Six-membered lactam compound and application thereof

Abstract

The invention discloses a six-membered lactam compound and application thereof, the compound has a structure as shown in a formula I or a stereoisomer, a tautomer, a racemate or pharmaceutically acceptable salt, ester, solvate, polymorphic substance, nitrogen oxide, isotope label, metabolite and hydrate thereof, according to the present invention, the structure of the compound represented by the formula I is # imgabs0, and the compound and the composition can be used for preparing MEK or Ras-MAPK signal channel inhibitors, have good activity, can completely inhibit the MEK or Ras-MAPK signal channel, and provide a new approach for the treatment of MEK or Ras-MAPK signal channel related diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present invention claims priority and benefits of the Chinese patent application with patent application number 202410174951.4 filed with the State Intellectual Property Office of China on February 7, 2024, entitled “A six-membered lactam compound and its application”, and incorporates the entire text of the patent application into this application by reference. Technical Field

[0003] The present invention relates to the technical field of drug synthesis, in particular to a six-membered lactam compound and application thereof. Background Art

[0004] MEK is a member of the mitogen-activated protein kinase kinase family and participates in the Ras / Raf / MEK / ERK pathway (the classic MAPK signaling pathway), mediating physiological processes such as cell proliferation, survival, differentiation, migration, and apoptosis. MEK inhibitors (PD0325901, CH4987655, trametinib, cobimetinib, selumetinib, etc.) have shown clinical efficacy in cancers with RAF mutations (such as malignant melanoma with BRAF mutations) as a single agent or in combination with RAF inhibitors. Although several MEK inhibitors have been approved by regulators, these MEK inhibitors have not yet achieved the expected clinical efficacy. In many tumors carrying RAS or RAF mutations, abnormal activation often occurs when BRAF or MEK inhibitors are used alone. Therefore, existing MEK inhibitors generally have the problem of insufficient activity and incomplete inhibition.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The purpose of the present invention is to provide a six-membered lactam compound and its application to improve the above technical problems.

[0007] The present invention is achieved in that:

[0008] In a first aspect, the present invention provides a six-membered lactam compound characterized by having a structure of Formula I or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, esters, solvates, polymorphs, nitrogen oxides, isotope labels, metabolites, or hydrates, wherein the structure of Formula I is:

[0009]

[0010] wherein R1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; in R1, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;

[0011] R2 is selected from hydrogen, deuterium, halogen, methyl, fluoromethyl, methoxy or fluoromethoxy;

[0012] R3 is selected from hydrogen, deuterium, halogen or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkenyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; in R3, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;

[0013] L is selected from O, NH or C(R 7a R 7b ), R 7a and R 7b independently selected from hydrogen, deuterium, fluorine or methyl;

[0014] X is selected from N or CR4; R4 is selected from hydrogen, deuterium, halogen, cyano, -N(R 8a R 8b ),-OR 8a 、-COR 8a 、-SR 8a 、-(CR 8c R 8d ) n OR a 、

[0015]

[0016] or the following group optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; in R4, the substituent is selected from: deuterium, halogen, -CN, -OR 9a 、-N(R 9a R 9b ) or -CON(R 9a R 9b ); In R4, the 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0017] R 8a and R 8b independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 5-10 Spiroalkyl, C 6-10 Bridged cycloalkyl, C 5-10 Heterospirocycloalkyl, C 6-10 hetero-bridged cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; R 8a and R 8b wherein the substituent is selected from the group consisting of deuterium, halogen, -CN, substituted or unsubstituted C 3-10 Cycloalkyl, -OR 9a 、-N(R 9a R 9b ) or -CON(R 9a R 9b );R 8a and R 8b wherein the 4-10 membered heterocycloalkyl, C 5-10 Heterospirocycloalkyl, C 6-10 The hetero-bridged cycloalkyl group or the 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0018] or R 8a and R 8b Together with the atoms to which they are attached, they form a 4-10 membered heterocycloalkyl group substituted with 0-6 substituents; R 8a and R 8b When forming a ring with the atoms to which they are attached, the substituents are selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; R 8a and R 8b When forming a ring with the atoms to which they are connected, the 4-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the substituted or unsubstituted C 3-10 The substituents in cycloalkyl are -OH, -NH2;

[0019] R 8c and R 8d independently selected from hydrogen, deuterium, fluorine or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R 8c and R 8d wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R 8c and R 8d wherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0020] n is an integer selected from 0 to 6;

[0021] R 9a and R 9b independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-16 Cycloalkyl, 4-16 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R 9a and R 9b wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R 9a and R 9b wherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0022] Y is selected from N or CR5;

[0023] Z is selected from N or CR6;

[0024] R5 and R6 are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R5 and R6, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; in R5 and R6, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O.

[0025] In a second aspect, the present invention also provides a method for synthesizing a six-membered lactam compound, the synthesis route of which is:

[0026]

[0027] Or, its synthetic route is:

[0028]

[0029] Or, its synthetic route is:

[0030]

[0031] Or, its synthetic route is:

[0032]

[0033] wherein R1, R2 and R3 are as defined in claim 1, and L is N, O or C.

[0034] In a third aspect, the present invention further provides a pharmaceutical composition comprising the above-mentioned six-membered lactam compound or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0035] In a fourth aspect, the present invention further provides the use of the above-mentioned six-membered lactam compound or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the MEK or Ras-MAPK signaling pathway;

[0036] And / or, use of the six-membered lactam compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11 in the preparation of an inhibitor that simultaneously inhibits phosphorylated MEK and phosphorylated ERK.

[0037] In a fifth aspect, the present invention also provides a pharmaceutical product comprising the above-mentioned six-membered lactam compound or the above-mentioned pharmaceutical composition.

[0038] The present invention has the following beneficial effects: providing a hexalactam compound, which can be used to prepare a MEK or Ras-MAPK signaling pathway inhibitor, has good activity, can fully inhibit the MEK or Ras-MAPK signaling pathway, and provides a new approach for treating diseases related to the MEK or Ras-MAPK signaling pathway. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0040] Figure 1 This is a graph showing the effect of compound W2 of Example 2 of the present invention on the phosphorylation of MEK and ERK in tumor cells;

[0041] Figure 2 This is a graph showing the changes in tumor volume in mice after treatment with compound W7 according to Example 7 of the present invention;

[0042] Figure 3 Statistical graph showing the therapeutic effects of compounds W49, W50 and W55 of the present invention in the HCT116 (G13D KRAS) mouse xenograft model;

[0043] Figure 4 Statistical graph showing the therapeutic effects of compounds W4-Na and W55 of the present invention in the OCI-AML-3 (NRAS Q61L) mouse xenograft model. DETAILED DESCRIPTION

[0044] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0045] Definition of terms:

[0046] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. It should be understood by those skilled in the art that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0047] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0048] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values disclosed herein (in the form "about a to b," or equivalently, "approximately a to b," or equivalently, "about a b") should be understood to represent each value and range encompassed within the broader range.

[0049] For example, the statement "C 1-6 " should be understood to include any sub-ranges therein and each point value, such as C 2-5 、C 3-4 、C 1-2 、C 1-3 、C 1-4 、C 1-5 etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression “C 3-10 ” should also be understood in a similar manner, for example, any sub-ranges and point values contained therein may be included, for example, C 3-9 、C 6-9 、C 6-8 、C 6-7 、C 7-10 、C 7-9 、C 7-8 、C 8-9 etc. and C3, C4, C5, C6, C7, C8, C9, C 10 etc. For another example, the expression "3-10 yuan" should be understood to include any sub-ranges and point values therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc. For another example, the expression "5-10 yuan" should also be understood in a similar manner, such as it can include any sub-ranges and point values contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc., as well as 5, 6, 7, 8, 9, 10 yuan, etc.

[0050] As used herein, unless otherwise stated, Indicates a single bond or a double bond.

[0051] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0052] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 C in "alkyl" 1-4 It refers to a group containing 1, 2, 3 or 4 carbon atoms in a straight or branched chain.

[0053] In the present invention, unless otherwise specified, "cycloalkyl", "carbocycle" or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl, etc. For example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). The cycloalkyl or cycloalkylene group of the present invention is optionally substituted with one or more substituents described herein.

[0054] In the present invention, unless otherwise specified, "heterocycloalkyl", "heterocycloalkylene" or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example, fused, bridged or spirocyclic) non-aromatic group, whose ring atoms are composed of carbon atoms and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur. If the valence requirements are met, the heterocycloalkyl group can be connected to the rest of the molecule through any ring atom. For example, "3-8 membered heterocycloalkyl" refers to a heterocycloalkyl group with 3 to 8 ring atoms. Common heterocycloalkyl groups include (but are not limited to) oxirane, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, etc. The heterocycloalkyl, heterocycloalkylene or heterocycle in the present invention are optionally substituted with one or more substituents (for example, oxo) described herein.

[0055] In the present invention, unless otherwise specified, "haloalkyl" refers to an alkyl group as described above, wherein one or more hydrogen atoms are replaced by halogen. For example, the term "C 1-6 "Haloalkyl" refers to a C1-6 Alkyl. It will be understood by those skilled in the art that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3. The haloalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0056] In the present invention, unless otherwise specified, "fluoroalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms. For example, the term "C 1-4 "Fluoroalkyl" refers to a C group optionally substituted by one or more (e.g. 1-3) fluorine atoms. 1-4 Alkyl. It will be understood by those skilled in the art that when there are more than one fluorine atom substituent, the fluorine atoms may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2CH2CF3, etc. The fluoroalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0057] In the present invention, unless otherwise specified, "alkenyl" refers to a linear or branched aliphatic hydrocarbon group having at least one C=C double bond. For example, "C 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. Common alkenyl groups include (but are not limited to) ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc. The alkenyl group in the present invention is optionally substituted with one or more substituents described herein.

[0058] In the present invention, unless otherwise specified, "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, "C 2-4 "Alkynyl" refers to an alkynyl group having 2 to 4 carbon atoms. Common alkynyl groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group in the present invention is optionally substituted with one or more substituents described herein.

[0059] In the present invention, unless otherwise specified, "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (such as bicyclic) aromatic group or aromatic ring with a conjugated π electron system. 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms. Examples include, but are not limited to, phenyl and naphthyl. The aryl or aromatic ring in the present invention is optionally substituted with one or more substituents described herein.

[0060] In the present invention, unless otherwise specified, "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring having a conjugated π-electron system, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. A heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, in particular 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups are, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; the term also encompasses heteroaryl or heteroaromatic rings that are optionally further fused to an aryl or heteroaryl ring to form a fused ring. The heteroaryl groups or heteroaryl rings of the present invention are optionally substituted with one or more substituents described herein.

[0061] In the present invention, unless otherwise specified, "oxo" or "=O" means that it forms C=O together with the carbon atom to which it is attached.

[0062] In the present invention, unless otherwise specified, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), hydroxyl, amino, C 1-8 Alkyl, C 3-7 Cycloalkyl, -OR', -SR', =O, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR'R", -C(O)NR'R", cyano, nitro, -S(O)2R', -OS(O)2OR', -OS(O)2R', -OP(O)(OR')(OR"); wherein R' and R" are independently C 1-8 Selected from -H, alkyl, C 1-8 In some embodiments, the above typical substituents may be further substituted, such as -OH or -NH2 substituted C 3-10 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(O)CH 3 , cyano, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0063] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0064] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of iodine (e.g. 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 34 S).

[0065] As used herein, "polymorph" refers to different solid crystalline phases of certain compounds of the present invention resulting from the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to encompass various crystalline forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of the present invention.

[0066] As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, only adventitious water or a mixture of water and a portion of an adventitious solvent may be retained. The compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also encompassed by the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0067] In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0068] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0069] Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, hexanoates, octanoates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbates, salicylates, 4-aminosalicylates, and naphthalene disulfonates. These salts can be prepared by methods known in the art. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline hexyl caffeine. These salts can be prepared by methods known to this patent.

[0070] In the present invention, unless otherwise indicated, "ester" refers to an ester derived from a compound described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compound of the present invention in the form of a free acid or alcohol). The compound of the present invention itself may also be an ester.

[0071] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0072] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750 (AR Katritzky and AJ Boulton, Eds., Academic Press); and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (AR Katritzky and AJ Boulton, Eds., Academic Press).

[0073] As used herein, "metabolite" refers to a substance formed in vivo upon administration of a compound of the present invention. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0074] In the present invention, " prodrug " refers to that some derivatives of the compounds of the present invention can be converted into the compound of the present invention with desired activity by, for example, hydrolytic cleavage when being administered to or on the body. Usually such prodrugs can be functional group derivatives of the compound, which are easily converted into desired therapeutically active compounds in vivo. Other information about the use of prodrugs can be found in " Pro-drugs as Novel Delivery Systems ", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrug of the present invention can be prepared, for example, by replacing the appropriate functional groups present in the compound of the present invention with some parts known to those skilled in the art as " front - part (pro-moiety) " (such as described in " Design of Prodrugs ", H. Bundgaard (Elsevier, 1985)).

[0075] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0076] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.

[0077] As used herein, the terms "drug combination," "drug combination," "combination therapy," "administration of an additional therapy," "administration of an additional therapeutic agent," and the like refer to a drug therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as separate entities, either in combination or sequentially at variable intervals. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0078] In the present invention, unless otherwise specified, "tumor" includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

[0079] As used herein, unless otherwise indicated, "treating" or "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0080] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0081] The six-membered lactam compounds provided by the present invention and their applications are described in detail below.

