coumarin compounds and applications thereof, and in particular, discloses compounds represented by formula (I) and pharma- ceutically acceptable salts thereof. [Background technology]

[0003] The mitogen-activated protein kinase (MAPK) signaling pathway is one of the important pathways in eukaryotic signal transduction networks. It is a key signaling pathway for cell proliferation, differentiation, apoptosis, and stress response under normal and pathological conditions. MAPKs are a group of evolutionarily conserved serine-threonine kinases. The RAS / RAF / MEK / ERK signaling pathway is one of the MAPK pathways. Overexpression or mutation of these proteins has been identified in many malignant tumors. The RAS / RAF / MEK / ERK signaling pathway is one of the typical signaling pathways in the oncology field.

[0004] According to statistics, 31% of non-small cell lung cancers in patients are caused by KRAS mutations, and 90% of pancreatic cancers in patients are caused by KRAS mutations; in addition, 21% of endometrial cancers, 45% of colorectal cancers, 5% of ovarian cancers, etc. are all caused by KRAS mutations; 28% of melanomas and 20% of multiple myelomas are caused by NRAS mutations; 60% of melanomas, 35-60% of ovarian cancers, 30-80% of papillary thyroid cancers, etc. are caused by BRAF mutations. There are a large number of these patients.

[0005] There are already several drugs on the market that target RAF and MEK, but the approved indications for the currently available RAF and MEK small molecule inhibitors are BRAF V600EIt is concentrated in melanomas associated with BRAF mutations. Under normal conditions, BRAF is phosphorylated by RAS and then dimerizes before it can become kinase-active, whereas BRAF mutants are constantly active. V600E In the case of RAS mutations, BRAF and CRAF form heterodimers and exert their effects. V600E However, it is only effective against RAF / MEK mutations, and not against tumors associated with RAS mutations upstream of MAPK. Novel second-generation small molecule RAF inhibitors are needed. MEK inhibitors, which are also on the market, are allosteric kinase inhibitors. Allosteric inhibitors are highly specific for MEK, but are susceptible to upstream kinase signals. Feedback control of MEK phosphorylation can reactivate RAS pathway signals, and MEK inhibition alone cannot effectively treat solid tumors associated with RAS mutations. Therefore, novel dual RAF / MEK inhibitors could be an option for treating diseases associated with MAPK pathway activation. Summary of the Invention

[0006] The present disclosure provides a method for producing a method of making a semiconductor device comprising formula (I): [ka] (I) or a pharma- ceutically acceptable salt thereof. [In the formula, T1 is selected from CH and N; R1 is pyrimidinyl and -C(=O)-C 1~4 alkylamino; R2 is a halogen; R3 is halogen, C 1~3 Alkyl, -CH2-C 1~4 alkylamino and -CH2- 4-6 membered nitrogen-containing heterocycloalkyl, 1~3 Alkyl, -CH2-C 1~4 alkylamino and -CH2-4 to 6-membered nitrogen-containing heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 halogens; R4 is halogen and C 1~3 alkyl, wherein C 1~3 The alkyl is optionally substituted with 1, 2 or 3 halogens; R5 is C 1~3 alkyl, where C 1~3 The alkyl is optionally substituted with one, two or three halogens.

[0007] In some embodiments of the present disclosure, R1 has the formula: [ka] and other variables are as defined in this disclosure.

[0008] In some embodiments of the present disclosure, R2 is F, and the other variables are as defined herein.

[0009] In some embodiments of the present disclosure, R3 is selected from F, Cl, Br, CH3, CH2CH3, CH2NHCH3, and CH2N(CH3)2, where CH3, CH2CH3, CH2NHCH3, and CH2N(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and other variables are as defined in the present disclosure.

[0010] In some embodiments of the present disclosure, R3 is selected from CH3 and CH2N(CH3)2, and other variables are as defined herein.

[0011] In some embodiments of the present disclosure, R4 is F, and the other variables are as defined in the present disclosure.

[0012] In some embodiments of the present disclosure, R5 is selected as CH3, and the other variables are as defined in the present disclosure.

[0013] Other embodiments of the present disclosure are obtained by combining any of the above variables.

[0014] The present disclosure also provides the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0015] (Technical effect) The compounds of the present disclosure can inhibit target MEK and target RAF in mice, effectively inhibit the proliferation of HCT116 cells, and provide high plasma free exposure, good oral bioavailability, and significant tumor inhibition effects.

[0016] (Related Definitions) Unless otherwise stated, the following terms and phrases used herein shall have the following meanings: A particular term or phrase should not be deemed unclear or indefinite due to the absence of a specific definition, but should be understood in its general sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredients.

[0017] The term "pharmaceutically acceptable" is used herein to refer to compounds, ingredients, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, and have a reasonably reasonable benefit / risk ratio.

[0018] The term "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein prepared by reacting a compound having certain substituents described herein with a relatively non-toxic acid or base. When a compound disclosed herein contains a relatively acidic functional group, the compound can be contacted with a sufficient amount of base in a pure solution or in a suitable inert solvent to obtain a base addition salt. Pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts, or magnesium salts or similar salts. When a compound disclosed herein contains a relatively basic functional group, the compound can be contacted with a sufficient amount of acid in a pure solution or in a suitable inert solvent to obtain an acid addition salt. Examples of pharma- ceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts, 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, and methanesulfonic acid, and the like; and amino acid salts (such as arginine), organic acid salts, such as glucuronic acid, and the like. Certain compounds disclosed herein contain both basic and acidic functional groups and can be converted into any base or acid addition salt.

