Novel kinase inhibitor

Abstract

The invention provides a novel kinase inhibitor as well as a preparation method and application thereof. The present invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions comprising these compounds, and the use of such compounds and compositions in the treatment of related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel pyrrolopyrimidine derivatives with protein kinase inhibitory activity, preparation methods and pharmaceutical compositions thereof, and also relates to the use of such compounds and pharmaceutical compositions thereof in treating diseases associated with protein kinase. Background Art

[0002] Chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene generate oncogenic fusion proteins that occur in 3% to 5% of patients with non-small cell lung cancer. These fusion proteins exhibit aberrant dimerization or oligomerization, leading to constitutive ALK activation.

[0003] Fusion of ALK with the echinoderm microtubule-associated protein-like 4 (EML4) gene to form EML4-ALK has been found to be highly oncogenic in preclinical NSCLC models. Targeting the kinase domain of EML4-ALK with small molecule ALK inhibitors has clinical benefits for patients with ALK-positive NSCLC.

[0004] Three generations of ALK inhibitors have been approved so far, including the first (crizotinib), second (alectinib, brigatinib, ceritinib) and third (lorlatinib) therapies. However, resistance has emerged with these therapies. Part of the reason for the development of resistance is the emergence of ALK mutations that interfere with drug binding. Crizotinib was approved in 2011 for patients with ALK-positive NSCLC, with an objective response rate of 74% in the first-line setting. However, crizotinib treatment can lead to resistance mutations in the ALK active site, such as G1269A and C1156Y, as well as gatekeeper residue L1196M mutations, which lead to the development of resistance. Second-generation ALK inhibitors (alectinib, brigatinib, ceritinib) have been approved for patients with ALK-positive NSCLC, but are also susceptible to resistance by ALK mutations, such as solvent front mutations (such as G1202R), found in 33% to 37% of relapsed patients, and I1171 mutations in the hydrophobic regulatory ridge (24% to 26%). The third-generation ALK inhibitor lorlatinib is approved for patients with ALK-positive NSCLC who have previously received crizotinib and at least one other ALK inhibitor, or who have received first-line treatment with alectinib or ceritinib. However, in plasma specimens from patients whose disease progressed after lorlatinib treatment, ALK mutations were detected in 76% of the following: L1196M (38%), G1202R (28%), D1203N (24%), F1174C / L (14%), and I1171X (14%);. These mutations are a mixture of single mutations and compound mutations, with compound mutations found in 35% to 48% of treated patients. The most common compound mutation is the G1202R / L1196M mutation, and currently approved ALK inhibitors have poor ALK kinase inhibition against the G1202R / L1196M mutation. The reappearance of single mutations such as L1196M and G1202R may be due to the moderate efficacy of lorlatinib against these mutations (L1196MIC 50 18-30nmol / L, G1202R IC 50 37-63nmol / L). Therefore, there is a need for a central nervous system (CNS) penetrant, highly potent wild-type (WT) ALK inhibitor that is not susceptible to resistance mutations arising from treatment with first-, second-, and third-generation ALK inhibitors. Summary of the invention

[0005] The present invention relates to a compound or a pharmaceutically acceptable salt thereof that can be used as an ALK inhibitor, which can be used to treat diseases mediated by ALK. The present invention also relates to a method for preparing the compound of the present invention or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases mediated by ALK.

[0006] The present invention also discloses a method for treating diseases mediated by ALK using the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0007] The present invention provides a novel ALK inhibitor, which has strong inhibitory activity on ALK kinase with G1202R / L1196M compound mutation.

[0008]

[0009] in,

[0010] R2 is selected from -(SO2)-R 10 、-(SO2)-NH-R 10 , or -(CO)-NH-R 10 ,

[0011] R 10 C 1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution,

[0012] R3 and R4 are each independently selected from H, C 1-3 alkyl, or R3 and R4 are linked together to form a 3-5 membered carbocyclic ring, wherein the alkyl or carbocyclic ring may be optionally substituted by halogen,

[0013] R5 is halogen, CN, C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0014] R6 is selected from H, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or 3-8 membered heterocyclic group or -(CO)-NH-R 11 , the heterocyclic group may be optionally substituted by R9,

[0015] R7 is H, halogen, CN, C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0016] R1 is selected from H, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 alkyl, or a 3-8 membered heterocyclic group, or -(CO)-NH-R8, the heterocyclic group may be optionally substituted by R9, or

[0017] R1 and R6 or R7 are linked together to form a nitrogen-containing heterocyclic ring, wherein the nitrogen in the heterocyclic ring may be optionally replaced by C 1-6 Alkyl or -(CH2) 0-1 -(CO)-(CH2) 0-1 -N(CH3)2 substitution,

[0018] R 11 Selected from C 1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, or R 11 and R1 are connected together to form a nitrogen-containing heterocyclic ring, wherein the alkyl, cycloalkyl, heterocyclic group, or heterocyclic ring may be optionally substituted by halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group,

[0019] R8 is selected from C 1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, or R8 and R6 or R7 are connected together to form a nitrogen-containing heterocyclic ring, and the alkyl, cycloalkyl, heterocyclic group, or heterocyclic ring can be optionally substituted by halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group,

[0020] R9 is selected from halogen, CN, =O, OR 10 , C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) 0-1 -(CO)-(CH2) 0-1 -N(CH3)2, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group may be optionally substituted by halogen, CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution,

[0021] R 10 Selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0022] n is 0, 1, or 2.

[0023] In some embodiments, R 10 C 1-6 alkyl.

[0024] In some embodiments, R1 is -(CO)-NH-R8, and R8 is as defined above.

[0025] In some embodiments, R3 and R4 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, or R3 and R4 are linked together to form a 3-4 membered carbocyclic ring.

[0026] In some embodiments, the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof:

[0027]

[0028]

[0029] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

[0030] On the other hand, the present invention provides a method for treating an ALK-mediated disease, the method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above-mentioned composition. In some embodiments, the ALK-mediated disease has an ALK site mutation of G1202R and / or an ALK site mutation of L1196M; preferably, the ALK-mediated disease has a compound mutation of the ALK site mutation of G1202R and the ALK site mutation of L1196M. In some embodiments, the ALK-mediated disease is ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, systemic histiocytosis, or neuroblastoma.

[0031] In some embodiments of the present invention, the subject involved in the present invention is a mammal including a human.

[0032] On the other hand, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above-mentioned composition in the preparation of a medicament for treating an ALK-mediated disease. In some embodiments, the ALK-mediated disease has an ALK site mutation of G1202R and / or an ALK site mutation of L1196M; preferably, the ALK-mediated disease has a compound mutation of an ALK site mutation of G1202R and an ALK site mutation of L1196M. In some embodiments, the ALK-mediated disease is ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, systemic histiocytosis, or neuroblastoma. DETAILED DESCRIPTION OF THE INVENTION

[0034] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and public materials cited in the entirety of this article are incorporated herein by reference in their entirety.

[0035] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any inventive subject matter.

[0036] Some chemical terms

[0037] The terms "optional", "optional" or "optionally" mean that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". In addition, the optionally substituted group can be unsubstituted (for example: -CH2CH3), fully substituted (for example: -CF2CF3), monosubstituted (for example: -CH2CH2F) or any level between monosubstituted and fully substituted (for example: -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0038] Definitions of standard chemical terms can be found in references (including Carey and Sundberg, Advanced Organic Chemistry, 4th edition, Volume A (2000) and Volume B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art are used, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy and pharmacological methods. Unless specifically defined, the relevant terms and experimental steps and techniques in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above techniques and methods can usually be implemented according to the descriptions in the multiple summary and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0039] Some of the chemical groups named herein may be abbreviated to indicate the total number of carbon atoms. For example, C 1-6 Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated in the shorthand notation does not include the carbon atoms in possible substituents.

[0040]

[0063] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0041]

[0063] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure having two or more rings sharing one or more atoms.

[0042] The term "alkyl" as used herein alone or as part of another component (such as a haloalkyl) refers to an optionally substituted straight chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, connected to the rest of the molecule by a single bond, such as methyl, ethyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-heptyl, 2-methylhexyl, n-octyl, and the like.

[0043] The term "cycloalkyl" used herein alone or as part of other components refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group, containing only carbon atoms and hydrogen atoms, which may include fused rings, spiro rings or bridged ring systems, containing 3-15 ring carbon atoms, preferably 3-10 ring carbon atoms, more preferably 3-8 ring carbon atoms, which may be saturated or unsaturated, and connected to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclohexyl, cyclohexanone, cyclooctyl, 1H-indenyl, decahydronaphthyl, etc.

[0044] The terms "heterocyclyl" and "heterocycle" used herein alone or as part of other components refer to a stable 3-18-membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused rings, spirocyclic or bridged ring systems, the nitrogen, carbon or sulfur on the heterocyclyl can be selectively oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclyl can be partially or fully saturated. The heterocyclyl can be connected to the rest of the molecule through a single bond through a carbon atom or heteroatom on the ring. The heterocyclyl containing fused rings can contain one or more aromatic rings or heteroaromatic rings, as long as the atoms on the non-aromatic rings are connected to the rest of the molecule. The heterocyclic group is preferably a stable 4-11-membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8-membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolane, morpholinyl, 2-oxopiperidinyl, tetrahydroisoquinolinyl, trithianyl, etc.