[0082] Some embodiments of the present invention provide a six-membered lactam compound having a structure of Formula I or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, esters, solvates, polymorphs, nitrogen oxides, isotope labels, metabolites, or hydrates, wherein the structure of Formula I is:

[0083]

[0084] wherein R1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; in R1, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;

[0085] R2 is selected from hydrogen, deuterium, halogen, methyl, fluoromethyl, methoxy or fluoromethoxy;

[0086] R3 is selected from hydrogen, deuterium, halogen or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkenyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; in R3, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;

[0087] L is selected from O, NH or C(R 7a R 7b ), R 7a and R 7b independently selected from hydrogen, deuterium, fluorine or methyl;

[0088] X is selected from N or CR4; R4 is selected from hydrogen, deuterium, halogen, cyano, -N(R 8a R 8b ),-OR 8a 、-COR 8a 、-SR 8a 、-(CR 8c R 8d ) n OR a 、

[0089]

[0090] or the following group optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; in R4, the substituent is selected from: deuterium, halogen, -CN, -OR 9a 、-N(R 9a R 9b ) or -CON(R 9a R 9b ); In R4, the 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0091] R 8a and R 8b independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 5-10 Spiroalkyl, C 6-10Bridged cycloalkyl, C 5-10 Heterospirocycloalkyl, C 6-10 hetero-bridged cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; R 8a and R 8b wherein the substituent is selected from the group consisting of deuterium, halogen, -CN, substituted or unsubstituted C 3-10 Cycloalkyl, -OR 9a 、-N(R 9a R 9b ) or -CON(R 9a R 9b );R 8a and R 8b wherein the 4-10 membered heterocycloalkyl, C 5-10 Heterospirocycloalkyl, C 6-10 Heterobridged cycloalkyl or 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from at least one of N, S, and O, substituted or unsubstituted C 3-10 The substituents in cycloalkyl are -OH, -NH2;

[0092] or R 8a and R 8b Together with the atoms to which they are attached, they form a 4-10 membered heterocycloalkyl group substituted with 0-6 substituents; R 8a and R 8b When forming a ring with the atoms to which they are attached, the substituents are selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; R 8a and R 8b When forming a ring with the atoms to which they are attached, the 4-10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0093] R 8c and R 8d independently selected from hydrogen, deuterium, fluorine or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R 8c and R 8d wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R 8c and R 8dwherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0094] n is an integer selected from 0 to 6;

[0095] R 9a and R 9b independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-16 Cycloalkyl, 4-16 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R 9a and R 9b wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R 9a and R 9b wherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0096] Y is selected from N or CR5;

[0097] Z is selected from N or CR6;

[0098] R5 and R6 are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R5 and R6, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; in R5 and R6, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O.

[0099] In some embodiments, R1 is selected from hydrogen, deuterium, or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; in R1, the 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N or O.

[0100] Furthermore, in some embodiments, R1 is selected from the following groups substituted with 0-3 substituents: C 1-4 Alkyl, C 3-4 In R1, the substituent is selected from: deuterium or fluorine.

[0101] Illustratively, R1 is selected from methyl, ethyl, cyclopropyl, isopropyl, deuterated methyl, deuterated ethyl, fluoroethyl or fluorocyclopropyl.

[0102] In a preferred embodiment, R1 is selected from methyl or ethyl.

[0103] In some embodiments, R2 is selected from hydrogen, deuterium, halogen or methyl; illustratively, R2 is selected from fluorine, chlorine or methyl, and in a preferred embodiment, R2 is fluorine.

[0104] In some embodiments, R3 is selected from hydrogen, deuterium, halogen, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, C 3-4 Cycloalkyl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0105] Furthermore, in some embodiments, R3 is selected from hydrogen, deuterium, halogen, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-4 Cycloalkyl; in R3, the substituent is selected from: deuterium or fluorine;

[0106] Exemplarily, R3 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-6 cycloalkenyl, deuterated methyl, fluoromethyl, deuterated ethyl, fluoroethyl, ethynyl, vinyl, -OCH3, -OCF2H, -OCF3, -OCD3, -SCH3, -SCF2H, -SCF3, -SCD3 or cyclopropyl.

[0107] In some embodiments, R3 is selected from hydrogen, chlorine, bromine, iodine, methyl, ethyl, propyl, butyl, cyclopropyl, isopropenyl, -CF3, isopropyl, cyclopentenyl, cyclohexenyl, cyclopropenyl, cyclohexyl, cyclopentyl, -SCH3, -SCF2H, ethynyl or vinyl.

[0108] In some preferred embodiments, R3 is selected from hydrogen, iodine, bromine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, vinyl, cyclopropyl, cyclopentenyl, cyclohexenyl, ethynyl, isopropenyl, cyclopentyl, cyclohexyl or -SCH3.

[0109] In some embodiments, L is selected from O, NH, CH2 or CD2, illustratively, L is selected from O or CH2.

[0110] In some embodiments, R4 is selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, fluoromethyl, cyclopropyl, -OR 8a 、-COR 8a 、 Among them, R 8a and R 8b independently selected from hydrogen or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; R 8a and R 8b wherein the substituent is selected from deuterium, fluorine, substituted or unsubstituted C 3-6 Cycloalkyl, hydroxy, amino, cyano, cyclopropyl or methoxy; R 8a and R 8b wherein the 4-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; or R 8a and R 8b Together with the atoms to which they are attached, they form a 4-6 membered heterocycloalkyl group substituted with 0-6 substituents; R 8a and R 8b When forming a ring with the atoms to which they are attached, the substituents are selected from: deuterium, fluorine, hydroxyl, amino, cyano, cyclopropyl or methoxy; R 8a and R 8b When forming a ring with the atoms to which they are connected, the 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the substituted or unsubstituted C 3-6 The substituents in cycloalkyl are -OH, -NH2;

[0111] In some embodiments, R4 is selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy, fluoromethoxy or the following groups:

[0112] or More preferably, R4 is selected from or

[0113] Exemplarily, R4 is selected from R 8a and R 8b are hydrogen, or R 8a For hydrogen and R 8b It is a methyl group.

[0114] In some embodiments, R5 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, cyano, deuterated methyl, fluoromethyl, ethyl, cyclopropyl, -OCH3, -OCF3 or -OCD3.

[0115] Illustratively, R5 is selected from hydrogen, fluorine, chlorine, -OCH3 or methyl.

[0116] In some embodiments, R6 is selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R6, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0117] In some embodiments, R6 is hydrogen, fluorine, chlorine, methoxy, or methyl.

[0118] Specifically, in some embodiments, the six-membered lactam compound is selected from any one of the following compounds:

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] Furthermore, in some embodiments, the six-membered lactam compound is selected from any one of the compounds shown in W1-W62:

[0137]

[0138]

[0139]

[0140]

[0141] In some embodiments, illustratively, the six-membered lactam compound is selected from any one of the following compounds:

[0142]

[0143]

[0144] Furthermore, some embodiments of the present invention also provide a method for synthesizing a six-membered lactam compound, the synthesis route of which is:

[0145]

[0146] Or, its synthetic route is:

[0147]

[0148] Or, its synthetic route is:

[0149]

[0150] Or, its synthetic route is:

[0151]

[0152] wherein R1, R2 and R3 are as defined in the above embodiment, and L is N, O or C.

[0153] It should be noted that, referring to the above synthesis route, the raw materials and intermediates of the synthesis route can be adaptively adjusted according to different target six-membered lactam compounds.

[0154] Furthermore, some embodiments of the present invention also provide a pharmaceutical composition comprising the above-mentioned six-membered lactam compound or a prodrug thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0155] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0156] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0157] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0158] Some embodiments of the present invention also relate to a pharmaceutical preparation or product, which uses the above-mentioned compound of formula I or its pharmaceutically acceptable form, or a mixture thereof, or a pharmaceutical composition according to an embodiment of the present invention as an active ingredient. In some embodiments, the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0159] Some embodiments of the present invention further provide an article of manufacture, for example, provided in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: any compound comprising Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0160] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or independent / batch sales. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or distributing pharmaceutical products. The second container is a container for holding the first container and optional package inserts. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package inserts can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or they can be placed inside the second container without any physical tools that adhere to the first container. Alternatively, the package inserts are located outside the second container. When located outside the second container, it is preferred that the package inserts be physically adhered via a cable tie, glue, staples, or other adhesion methods. Alternatively, they can abut or contact the outside of the second container without physical adhesion.

[0161] The package insert is a trademark, label, or indicia that lists information related to the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0162] In some embodiments of the present invention, there is provided the use of the above-mentioned six-membered lactam compound or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the MEK or Ras-MAPK signaling pathway.

[0163] In some embodiments of the present invention, there is provided use of the above-mentioned six-membered lactam compound or the above-mentioned pharmaceutical composition in the preparation of an inhibitor that simultaneously inhibits phosphorylated MEK and phosphorylated ERK.

[0164] Diseases related to the MEK or Ras-MAPK signaling pathway are tumors, specifically, tumors include but are not limited to any one of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, multiform lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, liposarcoma or acute myeloid leukemia.

[0165] In some embodiments, the drug is a MEK inhibitor.

[0166] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0167] It should be noted that it will be appreciated by those skilled in the art of organic synthesis that optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by conventional optimization procedures. In some cases, the order of the following reaction scheme and / or reaction steps may be changed to promote reaction or to avoid forming unwanted by-products. In addition, the functional groups present in each position of the molecule must be compatible with the proposed reagent and reaction. This limitation of substituents compatible with reaction conditions is apparent to those skilled in the art, and then alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, and it is assumed that such a protecting group (PG) is in the appropriate position if necessary. Conventional protecting groups can be used according to standard practices well known in the art (for explanation, see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis [protective groups in organic synthesis], 5th edition, publisher: John Wiley & Sons, 2014). Protective groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or protecting groups can be removed in subsequent reaction steps or post-processing.

[0168] Table 1 Abbreviations and their meanings in the present invention

[0169]

[0170]

[0171] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were measured at 10 -6 The units are given in ppm.

[0172] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0173] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0174] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm silica gel plate.

[0175] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0176] Unless otherwise specified, all reactions in the following examples were conducted under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. The hydrogenation reaction was typically performed by evacuating the flask and then filling it with hydrogen, repeating this process three times.

[0177] Examples 1 to 6 and Examples 49 to 58 refer to the following synthetic route 1:

[0178]

[0179] Example 1

[0180] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W1), the structural formula and steps of which are as follows:

[0181]

[0182] Step 1: Dissolve 2-fluoro-4-iodoaniline 1 (100 g, 425 mmol) in 300 mL of chloroform. Add triethylamine (120 mL, 960 mmol). Cool to 0°C and add CDI (140 g, 860 mmol). After addition, warm to room temperature and stir for 6 hours. Cool to 0°C and add 500 mL of aqueous ammonia in portions. Filter and wash the filter cake with water (200 mL x 2) to obtain crude 1-(2-fluoro-4-iodophenyl)urea 2 (70 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 281.0 [M+1]. + .

[0183] Step 2: Dissolve crude product 2 (70 g, 250 mmol) in 250 mL of N,N-dimethylformamide, add 2-cyanoacetic acid (26 g, 300 mmol), cool to 0°C, add methanesulfonyl chloride (28.5 g, 300 mmol), warm to room temperature, and stir for 2 hours. Add 500 mL of water, filter, and wash the filter cake with water (400 mL x 2) to obtain the crude title product, 2-cyano-((2-fluoro-4-iodophenyl)carbamoyl)acetamide 3 (60 g). The product was directly used in the next reaction without purification. LC-MS (ESI) m / z: 347.8 [M+1] + .

[0184] Step 3: Dissolve crude 2-cyano-((2-fluoro-4-iodophenyl)carbamoyl)acetamide 3 (60 g, 173 mmol) in 300 mL of water, add 2 M sodium hydroxide solution (8.6 mL, 17 mmol), heat to 85°C, and stir for 1 hour. Cool to 0°C, add 2 M hydrochloric acid dropwise until the pH reaches 3, filter, and wash the filter cake with water (200 mL x 3) and dry to obtain crude 6-amino-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione 4 (51 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 347.9 [M+1] + .

[0185] Step 4: Dissolve crude 6-amino-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione 4 (50 g, 368.80 mmol) in 250 mL of N,N-dimethylformamide. Add N,N-dimethylformamide dimethyl acetal (48 mL, 364 mmol) and stir at room temperature for 4.5 hours. Add 400 mL of water, filter, and wash the filter cake with water (200 mL x 3) and dry to obtain crude (E)-N'-(3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformamide 5 (45 g). The product was directly used in the next reaction without purification. LC-MS (ESI) m / z: 403.1 [M+1] + .

[0186] Step 5: Dissolve crude product 5 (40 g, 99 mmol) in 150 mL of N,N-dimethylformamide, add DBU (44.8 mL, 300 mmol) and 4-methoxybenzyl chloride (28 mL, 210 mmol), heat to 75°C, and stir for 3 hours. Cool to room temperature, add 1000 mL of water, and filter. Wash the filter cake with water (300 mL x 3) and dry to obtain crude (E)-N'-(3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformamide 6 (34 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 523.1 [M+1] + .

[0187] Step 6: Dissolve sodium borohydride (3.80 g, 100 mmol) in a mixture of 100 mL of ethanol and tert-butanol (v:v = 1:2), add crude product 6 (35 g, 67 mmol), heat to 65°C, and stir for 1 hour. Cool to 0°C, add 175 mL of water, and then add 140 mL of 10% citric acid. Filter, wash the filter cake with water (200 mL x 3), and dry to obtain crude 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-(methylamino)pyrimidine-2,4(1H,3H)-dione 7 (28 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 482.1 [M+1] + .

[0188] Step 7: Dissolve crude product 7 (28 g, 58 mmol) and malonic acid (24.2 g, 232 mmol) in 200 mL of 1,4-dioxane. Add acetyl chloride (27 g, 348 mmol) with stirring, and heat to 80°C for 4 hours. Cool to room temperature, add 1000 mL of ice water, filter, and wash the filter cake with water (300 mL x 3) and dry to obtain crude 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 8 (30 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 550.1 [M+1] + .

[0189] Step 8: Dissolve crude product 8 (30 g, 54.3 mmol) and DBU (16.5 g, 110 mmol) in 200 mL of DCM. Add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (29.2 g, 81 mmol) with stirring and react at room temperature for 4 hours. Add 1000 mL of ice water, filter, and wash the filter cake with water (300 mL x 3) and dry to obtain crude 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate 9 (35 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 682.1 [M+1] + .