[0019] The pharma- ceutically acceptable salts disclosed herein can be prepared from a parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the compound, in its free acid or free base form, with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0020] The compounds disclosed herein may exist in certain geometric or stereochemical forms. The present disclosure contemplates all compounds, including cis and trans isomers, (-) and (+) enantiomers, (R) and (S) enantiomers, diastereomers, (D) isomers, (L) isomers, and racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are included within the scope disclosed herein. Substituents, such as alkyl, may have additional asymmetric carbon atoms. These isomers and mixtures thereof are included within the scope disclosed herein.

[0021] The compounds disclosed herein may contain unnatural proportions of atomic isotopes in one or more of the elements that constitute the compounds. For example, the compounds may contain radioisotopes, such as tritium ( 3 H), Iodine-125( 125 I) or C14( 14 C). As another example, hydrogen may be replaced with deuterium to form a deuterated drug. The bond between deuterium and carbon is stronger than the normal hydrogen-carbon bond. Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, improved drug stability, enhanced efficacy, and increased biological half-life of the drug. All variations in the isotopic composition of the compounds disclosed herein, regardless of radioactivity, are within the scope of the disclosure.

[0022] The terms "optional" or "optionally" mean that the event or condition described thereafter may occur but need not occur, and are intended to include instances where the event or condition occurs as well as instances where the event or condition does not occur.

[0023] The term "substituted" means that one or more hydrogen atoms adjacent to a particular atom are replaced with a substituent, including deuterium and hydrogen variations, provided that the valence of the particular atom is normal and the compound is stable. If the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced. No position on an aromatic ring can be substituted with oxo. The term "optionally substituted" means that an atom may or may not be substituted with a substituent, and unless otherwise stated, the type and number of substituents can be any, provided that it is chemically achievable.

[0024] When any variable (e.g., R) occurs more than one time in any constituent or structure of the compound, each definition of that variable is independent at each occurrence. That is, for example, if a group is substituted with 0-2 R, then that group may optionally be substituted with up to 2 R, and where each definition of R is independent at each occurrence. Further, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0025] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0026] When one of the variables is a single bond, it means that the two groups linked by that single bond are directly linked. For example, if L in ALZ represents a single bond, then the structure ALZ is actually AZ.

[0027] If the listed linking group does not dictate a direction of the link, then the linkage may be oriented in any direction. For example, the structure: [ka] When the linking group L in the formula (I) is -MW-, -MW- is linked to ring A and ring B in the left to right reading order to form the structure: [ka] or can be linked to ring A and ring B in the reverse left-to-right reading order to form the structure: [ka] Combinations of linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0028] Unless otherwise stated, if a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups via a chemical bond. If the bonding position of the chemical bond is flexible and the bondable site(s) has hydrogen atom(s) and the bondable site(s) with hydrogen atom(s) bond to a chemical bond, the number of hydrogen atom(s) at the site decreases as the number of chemical bonds attached increases, and the group becomes a group of corresponding valency. The chemical bond between the site and other groups is represented by a solid straight line: [ka] Dashed lines: [ka] Or a wavy line: [ka] For example, the solid line in -OCH3 indicates that this group is attached to another group through an oxygen atom; [ka] The dashed straight lines in indicate that this group is attached to other groups through the two ends of the nitrogen atom in the group; the structure: [ka] The wavy lines in indicate that this group is attached to another group through carbon atoms 1 and 2 in the phenyl group; [ka] indicates that any available bonding site on the piperidinyl group can be bonded to another group via one chemical bond, and includes at least the following four bonding modes: [ka] Even if the H atom is depicted on the -N-, the structure: [ka] The structure: [ka] still includes the binding mode of Only when one chemical bond is attached will one H at this site be removed and the group will become the corresponding monovalent piperidinyl group.

[0029] Bonds represented by solid wedge lines, unless otherwise noted: [ka] and the dotted wedge bond: [ka] indicates the absolute configuration of the chiral center; a solid straight bond: [ka] and the bond represented by a dotted straight line: [ka] indicates the relative configuration of the asymmetric center; wavy line: [ka] is a solid wedge bond: [ka] or a dotted wedge bond: [ka] or a wavy line: [ka] is a solid line bond: [ka] or a dotted straight line bond: [ka] Shows.

[0030] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0031] Unless otherwise stated, the term "C 1~3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group containing 1 to 3 carbon atoms. 1~3 Alkyl is C 1~2 Alkyl, C 2~3 It may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methenyl). 1~3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0032] Unless otherwise stated, the term "C 1~4 "Alkylamino" means an alkyl group containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group. 1~4 The alkylamino group is C 1~3 , C 1~2 , C 2~4 , C4, C3 and C2 alkylamino groups. 1~4Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0033] The term "4-6 membered nitrogen containing heterocycloalkyl", alone or in combination with other terms, refers respectively to a saturated cyclyl group containing 4 to 6 ring atoms, in which 1, 2, 3 or 4 ring atoms are each independently selected from O, S and N, with at least one heteroatom being an N atom and the remainder being carbon atoms, in which the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). This includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro, fused and bridged rings. Additionally, for "4-6 membered nitrogen containing heterocycloalkyl", a heteroatom may be present at the attachment site of the heterocycloalkyl group to the remainder of the molecule. 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), hexahydropyridazinyl, etc.

