Ethylamino-substituted tricyclic heterocyclic compounds, compositions, formulations and uses thereof

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and relates to ethylamino-substituted tricyclic heterocyclic compounds, compositions, formulations and uses thereof. Specifically, the general structure of the tricyclic heterocyclic compound is shown as formula I. The compound of the present application has excellent in-vitro inhibitory activity against SOS1, so that it can be used as a SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good antitumor activity, and has good effects on treating neoplastic diseases of mammals (including humans).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology and relates to a series of novel ethylamino-substituted tricyclic heterocyclic compounds, pharmaceutical compositions and formulations containing the same, and their pharmaceutical uses. Background Technology

[0002] Mutations in the KRAS gene are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, bile duct cancer, and thyroid cancer. KRAS is a GTP-binding protein. In vivo, RAS exists in two main forms: an inactive state bound to GDP and an activated state bound to GTP. Its activity is regulated by two proteins: guanylate exchange factor (GEF) such as SOS1 promotes the release of GDP from the RAS protein, enabling GTP binding and activating RAS; GTPase activators activate the GTPase activity of the RAS protein, hydrolyzing the GTP bound to the RAS protein into GDP, thus inactivating RAS. In the GTP-bound state, RAS family proteins are active and bind effector proteins (including RAF and PI3K) to promote pathways such as RAF / MEK / ERK and PI3K / AKT / mTOR. These pathways influence various cellular processes, such as proliferation, survival, and metabolism.

[0003] SOS1 has two binding sites for RAS family proteins: one is a catalytic site that binds to GDP-binding RAS family proteins to promote guanine nucleotide exchange, and the other is an allosite that binds to GTP-binding RAS family proteins, thereby further increasing the catalytic GEF function of SOS1 (Biochem. Pharmacol., 2011, 82(9):1049-1056). SOS1 plays an important role in the activation of mutant KRAS and oncogenic signaling in cancer (Nat. Commun., 2012, 3:1168). In tumor cells carrying KRAS mutations, reducing SOS1 levels can decrease the proliferation rate of tumor cells, while no effect was observed in KRAS wild-type cell lines.

[0004] RAS, the first confirmed oncogene, is the most frequently mutated oncogene, accounting for 25% of human cancers. In recent decades, the interaction between RAS family proteins and the SOS1 protein has gained increasing recognition. Currently, only Boehringer Ingelheim's SOS1 inhibitor BI1701963 is in Phase I clinical trials; no other SOS1 inhibitors have been developed and marketed. Therefore, developing new SOS1 inhibitors has significant clinical value and broad market prospects. Summary of the Invention

[0005] The problem the invention aims to solve

[0006] In order to develop new SOS1 inhibitors, this invention aims to provide a novel ethylamino-substituted tricyclic heterocyclic compound and its composition, formulation and use, wherein the derivative has excellent SOS1 inhibitory activity, good pharmacodynamic properties and high metabolic stability.

[0007] Solution for solving the problem

[0008] In a first aspect, the present invention provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof:

[0009]

[0010] in:

[0011] Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 6-membered heterocyclic groups;

[0012] n is 0, 1, 2, or 3;

[0013] If it exists, each R 1 Selected independently from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 The cycloalkyl, 3- to 6-membered heterocyclic, amino, halogen, cyano, and nitro groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, amino, hydroxyl, -C 1-6 Alkyl-NH(C) 1-6 alkyl) and -C 1-6 Alkyl-N(C) 1-6 Alkyl)2;

[0014] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl groups and halogens;

[0015] R 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 3-14 cycloalkyl, C 3-14 Cycloalkenyl, 3- to 14-membered heterocyclic groups, C6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a -OR 4a -C(=O)OR 4a -NR 4a R 4b -P(=O)R 4a R 4b and -C(=O)NR 4a R 4b The alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: =O, =NH, -P(=O)R 4a R 4b nitro, carboxyl, cyano, amino, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-14 Cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-14 cycloalkyl, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)OC 1-6 alkyl;

[0016] If it exists, R 4a and R 4b Independently selected from hydrogen and C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 alkenyl, -C(=O)-C 3-14 Cycloalkyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic groups, -C(=O)NH-3 to 14-membered heterocyclic groups, -C(=O)-C 6-10 Aryl, -C(=O)-5 to 10-membered heteroaryl and -S(=O) m -C 1-6Alkyl, wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: amino, halogen, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups; m is 0, 1 or 2;