[0190] Step 9: Dissolve crude product 9 (1 g, 1.4 mmol), 2-fluoro-3-nitrophenol (0.44 g, 2.8 mmol), potassium phosphate (0.59 g, 2.8 mmol), and palladium acetate (0.09 g, 0.042 mmol) in 10 mL of toluene and react at 110°C under nitrogen for 6 h. Add 20 mL of water to the reaction solution, extract with EtOAc (3 × 15 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to afford 5-(2-fluoro-3-nitrophenoxy)-1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 10 (0.2 g). LC-MS (ESI) m / z: 688.9 [M+1] + .

[0191] Step 10: Dissolve the crude product 10 (0.2 g, 0.29 mmol) in 5 mL of water and THF (V:V = 1:4), add lithium hydroxide (0.02 g, 0.87 mmol), and react at 40°C for 10 min. Add 20 mL of water, filter, and wash the filter cake with water (10 mL x 3) and dry to obtain crude 4-(2-fluoro-3-nitrophenoxy)-2-((2-fluoro-4-iodophenyl)amino)-N-(4-methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide 11 (0.15 g). LC-MS (ESI) m / z: 662.9 [M+1] + .

[0192] Step 11: Intermediate 11 (0.15 g, 0.25 mmol) was dissolved in 3 mL of TFA at room temperature and heated to 80°C for 1 h. After completion of the reaction, trifluoroacetic acid was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 9-10 with saturated aqueous sodium hydroxide solution. The mixture was filtered and dried to obtain crude 4-(2-fluoro-3-nitrophenoxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide 12 (0.11 g). LC-MS (ESI) m / z: 542.9 [M+1]. + .

[0193] Step 12: Iron powder (0.2 g, 2.98 mmol) and ammonium chloride (0.4 g, 7.1 mmol) were added to a mixture of 5 mL of methanol and 5 mL of water at room temperature and activated for 30 min. Intermediate 12 (0.11 g, 0.19 mmol) was then added and the temperature was raised to 70°C for 2 h. After the reaction, celite was applied to the filtrate, 10 mL of water was added, and the pH was adjusted to 9-10 with saturated aqueous sodium hydroxide solution. The mixture was filtered and dried to obtain crude 4-(3-amino-2-fluorophenoxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide 13 (0.08 g). LC-MS (ESI) m / z: 512.9 [M+1] + .

[0194] Step 13: Intermediate 13 (0.08 g, 0.1 mmol) and DIPEA (0.38 g, 0.3 mmol) were dissolved in 3 mL of DCM, and methylaminosulfonyl chloride (0.19 g, 0.15 mmol) was added. The mixture was reacted at room temperature for 1 h. The mixture was concentrated and mixed, and purified by column chromatography to give 4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide 14 (0.05 g). LC-MS (ESI) m / z: 606.1 [M+1]+ .

[0195] Step 14: Intermediate 14 (0.05 g, 0.08 mmol), cyclopropylboronic acid (0.013 g, 0.16 mol), potassium carbonate (0.022 g, 0.16 mmol), and dppfPdCl2 (0.2 g, 0.19 mmol) were added to a mixture of 3 mL of toluene and 1 mL of water at room temperature and reacted at 85°C under nitrogen for 6 h. After completion of the reaction, the reaction solution was cooled and most of the solvent was removed by rotary evaporation. 20 mL of water was added, and the solution was extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting product was then purified by column chromatography to afford the target compound, 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide W1 (0.03 g). LC-MS (ESI) m / z: 520.1 [M+1] + . 1H NMR (400MHz, CDCl3-d1) δ11.82(s,1H),7.55(t,J=7.3Hz,1H),7.39(s,1H),7.22(td,J=8.3,1.3Hz,1H),7.01(t,J=7.3Hz,1H),6.92–6 .81(m,4H),5.89(s,1H),5.47(s,1H),4.75(s,1H),3.16(s,3H),2.78(s,3H),1.91–1.83(m,1H),1.04–0.97(m,2H),0.71–0.64(m,2H).

[0196] Example 2

[0197] This example provides a method for preparing 2-((4-cyclopropyl-2-fluorophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W2). The structural formula and preparation steps are as follows:

[0198]

[0199] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W2) Referring to Example 1. 1H NMR (400MHz, CDCl3-d1) δ12.02(s,1H),7.59(s,1H),7.43(d,J=7.7Hz,1H),7. 28(d,J=8.2Hz,1H),6.94(d,J=7.8Hz,1H),6.80(dd,J=7.0,5.1Hz,3H),5.74(s ,1H),5.20(s,1H),4.78(s,1H),3.13(s,3H),2.78(s,3H),2.16(s,3H),1.90–1 .85(m,1H),1.12–0.99(m,2H),0.75–0.53(m,2H).LC-MS(ESI)m / z:515.9[M+1] + .

[0200] Example 3

[0201] This example provides a method for preparing 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W3). The structural formula and steps are as follows:

[0202]

[0203] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W3) Referring to Example 1. 1 H NMR (400MHz, CDCl3-d1) δ12.02(s,1H),7.59(s,1H),7.43(d,J=7.9Hz,1H),7.29(d,J=8 .1Hz,1H),6.94(d,J=7.9Hz,1H),6.83–6.75(m,3H),5.71(s,1H),5.19(s,1H),4.66(s, 1H),3.16(d,J=6.7Hz,2H),3.13(s,3H),2.15(s,3H),1.87(td,J=8.4,4.2Hz,1H),1.20 (t,J=7.2Hz,3H),1.03–0.93(m,2H),0.70–0.62(m,2H).LC-MS(ESI)m / z:529.9[M+1]+.

[0204] Example 4

[0205] This example provides a method for preparing 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W4). The structural formula and steps are as follows:

[0206]

[0207] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W4) Referring to Example 1. 1 H NMR (400MHz, CDCl3-d1) δ11.83(s,1H),7.59(d,J=8.3Hz,1H),7.41(s,1H),7.35(t,J=8.3Hz,1H),7.01(d,J=8.1Hz,1H),6.89–6.74(m,3H),5 .76(s,1H),5.26(s,1H),3.15(s,3H),2.77(s,3H),1.98–1.86(m,1H),1.15–0.86(m,2H),0.66(q,J=4.9Hz,2H).LC-MS(ESI)m / z:536.1[M+1] + .

[0208] Example 5

[0209] This example provides a method for preparing 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-ethynyl-2-fluorophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W5). The structural formula and steps are as follows:

[0210]

[0211] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-ethynyl-2-fluorophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W5) Referring to Example 1. 1H NMR (400MHz, CDCl3-d1, CD3OD-d4) δ7.63(dd,J=8.4,1.3Hz,1H),7.39(s,1H),7.36–7.28(m,1H),7.24(d,J=8.8Hz,1H),7.02( dd,J=8.1,1.2Hz,1H),6.79(t,J=8.3Hz,1H),5.32(s,1H),3.23(s,3H),3.21(s,1H),2.70(s,3H).LC-MS(ESI)m / z:500.1[M+1] + .

[0212] Example 6

[0213] This example provides a method for preparing 2-((4-ethynyl-2-fluorophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W6). The structural formula and steps are as follows:

[0214]

[0215] Preparation of 2-((4-ethynyl-2-fluorophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W6) Referring to Example 1. 1 H NMR (400MHz, CDCl3-d1) δ12.07(s,1H),7.56(d,J=17.5Hz,1H),7.44(d,J=8.1Hz,1H),7.29(t,J=6.4Hz,1H),7.25(s,1H),7.24–7.19(m,1H),6.94( d,J=7.5Hz,1H),6.79(t,J=8.3Hz,1H),5.77(s,1H),5.27(s,1H),3.20(s ,3H),3.11(s,1H),2.79(s,3H),2.16(s,3H).LC-MS(ESI)m / z:520.1[M+1] + .

[0216] For Examples 7 to 44 and 59 to 62, see the following Synthesis Route 2:

[0217]

[0218] Example 7

[0219] This example provides a method for preparing 2-((4-iodo-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W8). The structural formula and steps are as follows:

[0220]

[0221] Step 1: Under ice-cooling conditions, intermediate 5 (40 g, 99.5 mmol) was dissolved in 400 mL of DMF. NaH (2.86 g, 120 mmol) was then added and stirred for 60 min. Methyl iodide (16.9 g, 120 mmol) was then slowly added dropwise. The mixture was allowed to warm to room temperature and reacted for 30 minutes. 1500 mL of water was added, filtered, and the filter cake was washed with water (500 mL x 3) and dried to obtain crude (E)-N'-(3-(2-fluoro-4-iodophenyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimide 6 (35 g). LC-MS (ESI) m / z: 416.9 [M+1] + .

[0222] Step 2: Dissolve sodium borohydride (4.80 g, 126 mmol) in a mixture of 100 mL of ethanol and tert-butanol (v:v = 1:2), add crude product 6 (35 g, 84 mmol), heat to 65°C, and stir for 1 hour. Cool to 0°C, add 175 mL of water, and then add 240 mL of 10% citric acid. Filter, wash the filter cake with water (200 mL x 3), and dry to obtain crude 1-(2-fluoro-4-iodophenyl)-3-methyl-6-(methylamino)pyrimidine-2,4(1H,3H)-dione 7 (25 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 376.1 [M+1] + .

[0223] Step 3: Dissolve crude product 7 (25 g, 66.7 mmol) and malonic acid (27.7 g, 266.8 mmol) in 200 mL of 1,4-dioxane. Add acetyl chloride (31.2 g, 400 mmol) with stirring, and heat to 80°C for 4 hours. Cool to room temperature, add 1000 mL of ice water, filter, and wash the filter cake with water (300 mL x 3) and dry to obtain crude 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 8 (24 g). The product was directly used in the next reaction without purification. LC-MS (ESI) m / z: 444.1 [M+1] + .

[0224] Step 4: Dissolve crude product 8 (24 g, 54.1 mmol) and DBU (16.5 g, 110 mmol) in 200 mL of DCM. Add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (29.4 g, 83 mmol) with stirring and react at room temperature for 4 hours. Add 1000 mL of ice water, filter, and wash the filter cake with water (300 mL x 3) and dry to obtain crude 1-(2-fluoro-4-iodophenyl)-3,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate 9 (28 g). The product was directly used in the next step without purification. LC-MS (ESI) m / z: 575.1 [M+1] + .

[0225] Step 5: Dissolve crude product 9 (1 g, 2.4 mmol), 2-methyl-3-nitrophenol (0.73 g, 4.8 mmol), potassium phosphate (1.02 g, 4.8 mmol), and palladium acetate (0.09 g, 0.042 mmol) in 10 mL of toluene and react at 110°C under nitrogen for 6 h. Add 20 mL of water to the reaction solution, extract with EtOAc (3 × 15 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to afford 1-(2-fluoro-4-iodophenyl)-3,8-dimethyl-5-(2-methyl-3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 10 (0.3 g). LC-MS (ESI) m / z: 578.9 [M+1] + .

[0226] Step 6: Dissolve the crude product 10 (0.3 g, 0.5 mmol) in 5 mL of water and THF (V:V = 1:4), add lithium hydroxide (0.036 g, 1.5 mmol), and react at 40°C for 10 min. Add 20 mL of water, filter, and wash the filter cake with water (10 mL x 3) and dry to obtain crude 2-((2-fluoro-4-iodophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide 11 (0.25 g). LC-MS (ESI) m / z: 552.9 [M+1] + .

[0227] Step 7: Iron powder (0.2 g, 2.98 mmol) and ammonium chloride (0.4 g, 7.1 mmol) were added to a mixture of 5 mL of methanol and 5 mL of water at room temperature and activated for 30 min. Intermediate 11 (0.25 g, 0.45 mmol) was then added and the temperature was raised to 70°C for 2 h. After completion of the reaction, the mixture was padded with celite and filtered. The filtrate was added with 10 mL of water and the pH was adjusted to 9-10 with saturated aqueous sodium hydroxide solution. The mixture was filtered and dried to afford crude 4-(3-amino-2-methylphenoxy)-2-((2-fluoro-4-iodophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide 12 (0.15 g). LC-MS (ESI) m / z: 522.9 [M+1] + .

[0228] Step 8: Intermediate 12 (0.15 g, 0.28 mmol) and DIPEA (0.108 g, 0.84 mmol) were dissolved in 3 mL of DCM, and methylaminosulfonyl chloride (0.108 g, 0.84 mmol) was added. The mixture was reacted at room temperature for 1 h, concentrated and mixed, and purified by column chromatography to give 2-((2-fluoro-4-iodophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide W8 (0.10 g). 1 H NMR (400MHz, CDCl3-d1) δ12.00(s,1H),7.65(d,J=4.7Hz,1H),7.47(dd,J=9.8,1.9 Hz,1H),7.45–7.41(m,1H),7.39(d,J=8.4Hz,1H),7.30(d,J=8.1Hz,1H),6.95(t,J= 7.8Hz,1H),6.72–6.57(m,1H),5.26(s,1H),4.77(d,J=5.1Hz,1H),3.21(s,3H),2.9 5(d,J=4.7Hz,3H),2.79(d,J=4.8Hz,3H),2.15(s,3H).LC-MS(ESI)m / z:616.1[M+1] + .