[0034] Unless otherwise stated, C n~n+m or C n ~C n+m includes all specific instances of n through n+m carbon atoms, e.g., C 1~12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 and any range from n to n+m, e.g., C 1~12is C 1~3 , C 1~6 , C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 and C 9~12 and the like; similarly, n-membered to n+m-membered indicates that the number of atoms in a ring is n to n+m, for example, a 3- to 12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, a 3- to 12-membered ring includes 3- to 6-membered ring, 3- to 9-membered ring, 5- to 6-membered ring, 5- to 7-membered ring, 6- to 7-membered ring, 6- to 8-membered ring, 6- to 10-membered ring, etc.

[0035] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those of skill in the art, such as the embodiments listed below, embodiments formed from the embodiments listed below in combination with other chemical synthetic methods, and equivalent substitutions known to those of skill in the art. Alternative embodiments include, but are not limited to, the embodiments disclosed herein.

[0036] The structure of the compounds disclosed herein can be determined by conventional methods known to those skilled in the art. When the present disclosure relates to the absolute configuration of a compound, the absolute configuration can be determined by conventional techniques in the art, such as single crystal X-ray diffraction (SXRD). In single crystal X-ray diffraction (SXRD), a Bruker D8 venture diffractometer is used with a CuKα source in Φ / ω scan mode to collect the diffraction intensity data of the single crystal produced; after collecting the relevant data, the crystal structure is further analyzed by a direct method (Shelxs97) to determine the absolute configuration.

[0037] The solvents used in this disclosure are commercially available.

[0038] Compounds are named according to naming conventions common in the art or in ChemDraw® software; commercially available compounds are named by their supplier's directory name. [Brief description of the drawings]

[0039] FIG. 1 is a graph showing the change in tumor volume in mice administered various doses of Compound 3 over a period of 28 days.

[0040] FIG. 2 is a graph showing the change in body weight in mice administered various doses of Compound 3 over a period of 28 days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The present disclosure is described in detail below by way of examples. However, these examples are not intended to have any limitations that are detrimental to the present disclosure. The present disclosure is described in detail herein, and embodiments are also disclosed herein. It will be apparent to those skilled in the art that various changes and modifications may be made to the embodiments disclosed herein without departing from the spirit and scope disclosed herein. EXAMPLES

[0042] Synthesis Route: [ka] Step 1: Synthesis of Compound 1-2 Compound 1-1 (50 g) was added to glacial acetic acid (500 mL). N-bromosuccinimide (68.84 g) and benzoyl peroxide (2.76 g) were added successively. The reaction system was stirred at 85° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated to dryness. Water (300 mL) was added, and the mixture was diluted with ethyl acetate (200 mL). * The layers were separated. The organic layers were combined and washed with saturated saline (150 mL). * 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:0 to 70:30) to obtain compound 1-2.

[0043] Compound 1-2 was characterized as follows: 1H NMR (400 MHz, CDCl3) δ: 8.07 - 7.99 (m, 1H), 7.76 - 7.69 (m, 1H), 7.34 - 7.28 (m, 1H), 4.58 - 4.53 (m, 2H).

[0044] Step 2: Synthesis of Compounds 1-3 60% pure sodium hydroxide (512.72 mg) was added to anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen conditions, and ethyl acetoacetate (1.67 g) was slowly added dropwise. The reaction was stirred at 0° C. for 0.5 hours. The reaction solution was added to a solution of compound 1-2 (3 g) in anhydrous tetrahydrofuran (15 mL) while maintaining the temperature at 0° C. After the addition was complete, the reaction was heated to 20° C. and stirred for 12 hours. After the reaction was complete, the reaction was quenched by adding saturated aqueous ammonium chloride solution (30 mL). The mixture was diluted with ethyl acetate (30 mL). * 3) and the layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:0 to 80:20) to obtain compound 1-3.

[0045] Characterization of compound 1-3: LCMS: m / z (ESI) = 284.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 7.95 - 7.88 (m, 1 H), 7.58 - 7.51 (m, 1 H), 7.23 - 7.16 (m, 1 H), 4.22 - 4.11 (m, 2 H), 3.86 - 3.66 (m, 1 H), 3.33 - 3.18 (m, 2 H), 2.27 (s, 3 H), 1.22 (t, J=7.2 Hz, 3 H).

[0046] Step 3: Synthesis of Compounds 1-4 Compound 1-3 (600 mg) was dissolved in 70% pure sulfuric acid aqueous solution (6 mL). 5-Fluororesorcinol (271.35 mg) was added, and the reaction system was stirred at 25°C for 16 hours. After the reaction was completed, the reaction system was directly filtered. The filter cake was rinsed with water (10 mL), and the solid was concentrated to dryness under reduced pressure. The solid was purified by column chromatography (eluent: dichloromethane / methanol = 100:0 to 98:2) to obtain compound 1-4.