[0045] The term "carbocycle" used herein alone or in combination refers to a structure of a carbon covalently closed ring, which may be saturated or partially unsaturated. The carbocycle may be formed by 3, 4, 5, 6, 7, 8, 9 or more atoms. The "carbocycle" herein may be a monocyclic ring or a polycyclic ring, and polycyclic carbocycles include spirocyclic rings, condensed rings and bridged rings. The carbocycle may be arbitrarily substituted. The "carbocycle" herein preferably comprises about 5 to about 20 or 5 to 10 or 5-8 or 5-6 skeleton ring atoms.

[0046]

[0046] The terms "halogen," "halo," or "halide," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, and iodine.

[0047] Unless otherwise specified, compounds of the present invention containing olefinic double bonds include both E and Z isomers.

[0048] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can be independently R or S configurations. Some compounds of the present invention may also exhibit cis-trans isomerism, which is apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

[0049] The term "pharmaceutically acceptable salt" used herein includes both acid-addition salts and base-addition salts.

[0050] "Pharmaceutically acceptable salts" refer to those which retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, and are reacted with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethylsulfonic acid, 2-hydroxyethanediol, formic acid, Salts formed by fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc. "Pharmaceutically acceptable base-added salts" refer to salts which retain the biological effectiveness and properties of the free acids of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic base or an organic base. Salts generated by reacting with an inorganic base 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, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0051] Organic bases for forming salts include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-dimethylethanolamine, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hybamine penicillin, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, meglumine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0052] The compound of the present invention or a salt thereof can be administered alone as an active substance, or preferably in the form of a pharmaceutical composition thereof.

[0053] The term "pharmaceutical composition" as used herein refers to a preparation containing a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). Such a medium includes all pharmaceutically acceptable carriers.

[0054] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0055] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0056] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.

[0057] The pharmaceutical composition of the present invention can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0058] Typical routes of administration of the compounds of the invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral administration.

[0059] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making sugar-coated pills methods, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0060] In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

[0061] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by the following method: the active compound is mixed with a solid excipient, the mixture is optionally ground, other suitable adjuvants are added if necessary, and then the mixture is processed into particles to obtain the core of a tablet or a sugar-coated agent. Suitable adjuvants include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc. Such as microcrystalline cellulose, glucose solution, acacia gum, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pre-cross-linked starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, etc. The core of the sugar-coated agent can be optionally coated according to methods known in common pharmaceutical practice, especially using enteric coatings.

[0062] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Appropriate excipients such as fillers, buffers or surfactants can be used. DETAILED DESCRIPTION

[0063] The compounds of the present invention, their preparation methods and uses are described below in conjunction with examples.

[0064] Synthesis Method A

[0065]

[0066] Step 1:

[0067] Trifluoroacetic acid (3.0 eq) was added to a trifluoroethanol solution of compound 1 (1.0 eq.) and compound 2 (1.0 eq.). The reaction solution was heated to 90°C and reacted for 24 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by rapid silica gel column chromatography to obtain compound 3.

[0068] Step 2:

[0069] Under nitrogen protection, a toluene solution of compound 3 (1.0 eq), compound 4 (1.5 eq), Pd2(dba)3 (0.1 eq), Davephos (0.2 eq) and cesium carbonate (2.0 eq) was heated to 110°C and reacted overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by rapid silica gel column chromatography to obtain compound 5.

[0070] Step 3:

[0071] At room temperature, concentrated sulfuric acid (0.1 eq) was added dropwise to a trifluoroacetic acid (5 mL / mmol) solution of compound 5, and stirring was continued until the reaction was completed. The reaction solution was poured into ice water, and the pH was adjusted to 8 with saturated sodium carbonate. Subsequently, the reaction solution was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by rapid silica gel column chromatography to obtain compound 6.

[0072] Example 1: 4-{[4-({2-[dioxy-2-yl)- 6 -thio]phenyl}amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-2-fluoro-5-methoxy-N-methylbenzamide

[0073]

[0074] Example 1 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.60 (s, 1H), 8.34-8.38 (m, 2H), 7.85 (dd, J=8.0Hz, 1.6Hz, 1H), 7.62-7.67 (m, 2H), 7.54 (d, J=6.8Hz, 1H), 7.17 (t, J=7 .2Hz, 1H), 6.72-6.81 (m, 1H), 4.64 (s, 1H), 3.93 (s, 3H), 3.74 (t, J=8.4Hz, 2H), 3.19-3.29 (m, 1H), 2.98-3.02 (m, 5H), 1.30 (d, J=7.2Hz, 6H).

[0075] Example 2: 4-{[4-({2-[dioxy-2-yl)-λ 6 -thio]phenyl}amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxybenzene-1-carboxamide

[0076]

[0077] Example 2 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.63 (s, 1H), 8.50 (d, J=8.8Hz, 1H), 8.41 (d, J=8.8Hz, 1H), 7.84 (dd , J=8.0Hz, 1.6Hz, 1H), 7.64 (s, 1H), 7.61 (t, J=8.0Hz, 1H), 7.44 (d, J=1.6Hz, 1H), 7.23 (dd , J=8.8Hz, 1.6Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 5.20-6.16 (br, 2H), 4.69 (s, 1H), 3.95 (s, 3H) ), 3.74 (t, J=8.4Hz, 2H), 3.21-3.31 (m, 1H), 2.99 (t, J=8.4Hz, 2H), 1.30 (d, J=6.8Hz, 6H).

[0078] Example 3: 5-{[4-({2-[dioxy-2-yl)- 6 -thio]phenyl}amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-6-methoxy-2,3-dihydro-1H-isoindol-1-one

[0079]

[0080] Step 1:

[0081] Compound 3-1 (500 mg) in ammonia / methanol solution (7N, 5 mL) was stirred overnight at room temperature, and after the reaction, the resulting reaction solution was concentrated under reduced pressure. The resulting residue 3-2 (410 mg) was used directly in the next step without further purification.

[0082] Step 2

[0083] Palladium-carbon catalyst (60 mg) was added to a methanol (10 mL) solution of compound 3-2 (400 mg), and the reaction solution was reacted at room temperature overnight under hydrogen. The reaction was also filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained residue 3-3 (357 mg) was directly used in the next step without further purification.

[0084] The compound of Example 3 was prepared by general synthesis step A using compound 3-3 as raw material. 1 H NMR (400MHz, CD3OD+CDCl3), 8.57 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.83 (dd, J=8.0Hz, 1.6Hz, 1H), 7.62 (td, J=8.0Hz, 1.6Hz, 1H), 7.27 (s, 1H ), 7.21 (t, J=8.0Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.71 (t, J=8.4Hz, 2H), 3.25-3.34 (m, 1H), 2.94 (t, J=8.4Hz, 2H), 1.26 (d, J=6.8Hz, 6H).

[0085] Example 4: 6-{[4-({2-[dioxy-2-yl)-λ 6 -thio]phenyl}amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-7-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one

[0086]

[0087] Step 1:

[0088] Under nitrogen protection, NBS (435 mg) and AIBN (9 mg) were added to a solution of compound 4-1 (430 mg) in carbon tetrachloride (10 mL). The reaction solution was heated to 80°C and continued to react overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound 4-2 (372 mg).

[0089] Step 2:

[0090] Compound 4-2 (360 mg) was added to a 10% methylamine ethanol solution (10 mL), and the reaction solution was reacted at room temperature overnight. The reaction solution was concentrated under pressure to obtain a crude compound 4-3 (370 mg).

[0091] Step 3:

[0092] Palladium-carbon catalyst (60 mg) was added to a methanol (10 mL) solution of compound 4-3 (370 mg), and the reaction solution was reacted at room temperature overnight under hydrogen. The reaction was also filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained residue 4-4 (357 mg) was directly used in the next step without further purification.

[0093] Example 4 was prepared using compound 4-4 as a raw material through general synthesis step A. 1 H NMR (400MHz, CD3OD), 8.02-8.16 (m, 1H), 7.62-7.98 (m, 3H), 7.45 (t, J=7.6Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 4.44 (s , 2H), 4.07 (s, 3H), 3.84-3.89 (m, 2H), 3.25-3.42 (m, 1H), 3.15 (s, 3H), 2.82-2.99 (m, 2H), 1.23 (d, J=6.8Hz, 6H).

[0094] Example 5: 2-(dimethylamino)-1-(6-{[4-({2-[dioxy-2-yl)- 6 -1H-indol-1-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one

[0095]

[0096] Example 5 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.89 (s, 1H), 8.39 (d, J = 8.4Hz, 1H), 7.72 (d, J = 8.4Hz, 1 H), 7.45(td, J=8.0Hz, 1.6Hz, 1H), 7.07(t, J=8.0Hz, 1H), 6.90(s, 1H), 4.16( t, J=8.4Hz, 2H), 3.85 (s, 3H), 3.67 (t, J=8.4Hz, 2H), 3.29-3.37 (m, 3H), 3.17 (t, J=8.4Hz, 2H), 2.87 (t, J=8.4Hz, 2H), 2.35 (s, 6H), 1.25 (d, J=6.8Hz, 6H).