[0229] Step 9: Intermediate W8 (0.10 g, 0.16 mmol), cyclopropylboronic acid (0.027 g, 0.32 mol), potassium carbonate (0.044 g, 0.32 mmol), and dppfPdCl2 (0.2 g, 0.19 mmol) were added to a mixture of 3 mL of toluene and 1 mL of water at room temperature and reacted at 85°C under nitrogen for 6 h. After completion of the reaction, the reaction solution was cooled and most of the solvent was removed by rotary evaporation. 20 mL of water was added, and the solution was extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting product was then purified by column chromatography to afford the target compound, 2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide W7 (0.08 g). 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.97(s,1H),8.08(d,J=4.6Hz,1H),7.35–7.28( m,2H),7.20(dd,J=9.7,4.8Hz,1H),7.04(dd,J=5.4,3.8Hz,1H),6.94(d,J=12.5Hz,1 H),6.89–6.78(m,2H),4.88(s,1H),3.16(s,3H),2.55(t,J=4.9Hz,6H),2.09(s,3H), 1.96–1.91(m,1H),0.98–0.90(m,2H),0.71–0.59(m,2H).LC-MS(ESI)m / z:529.9[M+1] + .

[0230] Example 8

[0231] This example provides a method for preparing 2-((4-iodo-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W8). The structural formula and steps are as follows:

[0232]

[0233] The preparation of 2-((4-iodo-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W8) was performed with reference to Example 7. 1H NMR (400MHz, CDCl3-d1) δ12.00(s,1H),7.65(d,J=4.7Hz,1H),7.47(dd,J=9.8,1.9 Hz,1H),7.45–7.41(m,1H),7.39(d,J=8.4Hz,1H),7.30(d,J=8.1Hz,1H),6.95(t,J= 7.8Hz,1H),6.72–6.57(m,1H),5.26(s,1H),4.77(d,J=5.1Hz,1H),3.21(s,3H),2.9 5(d,J=4.7Hz,3H),2.79(d,J=4.8Hz,3H),2.15(s,3H).LC-MS(ESI)m / z:616.1[M+1] + .

[0234] Example 9

[0235] This example provides a method for preparing 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((2-fluoro-4-iodophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W9). The structural formula and steps are as follows:

[0236]

[0237] The preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((2-fluoro-4-iodophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W9) was performed with reference to Example 7. 1 H NMR(400MHz, CDCl3-d1)δ12.00(s,1H),7.65(d,J=4.7Hz,1H),7.47(dd,J=9.8,1.9Hz,1H) ,7.44(d,J=8.2Hz,1H),7.38(d,J=8.4Hz,1H),7.30(d,J=8.1Hz,1H),6.93(d,J=8.0Hz,1H ),6.56(t,J=8.4Hz,1H),6.46(s,1H),5.26(s,1H),4.67(t,J=5.9Hz,1H),3.25–3.15(m,5 H),2.95(d,J=4.7Hz,3H),2.14(s,3H),1.21(t,J=7.2Hz,3H).LC-MS(ESI)m / z:630.1[M+1] + .

[0238] Example 10

[0239] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W10). The structural formula and steps are as follows:

[0240]

[0241] The preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W10) was described in Reference Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.64(s,1H),7.49–7.40(m,1H),7.29(d,J=4.6Hz,1H),7.13(td,J=8.3,1.7Hz,1H),6.95–6.89(m,1H),6.75–

[0242] 6.65(m,3H),5.29(s,1H),4.79(d,J=5.0Hz,1H),3.10(s,3H),2.88(d,J=4.7Hz,3H),2.72(d,J=5.1Hz,3H),1.7 9(td,J=8.4,4.2Hz,1H),0.91(td,J=6.5,4.7Hz,2H),0.58(dt,J=9.9,4.8Hz,2H).LC-MS(ESI)m / z:544.1[M+1] + .

[0243] Example 11

[0244] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W11). The structure and steps are as follows:

[0245]

[0246] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W11) Referring to Example 7. 1H NMR (400MHz, CDCl3-d1) δ11.64(s,1H),7.49–7.40(m,1H),7.29(d,J=4.6Hz,1H),7.13(td,J=8.3,1.7Hz,1H),6.95–6.89(m,1H),6.75–

[0247] 6.65(m,3H),5.29(s,1H),4.79(d,J=5.0Hz,1H),3.10(s,3H),2.88(d,J=4.7Hz,3H),2.72(d,J=5.1Hz,3H),1.7 9(td,J=8.4,4.2Hz,1H),0.91(td,J=6.5,4.7Hz,2H),0.58(dt,J=9.9,4.8Hz,2H).LC-MS(ESI)m / z:534.1[M+1] + .

[0248] Example 12

[0249] This example provides the preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W12). The structural formula and steps are as follows:

[0250]

[0251] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W12) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.62(s,1H),7.52(d,J=8.3Hz,1H),7.36(d,J=4.1Hz,1H),7.29(t ,J=8.3Hz,1H),7.08(q,J=8.2Hz,1H),6.93(d,J=8.1Hz,2H),6.75–6.64(m,3H),5.21(s,1H) ,4.75(d,J=4.7Hz,1H),3.10(s,3H),2.88(d,J=4.6Hz,3H),2.71(d,J=4.9Hz,3H),1.77(dd, J=8.4,4.9Hz,1H),0.92(q,J=5.7Hz,2H),0.58(q,J=5.2Hz,2H).LC-MS(ESI)m / z:550.1[M+1] + .

[0252] Example 13

[0253] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-methoxy-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W13). The structural formula and steps are as follows:

[0254]

[0255] The preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-methoxy-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W13) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.80(s,1H),7.53(d,J=4.6Hz,1H),7.44(dd,J=8.3,1.3Hz,1H),7.14(t,J=8.3Hz,1 H),7.05(s,1H),6.88(dd,J=8.3,1.3Hz,1H),6.81(d,J=1.7Hz,1H),6.79(d,J=1.2Hz,1H),6.78(d,J=2.0Hz,1H ),5.40(s,1H),4.68(dd,J=10.3,5.0Hz,1H),3.86(s,3H),3.17(s,3H),2.95(d,J=4.7Hz,3H),2.77(d,J=5.3Hz ,3H),1.88–1.84(m,1H),0.99(dd,J=8.4,1.8Hz,2H),0.65(dd,J=5.0,1.5Hz,2H).LC-MS(ESI)m / z:546.1[M+1] + .

[0256] Example 14

[0257] This example provides the preparation of 2-((4-bromo-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W14). The structural formula and steps are as follows:

[0258]

[0259] Preparation of 2-((4-bromo-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W14) Referring to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.94(s,1H),7.60(d,J=4.5Hz,1H),7.36(d,J=8.0Hz, 1H),7.27–7.20(m,2H),7.14(d,J=8.5Hz,1H),6.87(d,J=8.0Hz,1H),6.64(t,J= 8.6Hz,1H),6.59(s,1H),5.19(s,1H),4.83(d,J=5.2Hz,1H),3.13(s,3H),2.88( d,J=4.7Hz,3H),2.71(d,J=5.2Hz,3H),2.08(s,3H).LC-MS(ESI)m / z:568.1[M+1] + .

[0260] Example 15

[0261] This example provides the preparation of 2-((4-bromo-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W15). The structural formula and steps are as follows:

[0262]

[0263] Preparation of 2-((4-bromo-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W15) Reference Example 7. 1H NMR (400MHz, CDCl3-d1) δ11.98(s,1H),7.69(d,J=4.6Hz,1H),7.43(d,J=8.1Hz,1H),7.35– 7.28(m,1H),7.26(s,1H),7.21(d,J=8.6Hz,1H),6.92(d,J=8.0Hz,1H),6.84(s,1H),6.72( t,J=8.5Hz,1H),5.27(s,1H),5.07(t,J=5.8Hz,1H),3.20(s,3H),3.15(dd,J=13.6,6.8Hz, 2H),2.95(d,J=4.7Hz,3H),2.14(s,3H),1.18(t,J=7.2Hz,3H).LC-MS(ESI)m / z:572.1[M+1] + .

[0264] Example 16

[0265] The preparation of 2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W16) has the following structural formula and steps:

[0266]

[0267] Preparation of 2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W16) was performed with reference to Example 7. 1 H NMR(400MHz, CDCl3-d1)δ12.00(s,1H),7.65(d,J=4.6Hz,1H),7.42(t,J=9 .5Hz,2H),7.34(d,J=8.3Hz,1H),7.29(s,1H),6.98–6.88(m,2H),6.85(t,J =8.1Hz,1H),5.33(s,1H),5.12(d,J=5.1Hz,1H),3.26(s,3H),2.95(d,J=4 .6Hz,3H),2.76(d,J=5.1Hz,3H),2.16(s,3H).LC-MS(ESI)m / z:558.1[M+1] + .

[0268] Example 17

[0269] The preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W17) has the following structural formula and steps:

[0270]

[0271] Preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W17) Reference Example 7. 1 H NMR(400MHz, CDCl3-d1)δ12.02(s,1H),7.64(d,J=4.6Hz,1H),7.43(t,J=10.4Hz,2H), 7.34(d,J=8.4Hz,1H),7.29(d,J=8.2Hz,1H),6.93(d,J=8.0Hz,1H),6.84(t,J=8.1Hz, 1H),6.72(s,1H),5.33(s,1H),4.93(t,J=5.8Hz,1H),3.26(s,3H),3.21–3.10(m,2H), 2.96(d,J=4.7Hz,3H),2.15(s,3H),1.20(t,J=7.2Hz,3H).LC-MS(ESI)m / z:572.1[M+1] + .

[0272] Example 18

[0273] Preparation of 4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W18), the structural formula and steps are as follows:

[0274]

[0275] Preparation of 4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W18) Reference Example 7. 1H NMR(400MHz, CDCl3-d1)δ11.73(s,1H),7.56–7.47(m,1H),7.41(dd,J=10.6 ,1.4Hz,1H),7.34(d,J=6.6Hz,2H),7.20(td,J=8.3,1.6Hz,1H),7.04–6.93( m,1H),6.83(t,J=8.1Hz,1H),5.50(s,1H),5.08(d,J=4.5Hz,1H),3.27(s,3H ),2.96(d,J=4.8Hz,3H),2.78(d,J=4.3Hz,3H).LC-MS(ESI)m / z:562.1[M+1] + .

[0276] Example 19

[0277] The preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-fluorophenoxy)-2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W19) has the following structural formula and steps:

[0278]

[0279] Preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-fluorophenoxy)-2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W19) was performed with reference to Example 7. 1 H NMR(400MHz, CDCl3-d1)δ11.73(s,1H),7.55–7.48(m,1H),7.41(dd,J=10.6,1.6Hz ,1H),7.35(t,J=5.7Hz,2H),7.20(td,J=8.3,1.6Hz,1H),7.01–6.95(m,1H),6.83(t ,J=8.1Hz,1H),5.50(s,1H),5.03(t,J=5.7Hz,1H),3.27(s,3H),3.17(dd,J=7.1,6. 0Hz,2H),2.96(d,J=4.8Hz,3H),1.19(t,J=7.2Hz,3H).LC-MS(ESI)m / z:576.1[M+1] + .

[0280] Example 20

[0281] The preparation of 2-((4-bromo-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W20) has the following structural formula and steps:

[0282]

[0283] Preparation of 2-((4-bromo-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W20) Reference Example 7. 1 H NMR(400MHz, CDCl3-d1)δ11.77(s,1H),7.57–7.48(m,1H),7.37(d,J=4.6Hz, 1H),7.31(dd,J=10.0,2.1Hz,1H),7.25–7.18(m,2H),7.03–6.96(m,1H),6.84 (s,1H),6.70(t,J=8.6Hz,1H),5.42(s,1H),4.76(q,J=5.2Hz,1H),3.21(s,3 H),2.96(d,J=4.8Hz,3H),2.80(d,J=5.3Hz,3H).LC-MS(ESI)m / z:572.1[M+1] + .

[0284] Example 21

[0285] The preparation of 4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W21) has the following structural formula and steps:

[0286]

[0287] Preparation of 4-(2-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W21) Reference Example 7. 1H NMR(400MHz, CDCl3-d1)δ11.73(s,1H),7.55–7.47(m,1H),7.38(d,J=4.7Hz,1H),7.19(td,J=8.3,1.7Hz,1H),7.16–7.05(m,3H),7.02–6.97(m,1 H),6.90–6.79(m,1H),5.41(s,1H),5.00(q,J=5.1Hz,1H),3.20(s,3H),2.96(d,J=4.8Hz,3H),2.78(d,J=5.2Hz,3H).LC-MS(ESI)m / z:494.1[M+1] + .

[0288] Example 22

[0289] The preparation of 2-((2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W22) has the following structural formula and steps:

[0290]

[0291] The preparation of 2-((2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W22) was performed with reference to Example 7. 1 H NMR(400MHz, CDCl3-d1)δ11.98(s,1H),7.67(q,J=4.3Hz,1H),7.43(d,J=8.1Hz,1H),7.27(s,1H),7.16–7.05(m,3H),6.94(d,J=7.9Hz,1H),6.89–

[0292] 6.82(m,1H),6.75(s,1H),5.25(s,1H),5.01(d,J=4.9Hz,1H),3.19(s,3H),2.95( d,J=4.7Hz,3H),2.76(d,J=5.0Hz,3H),2.16(s,3H).LC-MS(ESI)m / z:490.1[M+1] + .

[0293] Example 23

[0294] The preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W23) has the following structural formula and steps:

[0295]

[0296] The preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W23) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.97(s,1H),7.68(d,J=4.7Hz,1H),7.43(d,J=7.7Hz,1H),7.28(s,1H),7.17–7.04(m,3H),6.93(d,J=7.7Hz,1H),6.90–

[0297] 6.86(m,2H),5.24(s,1H),5.08(t,J=5.9Hz,1H),3.19(s,3H),3.14(dt,J=13.2,6.6Hz,2H ),2.95(d,J=4.7Hz,3H),2.15(s,3H),1.19(t,J=7.2Hz,3H).LC-MS(ESI)m / z:504.1[M+1] + .