[0017] R 5 Selected from hydrogen, amino, halogen, nitro, C 1-6 Alkyl and -OC 1-6 alkyl;

[0018] Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 aryl, 5 to 10 heteroaryl, =O, =CH2, =NH, -C(=O)R 5a -OR 5a -C(=O)OR 5a -NR 5a R 5b and -C(=O)NR 5a R 5b Alternatively, any two of the substituents together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group;

[0019] If it exists, R 5a and R 5b Independently selected from hydrogen and C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0020] D is N or CR 6 ;

[0021] If it exists, R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, halogen, cyano, -OR 6a and -NR 6a R 6b ;

[0022] If it exists, R 6a and R 6b Independently selected from hydrogen and C 1-6 Alkyl, C 1-6Halogenated alkyl groups and C 3-6 cycloalkyl;

[0023] Indicates a single bond or a double bond;

[0024] The ring B is 5 to 15 nucleotides, preferably 5 to 8 nucleotides of heteroaryl or heterocyclic group;

[0025] p is 0, 1, 2, 3, 4, 5 or 6;

[0026] If it exists, each R 2 Independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 aryl and 5 to 10-membered heteroaryl, or two R groups simultaneously connected to any one ring atom. 2 Forms =O or =CH2;

[0027] The heterocyclic group and heteroaryl group each contain one or more heteroatoms selected from N, O, S and P as ring atoms.

[0028] Secondly, the present invention provides the following non-limiting examples of compounds having the structure of Formula I:

[0029] (1)(R)-1-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)imidazo[1,2-a]pyrido[3,2-e]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one;

[0030] (2)(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7,8-dimethoxyimidazo[1,2-a]quinazolin-5-amine;

[0031] (3)(R)-1-(4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one;

[0032] (4)(R)-1-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one;

[0033] (5)(R)-3-(1-((7-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]quinazolin-5-yl)amino)ethyl)-2-methylbenzonitrile;

[0034] (6)(R)-1-(4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)piperidin-1-yl)ethyl-1-one;

[0035] (7)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(3,6-dihydro-2H-pyran-4-yl)imidazo[1,2-a]quinazolin-5-amine;

[0036] (8)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(3,6-dihydro-2H-thiaran-4-yl)imidazo[1,2-a]quinazolin-5-amine;

[0037] (9)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]quinazolin-5-amine;

[0038] (10)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]quinazolin-5-amine;

[0039] (11)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-phenylimidazo[1,2-a]quinazolin-5-amine;

[0040] (12)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(pyridin-2-yl)imidazo[1,2-a]quinazolin-5-amine;

[0041] (13)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(pyridin-3-yl)imidazo[1,2-a]quinazolin-5-amine;

[0042] (14)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(pyridin-4-yl)imidazo[1,2-a]quinazoline-5-amine;

[0043] (15)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(thiophen-3-yl)imidazo[1,2-a]quinazolin-5-amine;

[0044] (16)4-(5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)-1-imino-1,2,3,6-tetrahydro-1λ 6 -Thiaran-1-oxide;

[0045] (17)N-(4-(5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)-1-oxo-3,6-dihydro-2H-1λ 6 -Thiaran-1-Ideoxy)acetamide;

[0046] (18)(R)-1-(4-(5-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one;

[0047] (19)(R)-1-(4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-[1,2,4]triazolo[1,5-a]quinazolin-7-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one;

[0048] (20)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)imidazo[1,2-a]quinazolin-5-amine;

[0049] (21)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-morpholinylimidazo[1,2-a]quinazoline-5-amine;

[0050] (22)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiperazin-1-yl)imidazo[1,2-a]quinazolin-5-amine;

[0051] (23)N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]quinazolin-5-amine;

[0052] (24)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-8,9-dihydro-[1,4]dioxaconzo[2,3-g]imidazo[1,2-a]quinazolin-5-amine;

[0053] (25)(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-8,9,11,12,14,15-hexahydro-[1,4,7,10]tetraoxane-dodecathatetraen[2,3-g]imidazo[1,2-a]quinazolin-5-amine

[0054] (26)(R)-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)dimethylphosphine oxide; and

[0055] (27)(R)-1-(4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinazolin-7-yl)-4-oxo-1,4-nitrophosphorus-1-yl)ethyl-1-one.