[0097] Example 6: 2-({4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}amino)-4-({2-[dioxy-2-yl)-[[[[[[[[[[[[[[[[[[[[[[[[ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0098]

[0099] Example 6 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.44 (s, 1H), 8.39 (d, J=8.0Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 7.84 (dd, J=8.0Hz, 1.6Hz, 1H), 7.51-7.56 (m, 1H), 7.15 (s, 1H), 7.13 (t, J=8.0Hz, 1H), 6.50 (d, J=2.4Hz, 1H), 6.37 (dd, J=8.8Hz, 2.4Hz , 1H), 4.57(s, 1H), 3.85(s, 3H), 3.62-3.66(m, 2H), 3.35(s, 2H), 3.24-3.31(m, 1H), 2.82-2.96(m, 1H), 2.7 1 (t, J=11.6Hz, 2H), 2.64 (s, 6H), 2.14-2.17 (m, 2H), 1.81-1.91 (m, 2H), 1.47 (s, 6H), 1.30 (d, J=6.8Hz, 6H).

[0100] Example 7: 4-({2-[dioxy-(propan-2-yl)-λ 6 -({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0101]

[0102] Example 7 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.43 (s, 1H), 8.41 (d, J=8.4Hz, 1H), 8.12 (d, J=8.4Hz, 1H), 7.83 (dd, J=8 .0Hz, 1.6Hz, 1H), 7.52-7.56 (m, 1H), 7.10-7.14 (m, 2H), 6.52 (d, J=2.4Hz, 1H), 6.37 (dd, J=8. 4Hz, 2.4Hz, 1H), 4.52(s, 1H), 3.84(s, 3H), 3.59-3.62(m, 2H), 3.34(s, 2H), 3.23-3.32(m, 1H) , 2.27-2.80 (14H), 1.93-1.96 (m, 2H), 1.66-1.76 (m, 2H), 1.47 (s, 6H), 1.29 (d, J=7.2Hz, 6H).

[0103] Example 8: 2-{[2-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-N-(propan-2-yl)benzenesulfonamide

[0104]

[0105] Example 8 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.20 (d, J=8.0Hz, 1H), 8.09 (d, J=8.8Hz, 1H), 7.91 (dd, J=8.8Hz, 1.6Hz, 1H ), 7.82 (s, 1H), 7.48-7.53 (m, 1H), 7.12-7.16 (m, 2H), 6.49 (d, J = 2.4Hz, 1H), 6.27 (dd, J = 8.8Hz, 2.4Hz, 1H), 4.57 (s, 1H), 4.26 (d, J=8.0Hz, 1H), 3.84 (s, 3H), 3.55-3.62 (m, 2H), 3.33-3.42 (m, 3 H), 2.38-2.98 (m, 14H), 1.92-204 (m, 2H), 1.60-1.78 (m, 2H), 1.46 (s, 6H), 0.97 (d, J=6.4Hz, 6H).

[0106] Example 9: 4-{[4-({2-[dioxy-2-yl)-λ 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0107]

[0108] Example 9 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.44 (s, 1H), 8.29 (d, J = 15.6Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 7.88 (dd, J = 8.0Hz, 1.6Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=7.2Hz, 1H), 7.27 (t, J=7.6Hz, 1H), 6.73-6 .79(m,1H),4.69(s,1H),4.12-4.24(m,1H),3.90(s,3H),3.62-3.88(m,2H),3.40-3.53(m,2H),3.39 (s, 2H), 3.19-3.30 (m, 1H), 2.61-2.81 (m, 5H), 2.05-2.20 (m, 2H), 1.49 (s, 6H), 1.29 (d, J=6.4Hz, 6H).

[0109] Example 10: 4-{[4-({2-[dioxy-2-yl)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-2-fluoro-5-methoxy-N-methylbenzamide

[0110]

[0111] Example 14 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.43 (s, 1H), 8.28 (d, J = 15.6Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 7 .88 (dd, J=8.0Hz, 1.2Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=7.2Hz , 1H), 7.20 (t, J=7.6Hz, 1H), 6.68-6.79 (m, 1H), 4.65 (s, 1H), 3.92 (s, 3H), 3.39 (s, 2H), 3.21-3.31 (m, 1H), 3.01 (d, J=4.4Hz, 3H), 1.49 (s, 6H), 1.29 (d, J=6.4Hz, 6H).

[0112] Example 11: 4-{[4-({2-[dioxy-2-yl)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxybenzene-1-carboxamide

[0113]

[0114] Example 11 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.47 (s, 1H), 8.44 (d, J=8.4Hz, 1H), 8.29 (d, J=8.8Hz, 1H), 7.87 (dd, J=8.0Hz, 1.6Hz, 1H), 7.58-7.62 (m, 2H), 7.41 (d, J=2.0Hz , 1H), 7.13-7.20(m, 2H), 5.10-6.12(br, 2H), 4.62-4.73(br, 1H), 3.94(s , 3H), 3.39 (s, 2H), 3.22-3.32 (m, 1H), 1.49 (s, 6H), 1.30 (d, J=6.8Hz, 6H).

[0115] Example 12: 2-({4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}amino)-5,5-dimethyl-4-({2-[(2-methylpropyl)dioxy-λ 6 -thio]phenyl}amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0116]

[0117] Example 12 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.69 (s, 1H), 8.33 (s, 1H), 8.09-8.22 (b, 1H), 8.06 (d, J=8.4Hz, 1H), 7 .94 (d, J=7.6Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.51-7.55 (m, 1H), 7.29-7.32 (m, 1H), 6.79 (s, 1H), 6.55 (d, J=8.8Hz, 1H), 3.90 (s, 3H), 3.71-3.81 (m, 2H), 3.59 (s, 2H), 3.03-3.18 (m, 2H) , 2.97 (d, J=6.8Hz, 2H), 2.86 (s, 6H), 2.17-2.35 (m, 6H), 1.52 (s, 6H), 1.01 (d, J=6.4Hz, 6H).

[0118] Example 13: 5-{[4-({2-[dioxy-2-yl)- 6-thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-6-methoxy-2,3-dihydro-1H-isoindol-1-one

[0119]

[0120] Example 13 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.53 (s, 1H), 8.42 (s, 1H), 8.23 ​​(d, J=8.0Hz, 1H), 7.88 (dd, J=8.0Hz, 1.6Hz, 1H), 7.67 (s, 1H), 7.54-7.58 (m, 1H), 7.28 (s, 1 H), 7.16-7.21(m, 1H), 6.15(s, 1H), 4.68(s, 1H), 4.17(s, 2H), 3.94(s, 3 H), 3.40 (s, 2H), 3.22-3.32 (m, 1H), 1.49 (s, 6H), 1.29 (d, J=6.8Hz, 6H).

[0121] Example 14: 2-(dimethylamino)-1-(6-{[4-({2-[dioxy-2-yl)- 6 -1H-indol-1-yl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one

[0122]

[0123] Example 14 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 9.22 (s, 1H), 8.44-8.46 (m, 2H), 7.79 (dd, J=8.4Hz, 1.2Hz, 1H), 7.48 (t, J=7.6Hz, 1H), 7.13 (s, 1H), 7.02 (t, J=7.6Hz, 1H), 6.70 ( s, 1H), 4.90-5.16 (br, 1H), 4.12 (t, J=8.0Hz, 2H), 3.83 (s, 3H), 3.27-3.37( m, 3H), 3.09-3.15 (m, 4H), 2.34 (s, 6H), 1.45 (s, 6H), 1.31 (d, J=6.8Hz, 6H).

[0124] Example 15: 4-{[4-({2-[dioxy-2-ylamino)-λ 6-(1-methylhexahydropyridin-4-yl)benzamide

[0125]

[0126] Example 15 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.21 (d, J=15.6Hz, 1H), 8.06 (d, J=8.4Hz, 1H), 7.96 (dd, J=8.0Hz, 1.2Hz, 1H), 7. 85 (s, 1H), 7.58-7.62 (m, 2H), 7.47 (d, J = 7.2Hz, 1H), 7.21 (t, J = 7.6Hz, 1H), 6.56-6.61 (m, 1H), 4.65 (s, 1H), 4.27 (d, J=8.0Hz, 1H), 3.94-4.05 (m, 1H), 3.90 (s, 3H), 3.36-3.45 (m, 3H), 2.74-2.88 (m, 2H), 2.3 1 (s, 3H), 2.12-2.23 (m, 2H), 1.99-2.08 (m, 2H), 1.54-1.66 (m, 2H), 1.49 (s, 6H), 0.96 (d, J=6.8Hz, 6H).

[0127] Example 16: 4-{[4-({2-[dioxy-2-yl)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-2-fluoro-5-methoxybenzene-1-carboxamide

[0128]

[0129] Example 16 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.45 (s, 1H), 8.31 (d, J = 15.2Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.88 (dd, J = 8.0Hz, 1.6Hz, 1H), 7.61-7.66 (m, 2H), 7.50 (d, J = 6.8Hz, 1H) ), 7.18-7.22 (m, 1H), 6.66 (d, J = 12.4Hz, 1H), 5.65 (s, 1H), 4.66 (s, 1H), 3.92 (s, 3H), 3.40 (s, 2H), 3.20-3.31 (m, 1H), 1.49 (s, 6H), 1.29 (d, J=7.2Hz, 6H).