[0298] Example 24

[0299] This example provides the preparation of 2-((2-fluoro-4-methylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W24). The structural formula and steps are as follows:

[0300]

[0301] Preparation of 2-((2-fluoro-4-methylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W24) Reference Example 9. 1H NMR (400MHz, CDCl3-d1) δ12.00(s,1H),7.65(d,J=4.5Hz,1H),7.44(d,J=7.6Hz,1H ),7.30(t,J=8.2Hz,1H),6.99–6.91(m,2H),6.87(d,J=8.2Hz,1H),6.76(t,J=8.3H z,1H),6.32(s,1H),5.20(s,1H),4.62–4.58(m,1H),3.17(s,3H),2.95(d,J=4.7Hz ,3H),2.81(d,J=5.3Hz,3H),2.32(s,3H),2.16(s,3H).LC-MS(ESI)m / z:504.1[M+1] + .

[0302] Example 25

[0303] This example provides the preparation of 2-((4-ethyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W25). The structural formula and steps are as follows:

[0304]

[0305] Preparation of 2-((4-ethyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W25) Reference Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.93(s,1H),7.70(d,J=4.7Hz,1H),7.43(d,J=8.2Hz,1H),7.25(d,J=8.1Hz,1H),6.98–6.8 8(m,3H),6.79(t,J=8.3Hz,1H),5.22(s,1H),4.59(d,J=4.7Hz,1H),3.17(s,3H),2.94(d,J=4.7Hz,3H),2.75(d,J=4.8

[0306] Hz,3H),2.62(q,J=7.6Hz,2H),2.16(s,3H),1.22(t,J=7.6Hz,3H).LC-MS(ESI)m / z:518.1[M+1] + .

[0307] Example 26

[0308] This example provides the preparation of 2-((4-ethynyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W26). The structural formula and steps are as follows:

[0309]

[0310] Preparation of 2-((4-ethynyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W26) Reference Example 7. 1 H NMR (400MHz, CDCl3-d1) δ12.04(s,1H),7.64(d,J=4.6Hz,1H),7.44(d,J=7.9Hz,1H),7.30 (d,J=8.1Hz,1H),7.25(d,J=1.6Hz,1H),7.20(d,J=8.3Hz,1H),6.94(d,J=7.9Hz,1H),6.73 (t,J=8.3Hz,1H),6.50(s,1H),5.28(s,1H),4.74(d,J=5.2Hz,1H),3.22(s,3H),3.10(s,1 H),2.95(d,J=4.7Hz,3H),2.79(d,J=5.1Hz,3H),2.15(s,3H).LC-MS(ESI)m / z:514.1[M+1] + .

[0311] Example 27

[0312] This example provides the preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((4-ethynyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W27). The structural formula and steps are as follows:

[0313]

[0314] Preparation of 4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-2-((4-ethynyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W27) Reference Example 7. 1H NMR (400MHz, CDCl3-d1) δ12.01(s,1H),7.65(q,J=4.4Hz,1H),7.43(d,J=7.8Hz,1H),7.29(d,J= 8.4Hz,1H),7.26–7.23(m,1H),7.20(d,J=8.3Hz,1H),6.93(d,J=7.7Hz,1H),6.73(t,J=8.3Hz,1H ),6.67(s,1H),5.28(s,1H),4.89(t,J=5.9Hz,1H),3.22(s,3H),3.16(dd,J=7.2,6.0Hz,2H),3.1 0(s,1H),2.95(d,J=4.8Hz,3H),2.14(s,3H),1.19(t,J=7.2Hz,3H).LC-MS(ESI)m / z:528.1[M+1] + .

[0315] Example 28

[0316] This example provides the preparation of 2-((4-chloro-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W28). The structural formula and steps are as follows:

[0317]

[0318] Preparation of 2-((4-chloro-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W28) Reference Example 7. 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.96 (s, 1H), 8.06 (d, J = 4.6Hz, 1H), 7.43 (dd, J = 10.9, 2.1Hz,1H),7.35–7.28(m,2H),7.18(dd,J=12.5,7.3Hz,2H),7.01(dd,J=5.9,3.2Hz,1H),6 .94(t,J=8.9Hz,1H),6.68(d,J=4.5Hz,1H),5.76(s,1H),4.95(s,1H),3.22(d,J=16.8Hz,3 H),2.56(d,J=4.9Hz,3H),2.44(d,J=5.1Hz,3H),2.09(s,3H).LC-MS(ESI)m / z:524.1[M+1] + .

[0319] Example 29

[0320] This example provides the preparation of 2-((4-chloro-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W29). The structural formula and steps are as follows:

[0321]

[0322] The preparation of 2-((4-chloro-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-methylphenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W29) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ12.02(s,1H),7.68(d,J=4.6Hz,1H),7.43(d,J=8.1Hz,1H),7. 27(s,1H),7.17(dd,J=10.2,2.2Hz,1H),7.07(d,J=8.6Hz,1H),6.93(d,J=8.0Hz,1H),6. 78(t,J=8.6Hz,1H),6.70(s,1H),5.26(s,1H),4.92(t,J=5.8Hz,1H),3.25–3.10(m,5H) ,2.95(d,J=4.7Hz,3H),2.14(s,3H),1.19(t,J=7.2Hz,3H).LC-MS(ESI)m / z:538.1[M+1] + .

[0323] Example 30

[0324] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(4-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W30). The structural formula and steps are as follows:

[0325]

[0326] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(4-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W30) Reference Example 7. 1H NMR (400MHz, CDCl3-d1) δ11.73(s,1H),7.57(q,J=4.2Hz,1H),7.32(d,J=2.4Hz,1 H),7.23(d,J=8.4Hz,1H),6.84–6.76(m,3H),6.72(t,J=8.3Hz,1H),5.36(s,1H), 3.14(s,3H),2.90(d,J=4.7Hz,3H),2.70(s,3H),2.31(s,3H),1.91–1.80(m,1H), 0.97(ddd,J=7.8,6.4,3.2Hz,2H),0.70–0.58(m,2H).LC-MS(ESI)m / z:530.1[M+1] + .

[0327] Example 31

[0328] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(4-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W31). The structural formula and steps are as follows:

[0329]

[0330] The preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(4-fluoro-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W31) was carried out in accordance with Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.73(s,1H),7.57(q,J=4.2Hz,1H),7.32(d,J=2.4Hz,1 H),7.23(d,J=8.4Hz,1H),6.84–6.76(m,3H),6.72(t,J=8.3Hz,1H),5.36(s,1H), 3.14(s,3H),2.90(d,J=4.7Hz,3H),2.70(s,3H),2.31(s,3H),1.91–1.80(m,1H), 0.97(ddd,J=7.8,6.4,3.2Hz,2H),0.70–0.58(m,2H).LC-MS(ESI)m / z:534.1[M+1] + .

[0331] Example 32

[0332] This example provides the preparation of 4-(4-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W32). The structural formula and steps are as follows:

[0333]

[0334] The preparation of 4-(4-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W32) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.68 (s, 1H), 7.46 (dd, J=5.7, 3.0Hz, 2H), 7.36 (d, J= 4.6Hz,1H),6.85(dd,J=8.7,2.7Hz,1H),6.82–6.73(m,3H),5.36(s,1H),5.06( s,1H),3.16(s,3H),2.91(d,J=4.7Hz,3H),2.75(s,3H),1.85(ddd,J=13.4,8.5 ,5.1Hz,1H),1.03–0.94(m,2H),0.70–0.62(m,2H).LC-MS(ESI)m / z:550.1[M+1] + .

[0335] Example 33

[0336] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(4-methoxy-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W33). The structural formula and steps are as follows:

[0337]

[0338] The preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(4-methoxy-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W33) was performed with reference to Example 7. 1H NMR (400MHz, CDCl3-d1) δ11.68 (s, 1H), 7.46 (dd, J=5.7, 3.0Hz, 2H), 7.36 (d, J= 4.6Hz,1H),6.85(dd,J=8.7,2.7Hz,1H),6.82–6.73(m,3H),5.36(s,1H),5.06( s,1H),3.16(s,3H),2.91(d,J=4.7Hz,3H),2.75(s,3H),1.85(ddd,J=13.4,8.5 ,5.1Hz,1H),1.03–0.94(m,2H),0.70–0.62(m,2H).LC-MS(ESI)m / z:546.1[M+1] + .

[0339] Example 34

[0340] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2,4-dimethyl-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W34). The structural formula and steps are as follows:

[0341]

[0342] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2,4-dimethyl-3-((N-methylaminosulfonyl)amino)phenoxy)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W34) Reference Example 9. 1 H NMR (400MHz, CDCl3-d1) δ11.98(s,1H),7.71(d,J=4.6Hz,1H),7.17(d,J=8.3Hz,1H),6 .97(d,J=8.3Hz,1H),6.84–6.67(m,3H),6.26(s,1H),5.19(s,1H),4.75(d,J=4.8Hz,1H ),3.15(s,3H),2.94(d,J=4.7Hz,3H),2.86(d,J=4.4Hz,3H),2.46(s,3H),2.26(s,3H) ,1.93–1.79(m,1H),1.05–0.92(m,2H),0.72–0.58(m,2H).LC-MS(ESI)m / z:544.1[M+1] + .

[0343] Example 35

[0344] This example provides the preparation of 2-((2-fluoro-4-propylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W35), whose structural formula and steps are as follows:

[0345]

[0346] Preparation of 2-((2-fluoro-4-propylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W35) Reference Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.96(s,1H),7.67(d,J=4.7Hz,1H),7.43(d,J=8.0Hz,1H),7.27( t,J=8.1Hz,1H),6.97–6.91(m,2H),6.88(d,J=8.2Hz,1H),6.78(t,J=8.2Hz,1H),5.21(s,1 H),4.93(s,1H),3.17(s,3H),2.95(d,J=4.7Hz,3H),2.77(s,3H),2.55(t,J=7.6Hz,2H),2. 15(s,3H),1.61(dt,J=14.7,7.4Hz,2H),0.92(t,J=7.3Hz,3H).LC-MS(ESI)m / z:532.1[M+1] + .

[0347] Example 36

[0348] This example provides the preparation of 2-((2-fluoro-4-(prop-1-en-2-yl)phenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W36). The structural formula and steps are as follows:

[0349]

[0350] Preparation of 2-((2-fluoro-4-(prop-1-en-2-yl)phenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W36) Reference Example 7. 1HNMR (400MHz, CDCl3-d1) δ12.02(s,1H),7.65(dd,J=9.0,4.3Hz,1H),7.44(d,J=7.5Hz,1H),7.30( d,J=8.1Hz,1H),7.23(dd,J=12.3,2.0Hz,1H),7.18(dd,J=8.3,1.9Hz,1H),6.95(d,J=7.6Hz,1H),6 .79(t,J=8.4Hz,1H),5.36(s,1H),5.24(s,1H),5.11(d,J=1.2Hz,1H),4.82(s,1H),3.21(s,3H),2 .95(d,J=4.7Hz,3H),2.79(s,3H),2.16(s,3H),2.11(d,J=0.4Hz,3H).LC-MS(ESI)m / z:530.1[M+1] + .

[0351] Example 37

[0352] This example provides the preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-ethynyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W37). The structural formula and steps are as follows:

[0353]

[0354] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-ethynyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W37) Reference Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.75(s,1H),7.60(dd,J=8.4,1.3Hz,1H),7.47–7.39(m,2H),7.39–7.32(m,2H),7.01(dd,J=8.2,1.3Hz,1H),6.78(t,J=8 .4Hz,1H),5.75(d,J=2.0Hz,1H),5.54(d,J=2.0Hz,1H),5.35(s,1H),3.2 4(s,3H),2.96(d,J=4.8Hz,3H),2.78(s,3H).LC-MS(ESI)m / z:534.1[M+1] + .

[0355] Example 38

[0356] This example provides the preparation of 2-((4-butyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W38). The structural formula and steps are as follows:

[0357]

[0358] The preparation of 2-((4-butyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W38) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.97(s,1H),7.65(d,J=4.4Hz,1H),7.44(d,J=8.0Hz,1H),7.30(d,J=8.1Hz,1H) ,6.99–6.91(m,2H),6.88(d,J=8.1Hz,1H),6.78(t,J=8.2Hz,1H),6.51(s,1H),5.21(s,1H),4.76(dd,J=10 .2,5.0Hz,1H),4.22(s,2H),3.17(s,3H),2.95(d,J=4.7Hz,3H),2.79(d,J=5.2Hz,3H),2.57(t,J=7.7Hz,2 H),2.16(s,3H),1.62–1.56(m,2H),1.42–1.33(m,2H),0.92(t,J=7.3Hz,3H).LC-MS(ESI)m / z:546.1[M+1] + .

[0359] Example 39

[0360] This example provides the preparation of 2-((2-fluoro-4-vinylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W39). The structural formula and steps are as follows:

[0361]

[0362] The preparation of 2-((2-fluoro-4-vinylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W39) was performed with reference to Example 7. 1H NMR (400MHz, CDCl3-d1) δ12.03(s,1H),7.65(d,J=4.6Hz,1H),7.44(d,J=8.1Hz,1H),7.34–7 .24(m,1H),7.19(dd,J=11.8,1.3Hz,1H),7.09(d,J=8.2Hz,1H),6.95(d,J=8.1Hz,1H),6.79 (t,J=8.3Hz,1H),6.72–6.63(m,1H),5.69(d,J=17.5Hz,1H),5.32–5.21(m,2H),4.77(s,1H) ,3.21(s,3H),2.95(d,J=4.7Hz,3H),2.79(s,3H),2.16(s,3H).LC-MS(ESI)m / z:516.1[M+1] + .

[0363] Example 40

[0364] This example provides the preparation of 2-((2-fluoro-4-isopropylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W40). The structural formula and steps are as follows:

[0365]

[0366] Preparation of 2-((2-fluoro-4-isopropylphenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W40) Reference Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.96(s,1H),7.63(d,J=4.6Hz,1H),7.44(d,J=7.7Hz,1H),7.29(t,J=8.1Hz,1H),7.03–6.88(m,3H),6.79(t,J=8.3Hz,1H ),5.21(s,1H),3.18(s,3H),2.95(d,J=4.7Hz,3H),2.92–2.88(m,1H),2.8 0(s,3H),2.16(s,3H),1.23(d,J=6.9Hz,6H).LC-MS(ESI)m / z:532.1[M+1] + .