[0056] Thirdly, the present invention provides a pharmaceutical composition comprising the compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0057] Preferably, in the above-described pharmaceutical composition, the pharmaceutically acceptable carrier includes (but is not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odor-correcting agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, opacifiers, etc.

[0058] Fourthly, the present invention provides a pharmaceutical formulation made from the compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or from the pharmaceutical composition described above.

[0059] Fifthly, the present invention provides the use of the above-described compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or the above-described pharmaceutical composition, or the above-described pharmaceutical preparation, in the preparation of a medicament for the prevention and / or treatment of diseases at least partially mediated by the SOS1 protein.

[0060] Preferably, in the above-described uses, the diseases at least partially mediated by the SOS1 protein are cancers, particularly those selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0061] In a sixth aspect, the present invention provides a pharmaceutical combination comprising the compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or the pharmaceutical composition thereof, or the pharmaceutical formulation thereof, and at least one additional cancer therapeutic agent.

[0062] The effects of the invention

[0063] The compounds of this invention exhibit excellent in vitro inhibitory activity against SOS1, enabling them to function as SOS1 inhibitors. They inhibit cell proliferation and angiogenesis, demonstrating good anti-tumor activity and showing promising efficacy in treating neoplastic diseases in mammals (including humans). Detailed Implementation

[0064] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for description only and not for limiting the specific embodiments.

[0065] [Terminology Definition]

[0066] Unless otherwise stated, the following terms have the following meanings.

[0067] The term "pharmaceutically acceptable salt" refers to a salt of a compound having the structure of Formula I that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compounds of this invention with pharmaceutically acceptable inorganic or organic acids; such salts are also known as acid addition salts. Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (which can form sulfates or acid sulfates), and phosphoric acid (which can form phosphates or acid phosphates). Common organic acids include (but are not limited to) trifluoroacetic acid, citric acid (which can form mono-, di-, or tri-salts of citrate), maleic acid (which can form mono- or di-salts of maleic acid), fumaric acid (which can form mono- or di-salts of fumaric acid), succinic acid (which can form mono- or di-salts of succinic acid), tartaric acid (which can form mono- or di-salts of tartaric acid), oxalic acid (which can form mono- or di-salts of oxalic acid), oxalic acid (which can form mono- or di-salts of oxalic acid), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0068] The term "hydrate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with water through non-covalent intermolecular forces. Common hydrates include (but are not limited to) hemihydrates, monohydrates, dihydrates, and trihydrates.

[0069] The term "solvent" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces. The term "solvent" includes "hydrate." Common solvates include (but are not limited to) hydrates, ethanol compounds, acetone compounds, etc. It should be understood that the present invention covers all solvate forms possessing SOS1 inhibitory activity.

[0070] The term "isomer" refers to compounds that have the same number and type of atoms and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms.

[0071] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Because the compounds of this invention and their salts comprise asymmetric carbon atoms, they can exist as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched with single stereoisomers (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). As described below, a single stereoisomer of a compound is synthesized from an optically active starting material containing the desired chiral center, or prepared by separating or resolving a mixture of enantiomers, for example, by converting it into a mixture of diastereomers and then separating or recrystallizing, chromatographically processing, using chiral resolving reagents, or by directly separating the enantiomers on a chiral chromatographic column. Starting compounds with specific stereochemistry are commercially available or prepared according to the methods described below and then resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other. The term "diastereomer" or "diastereomer" refers to an optically active isomer that is not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomers of the compounds of this invention are within the scope of this invention.

[0072] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0073] The term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) on opposite sides of a double bond or ring system relative to a reference plane; in the cis isomer, the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise stated, all cis-trans isomers of the compounds of this invention are within the scope of this invention.

[0074] The term "isotope-labeled compound" refers to a compound formed by replacing specific atoms in a structure with their isotopic atoms. Unless otherwise indicated, the compounds of this invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as... 2 H(D), 3 H(T), 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.

[0075] The term "prodrug" refers to a derivative compound that, when administered to a patient, can directly or indirectly provide the compounds of the present invention. Particularly preferred derivative compounds or prodrugs are those that, when administered to a patient, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise stated, all prodrug forms of the compounds of the present invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0076] The term "aryl" refers to a monovalent group, either a monocyclic or fused polycyclic aromatic ring, whose ring atoms are all carbon atoms, for example, it can have 6 to 20, 6 to 14, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include (but are not limited to) phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene, etc. 6-10 "Aryl" refers to an aryl group having 6-10 carbon atoms. 6-10 Non-limiting examples of aryl groups include (but are not limited to) phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalene.