[0130] Example 17: 4-{[4-({2-[dioxy-2-yl)- 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0131]

[0132] Step 1:

[0133] At room temperature, HATU (810 mg) was added to a solution of compound 17-1 (300 mg), compound 17-2 (244 mg) and DIEA (0.46 mL) in THF (10 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (100 mL) and washed with 1N hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL) and saturated brine (20 mL) in sequence. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by rapid silica gel column chromatography to obtain compound 17-3 (311 mg).

[0134] Step 2:

[0135] Palladium-carbon catalyst (50 mg) was added to a solution of compound 17-3 (300 mg) in methanol (10 mL), and the reaction solution was reacted at room temperature overnight under hydrogen. The filtrate was filtered through celite and concentrated under reduced pressure to obtain 17-4 (285 mg), which was directly used in the next step without further purification.

[0136] Example 17 was prepared using compound 17-4 as a raw material through general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.41 (s, 1H), 8.25 (d, J=8.0Hz, 1H), 8.21 (s, 1H), 7.86 (dd, J=8.0Hz, 1.6Hz, 1 H), 7.53-7.58 (m, 1H), 7.42 (s, 1H), 7.14 (t, J=7.6Hz, 1H), 6.88 (s, 1H), 5.54 (d, J=8.0Hz, 1H), 4.59 (s, 1H), 3.91-4.02 (m, 1H), 3.86 (s, 3H), 3.37 (s, 2H), 3.23-3.35 (m, 1H), 2.77-2.86 (m, 2H), 2.30 (s , 3H), 2.10-2.21(m, 5H), 2.01-2.09(m, 2H), 1.51-1.61(m, 2H), 1.48(s, 6H), 1.29(d, J=7.2Hz, 6H).

[0137] Example 18: 4-{[4′-({2-[dioxy-2-yl)-λ 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0138]

[0139] Example 18 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.22 (d, J=14.8Hz, 1H), 7.93 (d, J=8.0Hz, 1H), 7.80 (dd, J=8.0Hz, 1. 2Hz, 1H), 7.65 (t, J=8.0Hz, 1H), 7.20-7.24 (m, 2H), 4.10-4.18 (m, 1H), 3.92 (s, 3H), 3.58 (s , 2H), 3.44-3.53 (m, 2H), 3.21-3.30 (m, 1H), 3.14 (t, J = 11.6Hz, 2H), 2.85 (s, 3H), 2.15-2. 23 (m, 2H), 1.88-1.99 (m, 2H), 1.50-1.53 ​​(m, 2H), 1.22 (d, J=6.8Hz, 6H), 0.85-0.88 (m, 2H).

[0140] Example 19: 2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-N-(propan-2-yl)benzenesulfonamide

[0141]

[0142] Example 19 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.36-8.52 (br, 1H), 7.91-8.04 (m, 1H), 7.85 (d, J=7.2Hz, 1H), 7.31-7.42 (m, 1H), 7.20 (t, J=7.2Hz, 1H), 7.08 (s, 1H), 4.30 (s , 2H), 4.11 (t, J=8.0Hz, 2H), 3.85 (s, 3H), 3.56 (s, 2H), 3.36-3.45 (m, 1H) , 3.31 (t, J=8.0Hz, 2H), 2.98 (s, 6H), 1.51 (s, 6H), 1.06 (d, J=6.8Hz, 6H).

[0143] Example 20: 2-chloro-4-{[4-({2-[dioxy-2-yl)- 6 -(1-methylpiperidin-4-yl)benzamide

[0144]

[0145] The synthesis method of the compound in Example 20 is the same as that of the compound in Example 17. 1H NMR (400MHz, CDCl3), 8.45 (s, 1H), 8.42 (s, 1H), 8.17 (d, J=8.4Hz, 1H), 7.87 (dd, J=8.4Hz, 1.6Hz , 1H), 7.62-7.66 (m, 1H), 7.48 (s, 1H), 7.33 (s, 1H), 7.18 (t, J=8.0Hz, 1H), 6.57 (d, J=7.2Hz, 1H) , 4.62 (s, 1H), 3.98-4.10 (m, 1H), 3.90 (s, 3H), 3.39 (s, 2H), 3.23-3.33 (m, 1H), 2.81-2.97 (m, 2H ), 2.22-2.44(m, 5H), 2.04-2.13(m, 2H), 1.64-1.80(m, 2H), 1.49(s, 6H), 1.29(d, J=7.2Hz, 6H).

[0146] Example 21: 5-{[4-({2-[dioxy-2-yl)- 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-6-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one

[0147]

[0148] Example 21 was prepared by general synthetic procedure A. 1 H NMR (400MHz, DMSO), 8.37 (s, 1H), 8.29 (s, 1H), 8.15 (d, J=8.0Hz, 1H), 7.78 (dd, J=7.6Hz, 1.6Hz, 1H), 7.71-7.75 (m, 1H), 7.53 (s, 1H), 7.29 (t, J=7.6Hz, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 4.15 (s, 2H), 3.91 (s, 3H), 3.22-3.34 (m, 3H), 3.02 (s, 3H), 1.37 (s, 6H), 1.14 (d, J=6.4Hz, 6H).

[0149] Example 22: 5-{[4-({2-[dioxy-2-yl)- 6 -1-methylhexahydropyridin-4-yl)-2,3-dihydro-1H-isoindol-1-one trifluoroacetate

[0150]

[0151] The synthesis method of the compound in Example 22 is the same as that of the compound in Example 3. 1 H NMR (400MHz, DMSO), 9.37-9.47 (brs, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.08 (d, J=8.4Hz , 1H), 7.86 (s, 1H), 7.82 (d, J=7.6Hz, 1H), 7.78 (t, J=7.6Hz, 1H), 7.25-7.46 (m, 2H), 7. 19(s, 1H), 4.16-4.26(m, 1H), 4.12(s, 2H), 3.91(s, 3H), 3.45-3.55(m, 2H), 3.10-3.34 (m, 5H), 2.79 (d, J=4.4Hz, 3H), 1.90-2.08 (m, 4H), 1.39 (s, 6H), 1.14 (d, J=6.8Hz, 6H).

[0152] Example 23: 1-(6-{[4-({2-[dioxy-2-yl)- 6 -thio]phenyl}amino)-5,5-dimethyl-6,77-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one

[0153]

[0154] Example 23 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 9.14 (s, 0.5H), 8.59 (s, 0.5H), 8.46 (s, 0.5H), 8.41 (d, J=8.8Hz, 0.5H), 8.36 (s, 0.5H), 8.30 (d, J=8.8Hz, 0.5H), 7.85 (d, J=8.0Hz, 0.5H), 7.79 (d, J=8.0Hz, 0.5H), 7.38-7.47 (m, 1H), 7.34 (s, 0.5H), 7.09-7.13 (m, 1H), 7.03 (t, J=8.0Hz, 0.5H), 6.77 (s, 0.5H) 3 .27-3.34 (m, 2H), 3.13 (t, J=8.4Hz, 1H), 2.99 (t, J=8.4Hz, 1H), 2.15 (s, 1.5H), 1.48 (s, 3H), 1.45 (s, 3H), 1.42 (s, 1.5H), 1.31-1.34 (m, 6H).

[0155] Example 24: 4-{[4′-({2-[dioxy-2-yl)-λ 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0156]

[0157] Example 24 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.03 (d, J=8.4Hz, 1H), 7.98 (dd, J=8.0Hz, 1.6Hz, 1H), 7.78 -7.87 (m, 2H), 7.52 (t, J=8.0Hz, 1H), 7.34 (d, J=6.4Hz, 1H), 4.10-4.22 (m, 1H), 4. 03(s, 2H), 3.99(s, 3H), 3.55-3.63(m, 2H), 3.32-3.42(m, 1H), 3.13-3.23(m, 2H) , 2.80-2.92 (m, 5H), 2.08-2.34 (m, 6H), 1.86-1.98 (m, 2H), 1.23 (d, J=6.8Hz, 6H).

[0158] Example 25: 2-({5-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}amino)-4-({2-[dioxy-2-yl)-[[[[[[[[[[[[[[[[[[[[[[[[[[ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0159]

[0160] Step 1:

[0161] Under nitrogen protection, Pd2(dba)3 (200 mg) was added to a toluene (20 mL) solution of compound 25-1 (500 mg), 25-2 (415 mg), Xantphos (250 mg), and anhydrous cesium carbonate (1.4 g). The reaction solution was heated to 110°C and reacted overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by rapid silica gel column chromatography (dichloromethane: methanol = 30: 1) to obtain compound 25-3 (510 mg).

[0162] Step 2:

[0163] Palladium carbon catalyst (100 mg) was added to a solution of compound 25-3 (500 mg) in methanol (20 mL), and the reaction solution was reacted at room temperature overnight under hydrogen. The filtrate was filtered through celite and concentrated under reduced pressure to obtain 25-4 (285 mg), which was directly used in the next step without further purification.