[0047] Characterization of compound 1-4: LCMS: m / z (ESI) =348.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 10.97-10.77 (m, 1 H), 7.99 (t, J=7.2 Hz, 1 H), 7.57 (t, J=7.2 Hz, 1 H), 7.32 (t, J=8.0 Hz, 1 H), 6.69 - 6.56 (m, 2 H), 4.03 (s, 2 H), 2.47 (s, 3 H).

[0048] Step 4: Synthesis of Compounds 1-5 Compound 1-4 (100 mg) was dissolved in N,N-dimethylformamide (2.5 mL). Cesium carbonate (112.59 mg) and 2-bromopyrimidine (183.12 mg) were added, and the reaction system was stirred at 80° C. for 1 hour. After the reaction was completed, saturated saline (5 mL) was added to the system, and the mixture was dissolved in ethyl acetate (5 mL). * 3), and the layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: dichloromethane / methanol = 100:0 to 98:2) to obtain compound 1-5.

[0049] Characterization of compounds 1-5: LCMS: m / z (ESI) =426.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ: 8.71 (d, J=4.4 Hz, 2 H), 8.00 (t, J=7.2 Hz, 1 H), 7.63 (t, J=7.2 Hz, 1 H), 7.41 - 7.25 (m, 4 H), 4.10 (s, 2 H), 2.56 (d, J=6.0 Hz, 3 H).

[0050] Step 5: Synthesis of Compounds 1-6 Compound 1-5 (35 mg) was dissolved in ethyl acetate (2 mL). Tin(II) chloride dihydrate (74.27 mg) was added, and the reaction system was stirred at 80° C. for 4 hours to react. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate (5 mL) was added to quench the system, and ethyl acetate (5 mL) was added. * 3), and the layers were separated. The organic layers were combined and filtered. The filtrate was concentrated under reduced pressure to give compound 1-6.

[0051] Characterization of compounds 1-6: LCMS: m / z (ESI) =396.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 8.71 (d, J=4.8 Hz, 2 H), 7.37 (t, J=4.8 Hz, 1 H), 7.31 - 7.24 (m, 2 H), 6.78 - 6.68 (m, 1 H), 6.66 - 6.57 (m, 1 H), 6.28 - 6.26 (m, 1 H), 5.08 (s, 2 H), 3.93 (s, 2 H), 2.51 - 2.49 (m, 3 H).

[0052] Step 6: Synthesis of Compound 1 Compound 1-6 (40 mg) was dissolved in N,N-dimethylformamide (2 mL). A solution of pyridine (80.03 mg) and methylaminosulfonyl chloride (98.32 mg) in acetonitrile (1 mL) was added, and the reaction system was stirred at 20° C. for 2 hours. After the reaction was completed, the system was quenched by adding saturated saline (5 mL), and ethyl acetate (5 mL) was added. *5). The layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative high performance liquid chromatography (HPLC preparative method: Phenomenex preparative chromatograph; column: C18 75 * 30mm * 3 μm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution (containing 0.05% aqueous ammonia), mobile phase B: acetonitrile; running gradient: B%: 25% to 60% (8 min)), and compound 1 was obtained.

[0053] Characterization of compound 1: LCMS: m / z (ESI) =489.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.36 (br s, 1 H), 8.71 (d, J=4.8 Hz, 2 H), 7.37 (t, J=4.8 Hz, 1 H), 7.32 - 7.25 (m, 3 H), 7.22-7.20 (m, 1 H), 7.04-7.02 (m, 1 H), 6.95 - 6.92 (m, 1 H), 3.99 (s, 2 H), 2.57 - 2.51 (m, 6 H). EXAMPLES

[0054] Synthesis Route: [ka] Step 1: Synthesis of Compound 2-1 Compound 1-4 (100 mg) was dissolved in N,N-dimethylformamide (2.5 mL). Potassium carbonate (119.39 mg) was added. The mixture was stirred at 0°C for 0.5 hours, and then dimethylaminoformyl chloride (37.16 mg) was added. The mixture was stirred at 20°C for 2 hours to react. After the reaction was completed, saturated saline (5 mL) was added to the system, and the mixture was diluted with ethyl acetate (5 mL). *3), and the layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether / ethyl acetate=100:0-60:40) to obtain compound 2-1.

[0055] Characterization of compound 2-1: LCMS: m / z (ESI) =419.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 8.07-8.00 (m, 1 H), 7.68-7.62 (m, 1 H), 7.34 - 7.27 (m, 1 H), 7.21 - 7.14 (m, 2 H), 4.08 (s, 2 H), 3.05 (s, 3 H), 2.93 (s, 3 H), 2.54 (d, J=6.0 Hz, 3 H).

[0056] Step 2: Synthesis of Compound 2-2 Compound 2-1 (100 mg) was dissolved in ethyl acetate (5 mL). Tin(II) chloride dihydrate (215.75 mg) was added. The reaction system was stirred at 80° C. for 4 hours to react. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate (5 mL) was added to quench the system, and ethyl acetate (5 mL) was added. * 3), and the layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 2-2.