[0077] The term "heteroaryl" refers to a monovalent group that is aromatic, either monocyclic or fused polycyclic, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, S, and P, and the remaining ring atom is C, for example, a 5- to 10-membered ring, especially a 5- to 8-membered ring. Non-limiting examples of heteroaryls include (but are not limited to) The term “5 to 10-membered heteroaryl” refers to a heteroaryl group having 5 to 10 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P. Non-limiting examples of 5 to 10-membered heteroaryl groups include (but are not limited to) furanyl, pyrroleyl, thiophenyl, pyridyl, indolyl and quinolinyl, etc.

[0078] The term "heterocyclic group" refers to a fully saturated or partially unsaturated (but not fully unsaturated, e.g., having one or two double bonds) monocyclic, bridged, or spirocyclic monocyclic group, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C, for example, it can be a 3- to 14-membered ring, or even a 3- to 6-membered ring. The term "3- to 14-membered heterocyclic group" refers to a heterocyclic group having 3 to 14 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S, and P; the term "3- to 6-membered heterocyclic group" refers to a heterocyclic group having 3 to 6 ring atoms, which may contain 1 or 2 heteroatoms selected from N, O, S, and P; the term "5- to 15-membered heterocyclic group" refers to a heterocyclic group having 5 to 15 ring atoms, which may contain 1 to 5 heteroatoms selected from N, O, S, and P.

[0079] Non-limiting examples of saturated 3-membered heterocyclic groups include (but are not limited to) ethylene oxide, cyclothioalkyl, cycloazoalkyl, etc.; non-limiting examples of saturated 4-membered heterocyclic groups include (but are not limited to) acridineyl, oxadiidineyl, thiamethidineyl, etc.; non-limiting examples of saturated 5-membered heterocyclic groups include (but are not limited to) tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, etc.; non-limiting examples of saturated 6-membered heterocyclic groups include (but are not limited to) piperidinyl, tetrahydropyrazolyl, etc. Dynanoyl, tetrahydrothiaranyl, cyclopentyl sulfoxide, cyclopentyl sulfone, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, 1,4-diphosphine hexane, 1,4-nitrophosphine hexane, 4-oxo-1,4-nitrophosphine hexane, thiomorpholinyl, 1,3-dithiaalkyl, 1,4-dithiaalkyl, etc.; non-limiting examples of saturated 7-membered heterocyclic groups include (but are not limited to) azirhepyl, oxehepyl, thiohepyl, 2,6-diazaspiro[3.3]hepyl, 2-oxa-6-azaspiro[3.3]hepyl, etc.

[0080] Non-limiting examples of partially unsaturated heterocyclic groups include (but are not limited to) wait.

[0081] The term "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group that does not contain unsaturation. The term "C"... 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms; the term "C" is used in this context. 1-6"Alkyl" refers to an alkyl group having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkyl groups include (but are not limited to) methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), sec-butyl (-CH(CH3)CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), neopentyl (-CH2C(CH3)3), etc.

[0082] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds, and can have, for example, 2 to 20 carbon atoms. The term "C"... 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms; the term "C" 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkenyl groups include (but are not limited to) vinyl, propenyl, allyl, butenyl, 2-methyl-2-buten-1-yl, pentenyl, hexenyl, etc.

[0083] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds, and can have, for example, 2 to 20 carbon atoms. The term "C"... 2-6 "Alkyne group" refers to an alkynyl group having 2 to 6 carbon atoms; the term "C" 2-4 "Alkyne group" refers to an alkynyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkynyl groups include (but are not limited to) ethynyl, propynyl, 1-propynyl, 1-butynyl, pentyynyl, hexynyl, etc.

[0084] The term "haloalkyl" refers to a straight-chain or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a halogen atom, and it does not contain unsaturation. The term "C"... 1-6 "Halogenated alkyl" refers to an alkyl halogroup having 1 to 6 carbon atoms; the term "C" 1-4 "Halogenated alkyl" refers to an alkyl halogroup having 1 to 4 carbon atoms. C 1-6 Non-limiting examples of haloalkyl groups include (but are not limited to) -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, etc.