[0164] Example 25 was prepared using compound 25-4 as a raw material by general synthesis procedure A. 1HNMR (400 MHz, CD3OD), 8.00 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.58-7.64 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 3.84 (s, 3H ), 3.57(s, 2H), 3.45-3.53(m, 2H), 3.38-3.44(m, 1H), 3.19-3.29(m, 1H), 2.88(s, 6H), 2.60( t, J=12.0Hz, 2H), 2.03-2.06 (m, 2H), 1.71-1.82 (m, 2H), 1.51 (s, 6H), 1.29 (d, J=7.2Hz, 6H).

[0165] Example 26: 4-({2-[dioxy-2-yl)-λ 6-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine trifluoroacetate)

[0166]

[0167] The synthesis method of Example 26 is the same as that of Example 25. 1 H NMR (400MHz, CD3OD), 8.00 (d, J=8.0Hz, 1H), 7.90 (dd, J=8.0Hz, 1.6Hz, 1H), 7.58-7.64 (m, 2 H), 7.35 (t, J=7.6Hz, 1H), 6.98 (d, J=8.8Hz, 1H), 6.81 (dd, J=8.8Hz, 2.8Hz, 1H), 3.84 (s, 3H) , 3.57(s, 2H), 3.45-3.53(m, 2H), 3.38-3.44(m, 1H), 3.19-3.29(m, 1H), 2.88(s, 6H), 2.60( t, J=12.0Hz, 2H), 2.03-2.06 (m, 2H), 1.71-1.82 (m, 2H), 1.51 (s, 6H), 1.29 (d, J=7.2Hz, 6H).

[0168] Example 27: 4-{[4-({2-[dioxy-2-ylamino)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxybenzene-1-carboxamide

[0169]

[0170] Example 27 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD+CDCl3), 8.32 (d, J=8.4Hz, 1H), 8.06 (d, J=8.8Hz, 1H), 7.83 (dd, J=8.0Hz, 1.6Hz, 1H), 7.47-7.52 ( m, 1H), 7.35 (d, J=2.0Hz, 1H), 7.09-7.14 (m, 2H), 3.90 (s, 3H), 3.33-3.40 (m, 3H), 1.42 (s, 6H), 0.94 (d, J=6.4Hz, 6H).

[0171] Example 28: 2-chloro-4-{[4-({2-[dioxy-2-ylamino)-λ 6-(1-methylhexahydropyridin-4-yl)benzamide

[0172]

[0173] The synthesis method of Example 28 is the same as that of Example 20. 1 H NMR (400MHz, DMSO), 8.39 (s, 1H), 8.26-8.28 (m, 2H), 8.12 (d, J=8.4Hz, 1H), 7. 77 (s, 1H), 7.75 (s, 1H), 7.51 (t, J = 7.6Hz, 1H), 7.41 (s, 1H), 7.09 (t, J = 7.6Hz, 1H), 7.03(s, 1H), 6.96(s, 1H), 3.78-3.94(m, 4H), 3.07-3.30(m, 7H), 2.53(s, 3H), 1.86-1.96 (m, 2H), 1.60-1.74 (m, 2H), 1.36 (s, 6H), 0.94 (d, J=6.4Hz, 6H).

[0174] Example 29: 4-{[4-({2-[dioxy-2-ylamino)-λ 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0175]

[0176] The synthesis method of Example 29 is the same as that of Example 17. 1 H NMR (400MHz, DMSO), 8.26 (s, 1H), 8.13-8.14 (m, 2H), 8.00 (d, J=7.6Hz, 1H), 7.74-7.77 ( m, 2H), 7.47 (t, J=7.6Hz, 1H), 7.31 (s, 1H), 7.09 (t, J=7.6Hz, 1H), 6.93 (s, 1H), 6.88 (s, 1H), 3.84(s, 3H), 3.71-3.83(m, 1H), 3.24-3.52(m, 5H), 2.92-3.09(m, 2H), 2.41(s, 3H) , 2.00 (s, 3H), 1.80-1.90 (m, 2H), 1.52-1.66 (m, 2H), 1.36 (s, 6H), 0.93 (d, J=6.4Hz, 6H).

[0177] Example 30: 2-(dimethylamino)-1-(7-{[4-({2-[dioxy-2-yl)- 6 -1,2,3,4-tetrahydroquinolin-1-yl)ethan-1-one trifluoroacetate

[0178]

[0179] Example 30 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.48 (s, 1H), 8.38 (d, J=8.4Hz, 1H), 8.12-8.28 (brs, 1H), 7.82 (dd, J=8.4Hz, 1.2Hz, 1H), 7.52 (t, J=7.2Hz, 1H), 7.16-7.28 (brs, 1H), 7.10 (t, J=7.6 Hz, 1H), 6.64 (s, 1H), 5.80-6.19 (brs, 1H), 3.64-4.04 (m, 8H), 3.38 (s, 2H), 3.23-3. 33 (m, 1H), 2.56-2.84 (m, 8H), 1.93-1.99 (m, 2H), 1.45 (S, 6H), 1.31 (d, J=7.2Hz, 6H).

[0180] Example 31: 2-Fluoro-4-{[(5S)-4-({2-[dioxy-2-yl)- 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0181]

[0182] Example 31 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.56 (s, 1H), 8.33 (d, J=15.2Hz, 1H), 8.29 (d, J=8.8Hz, 1H), 7.86 (d, J=8 .0Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.61 (s, 1H), 7.45 (d, J=6.8Hz, 1H), 7.24 (t, J=7.6Hz, 1H), 6 .68-6.82(m, 1H), 4.64(s, 1H), 4.07-4.21(m, 1H), 3.54-3.96(m, 6H), 3.40-3.49(m, 1H), 3.21 -3.29 (m, 2H), 2.40-2.90 (m, 5H), 1.90-2.20 (m, 4H), 1.38 (d, J=6.8Hz, 3H), 1.27-1.31 (m, 6H).

[0183] Example 32: 2-Fluoro-4-{[(5S)-4-({2-[dioxy-2-ylamino)-λ 6 -(1-methylhexahydropyridin-4-yl)benzamide

[0184]

[0185] Example 32 was prepared by general synthetic procedure A. 1 H NMR (400 MHz, CD3OD), 1 H NMR (400MHz, DMSO), 8.37 (d, J=14.8Hz, 1H), 8.12 (d, J=8.4Hz, 1H), 7.87 (dd, J=8.4Hz, 1.6Hz, 1H), 7.5 7 (t, J=8.0Hz, 1H), 7.24 (d, J=7.2Hz, 1H), 7.13 (t, J=7.6Hz, 1H), 4.10-4.20 (m, 1H), 3.93 (s, 3H), 3.82 ( t, J=9.2Hz, 1H), 3.42-3.56 (m, 3H), 3.31-3.39 (m, 1H), 3.23 (dd, J=9.2Hz, 4.0Hz, 1H), 2.99-3.14 (m, 2H ), 2.84 (s, 3H), 1.96-2.20 (m, 4H), 1.32 (d, J = 6.4Hz, 3H), 1.02 (d, J = 6.8Hz, 3H), 0.91 (d, J = 6.8Hz, 3H).

[0186] Example 33: 2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-N-(propan-2-yl)benzenesulfonamide

[0187]

[0188] Example 33 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.52 (s, 1H), 7.90 (d, J=7.6Hz, 1H), 7.62-7.79 (m, 1H ), 7.45-7.56 (m, 1H), 7.28 (t, J=7.6Hz, 1H), 7.08 (s, 1H), 4.31 (s, 2H), 4.1 1(t,J=8.4Hz, 2H), 3.86(s, 3H), 3.79(t,J=8.4Hz, 2H), 3.34-3.43(m, 1H), 3.29-3.33 (m, 2H), 2.99 (s, 6H), 2.72-2.83 (m, 2H), 1.02 (d, J=6.8Hz, 6H).

[0189] Example 34: 2-Fluoro-4-{[4-({3-fluoro-2-[(methylamino)carbonyl]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

[0190]

[0191] Example 34 compound was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 10.23 (s, 1H), 8.39 (d, J = 15.6Hz, 1H), 8.11 (d, J = 8.4Hz, 1H) , 7.59 (s, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 6.81 (dd, J=12.0Hz, 8.4Hz, 1H), 6.73 (dd J=15.6Hz, 8.0Hz, 1H), 6.59-6.70 (m, 1H), 4.68 (s, 1H), 4.14-4.27 (m, 1H), 3.89 (s, 3H), 3. 30-3.45 (m, 4H), 3.01 (d, J=4.8Hz, 3H), 2.62-2.80 (m, 5H), 2.06-2.24 (m, 4H), 1.53 (s, 6H).

[0192] Example 35: 4-{[4-({2-[dioxy-2-yl)-λ 6 -(1-methylpiperidin-4-yl)benzamide

[0193]

[0194] Example 35 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.25 (d, J=8.4Hz, 1H), 7.81 (dd, J=8.0Hz, 1.6Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 7.57-7.61 (m, 1H), 7.15-7.20 (m, 2H), 3. 91-4.01(m, 1H), 3.67(s, 3H), 3.32-3.38(m, 3H), 2.95-3.08(m, 2H), 2.42-2.58( m, 5H), 2.00-2.09 (m, 2H), 1.63-1.76 (m, 2H), 1.45 (s, 6H), 1.26 (d, J=7.2Hz, 6H).