[0057] Characterization of compound 2-2: LCMS: m / z (ESI) =389.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 7.19 - 7.11 (m, 2 H), 6.75 - 6.68 (m, 1 H), 6.65 - 6.56 (m, 1 H), 6.33 - 6.24 (m, 1 H), 5.08 (s, 2 H), 3.91 (s, 2 H), 3.05 (s, 3 H), 2.93 (s, 3 H), 2.56 - 2.47 (m, 3 H).

[0058] Step 3: Synthesis of Compound 2 Compound 2-2 (100 mg) was dissolved in N,N-dimethylformamide (3 mL). A solution of pyridine (203.67 mg) and methylaminosulfonyl chloride (250.21 mg) in acetonitrile (1.5 mL) was added, and the reaction system was stirred at 20° C. for 2 hours. After the reaction was completed, the system was quenched by adding saturated saline (15 mL), and ethyl acetate (15 mL) was added. * 5). The layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative high performance liquid chromatography (HPLC preparative method: Phenomenex preparative chromatograph; column: C18 75 * 30mm * 3 μm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution (containing 0.05% aqueous ammonia), mobile phase B: acetonitrile; running gradient: B%: 25% to 60% (8 min)), and compound 2 was obtained.

[0059] Characterization of compound 2: LCMS: m / z (ESI) =482.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 7.41 (t, J=8.0 Hz, 1 H), 7.03 (t, J=8.0 Hz, 1 H), 7.00 - 6.87 (m, 3 H), 6.60 (s, 1 H), 4.44 - 4.35 (m, 1 H), 4.08 (s, 2 H), 3.12 (s, 3 H), 3.04 (s, 3 H), 2.77 (d, J=5.2 Hz, 3 H), 2.56 (d, J=6.0 Hz, 3 H). EXAMPLES

[0060] Synthesis Route: [ka] Step 1: Synthesis of compound 3-2 Compound 3-1 (41 g) was dissolved in anhydrous methanol (410 mL). Sodium borohydride (10.77 g) was added batchwise at 0° C. The mixture was stirred at 20° C. under nitrogen for 2 hours. Acetone (50 mL) was slowly added dropwise to the reaction solution under nitrogen flow. The mixture was stirred for 1 hour. The mixture was concentrated to dryness under reduced pressure to remove the solvent. Ethyl acetate (500 mL), saturated saline (200 mL) and water (200 mL) were added to the crude product. The layers were separated. The organic layers were combined and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure to remove the solvent to give compound 3-2.

[0061] Compound 3-2 was characterized as follows: LCMS: m / z (ESI) =161.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.18 (d, J=4.8 Hz, 1 H), 7.47 (t, J=4.8 Hz, 1 H), 4.86 (s, 2 H), 2.77 (s, 1 H).

[0062] Step 2: Synthesis of compound 3-3 Compound 3-2 (10 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and then triethylamine (12.53 g) was added. Methanesulfonic anhydride (12.94 g) was added in batches, and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated to dryness under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=100:0 to 70:30) to obtain compound 3-3.

[0063] Compound 3-3 was characterized as follows: LCMS: m / z (ESI) =239.9 [M+H] + . 1 H NMR (400 MHz, CDCl3), δ: 8.28 (d, J=4.8 Hz, 1 H), 7.40 (t, J=4.8 Hz, 1 H), 5.34 (s, 2 H), 3.13 (s, 3 H).

[0064] Step 3: Synthesis of Compound 3-4 Sodium iodide (625.45 mg) and ethyl acetoacetate (1.09 g) were dissolved in anhydrous tetrahydrofuran (10 mL), and a solution of lithium tert-butoxide in tetrahydrofuran (2.2 M, 2.09 mL) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour and then cooled to 0°C. A solution of compound 3-3 (1 g) in anhydrous tetrahydrofuran (5 mL) was added under nitrogen. After the addition was complete, the mixture was stirred at 20°C for 1 hour. Saturated saline (20 mL), water (20 mL), and ethyl acetate (20 mL) were added, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to remove the solvent. The crude product was purified by alumina column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 90:10) to give compound 3-4.

[0065] Compound 3-4 was characterized as follows: LCMS: m / z (ESI) =273.9 [M+H] + .

[0066] Step 4: Synthesis of Compound 3-5 Compound 3-4 (0.11 g) was dissolved in 98% concentrated sulfuric acid (788.39 mg). The solution was cooled to 0°C, and 5-fluororesorcinol (51.49 mg) was added. The mixture was stirred at 20°C for 16 hours. After the reaction was completed, ethyl acetate (5 mL), saturated saline (3 mL), and water (3 mL) were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 0:100) to obtain compound 3-5.

[0067] Compound 3-5 was characterized as follows: LCMS: m / z (ESI) =337.9 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: 11.00 (s, 1 H), 8.13-8.11 (d, J=5.2 Hz, 1 H), 7.30-7.20 (t, J=5.2 Hz, 1 H), 6.69 - 6.51 (m, 2 H), 4.02 (s, 2 H), 2.50-2.45 (d, J=6.0 Hz, 3 H).

[0068] Step 5: Synthesis of Compounds 3-6 Compound 3-5 (310 mg) was dissolved in N,N-dimethylformamide (3 mL). Cesium carbonate (358.91 mg) and 2-bromopyrimidine (175.13 mg) were added, and the mixture was stirred at 80° C. for 8 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=100:0 to 70:30) to give compound 3-6.