[0367] Example 41

[0368] This example provides the preparation of 2-((4-(cyclopenten-1-yl)-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W41). The structural formula and steps are as follows:

[0369]

[0370] Preparation of 2-((4-(cyclopenten-1-yl)-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W41) Reference Example 7. 1 HNMR(400MHz, CDCl3-d1)δ12.04(s,1H),7.65(d,J=4.6Hz,1H),7.44(d,J=8.0Hz,1H),7.3 0(d,J=8.1Hz,1H),7.23–7.07(m,2H),6.95(d,J=7.9Hz,1H),6.79(t,J=8.4Hz,1H),6.16(s ,1H),5.23(s,1H),4.74(s,1H),3.19(s,3H),2.95(d,J=4.7Hz,3H),2.79(s,3H),2.71–2. 60(m,2H),2.59–2.48(m,2H),2.16(s,3H),2.08–1.97(m,2H).LC-MS(ESI)m / z:556.1[M+1] + .

[0371] Example 42

[0372] This example provides the preparation of 2-((4-cyclopentyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W42). The structural formula and steps are as follows:

[0373]

[0374] Preparation of 2-((4-cyclopentyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W42) was performed with reference to Example 7. 1H NMR (400MHz, CDCl3-d1) δ11.95(s,1H),7.65(d,J=4.7Hz,1H),7.43(d,J=8.0Hz,1H),7.28( d,J=8.1Hz,1H),6.99(dd,J=12.0,1.6Hz,1H),6.96–6.90(m,2H),6.77(t,J=8.3Hz,1H),5.2 1(s,1H),4.86(s,1H),3.18(s,3H),2.94(d,J=4.7Hz,4H),2.78(s,3H),2.15(s,3H),2.11–2 .01(m,2H),1.79(m,2H),1.71–1.64(m,2H),1.58–1.48(m,2H).LC-MS(ESI)m / z:558.1[M+1] + .

[0375] Example 43

[0376] This example provides the preparation of 2-((3-fluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W43). The structural formula and steps are as follows:

[0377]

[0378] Preparation of 2-((3-fluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W43) Reference Example 7. 1H NMR (400MHz, CDCl3-d1) δ12.01(s,1H),7.65(d,J=4.6Hz,1H),7.43(d,J=8.1Hz,1H),7.29(d,J =8.1Hz,1H),7.14(m,1H),7.09(d,J=8.4Hz,1H),6.94(d,J=8.1Hz,1H),6.78(t,J=8.4Hz,1H),6 .13(s,1H),5.22(s,1H),3.19(s,3H),2.95(d,J=4.7Hz,3H),2.78(s,3H),2.34(s,2H),2.21(d ,J=3.3Hz,2H),2.16(s,3H),1.84–1.75(m,2H),1.72–1.65(m,2H).LC-MS(ESI)m / z:570.1[M+1] + .

[0379] Example 44

[0380] This example provides the preparation of 2-((4-cyclohexyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W44). The structural formula and steps are as follows:

[0381]

[0382] Preparation of 2-((4-cyclohexyl-2-fluorophenyl)amino)-N,1-dimethyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W44) was performed with reference to Example 7. 1 H NMR (400MHz, CDCl3-d1) δ11.93(s,1H),7.65(q,J=4.2Hz,1H),7.43(d,J=7.7Hz,1H) ,7.29(d,J=8.1Hz,1H),7.02–6.86(m,3H),6.78(t,J=8.3Hz,1H),5.21(s,1H),4.99– 4.95(m,1H),3.17(s,3H),2.94(d,J=4.7Hz,3H),2.78(s,3H),2.47(m,1H),2.15(s, 3H),1.92–1.81(m,4H),1.76(s,2H),1.42–1.36(m,4H).LC-MS(ESI)m / z:572.1[M+1] + .

[0383] For Examples 45 and 46, see the following Synthesis Route 3:

[0384]

[0385] Example 45

[0386] This example provides a method for preparing 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)benzyl)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W45). The structural formula and steps are as follows:

[0387]

[0388] Step 1: At room temperature, intermediate 9 (0.1 g, 0.20 mmol), 2-(2-fluoro-3-nitrobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.11 g, 0.40 mol), potassium carbonate (0.056 g, 0.40 mmol) and dppfPdCl2 (0.036 g, 0.05 mmol) were added to a mixed solvent of 3 mL of toluene and 1 mL of water, and the reaction was carried out at 85 ° C under nitrogen protection for 6 h. After the reaction was completed, the reaction solution was cooled and most of the solvent was removed by rotary evaporation. 20 mL of water was added, and the mixture was extracted with EtOAc. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by column chromatography to obtain 1-(4-cyclopropyl-2-fluorophenyl)-5-(2-fluoro-3-nitrobenzyl)-3,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 10 (0.06 g). LC-MS (ESI) m / z: 495.1 [M+1]. + .

[0389] Step 2: Dissolve the crude product 10 (0.06 g, 0.12 mmol) in 5 mL of water and THF (V:V = 1:4), add lithium hydroxide (0.02 g, 0.87 mmol), and react at 40°C for 10 min. Add 20 mL of water, filter, and wash the filter cake with water (10 mL x 3) and dry to obtain crude 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-nitrobenzyl)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide 11 (0.05 g). LC-MS (ESI) m / z: 468.9 [M+1] + .

[0390] Step 3: Iron powder (0.2 g, 2.98 mmol) and ammonium chloride (0.4 g, 7.1 mmol) were added to a mixture of 5 mL of methanol and 5 mL of water at room temperature and activated for 30 min. Intermediate 12 (0.05 g, 0.09 mmol) was then added and the temperature was raised to 70°C for 2 h. After the reaction, celite was applied to the filtrate, 10 mL of water was added, and the pH was adjusted to 9-10 with saturated sodium hydroxide solution. The mixture was filtered and dried to obtain crude 4-(3-amino-2-fluorobenzyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide 12 (0.04 g). LC-MS (ESI) m / z: 439.1 [M+1]. + .

[0391] Step 4: Intermediate 12 (0.04 g, 0.09 mmol) and DIPEA (0.034 g, 0.27 mmol) were dissolved in 3 mL of DCM, and methylaminosulfonyl chloride (0.017 g, 0.14 mmol) was added. The mixture was reacted at room temperature for 1 h, concentrated and mixed, and purified by column chromatography to give 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(2-fluoro-3-((N-methylaminosulfonyl)amino)benzyl)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide W45 (0.02 g). 1 H NMR (400MHz, DMSO-d6) δ9.35(s,1H),7.94(d,J=4.6Hz,1H),7.77(s,1H),7.35(t,J=7.6Hz,1H),7. 21(q,J=4.7Hz,1H),7.09(t,J=7.8Hz,1H),6.95(t,J=6.9Hz,1H),6.86(d,J=12.8Hz,1H),6.79(d,J =8.3Hz,1H),6.64(t,J=8.6Hz,1H),5.73(s,1H),3.81(s,2H),3.30(s,3H),2.53(s,3H),2.38(d,J =4.5Hz,3H),1.93–1.80(m,1H),0.98–0.83(m,2H),0.72–0.51(m,2H).LC-MS(ESI)m / z:532.1[M+1] + .

[0392] Example 46

[0393] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-fluorobenzyl)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W46). The structural formula and steps are as follows:

[0394]

[0395] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-(3-((N-ethylaminosulfonyl)amino)-2-fluorobenzyl)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W46) Reference Example 45. 1 H NMR(400MHz, DMSO-d6)δ9.33(s,1H),7.94(d,J=4.5Hz,1H),7.77(s,1H),7.40–7.29(m,2H),7.09( t,J=7.9Hz,1H),6.93(t,J=6.9Hz,1H),6.90–6.86(m,1H),6.79(d,J=8.3Hz,1H),6.64(t,J=8.6Hz ,1H),5.72(s,1H),3.80(s,2H),3.30(s,3H),2.99–2.87(m,2H),2.38(d,J=4.6Hz,3H),1.89–1.87 (m,1H),1.01(t,J=7.2Hz,3H),0.95–0.86(m,2H),0.67–0.58(m,2H).LC-MS(ESI)m / z:546.1[M+1] + .

[0396] For Examples 47 and 48, see the following Synthesis Route 4:

[0397]

[0398] Example 47

[0399] This example provides a method for preparing 2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-4-((3-((N-methylaminosulfonyl)amino)phenyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide (W47). The structural formula and steps are as follows:

[0400]

[0401] Step 1: At room temperature, intermediate 9 (0.1 g, 0.20 mmol), 3-nitroaniline (0.06 g, 0.40 mol), cesium carbonate (0.13 g, 0.40 mmol), Pd2(bda)3 (0.045 g, 0.05 mmol) and Xantphos (0.025 g, 0.05 mmol) were added to 3 mL of 1,4-dioxane and reacted at 85 °C under nitrogen protection for 6 h. After the reaction was completed, the reaction solution was cooled and most of the solvent was removed by rotary evaporation. 20 mL of water was added, and the mixture was extracted with EtOAc. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by column chromatography to obtain 1-(4-cyclopropyl-2-fluorophenyl)-3,8-dimethyl-5-((3-nitrophenyl)amino)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 10 (0.08 g). LC-MS (ESI) m / z: 478.1 [M+1]. + .

[0402] Step 2: Dissolve crude product 10 (0.08 g, 0.16 mmol) in 5 mL of water and THF (V:V = 1:4), add lithium hydroxide (0.01 g, 0.48 mmol), and react at 40°C for 10 min. Add 20 mL of water, filter, and wash the filter cake with water (10 mL x 3) and oven dry to obtain crude 2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-4-((3-nitrophenyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide 11 (0.06 g). LC-MS (ESI) m / z: 452.1 [M+1]+.

[0403] Step 3: Iron powder (0.2 g, 2.98 mmol) and ammonium chloride (0.4 g, 7.1 mmol) were added to a mixture of 5 mL of methanol and 5 mL of water at room temperature and activated for 30 min. Intermediate 12 (0.06 g, 0.13 mmol) was then added and the temperature was raised to 70°C for 2 h. After the reaction, celite was applied to the filtrate, 10 mL of water was added, and the pH was adjusted to 9-10 with saturated sodium hydroxide solution. The mixture was filtered and dried to obtain crude 4-((3-aminophenyl)amino)-2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide 12 (0.05 g). LC-MS (ESI) m / z: 422.1 [M+1] + .

[0404] Step 4: Intermediate 12 (0.05 g, 0.12 mmol) and DIPEA (0.04 g, 0.36 mmol) were dissolved in 3 mL of DCM, and methylaminosulfonyl chloride (0.02 g, 0.18 mmol) was added. The mixture was reacted at room temperature for 1 h, concentrated and mixed, and purified by column chromatography to give 2-((4-cyclopropyl-2-fluorophenyl)amino)-N,1-dimethyl-4-((3-((N-methylaminosulfonyl)amino)phenyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide W47 (0.03 g). 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.15 (d, J = 8.0Hz, 1H), 7.07 (s, 1H), 6.94 (s, 1H), 6. 80(d,J=7.7Hz,1H),6.77–6.70(m,3H),6.69–6.59(m,2H),5.90(s,1H),5.48(s,1H),5.2 8(dd,J=7.4,5.0Hz,1H),3.29(s,3H),2.62(d,J=3.4Hz,3H),2.53(d,J=4.6Hz,3H),1.80 –1.74(m,1H),0.89(d,J=9.6Hz,2H),0.56(d,J=6.2Hz,2H).LC-MS(ESI)m / z:515.1[M+1] + .

[0405] Example 48

[0406] This example provides the preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-((2-fluoro-3-((N-methylaminosulfonyl)amino)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W48). The structural formula and steps are as follows:

[0407]

[0408] Preparation of 2-((4-cyclopropyl-2-fluorophenyl)amino)-4-((2-fluoro-3-((N-methylaminosulfonyl)amino)phenyl)amino)-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W48) Reference Example 47. 1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.24(s,1H),7.94(d,J=4.7Hz,1H),7.83(s,1H),7 .22–7.16(m,1H),7.16–7.11(m,1H),7.08(dd,J=7.7,3.9Hz,2H),6.90–6.82(m,1H),6. 78–6.68(m,2H),5.35(s,1H),2.47(d,J=5.0Hz,3H),2.27(d,J=4.6Hz,3H),1.93(s,3H) ,1.86–1.75(m,1H),0.92–0.82(m,2H),0.61–0.48(m,2H).LC-MS(ESI)m / z:533.1[M+1] + .

[0409] Example 49

[0410] This example provides the preparation of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W49). The structural formula and steps are as follows:

[0411]

[0412] Preparation of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W49) Reference Example 1. 1 H NMR (400MHz, DMSO) δ7.77–7.58(m,3H),7.48(dd,J=8.4,1.1Hz,1H),7.40–7.32(m,2H),7.10(dd,J=6 .5,2.7Hz,1H),6.72(t,J=8.7Hz,1H),5.06(d,J=22.1Hz,1H),3.20(s,3H),2.61(s,3H),2.16(s,3H).

[0413] LC-MS (ESI) m / z: 602.1 [M+1] + .

[0414] Example 50

[0415] This example provides the preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W50). The structural formula and steps are as follows:

[0416]

[0417] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W50) Reference Example 1. 1 H NMR (400MHz, DMSO) δ9.94(s,1H),9.23(s,1H),7.73–7.62(m,2H),7.56(s,1H),7.51(dd,J=8.1,0.9Hz,1H),7.46(t,J=8.2Hz,4H),7. 36(s,1H),7.27(d,J=7.8Hz,1H),6.69(t,J=8.7Hz,1H),5.03(s,1H),3.16(s,3H),2.55(d,J=3.9Hz,3H).LC-MS(ESI)m / z:622.1[M+1] + .