[0195] Example 36: 2-(8-{[4-({2-[dioxy-2-yl)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepan-3-yl)-N,N-dimethylacetamide

[0196]

[0197] Example 36 was prepared by general synthetic procedure A. 1 H NMR (400MHz, DMSO), 8.28 (s, 1H), 8.21 (d, J=8.0Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J=8.0Hz, 1.2Hz, 1H), 7.53-7.56 (m, 1H), 7.23 (s, 1H), 7.18 (t, J=7.6Hz, 1H), 6.89 (s, 1H), 6.77 (s, 1H), 3.78 (s, 3H), 3.22-3.46 (m, 11 H), 2.99 (s, 3H), 2.76-2.90 (m, 5H), 1.35 (s, 6H), 1.15 (d, J=6.8Hz, 6H).

[0198] Example 37: 2-({2-[(6-methoxy-2-methyl-1-oxoylidene-2,3-dihydro-1H-isoindol-5-yl)amino]-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-N-(propan-2-yl)benzenesulfonamide

[0199]

[0200] Example 37 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.44 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.97 (dd, J=8.0Hz, 1.6Hz, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.50-7.54 (m, 1H), 7.24 (s, 1H), 7. 20(t, J=7.6Hz, 1H), 4.68(s, 1H), 4.27(d, J=7.6Hz, 1H), 3.98(s, 2H), 3.93( s, 3H), 3.28-3.46 (m, 3H), 3.15 (s, 3H), 1.49 (s, 6H), 0.96 (d, J=6.8Hz, 6H).

[0201] Example 38: 2-[(2-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(propan-2-yl)benzenesulfonamide

[0202]

[0203] Example 38 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.16 (d, J=8.4Hz, 1H), 8.10 (d, J=2.8Hz, 1H), 7.91-7.94 (m, 2H), 7.4 4-7.48 (m, 1H), 7.40 (s, 1H), 7.07 (t, J=8.0Hz, 1H), 6.74 (d, J=8.8Hz, 1H), 6.40 (dd, J=8.8H z, 2.8Hz, 1H), 4.81-4.91 (brs, 1H), 4.76 (s, 1H), 3.82 (s, 3H), 3.44-3.52 (m, 1H), 3.37 (s, 2 H), 2.91-2.94 (m, 4H), 2.56-2.66 (m, 4H), 2.47 (s, 3H), 1.46 (s, 6H), 1.08 (d, J=6.8Hz, 6H).

[0204] Example 39: 6-{[4-({2-[dioxy-2-yl)- 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one

[0205]

[0206] Step 1:

[0207] Under ice bath, NaH (50 mg) was added to the DMF solution (5 mL) of compound 39-1 (300 mg). The reaction solution continued to react for 0.5 h under ice bath, and then iodomethane (0.25 mL) was added dropwise thereto. The reaction solution was slowly warmed to room temperature and reacted overnight. Saturated ammonium chloride solution (50 mL) was added to the compound to quench. The resulting solution was extracted with ethyl acetate (30 mL × 3), the extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was separated and purified by rapid silica gel column chromatography to obtain compound 39-2 (294 mg).

[0208] Palladium-carbon catalyst (50 mg) was added to a solution of compound 39-2 (285 mg) in methanol (10 mL), and the reaction solution was reacted at room temperature overnight under hydrogen. The filtrate was filtered through celite and concentrated under reduced pressure to obtain 39-3 (260 mg), which was directly used in the next step without further purification.

[0209] Example 39 was prepared using compound 39-3 as a raw material by general synthesis procedure A. 1HNMR (400 MHz, CDCl3), 8.42 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 7.87 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.61 (s, 1H), 7.51-7.56 (m, 2H), 7.14 (t, J = 7.6 Hz, 1 H), 4.85 (s, 1H), 3.91 (s, 3H), 3.46 (t, J=6.4Hz, 2H), 3.38 (s, 2H), 3.23-3.34 ( m, 1H), 3.11 (s, 3H), 2.64 (t, J=6.4Hz, 2H), 1.48 (s, 6H), 1.29 (d, J=6.8Hz, 6H).

[0210] Example 40: 2-{[(5S)-2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-N-(propan-2-yl)benzenesulfonamide

[0211]

[0212] Example 40 was prepared by general synthetic procedure A. 1 H NMR (400MHz, DMSO), 8.55 (d, J=8.4Hz, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.80 (d, J=8.0Hz, 1H ), 7.67 (d, J=8.0Hz, 1H), 7.46 (s, 1H), 7.24 (t, J=7.6Hz, 1H), 6.92-6.96 (m, 2H), 6.65 (s, 1H ), 4.14 (t, J = 8.4Hz, 2H), 3.73 (s, 3H), 3.65 (t, J = 9.2Hz, 1H), 3.19-3.35 (m, 4H), 3.04-3.1 2 (m, 3H), 2.25 (s, 6H), 1.15 (d, J=7.2Hz, 3H), 1.00 (d, J=6.4Hz, 3H), 0.89 (d, J=6.4Hz, 3H).

[0213] Example 41: 2-(Dimethylamino)-1-(6-{[(5S)-4-({2-[dioxy-2-yl)- 6-1H-indol-1-yl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one trifluoroacetate

[0214]

[0215] Example 41 was prepared by general synthetic procedure A. 1 H NMR (400MHz, DMSO), 9.38-9.94 (brs, 1H), 8.58 (s, 1H), 8.53 (d, J=8.8Hz, 1H), 8.41 (s, 1H), 7.6 6 (dd, J=8.0Hz, 1.6Hz, 1H), 7.58 (s, 1H), 7.39 (t, J=8.0Hz, 1H), 7.05 (t, J=7.6Hz, 1H), 6.99 (s, 1 H), 6.71 (s, 1H), 4.17 (s, 2H), 4.05 (t, J=8.4Hz, 2H), 3.75 (s, 3H), 3.66 (t, J=9.6Hz, 1H), 3.31- 3.39 (m, 1H), 3.16-3.26 (m, 3H), 3.06 (dd, J=9.6Hz, 4.0Hz, 1H), 2.74 (s, 6H), 1.14-1.18 (m, 9H).

[0216] Example 42: 2-(Dimethylamino)-1-(7-{[4-({2-[dioxy-2-yl)- 6 -1H-3-benzazepan-3-yl]ethyl-1-one (5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepan-3-yl)-1-one

[0217]

[0218] Example 42 compound was prepared by general synthetic procedure A. 1H NMR (400MHz, CD3OD), 8.16 (d, J=8.0Hz, 0.5H), 8.11 (d, J=8.0Hz, 0.5H), 8.05 (s, 0.5H), 8.00 (s, 0.5H), 7 .84-7.87(m,1H),7.59-7.66(m,1H),7.23-7.29(m,1H),6.77(s,1H),4.22(s,1H),4.19(s,1H),3.88(s,1 .5H), 3.87(s, 1.5H), 3.71-3.74(m, 1H), 3.62-3.64(m, 1H), 3.49-3.53(m, 1H), 3.42-3.46(m, 1H), 3.30-3 .39 (m, 3H), 2.80-2.98 (m, 8H), 2.61-2.64 (m, 1H), 2.51-2.54 (m, 1H), 1.46 (s, 6H), 1.26 (d, J=7.2Hz, 6H).

[0219] Example 43: 2,2,2-trifluoroacetic acid 2-[(4-{3-[2-(dimethylamino)ethyl]-2-oxo-ylidenetetrahydro-1H-imidazol-1-yl}-2-methoxyphenyl)amino]-4-({2-[dioxy-ylidene(propan-2-yl)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0220]

[0221] Example 43 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.44 (s, 1H), 8.36 (d, J=8.0Hz, 1H), 8.23 ​​(d, J=9.2Hz, 1H), 7.84 (dd, J=8.0Hz, 1.6Hz, 1H), 7.53-7.58 (m, 1H), 7.51 (s, 1H), 7.11-7.15 (m, 1H), 6.55 (dd, J=9.2H z, 2.4Hz, 1H), 4.61 (s, 1H), 3.88 (s, 3H), 3.82-3.86 (m, 2H), 3.50-3.63 (m, 4H), 3.35 (s, 2H) ), 3.24-3.31 (m, 1H), 2.84-3.03 (m, 2H), 2.62 (s, 6H), 1.47 (s, 6H), 1.30 (d, J=6.8Hz, 6H).

[0222] Example 44: 4-{[4-({2-[dioxy-2-yl)-λ 6-(1-methylhexahydropyridin-4-yl)benzamide

[0223]

[0224] Step 1:

[0225] At room temperature, HATU (839 mg) was added to a DMF (10 mL) solution of compound 44-1 (500 mg), 44-2 (25 mg) and DIEA (1 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by rapid silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain compound 44-3 (415 mg).

[0226] Step 2:

[0227] Under nitrogen protection, Pd2(dba)3 (20 mg) was added to a toluene (15 mL) solution of compound 44-3 (300 mg), benzophenone imine (189 mg), cesium carbonate (340 mg) and Davephos (20 mg). The reaction solution was heated to 120°C and reacted overnight. After cooling to room temperature, 1N hydrochloric acid (15 mL) was added to the reaction solution and stirred for 30 minutes. The pH value of the aqueous phase was then adjusted to 8 with a saturated sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by rapid silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain compound 44-4 (210 mg).