[0069] Compound 3-6 was characterized as follows: LCMS: m / z (ESI) =416.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.63 (d, J=4.8 Hz, 2 H), 8.10 (d, J=4.8 Hz, 1 H), 7.18-7.14 (m, 2 H), 7.12 - 7.07 (m, 1 H), 6.96 (m, 1 H), 4.13 (s, 2 H), 2.61 (d, J=6.0 Hz, 3 H).

[0070] Step 6: Synthesis of Compounds 3-7 Compound 3-6 (140 mg), benzophenone imine (82.47 mg), tris(dibenzylacetone)dipalladium (30.83 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.97 mg), and cesium carbonate (329.13 mg) were dissolved in anhydrous toluene (5 mL), and the mixture was stirred at 110° C. for 3 hours under nitrogen conditions. The mixture was concentrated to dryness under reduced pressure, the solvent was removed, and the crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=100:0 to 50:50) to obtain compound 3-7.

[0071] Compound 3-7 was characterized as follows: LCMS: m / z (ESI) =561.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.63 (d, J=4.8 Hz, 2 H), 8.02 (d, J=5.2 Hz, 1 H), 7.47 - 7.28 (m, 9 H), 7.17 (t, J=4.8 Hz, 2 H), 7.07 (s, 1 H), 6.98 - 6.92 (m, 1 H), 6.81 (s, 1 H), 3.94 (s, 2 H), 2.30 (m, 3 H).

[0072] Step 7: Synthesis of Compounds 3-8 Compound 3-7 (130 mg) was dissolved in anhydrous tetrahydrofuran (5.2 mL), and then 1M dilute hydrochloric acid (260.00 μL) was added. The mixture was stirred at 20° C. for 2 hours. Ethyl acetate (10 mL), saturated saline (5 mL), and water (5 mL) were added to the reaction solution, and the layers were separated. The aqueous layer was collected and adjusted to pH 9 with saturated sodium carbonate solution, and then ethyl acetate (10 mL) was added. The layers were separated. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the solvent was removed to give compound 3-8.

[0073] Compound 3-8 was characterized as follows: LCMS: m / z (ESI) =397.0 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: ppm 8.63 (d, J=4.8 Hz, 2 H), 7.70 (d, J=5.4 Hz, 1 H), 7.17 (t, J=4.8 Hz, 1 H), 7.11 - 7.02 (m, 1 H), 7.00 - 6.90 (m, 1 H), 6.53 (t, J=5.4 Hz, 1 H), 5.19 - 5.01 (m, 2 H), 4.07 (s, 2 H), 2.58 (d, J=6.0 Hz, 3 H).

[0074] Step 8: Synthesis of Compound 3 Compound 3-8 (103 mg) was dissolved in N,N-dimethylformamide (1.2 mL). A solution of pyridine (113.06 mg) and methylaminosulfonyl chloride (101.01 mg) in acetonitrile (0.6 mL) was added. The mixture was stirred at 20° C. for 2 hours. The reaction solution was purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; column: C18 100 * 30mm * Compound 3 was obtained by separation and purification using a 10 μm separator; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; running gradient: B%: 25% to 55% (8 min)).

[0075] Compound 3 was characterized as follows: LCMS: m / z (ESI) =490.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: ppm 8.71 (d, J=4.8 Hz, 2 H), 7.87 (d, J=5.0 Hz, 1 H), 7.44 - 7.23 (m, 3 H), 6.80 - 6.60 (m, 1 H), 4.00 (s, 2 H), 2.53 (m, 3 H), 2.48 (s, 3 H). EXAMPLES

[0076] Synthesis Route: [ka] Step 1: Synthesis of compound 4-1 Compound 3-5 (300 mg) was dissolved in N,N-dimethylformamide (3 mL) under nitrogen and potassium carbonate (368.34 mg) was added. Dimethylaminoformyl chloride (124.19 mg) was added at 0° C. The mixture was stirred at 20° C. for 3 hours. Water (6 mL) was added to the reaction solution and the mixture was stirred for 30 minutes and filtered. The filter cake was rinsed with water (2 mL), collected and dried on a rotary evaporator under vacuum to give compound 4-1.

[0077] Compound 4-1 was characterized as follows: LCMS: m / z (ESI) =409.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 8.13 (d, J=5.0 Hz, 1 H), 7.32 (s, 1 H), 7.25 - 7.10 (m, 2 H), 4.08 (s, 2 H), 3.05 (s, 3 H), 2.93 (s, 3 H), 2.53 (d, J=6.0 Hz, 3H).

[0078] Step 2: Synthesis of compound 4-2 Compound 4-1 (360 mg), benzophenone imine (215.47 mg), tris(dibenzylacetone)dipalladium (80.64 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (101.91 mg), and cesium carbonate (860.81 mg) were dissolved in toluene (5 mL). The mixture was stirred at 110° C. for 3 hours under nitrogen conditions. The mixture was concentrated to dryness under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=100:0 to 50:50) to obtain compound 4-2.