[0418] Example 51

[0419] This example provides the preparation of 2-((4-bromo-2-fluorophenyl)amino)-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W51). The structural formula and steps are as follows:

[0420]

[0421] Preparation of 2-((4-bromo-2-fluorophenyl)amino)-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W51) Referring to Example 1. 1H NMR (400MHz, DMSO) δ9.87(s,1H),9.22(s,1H),7.61(s,1H),7.52(dd,J=10.5,2.1Hz,2H),7.45(dd,J=8.2,1.5Hz,1H),7.40(t,J=8.1Hz,1H), 7.34(q,J=4.9Hz,1H),7.28–7.16(m,2H),6.79(t,J=8.9Hz,1H),4.96(s,1H),3.10(s,3H),2.49(d,J=4.9Hz,3H).LC-MS(ESI)m / z:574.1[M+1] + .

[0422] Example 52

[0423] This example provides the preparation of 2-((4-bromo-2-fluorophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W52). The structural formula and steps are as follows:

[0424]

[0425] Preparation of 2-((4-bromo-2-fluorophenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W52) Referring to Example 1. 1 H NMR (400MHz, DMSO) δ9.80(s,1H),8.91(s,1H),7.63–7.41(m,3H),7.22(dd,J=13.1,1.5Hz,2H),7.13(q,J=4.9Hz,1H),7.05–6 .94(m,1H),6.76(t,J=8.9Hz,1H),4.90(s,1H),3.08(s,3H),2.49(d,J=5.0Hz,3H),2.04(s,3H).LC-MS(ESI)m / z:554.1[M+1] + .

[0426] Example 53

[0427] This example provides the preparation of 2-((2-fluoro-4-isopropylphenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W53). The structural formula and steps are as follows:

[0428]

[0429] Preparation of 2-((2-fluoro-4-isopropylphenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W53) Referring to Example 1. 1 H NMR (400MHz, MeOD) δ7.46(d,J=7.9Hz,1H),7.29(t,J=8.1Hz,1H),6.98(ddd,J=12.1,10.6,2.9Hz,1H),6.84(t,J=8.3Hz,1H),5. 19(s,1H),3.16(s,3H),2.90(hept,J=6.9Hz,1H),2.74(s,3H),2.18(s,3H),1.24(d,J=6.9Hz,6H).LC-MS(ESI)m / z:518.1[M+1] + .

[0430] Example 54

[0431] This example provides the preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-isopropylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W54). The structural formula and steps are as follows:

[0432]

[0433] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-isopropylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W54) Reference Example 1. 1 H NMR (400MHz, DMSO) δ10.58(s,1H),9.29(s,1H),7.78(s,1H),7.60(s,1H),7. 55–7.44(m,2H),7.39(s,1H),7.31(d,J=7.6Hz,1H),7.19(d,J=12.4Hz,1H),7 .03(d,J=7.7Hz,1H),6.84(t,J=8.1Hz,1H),4.97(s,1H),3.09(s,3H),2.98– 2.84(m,1H),2.56(s,3H),1.20(d,J=6.6Hz,6H).LC-MS(ESI)m / z:538.1[M+1] + .

[0434] Example 55

[0435] This example provides the preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-vinylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W55). The structural formula and steps are as follows:

[0436]

[0437] Preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-vinylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W55) Reference Example 1. 1 H NMR (400MHz, CDCl3) δ11.88(s,1H),7.61(d,J=8.4Hz,1H),7.38(dd,J=15.6,7.3H z,2H),7.20(dd,J=11.7,1.5Hz,1H),7.11(d,J=8.3Hz,1H),7.02(dd,J=8.1,1.0H z,1H),6.84(t,J=8.3Hz,1H),6.64(dd,J=17.5,10.9Hz,1H),5.73(s,1H),5.29(t ,J=5.4Hz,2H),3.16(d,J=26.4Hz,3H),2.78(s,3H).LC-MS(ESI)m / z:522.1[M+1] + .

[0438] Example 56

[0439] This example provides the preparation of 4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-vinylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W56). The structural formula and steps are as follows:

[0440]

[0441] Preparation of 4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((2-fluoro-4-vinylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (W56) Reference Example 1. 1H NMR(400MHz,MeOD)δ7.46(d,J=1.8Hz,1H),7.31(t,J=8.1Hz,1H),7.23(dd,J=11.8 ,1.7Hz,1H),7.15(dd,J=8.3,1.3Hz,1H),6.98(d,J=8.0Hz,1H),6.85(t,J=8.3Hz, 1H),6.66(dd,J=17.5,10.9Hz,1H),5.73(d,J=17.5Hz,1H),5.30(d,J=10.9Hz,1H) ,5.23(s,1H),3.21(s,3H),2.73(s,3H),2.21(s,3H).LC-MS(ESI)m / z:502.1[M+1] + .

[0442] Example 57

[0443] This example provides the preparation of 2-((2-fluoro-4-(prop-1-en-2-yl)phenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W57). The structural formula and steps are as follows:

[0444]

[0445] Preparation of 2-((2-fluoro-4-(prop-1-en-2-yl)phenyl)amino)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W57) Reference Example 1. 1 H NMR (400MHz, DMSO) δ10.25(s,1H),8.98(s,1H),7.67(d,J=7.9Hz,2H),7.43(dd,J=13.0, 1.9Hz,1H),7.32(d,J=1.3Hz,1H),7.27(dd,J=8.4,1.7Hz,1H),7.20(q,J=4.7Hz,1H),7. 10(dd,J=9.3,4.1Hz,1H),6.84(t,J=8.7Hz,1H),5.45(s,1H),5.10(s,1H),4.96(s,1H), 3.13(s,3H),2.57(d,J=4.8Hz,3H),2.10(d,J=14.0Hz,6H).LC-MS(ESI)m / z:516.1[M+1] + .

[0446] Example 58

[0447] This example provides the preparation of 2-((2-fluoro-4-(prop-1-en-2-yl)phenyl)amino)-1-methyl-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W58). The structural formula and steps are as follows:

[0448]

[0449] Preparation of 2-((2-fluoro-4-(prop-1-en-2-yl)phenyl)amino)-1-methyl-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W58) Reference Example 1. 1 H NMR (400MHz, CDCl3) δ11.88(s,1H),7.61(d,J=8.3Hz,1H),7.46–7.35(m,2H),7.25–7.18(m,2H),7.03(d,J=7.8Hz,1H),6.85(t,J=8.1Hz, 1H),5.67(s,1H),5.37(s,1H),5.29(s,1H),5.12(s,1H),4.66(s,1H),3.19(s,3H),2.78(s,3H),2.12(s,3H).LC-MS(ESI)m / z:536.1[M+1] + .

[0450] Example 59

[0451] This example provides the preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W59). The structural formula and steps are as follows:

[0452]

[0453] The preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W59) was performed with reference to Example 7. 1H NMR (400MHz, CDCl3) δ11.80(s,1H),8.09(s,1H),7.44(dd,J=28.7,7.7Hz,4 H),7.27(s,1H),7.17–7.02(m,1H),6.93(d,J=7.9Hz,1H),6.55(dd,J=24.4, 16.5Hz,3H),5.28(s,1H),4.92(s,1H),3.76(s,2H),3.56(d,J=4.6Hz,2H),3 .19(s,3H),2.77(d,J=4.3Hz,3H),2.15(s,3H).LC-MS(ESI)m / z:646.1[M+1] + .

[0454] Example 60

[0455] This example provides the preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W60). The structural formula and steps are as follows:

[0456]

[0457] Preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W60) Reference Example 7. 1 H NMR (400MHz, CDCl3) δ11.53 (s, 1H), 7.88 (t, J = 5.2Hz, 1H), 7.64–7.52 (m, 1H), 7.48 (dd,J=9.8,1.6Hz,1H),7.40(d,J=8.3Hz,1H),7.32(t,J=8.3Hz,1H),7.14(s,1H),7 .03–6.94(m,1H),6.57(t,J=8.4Hz,1H),5.34(s,1H),3.82–3.67(m,2H),3.56(dd,J =10.1,5.1Hz,2H),3.20(s,3H),2.74(d,J=5.1Hz,3H).LC-MS(ESI)m / z:666.1[M+1] + .

[0458] Example 61

[0459] This example provides the preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxypropyl)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W61). The structural formula and steps are as follows:

[0460]

[0461] Preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxypropyl)-1-methyl-4-(2-methyl-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W61) Reference Example 7. 1 H NMR (400MHz, DMSO) δ8.97(d,J=9.0Hz,2H),8.13(t,J=5.1Hz,1H),7.59(d,J=10.3Hz,1H),7.4 0(d,J=8.2Hz,1H),7.31(d,J=4.2Hz,2H),7.19(d,J=4.8Hz,1H),7.08–6.97(m,1H),6.68(t,J= 8.6Hz,1H),4.99(s,1H),4.41(t,J=4.8Hz,1H),3.34(d,J=5.4Hz,2H),3.23(s,3H),3.04(dd, J=11.8,5.8Hz,2H),2.56(s,3H),2.10(s,3H),1.53–1.36(m,2H).LC-MS(ESI)m / z:660.1[M+1] + .

[0462] Example 62

[0463] This example provides the preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxypropyl)-1-methyl-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W62). The structural formula and steps are as follows:

[0464]

[0465] The preparation of 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxypropyl)-1-methyl-4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (W62) was performed with reference to Example 7. 1H NMR (400MHz, DMSO) δ9.25 (s, 1H), 9.03 (s, 1H), 8.06 (t, J = 5.6Hz, 1H), 7.60 (dd, J = 10.5, 1.7Hz, 1H), 7. 49(dd,J=8.2,1.5Hz,1H),7.45(d,J=8.0Hz,1H),7.40(dd,J=9.6,5.1Hz,2H),7.22(dd,J=7.8,1.5Hz,1 H),6.68(t,J=8.7Hz,1H),5.04(s,1H),4.39(t,J=5.1Hz,1H),3.36–3.31(m,2H),3.23(d,J=11.5Hz,3H ),3.02(dd,J=12.7,6.6Hz,2H),2.55(d,J=4.9Hz,3H),1.49–1.38(m,2H).LC-MS(ESI)m / z:680.1[M+1] + .

[0466] Example 63

[0467] This embodiment provides a method for preparing 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-2-((4-cyclopropyl-2-fluorophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide sodium salt (W4-Na). The structural formula and steps are as follows:

[0468]

[0469] 30 mg of W4 was dissolved in 5 mL of DCM / MeOH (1:1), and an equal amount of sodium hydroxide was added. After stirring at room temperature for 1 h, the organic solvent was evaporated under reduced pressure, and 32 mg of the sodium salt of W4 was obtained after drying. 1 H NMR (400MHz, DMSO) δ10.93(s,1H),7.78(s,1H),7.48(s,1H),7.31(dd,J=8.5,1.3Hz,1H) ,6.98(dd,J=10.1,6.3Hz,2H),6.89(dd,J=8.4,1.5Hz,1H),6.79(t,J=8.6Hz,1H),6.44( dd,J=7.8,1.1Hz,1H),5.01(s,1H),3.03(s,3H),2.34(d,J=5.4Hz,3H),1.91(ddd,J=13. 4,8.5,5.1Hz,1H),0.98–0.92(m,2H),0.71–0.61(m,2H).LC-MS(ESI)m / z:536.1[M+1]+.

[0470] Reference compound I-2

[0471] This example provides the preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-2). The structural formula and steps are as follows:

[0472]

[0473] The preparation of 4-(2-chloro-3-((N-methylaminosulfonyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-2) was obtained by synthesis according to the synthesis method of Example 7 in patent WO2023230205. 1 HNMR (400MHz, CDCl3) δ10.55(s,1H),7.45(d,J=9.9Hz,1H),7.35(t,J=9.3Hz,2H),7. 12(t,J=8.4Hz,1H),7.08(s,1H),6.99(d,J=3.0Hz,1H),6.46(t,J=8.4Hz,1H),6.36(d ,J=8.4Hz,1H),4.98(q,J=5.1Hz,1H),3.34(s,3H),2.76(d,J=5.2Hz,3H),2.66–2.57 (m,1H),1.92(s,3H),0.66(d,J=7.1Hz,2H),0.20(s,2H).LC-MS(ESI)m / z:676.1[M+1] + .

[0474] Biological activity test

[0475] 1. Inhibitory activity of compounds against HCT116

[0476] Human colorectal cancer cell line HCT116 was cultured in the corresponding culture medium containing 10% fetal bovine serum (FBS, Yeast, China) and penicillin / streptomycin (Thermo, USA) in an incubator with 5% CO2 and a temperature of 37°C. The cytotoxicity of the target compounds against HCT116 cells was investigated using CCK-8 (Meilune, CHN). Approximately 3,000 cells were seeded per well of a 96-well plate. After cell attachment, 200 μL of fresh culture medium containing various concentrations of the compounds was added. After incubation for 72 hours, 10 μL of CCK-8 was added to each well and incubated for an additional 2 hours. The plate was shaken for approximately 20 seconds, and the absorbance was measured at a wavelength of 450 nm using a microplate reader. Reference compounds binimetinib and avutometinib were purchased from Shanghai MedChemExpress. The experimental results are shown in Table 2.

[0477] Table 2 Test results of the inhibitory activity of compounds on HCT116 cells

[0478]

[0479]

[0480] Conclusion: The compounds of the present invention significantly inhibit the anti-proliferative activity of HCT116 cells. The anti-tumor activity of the preferred compounds is significantly better than that of the MEK1 / 2 inhibitor binimetinib and the MEK / RAF dual inhibitor avutometinib.