[0228] Example 44 was prepared using compound 44-4 as a raw material by general synthesis procedure A. 1HNMR (400 MHz, CDCl3), 8.47 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.54-7.58 (m, 1H), 7.35 (s, 1H), 7.17 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 7.11-7.15 (m, 1H), 6.75 (s, 1H), 6.13 (d, J = 7.6 Hz, 1 H), 4.87 (s, 1H), 3.95-4.07 (m, 1H), 3.60 (s, 3H), 3.36 (s, 2H), 3.19-3.30 (m, 1H), 2.87-2.90 (m, 2H), 2. 35 (s, 3H), 2.23-2.29 (m, 2H), 2.01-2.09 (m, 2H), 1.57-1.67 (m, 2H), 1.46 (s, 6H), 1.27 (d, J=6.8Hz, 6H).

[0229] Example 45: 4-({2-[dioxy-2-yl)-λ 6 -{[2-methoxy-4-methyl-5-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0230]

[0231] The synthesis method of the compound in Example 45 is the same as that of the compound in Example 25. 1 H NMR (400MHz, CDCl3), 8.43 (s, 1H), 8.29 (d, J=8.4Hz, 1H), 8.17 (s, 1H), 7.81 (dd , J=8.0Hz, 1.6Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.20 (s, 1H), 7.06 (t, J=7.6Hz, 1H) , 6.66(s, 1H), 4.87(s, 1H), 3.82(s, 3H), 3.28-3.39(m, 3H), 2.64-2.74(m, 4H), 2 .41-2.54(m, 4H), 2.31(s, 3H), 2.23(s, 3H), 1.45(s, 6H), 1.32(d, J=6.8Hz, 6H).

[0232] Example 46: 2-[(2-{[2-methoxy-4-methyl-5-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(propan-2-yl)benzenesulfonamide

[0233]

[0234] The synthesis method of the compound in Example 46 is the same as that in Example 25. 1 H NMR (400MHz, CDCl3), 8.10-8.13 (m, 2H), 7.88-7.91 (m, 2H), 7.42 (t, J=8.0Hz, 1H), 7.24(s, 1H), 7.03(t, J=8.0Hz, 1H), 6.65(s, 1H), 4.98(s, 1H), 4.76(s, 1H), 3.82(sr 3H), 3.47-3.55 (m, 1H), 3.34 (s, 2H), 2.53-2.63 (m, 4H), 2.37-2.48 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H), 1.45 (s, 6H), 1.09 (d, J=6.0Hz, 6H).

[0235] Example 47: 2-[(2-{[2-methoxy-4-(5-methyl-2,5-diazepin-2-yl)phenyl]amino}-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(propan-2-yl)benzenesulfonamide

[0236]

[0237] Example 47 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.23 ​​(d, J=8.4Hz, 1H), 8.01 (d, J=8.8Hz, 1H), 7.88-7.92 (m, 2H), 7.46-7.50 (m, 1H), 7.10-7.14 (m, 2H), 6.38 (d, J=2.8Hz, 1H), 6.13 (dd, J=9.2Hz, 2.8Hz , 1H), 4.76-4.94 (brs, 1H), 4.31 (d, J=7.6Hz, 1H), 3.85 (s, 3H), 3.57 (t, J=7.2Hz, 2H), 3.35-3.44 (m, 3H), 2.82-2.94 (m, 5H), 2.62 (s, 6H), 1.46 (s, 6H), 0.99 (d, J=6.8Hz, 6H).

[0238] Example 48: 2-[(2-{[5-fluoro-2-methoxy-4-(5-methyl-2,5-diazepin-2-yl)phenyl]amino}-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(propan-2-yl)benzenesulfonamide

[0239]

[0240] Example 48 compound was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD+CDCl3), 7.95-8.02 (m, 2H), 7.84 (d, J=8.0Hz, 1H), 7.47 (t, J=8.0Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 6.58 (d, J=8 .0Hz, 1H), 3.81 (s, 3H), 3.28-3.40 (m, 5H), 3.16 (t, J=5.6Hz, 2H), 2.83 (s, 6H), 2.73 (s, 3H), 1.44 (s, 6H), 0.96 (d, J=6.4Hz, 6H).

[0241] Example 49: 2-({2-[(4-{3-[2-(dimethylamino)ethyl]-2-oxoylidetetrahydro-1H-imidazol-1-yl}-2-methoxyphenyl)amino]-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-N-(propan-2-yl)benzenesulfonamide

[0242]

[0243] Example 49 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.15-8.19 (m, 2H), 7.90 (d, J=7.6Hz, 1H), 7.86 (s, 1H), 7.48-7.52 (m, 2H), 7.24 (s, 1H), 7.11 (t, J = 7.6Hz, 1H), 6.45 (dd, J = 8.8Hz, 2.4Hz, 1H), 4.77 (s, 1H), 4.56 ( d, J=7.6Hz, 1H), 3.86 (s, 3H), 3.76-3.80 (m, 2H), 3.51-3.55 (m, 2H), 3.49 (t, J=6.4Hz, 2H), 3.33-3.42 (m, 3H), 2.78 (t, J=6.4Hz, 2H), 2.50 (s, 6H), 1.45 (s, 6H), 0.97 (d, J=6.4Hz, 6H).

[0244] Example 50: 6-{[2-({1-[2-(dimethylamino)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-2-fluoro-N-methylbenzamide

[0245]

[0246] Example 50 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 9.90 (s, 1H), 8.47 (s, 1H), 8.02 (s, 1H), 7.42 (s, 1H), 7.30 (s, 1H), 7.14-7.20 (m, 1H), 6.65-6.70 (m, 1H), 6.59 (s, 1H), 4 .64(s, 1H), 3.85(s, 3H), 3.71-3.80(m, 2H), 3.35(s, 2H), 2.85-3.08(m , 5H), 2.53-2.71(m, 2H), 2.11(s, 6H), 1.87-1.94(m, 2H), 1.50(s, 6H).

[0247] Example 51: 2-{[(5S)-2-({1-[2-(dimethylamino)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-N-(propan-2-yl)benzenesulfonamide

[0248]

[0249] Example 51 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD+CDCl3), 8.14 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.63-7.79 (m, 1H), 7.36 (t, J=7.6Hz, 1H), 7.08 (t, J=7.6Hz, 1H), 6.61 (s , 1H), 3.58-3.89(m, 8H), 3.40-3.52(m, 1H), 3.14-3.30(m, 2H), 2.72(s, 6H), 2.61(t, J=6.4Hz, 2H), 1.84-1.94(m, 2H), 1.08-1.13(m, 9H).

[0250] Example 52: 6-Fluoro-2-{[(5S)-2-({1-[2-(dimethylamino)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino)-5-methyl-6,7-.hydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-N-methylbenzamide

[0251]

[0252] Example 52 was prepared by general synthetic procedure A. 1 H NMR(400MHz, CD3OD+CDCl3), 8.13 / (s, 1H), 7.77-7.88(m, 1H), 7.08-7.16(m, 1H), 6.66-6.71(m, 1H), 6.63(s, 1H), 3.48-3.90(m, 8H ), 3.30-3.40 (m, 1H), 3.22-3.25 (m, 1H), 2.92 (s, 3H), 2.68 (s, 6H), 2.63 (t, J=6.4Hz, 2H), 1.86-1.96 (m, 2H), 1.26 (d, J=6.8Hz, 3H).

[0253] Example 53: 2-(Dimethylamino)-1-(7-{[(5S)-4-({2-[dioxy-2-yl)- 6 -1-yl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)ethan-1-one

[0254]

[0255] Example 53 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.64 (s, 1H), 8.30-8.40 (m, 1H), 7.95-8.14 (m, 1H), 7 .76(d, J=8.0Hz, 1H), 7.36-7.50(m, 1H), 7.05(t, J=8.0Hz, 1H), 6.65(s, 1H ), 4.14-4.37(m, 2H), 3.54-3.94(m, 3.54-3.94(m, 8H), 3.18-3.23(m, 3H), 2.93 (s, 6H), 2.67 (t, J=6.4Hz, 2H), 1.87-1.97 (m, 2H), 1.14-1.36 (m, 9H).

[0256] Example 54: 2-{[2′-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-6′,7′-dihydrospiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-4′-yl]amino}-N-(propan-2-yl)benzenesulfonamide

[0257]

[0258] Example 54 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CD3OD), 8.90 (s, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.75 (d, J = 8.4Hz, 1H) , 7.33 (t, J=7.6Hz, 1H), 6.97 (t, J=7.6Hz, 1H), 6.84 (s, 1H), 4.08 (t, J=8.0Hz, 2 H), 3.83 (s, 3H), 3.55 (s, 2H), 3.42 (s, 2H), 3.31-3.38 (m, 1H), 3.12 (t, J=8.0Hz , 2H), 2.46 (s, 6H), 1.49-1.52 (m, 2H), 1.03 (d, J=6.4Hz, 6H), 0.78-0.81 (m, 2H).