[0079] Compound 4-2 was characterized as follows: LCMS: m / z (ESI) =554.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, J=5.0 Hz, 1 H), 7.91 - 7.72 (m, 2 H), 7.53 - 7.32 (m, 4 H), 7.23 - 7.06 (m, 4 H), 7.00-6.97 (m, 1 H), 6.95-6.90 (m, 1 H), 6.80 (t, J=5 Hz, 1 H), 3.92 (s, 2 H), 3.13 (s, 3 H), 3.05 (s, 3 H), 2.27 (d, J=6.0 Hz, 3 H).

[0080] Step 3: Synthesis of compound 4-3 Compound 4-2 (190 mg) was dissolved in anhydrous tetrahydrofuran (7.6 mL), and then 1 M dilute aqueous hydrochloric acid (384.80 μL) was added. The mixture was stirred at 20° C. for 2 hours. The reaction solution was directly filtered, and the filter cake was rinsed with anhydrous tetrahydrofuran (0.5 mL). The filter cake was dried under vacuum on a rotary evaporator to obtain the hydrochloride salt of compound 4-3.

[0081] Compound 4-3 was characterized as follows: LCMS: m / z (ESI) =390.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 7.65 (d, J=6.0 Hz, 1 H), 7.26 - 7.12 (m, 2 H), 6.60 (s, 1 H), 4.03 (s, 2 H), 3.05 (s, 3 H), 2.93 (s, 3 H), 2.53 (s, 3 H).

[0082] Step 4: Synthesis of Compound 4 The hydrochloride salt of compound 4-3 (98 mg) was dissolved in N,N-dimethylformamide (1 mL). A solution of pyridine (100.13 mg) and methylaminosulfonyl chloride (89.46 mg) in acetonitrile (0.5 mL) was added. The mixture was stirred at 20° C. for 2 hours. The reaction solution was purified by preparative HPLC (Preparative HPLC method: Phenomenex Preparative Chromatograph; Column: C18 75 * 30mm* The compound was separated and purified using a 3 μm separator; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; running gradient: B%: 25% to 45% (8 min)) to obtain compound 4.

[0083] Compound 4 was characterized as follows: LCMS: m / z (ESI) =483.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 7.80 (d, J=4.6 Hz, 1 H), 7.23 - 7.06 (m, 2 H), 6.62 (s, 1 H), 3.97 (s, 2 H), 3.06 (s, 3 H), 2.94 (s, 3 H), 2.55 - 2.51 (m, 3 H), 2.45 (s, 3 H).

[0084] (Rating System) Assay Example 1: In vitro cytological activity evaluation of HCT116 Assay materials: McCoy's 5A medium, penicillin / streptomycin antibiotics purchased from Vicente, fetal bovine serum purchased from Biosera, 3D CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent purchased from Promega, HCT116 cell line purchased from Nanjing Kebai Biotechnology Co., Ltd., Envision multilabel analyzer (PerkinElmer).

[0085] Assay method: HCT116 cells were seeded in ultra-low attachment 96-well U-shaped plates with 80 μL of cell suspension (containing 1000 HCT116 cells) per well. The cell plates were cultured overnight in a CO2 incubator.

[0086] The compounds to be tested were serially diluted in nine steps of 5-fold using a pipette, i.e., a dilution series from 2 mM to 5.12 nM was created and replicated. 78 μL of culture medium was added to the middle plate, and then 2 μL of the diluted compound was transferred per well to the corresponding position of the middle plate. After thorough mixing, 20 μL of the mixture was transferred to each well of the cell plate. The concentration range of the compounds transferred to the cell plate was 10 μM to 0.0256 nM. The cell plate was placed in a CO2 incubator and cultured for 5 days. Another cell plate was prepared, and the signal value was read for data analysis with the day of drug addition as the maximum value (maximum value of the following equation).

[0087] 100 μL of cell viability chemiluminescence detection reagent was added to the cell plate, and the mixture was incubated at room temperature for 10 minutes to stabilize the luminescence signal. The plate was read on the Multilabel Analyzer.

[0088] Data Analysis: (Sample-Min) / (Max-Min) * Convert raw data into percentage inhibition using the 100% formula and IC 50 Values ​​may be obtained by four-parameter curve fitting (obtained by "log(inhibitor) vs. response-variable slope" mode in GraphPad Prism). The assay results of the inhibitory activity of the compounds of the present disclosure against the proliferation of HCT116 cells are shown in Table 1. Table 1: In vitro screening assay results for compounds of the present disclosure. [Table 1] Conclusion: The compounds of the present disclosure exhibit good cell proliferation inhibitory activity in HCT116 cell line.

[0089] Assay Example 2: In vitro pharmacokinetic study of compound 3 Pharmacokinetic study of test compounds after oral and intravenous administration in male CD-1 mice. Test compounds were mixed with 10% dimethyl sulfoxide / 30% PEG-400 / 60% aqueous solution, vortexed and sonicated to prepare a clear solution of 0.20 mg / mL. The clear solution was filtered through a microporous filter for later use. Male CD-1 mice aged 7-10 weeks were selected and the candidate compound solution and the reference compound VS-6766 solution were intravenously injected. The reference compound and the test compound were mixed with 20% sulfobutyl-β-cyclodextrin / 80% aqueous solution, vortexed and sonicated to prepare a nearly clear solution of 0.20 mg / mL containing fine particles, and the candidate compound solution was orally administered. Whole blood was collected after a certain period of time, and serum was prepared. Drug concentrations were analyzed by LC-MS / MS method, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The assay results are shown in Table 2. Table 2. Pharmacokinetic results of test compounds [Table 2] Assay Conclusions: In PK studies, compounds of the present disclosure show good bioavailability with high plasma free exposure in mice.