[0481] 2. Immunoblotting of Compound W2

[0482] Protein samples were extracted using RIPA lysis buffer (biosharp, China). Cellular proteins were separated by 10% SDS-PAGE and transferred to polyvinylidene difluoride membranes (Millipore, IRL). The membranes were blocked with 5% skim milk powder dissolved in PBST. The membranes were incubated overnight at 4°C with the following primary antibodies: rabbit monoclonal antibodies against MEK1 / 2 (D1A5) (CST, USA), rabbit monoclonal antibodies against phospho-MEK1 (S217 / 221) (41G9) (CST, USA), rabbit monoclonal antibodies against ERK1 / 2 (ZENBIO, China), rabbit monoclonal antibodies against phospho-Erk1 (T202 / Y204) and Erk2 (T185 / Y187) (Abways, China), GAPDH (Abways, China), and β-actin (Abways, China). Compound VS-6766 was purchased from MedChemExpress, Shanghai. The membrane was washed four times with PBST and then incubated with horseradish peroxidase-linked secondary antibody (diluted in 5% milk) for 45 minutes. TMSpecific bands were detected using WestFemto Highest Sensitivity Substrate (Abbkine, USA) and photographed using ChemiScope 6100 (clinx, China). KRAS mutant pancreatic cancer cells MIAPaCa-2 were treated with W2, VS-6766, and Binimetinib for 4 hours, and the phosphorylation status of MEK and ERK was analyzed. Figure 1 As shown, W2 and the MEK / RAF dual-target inhibitor VS-6766 reduced the levels of phosphorylated MEK and phosphorylated ERK, while the MEK inhibitor Binimetinib only inhibited the level of phosphorylated ERK.

[0483] Conclusion: W2 inhibits both phosphorylated MEK and phosphorylated ERK.

[0484] 3. Pharmacokinetic evaluation of the compound in Balb / c mice

[0485] Experimental purpose: To understand the pharmacokinetics of the compound.

[0486] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0487] Experimental plan: The pharmacokinetics of the compound were investigated by oral administration to mice (5 mg·kg-1).

[0488] Sample preparation: Weigh the compound and dissolve it in DMSO, then add sodium chloride solution for injection to make 0.5 mg mL -1 The compound solution is ready for administration.

[0489] Sample collection: 3 Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 5 mg kg -1 Oral administration (PO) was performed. Approximately 0.05 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected and frozen at -40 °C for testing. The plasma concentration was quantitatively analyzed by LC-MS / MS analysis, and pharmacokinetic parameters such as the area under the concentration-time curve (AUC(0-t)) and the mean residence time (MRT) of the drug in the body were calculated. (0-t) ), half-life (T1 / 2), clearance (CL), apparent volume of distribution at steady state (V dss ), peak time (Cmax), etc.

[0490] The results of pharmacokinetic evaluation are shown in Table 3.

[0491] Table 3 Pharmacokinetic test results of the compounds in Balb / c mice

[0492]

[0493] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life and clearance.

[0494] 4. Therapeutic effect of compound W7 in the HCT116 (G13D KRAS) mouse xenograft model

[0495] All animal experiments were approved by the Animal Ethics Committee of West China Hospital, Sichuan University and performed in accordance with the Guiding Principles of Animal Experimentation. Female nude mice (NU / NU, 4-6 weeks old) were injected subcutaneously with HCT116 cells (4.0 × 10 6 When the tumor size reaches 100-200 mm 3 At (V=LW2 / 2), mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group (2% ethanol plus 98% saline), a binimetinib treatment group (30 mg / kg, 2% ethanol plus 98% saline), and a W7 treatment group (30 mg / kg, 2% ethanol plus 98% saline). The drug was administered orally once a day for 16 days. Tumor size and body weight were measured during the treatment period. Nude mice were sacrificed after 17 days. The experimental results are shown in Figure 2. Figure 2 shown.

[0496] Conclusion: Oral administration of 30 mg / kg of W7 has a significant anti-tumor effect, with a tumor growth inhibition rate (TGI) of 87%, which is better than binimetinib (30 mg / kg, TGI 75%). In addition, no mice died during the treatment period, and there was no significant change in body weight.

[0497] 5. Therapeutic effects of compounds W49, W50, and W55 in the HCT116 (G13D KRAS) mouse xenograft model

[0498] All animal experiments were approved by the Animal Ethics Committee of West China Hospital, Sichuan University and performed in accordance with the Guiding Principles of Animal Experimentation. Female nude mice (NU / NU, 4-6 weeks old) were injected subcutaneously with HCT116 cells (4.0 × 10 6 When the tumor size reaches 100-200 mm 3When (V=LW2 / 2), the mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group (2% ethanol plus 98% saline), an I-2 treatment group (6 mg / kg, 2% ethanol plus 98% saline), a W55 treatment group (6 mg / kg, 2% ethanol plus 98% saline), which were orally administered once every two days, and W49 and W50 treatment groups (0.6 mg / kg, suspended in 5% castor oil, 5% ethanol plus 90% saline injection), which were injected into the tail vein once every two days for a total of 17 days. Tumor size and body weight were measured during the treatment period. The nude mice were sacrificed after 18 days. The experimental results are shown in Figure 2. Figure 3 shown.

[0499] Conclusion: Oral administration of 6 mg / kg of W55 demonstrated significant antitumor activity, surpassing that of reference compound I-2. No mice died during treatment, and there was no significant change in body weight. W49 and W50, administered via tail vein injection, demonstrated significant antitumor activity at a low dose (0.6 mg / kg), surpassing the antitumor efficacy of reference compound I-2 at 6 mg / kg.

[0500] 6. Therapeutic effects of compounds W4-Na and W55 in the OCI-AML-3 (NRAS Q61L) mouse xenograft model

[0501] All animal experiments were approved by the Animal Ethics Committee of West China Hospital, Sichuan University and performed in accordance with the Guiding Principles of Animal Experimentation. Female nude mice (NU / NU, 4-6 weeks old) were injected subcutaneously with OCI-AML-3 cells (4.0×10 6 When the tumor size reaches 200 mm 3 When (V=LW2 / 2), the mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group (2% ethanol plus 98% saline), an I-2 treatment group (6 mg / kg, 2% ethanol plus 98% saline), a W4-Na treatment group (6 mg / kg, 2% ethanol plus 98% saline), and a W55 treatment group (6 mg / kg, 2% ethanol plus 98% saline). The drugs were orally administered once every two days for a total of 15 days. Tumor size and body weight were measured during the treatment period. The nude mice were sacrificed after 16 days. The experimental results are shown in Figure 2. Figure 4 shown.

[0502] Conclusion: Oral administration of 6 mg / kg of W4-Na has a significant anti-tumor effect, which is comparable to that of the reference compound I-2, while the in vivo anti-tumor activity of 6 mg / kg of W55 is significantly better than that of the reference compound I-2. In addition, no mice died during the treatment period and there was no significant change in body weight, indicating that this series of inventive compounds has a high safety in vivo.

[0503] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A six-membered lactam compound, characterized in that: A compound having a structure of Formula I or a stereoisomer, tautomer, racemate, or a pharmaceutically acceptable salt, ester, solvate, polymorph, nitrogen oxide, isotope-labeled substance, metabolite, or hydrate thereof, wherein the structure of Formula I is: wherein R1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; in R1, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O; R2 is selected from hydrogen, deuterium, halogen, methyl, fluoromethyl, methoxy or fluoromethoxy; R3 is selected from hydrogen, deuterium, halogen or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkenyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; in R3, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O; L is selected from O, NH or C(R 7a R 7b ), R 7a and R 7b independently selected from hydrogen, deuterium, fluorine or methyl; X is selected from N or CR4; R4 is selected from hydrogen, deuterium, halogen, cyano, -N(R 8a R 8b ),-OR 8a 、-COR 8a 、-SR 8a 、-(CR 8c R 8d ) n OR a 、 or the following group optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; in R4, the substituent is selected from: deuterium, halogen, -CN, -OR 9a 、-N(R 9a R 9b ) or -CON(R 9a R 9b ); In R4, the 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 8a and R 8b independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 5-10 Spiroalkyl, C 6-10 Bridged cycloalkyl, C 5-10 Heterospirocycloalkyl, C 6-10 hetero-bridged cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; R 8a and R 8b wherein the substituent is selected from the group consisting of deuterium, halogen, -CN, substituted or unsubstituted C 3-10 Cycloalkyl, -OR 9a 、-N(R 9a R 9b ) or -CON(R 9a R 9b );R 8a and R 8b wherein the 4-10 membered heterocycloalkyl, C 5-10 Heterospirocycloalkyl, C 6-10 The hetero-bridged cycloalkyl or 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the substituted or unsubstituted C 3-10 The substituents in cycloalkyl are -OH, -NH2; or R 8a and R 8b Together with the atoms to which they are attached, they form a 4-10 membered heterocycloalkyl group substituted with 0-6 substituents; R 8a and R 8b When forming a ring with the atoms to which they are attached, the substituents are selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; R 8a and R 8b When forming a ring with the atoms to which they are attached, the 4-10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 8c and R 8d independently selected from hydrogen, deuterium, fluorine or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R 8c and R 8d wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R 8c and R 8d wherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; n is an integer selected from 0 to 6; R 9a and R 9b independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-16 Cycloalkyl, 4-16 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R 9a and R 9b wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R 9a and R 9b wherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; Y is selected from N or CR5; Z is selected from N or CR6; R5 and R6 are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -OC 4-6 Heterocycloalkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R5 and R6, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; in R5 and R6, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O.

2. The six-membered lactam compound according to claim 1, characterized in that R1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2, methoxy or -CN; in R1, the 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N or O; Preferably, R1 is selected from the following groups substituted with 0-3 substituents: C 1-4 Alkyl, C 3-4 In R1, the substituent is selected from: deuterium or fluorine; More preferably, R1 is selected from methyl, ethyl, cyclopropyl, isopropyl, deuterated methyl, deuterated ethyl, fluoroethyl or fluorocyclopropyl; More preferably, R1 is selected from methyl or ethyl.

3. The six-membered lactam compound according to claim 1, characterized in that R2 is selected from hydrogen, deuterium, halogen or methyl; Preferably, R2 is selected from fluorine, chlorine or methyl; More preferably, R2 is fluorine.

4. The six-membered lactam compound according to claim 1, characterized in that R3 is selected from hydrogen, deuterium, halogen or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, C 3-4 Cycloalkyl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R3 is selected from hydrogen, deuterium, halogen or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-4 Cycloalkyl; in R3, the substituent is selected from: deuterium or fluorine; More preferably, R3 is selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkenyl, deuterated methyl, fluoromethyl, deuterated ethyl, fluoroethyl, ethynyl, vinyl, -OCH3, -OCF2H, -OCF3, -OCD3, -SCH3, -SCF2H, -SCF3, -SCD3 or cyclopropyl; Further preferably, R3 is selected from hydrogen, chlorine, bromine, iodine, methyl, ethyl, propyl, butyl, cyclopropyl, isopropenyl, -CF3, isopropyl, cyclopentenyl, cyclohexenyl, cyclopropenyl, cyclohexyl, cyclopentyl, -SCH3, -SCF2H, ethynyl or vinyl; Most preferably, R3 is selected from hydrogen, iodine, bromine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, vinyl, cyclopropyl, cyclopentenyl, cyclohexenyl, ethynyl, isopropenyl, cyclopentyl, cyclohexyl or -SCH3.

5. The six-membered lactam compound according to claim 1, characterized in that L is selected from O, NH, CH2 or CD2; Preferably, L is selected from O or CH2.

6. The six-membered lactam compound according to claim 1, characterized in that R4 is selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, fluoromethyl, cyclopropyl, -OR 8a 、-COR 8a 、 Among them, R 8a and R 8b independently selected from hydrogen or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; R 8a and R 8b wherein the substituent is selected from deuterium, fluorine, substituted or unsubstituted C 3-6 Cycloalkyl, hydroxy, amino, cyano, cyclopropyl or methoxy; R 8a and R 8b wherein the 4-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; or R 8a and R 8b Together with the atoms to which they are attached, they form a 4-6 membered heterocycloalkyl group substituted with 0-6 substituents; R 8a and R 8b When forming a ring with the atoms to which they are attached, the substituents are selected from: deuterium, fluorine, hydroxyl, amino, cyano, cyclopropyl or methoxy; R 8a and R 8b When forming a ring with the atoms to which they are connected, the 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the substituted or unsubstituted C 3-6 The substituents in cycloalkyl are -OH, -NH2; Preferably, R4 is selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy, fluoromethoxy or the following groups: More preferably, R4 is selected from 7. The six-membered lactam compound according to claim 1, characterized in that R5 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, cyano, deuterated methyl, fluoromethyl, ethyl, cyclopropyl, -OCH3, -OCF3 or -OCD3; Preferably, R5 is selected from hydrogen, fluorine, chlorine, -OCH3 or methyl.

8. The six-membered lactam compound according to claim 1, characterized in that R6 is selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH-C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R6, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R6 is hydrogen, fluorine, chlorine, methoxy or methyl.

9. The six-membered lactam compound according to any one of claims 1 to 8, characterized in that The six-membered lactam compound is selected from any one of the following compounds: Preferably, the six-membered lactam compound is selected from any one of the compounds shown in W1-W62: More preferably, the six-membered lactam compound is selected from any one of the following compounds:

10. A method for synthesizing a six-membered lactam compound, characterized in that: Its synthetic route is: Or, its synthetic route is: Or, its synthetic route is: Or, its synthetic route is: wherein R1, R2 and R3 are as defined in the above embodiment, and L is N, O or C.

11. A pharmaceutical composition, characterized in that The invention comprises as an active ingredient the six-membered lactam compound or a prodrug thereof according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier or excipient.

12. Use of the six-membered lactam compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11 in the preparation of a drug for preventing and / or treating diseases related to the MEK or Ras-MAPK signaling pathway; And / or, use of the six-membered lactam compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11 in the preparation of an inhibitor that simultaneously inhibits phosphorylated MEK and phosphorylated ERK.

13. The use according to claim 12, characterized in that The MEK or Ras-MAPK signaling pathway-related disease is a tumor, preferably, the tumor is selected from any one of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, liposarcoma or acute myeloid leukemia; Preferably, the drug is a MEK inhibitor.

14. A pharmaceutical product, characterized in that It comprises the six-membered lactam compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11.

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