[0259] Example 55: 2-(dimethylamino)-N-(3-{[4-({2-[dioxy-2-yl)- 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-4-methoxyphenyl)-N-methylacetamide

[0260]

[0261] At room temperature, HATU (940 mg) was added to a solution of compound 55-1 (300 mg), compound 55-2 (255 mg) and DIEA (0.55 mL) in THF (10 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (100 mL), and washed with 1N hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL) and saturated brine (20 mL) in sequence, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by rapid silica gel column chromatography to obtain compound 55-3 (323 mg).

[0262] Palladium-carbon catalyst (50 mg) was added to a solution of compound 55-3 (300 mg) in methanol (10 mL), and the reaction solution was reacted at room temperature overnight under hydrogen. The filtrate was filtered through celite and concentrated under reduced pressure to obtain 55-4 (295 mg), which was used directly in the next step without further purification.

[0263] Compound 55-4 was prepared by general synthetic procedure A to give Example 55. 1 H NMR (400MHz, CDCl3), 8.39 (s, 1H), 8.28 (d, J = 2.0Hz, 1H), 8.16 (d, J = 8.0Hz, 1H), 8.34 (dd , J=8.0Hz, 1.6Hz, 1H), 7.52 (t, J=8.0Hz, 1H), 7.44 (s, 1H), 7.19 (t, J=8.0Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 6.64 (dd, J=8.4Hz, 2.0Hz, 1H), 4.78 (s, 1H), 3.90 (s, 3H), 3.38 (s, 2H), 3.19 -3.28 (m, 1H), 3.02 (s, 3H), 2.93 (s, 2H), 2.29 (s, 6H), 1.47 (s, 6H), 1.26 (d, J=6.8Hz, 6H).

[0264] Example 56: 2-(dimethylamino)-N-(3-{[4-({2-[dioxyylidene(propan-2-ylamino)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-4-methoxyphenyl)-N-methylacetamide

[0265]

[0266] Example 56 was prepared by general synthetic procedure A. 1H NMR (400MHz, CDCl3), 8.19 (d, J=2.0Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.91 (d, J=8.0Hz, 1 H), 7.83 (s, 1H), 7.45 (t, J=7.6Hz, 1H), 7.43 (s, 1H), 7.17 (t, J=7.6Hz, 1H), 6.77 (d, J= 8.4Hz, 1H), 6.60 (dd, J=8.4Hz, 2.4Hz, 1H), 4.81-4.95 (brs, 2H), 3.87 (s, 3H), 3.32-3. 43 (m, 3H), 2.96 (s, 3H), 2.88 (s, 2H), 2.29 (s, 6H), 1.44 (s, 6H), 0.98 (d, J=6.4Hz, 6H).

[0267] Example 57: 2-[(5-{3-[2-(dimethylamino)ethyl]-2-oxoylidetetrahydro-1H-imidazol-1-yl}-2-methoxyphenyl)amino]-4-({2-[dioxyidene(propan-2-yl)-λ 6 -thio]phenyl}amino)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0268]

[0269] Example 57 was prepared by general synthetic procedure A. 1 H NMR (400MHz, CDCl3), 8.42 (s, 1H), 8.33 (d, J=2.4Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 7.82 (dd, J =8.4Hz, 1.6Hz, 1H), 7.47 (t, J = 8.0Hz, 1H), 7.33 (s, 1H), 7.22 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.0 6(t, J=8.0Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 4.99 (s, 1H), 3.84 (s, 3H), 3.46 (t, J=6.4Hz, 2H), 3.29-3.42 (m, 7H), 2.81 (t, J=6.4Hz, 2H), 2.53 (s, 6H), 1.45 (s, 6H), 1.30 (d, J=7.2Hz, 6H).

[0270] Biological activity test

[0271] 1. Compounds inhibit ALK G1202R / L1196M In vitro enzyme activity assay

[0272] In this patent, the ALK G1202R / L1196M Kinase activity detection platform to measure the activity of the compound. Prepare the reaction buffer: 50mM HEPES, pH 7.5; 0.1mMNa3VO4; 0.001% Tween-20; 5mM MnCl2; 1mM DTT; 50nM SEB (purchased from Cisbio) and 0.01% BSA. The compound was diluted 5 times with DMSO starting from 1mM (a total of 10 concentrations), and 2μL of each diluted compound was added to 48μL reaction buffer for dilution and mixing. Take 2.5μL of the diluted compound and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 2.5μL of ATP (final concentration of 4μM) and TK peptide substrate (final concentration of 2μM, purchased from Cisbio) mixture, and then add 5μL His-ALK G1202R / L1196M (final concentration of 0.5nM), centrifuged, started the reaction, the total reaction volume was 10μL. The 384-well plate was placed in an incubator at 23°C for 1 hour, and then 5μL LTKAntibody (purchased from Cisbio) and 5μL Streptavidin-XL665 (purchased from Cisbio) were added to stop the reaction. After incubation in the incubator for another 1 hour, the fluorescence value was read on the Envision machine (purchased from PerkinElmer) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is ALK G1202R / L1196M The signal value of the compound at each concentration was measured, and the activity signal value of the compound on His-ALK was calculated using GraphPad Prism software. G1202R / L1196M IC of enzyme inhibition 50 value.

[0273] Table 1. Effects of Example Compounds on ALK G1202R / L1196M The inhibitory effect

[0274]

[0275] 2. Compounds inhibit BaF3 EML4-ALK G1202R / L1196M Cell proliferation activity assay

[0276] Baf3 EML4-ALK V1 G1202R / L1196MThe cells were cultured in suspension using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, purchased from Gibco, Brazil) and 1% penicillin / streptomycin (P / S, purchased from Life Technology). The cells were cultured in a cell culture incubator at 37°C and 5% CO2. The day before the compound test, Baf3 EML4-ALKV1 G1202R / L1196M The cells were plated in a 96-well plate (purchased from Corning) at a density of 2000 cells / 195 μL / well. After 24 hours, the compound was diluted 3-fold with DMSO starting from 10 mM (a total of 11 concentrations), and then 2 μL of each concentration was added to 48 μL of serum-free culture medium for further dilution. 5 μL of each concentration of the diluted compound was added to the cell culture plate and placed in a cell culture incubator for further culture for 3 days. After 3 days, 35 μL of Cell-Titer Glo reagent (purchased from Promega) was added directly to the culture medium. Incubate at room temperature for 5-10 minutes. The fluorescence signal value was read on the Envision machine, and the IC value of the compound for inhibition of cell proliferation was calculated using GraphPadPrism software. 50 value.

[0277] Table 2. Effect of Example Compounds on BaF3 EML4-ALK G1202R / L1196M Inhibition of cell proliferation

[0278]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof: in, R2 is selected from -(SO2)-R 10 、-(SO2)-NH-R 10 , or -(CO)-NH-R 10 , R 10 C 1-6 alkyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution, R3 and R4 are each independently selected from H, C 1-3 alkyl, or R3 and R4 are linked together to form a 3-5 membered carbocyclic ring, wherein the alkyl or carbocyclic ring may be optionally substituted by halogen, R5 is halogen, CN, C 1-6 Alkyl or halogenated C 1-6 alkyl, R6 is selected from H, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or 3-8 membered heterocyclic group or -(CO)-NH-R 11 , the heterocyclic group may be optionally substituted by R9, R7 is H, halogen, CN, C 1-6 Alkyl or halogenated C 1-6 alkyl, R1 is selected from H, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 alkyl, or a 3-8 membered heterocyclic group, or -(CO)-NH-R8, the heterocyclic group may be optionally substituted by R9, or R1 and R6 or R7 are linked together to form a nitrogen-containing heterocyclic ring, wherein the nitrogen in the heterocyclic ring may be optionally replaced by C 1-6 Alkyl or -(CH2) 0-1 -(CO)-(CH2) 0-1 -N(CH3)2 substitution, R 11 Selected from C 1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, or R 11 and R1 are connected together to form a nitrogen-containing heterocyclic ring, wherein the alkyl, cycloalkyl, heterocyclic group, or heterocyclic ring may be optionally substituted by halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, R8 is selected from C 1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, or R8 and R6 or R7 are connected together to form a nitrogen-containing heterocyclic ring, and the alkyl, cycloalkyl, heterocyclic group, or heterocyclic ring can be optionally substituted by halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, R9 are each independently selected from halogen, CN, =O, OR 10 , C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) 0-1 -(CO)-(CH2) 0-1 -N(CH3)2, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group may be optionally substituted by halogen, CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution, R 10 Selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl, n is 0, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R 10 C 1-6 alkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R1 is -(CO)-NH-R8, and R8 is as defined in claim 1.

4. The compound or pharmaceutically acceptable salt, solvate, polymorph or isomer according to claim 1, wherein R3 and R4 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, or R3 and R4 are linked together to form a 3-4 membered carbocyclic ring.

5. The following compound or its pharmaceutically acceptable salt, solvate, polymorph, or isomer:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a composition according to claim 6 in the preparation of a medicament for treating ALK-mediated diseases.

8. The use according to claim 7, wherein the ALK-mediated disease has an ALK site mutation of G1202R and / or an ALK site mutation of L1196M.

9. The use according to claim 8 or 9, wherein the ALK-mediated disease is ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, systemic histiocytosis, or neuroblastoma.

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