[0090] Assay Example 3: In vitro pharmacodynamics study of compound 3 (In vitro pharmacodynamics study of test agents against human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model in female BALB / c nude mice) 1. Cell culture: Human lung cancer cells NCI-H358 (ECACC-95111733) were reactivated and cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% dual antibodies. Cells were cultured in a cell incubator containing 5% CO2 at 37°C and passaged twice a week. When NCI-H358 cells reached 80%-90% saturation, the cells were harvested, counted, and seeded.

[0091] 2. Animals: BALB / c nude mice (female, 6-8 weeks old, weighing 18-22 g).

[0092] Tumor implantation: 5×10 6 NCI-H358 cells were implanted in the right side of the neck of each mouse in a volume of 0.1 mL. The cell suspension was a mixture of PBS and Matrigel (3:1). The mean tumor volume was 150-200 mm. 3 At the time, the mice were randomly assigned to drug administration groups. The drug administration scheme and the number of test animals in each group are shown in Table 3 below: Table 3. Test animal groups and dosing regimens [Table 3] However, QD means once a day.

[0093] 4. Tumor Measurements and Assay Parameters The assay endpoint was to assess whether tumor growth was inhibited, slowed, or reversed. Tumor diameters were measured twice weekly using calipers. Tumor volume was calculated using the formula: V = 0.5a × b 2 where a and b represent the long and short diameters of the tumor, respectively.

[0094] The anticancer activity of the compounds was evaluated by TGI (%) or relative tumor growth rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. TGI (%) was calculated as follows: TGI (%) = [1-(mean tumor volume of a particular treatment group at a particular measurement - mean tumor volume of the treatment group at the time of group formation) / (mean tumor volume of the vehicle control group at the same measurement - mean tumor volume of the vehicle control group at the time of group formation)] x 100%. Relative tumor growth rate T / C (%): Calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV : RTV in the treatment group; C RTV Relative tumor volume (RTV) was calculated based on the tumor measurements. The formula is RTV=V t / V0, where V0 is the mean tumor volume measured at the time of group formation (i.e., PG-D0), and V tis the mean tumor volume at a particular measurement, and T RTV and C RTV are recorded on the same day.

[0095] TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1-(mean tumor volume at the end of treatment group - mean tumor volume at the start of treatment group)) / (mean tumor volume at the end of treatment for vehicle control group - mean tumor volume at the start of treatment for vehicle control group)] x 100%.

[0096] 5. Assay Results The assay results are shown in Figures 1 and 2. The results after 28 days of dosing are shown in Table 4. Table 4. T / C and TGI on the 28th day after administration [Table 4] Assay conclusion: The compounds of the present disclosure have significant tumor-inhibitory effects.

[0097] The dose and intermittent administration described herein may achieve maximum tumor suppression effect on this target. In future in vivo efficacy studies, it is considered to adopt a reduced dosage or intermittent administration to show dose dependency and improve animal tolerability.

Claims

1. Formula (I): 【Chemistry 1】 (I) or a pharma- ceutically acceptable salt thereof [In the formula, T １ is selected from CH and N; R １ is pyrimidinyl and -C(=O)-C １～４ alkylamino; R ２ is a halogen; R ３ is halogen, C １～３ Alkyl, -CH ２ -C １～４ Alkylamino and -CH ２ - 4 to 6 membered nitrogen containing heterocycloalkyl, where C １～３ Alkyl, -CH ２ -C １～４ Alkylamino and -CH ２ - each 4 to 6 membered nitrogen-containing heterocycloalkyl is independently optionally substituted with 1, 2 or 3 halogens; R ４ is halogen and C １～３ alkyl, wherein C １～３ The alkyl is optionally substituted with 1, 2 or 3 halogens; R ５ is C １～３ alkyl, where C １～３ The alkyl is optionally substituted with one, two or three halogens.

2. R １ The structure is: 【Chemistry 2】 2. The compound of claim 1, selected from:

3. R ２ is F, or a pharma- ceutically acceptable salt thereof.

4. R ３ is F, Cl, Br, CH ３ , C.H. ２ CH ３ , C.H. ２ N.H.C.H. ３ and C.H. ２ N (CH ３ ) ２ wherein CH ３ , C.H. ２ CH ３ , C.H. ２ N.H.C.H. ３ and C.H. ２ N (CH ３ ) ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is optionally substituted with 1, 2 or 3 halogens.

5. R ３ CH ３ and C.H. ２ N (CH ３ ) ２ 5. The compound according to claim 1 or 4, or a pharma- ceutically acceptable salt thereof, selected from:

6. R ４ is F, or a pharma- ceutically acceptable salt thereof.

7. R ５ CH ３ 2. The compound of claim 1, wherein:

8. The following formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

Images