[0085] The term "hydroxyalkyl" refers to a straight-chain or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a hydroxyl group, and it does not contain unsaturation. The term "C"... 1-6"Hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 6 carbon atoms; the term "C" 1-4 "Hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 4 carbon atoms. 1-6 Non-limiting examples of hydroxyalkyl groups include (but are not limited to) -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, etc.

[0086] The term "cycloalkyl" refers to a fully saturated monocyclic or polycyclic (e.g., spirocyclic, fused, or bridged) monocyclic hydrocarbon group, which may have 3 to 20, 3 to 12, 3 to 6, or 5 to 6 carbon atoms. The term "C" refers to a cycloalkyl group. 3-14 "Cycloalkyl" refers to a cycloalkyl group having 3 to 14 carbon atoms; the term "C" 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. A monocyclic C 3-14 Non-limiting examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.; polycyclic C 3-14 Cycloalkyl groups include (but are not limited to) decahydronaphthyl, adamantyl, etc.

[0087] The term "cycloalkenyl" refers to a monovalent cyclic hydrocarbon group (e.g., spirocyclic, fused, or bridged, but not aromatic) having one or more carbon-carbon double bonds, and may have, for example, 3 to 20, 3 to 12, 3 to 6, or 5 to 6 carbon atoms. The term "C" refers to... 3-14 "Cycloalkenyl" refers to a cycloalkenyl group having 3 to 14 carbon atoms. 3-14 Non-limiting examples of cycloalkenyl groups include (but are not limited to) cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, etc.

[0088] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), which are located in Group VII of the periodic table.

[0089] The term "hydroxyl group" refers to the -OH group.

[0090] The term "amino" refers to the -NH2 group. In some cases, amino can also indicate that at least one H atom in the structure is further surrounded by an alkyl group (e.g., C). 1-6 Monovalent groups formed by alkyl substitution.

[0091] The term "nitro" refers to the -NO2 group.

[0092] The term "cyano" refers to the -CN group.

[0093] The term "oxo" refers to the =O group attached to a carbon atom, while the term "oxidation group" refers to the =O group attached to a sulfur or phosphorus atom.

[0094] The term "single bond" refers to a chemical bond between atoms that connects or interacts with each other, such as ionic bonds, covalent bonds, and coordinate bonds; in the molecular structure of organic compounds, single bonds are usually covalent bonds.

[0095] The term "optionally" means that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, "optionally" substituted with a halogen means that the heterocyclic group may be unsubstituted or monosubstituted, polysubstituted, or fully substituted with a halogen atom. Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or synthetically unsynthetic is introduced.

[0096] [Ethylamino-substituted tricyclic heterocyclic compounds]

[0097] This invention provides a series of novel ethylamino-substituted tricyclic heterocyclic compounds or pharmaceutically acceptable forms thereof, such as salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels, or prodrugs of such compounds.

[0098] In one embodiment of the present invention, the structure of this type of compound is shown in Formula I:

[0099]

[0100] in:

[0101] Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 6-membered heterocyclic groups;

[0102] n is 0, 1, 2, or 3;

[0103] If it exists, each R 1 Selected independently from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 The cycloalkyl, 3- to 6-membered heterocyclic, amino, halogen, cyano, and nitro groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, amino, hydroxyl, -C 1-6 Alkyl-NH(C) 1-6 alkyl) and -C 1-6 Alkyl-N(C) 1-6 Alkyl)2;

[0104] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl groups and halogens;

[0105] R 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 3-14 cycloalkyl, C 3-14 Cycloalkenyl, 3- to 14-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a -OR 4a -C(=O)OR 4a -NR 4a R 4b -P(=O)R 4a R 4b and -C(=O)NR 4a R 4b The alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: =O, =NH, -P(=O)R 4a R 4b nitro, carboxyl, cyano, amino, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-14 Cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-14 cycloalkyl, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)OC 1-6 alkyl;

[0106] If it exists, R 4a and R 4b Independently selected from hydrogen and C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, -C(=O)-C1-6 Alkyl, -C(=O)-C 2-6 alkenyl, -C(=O)-C 3-14 Cycloalkyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic groups, -C(=O)NH-3 to 14-membered heterocyclic groups, -C(=O)-C 6-10 Aryl, -C(=O)-5 to 10-membered heteroaryl and -S(=O) m -C 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: amino, halogen, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups; m is 0, 1 or 2;

[0107] R 5 Selected from hydrogen, amino, halogen, nitro, C 1-6 Alkyl and -OC 1-6 alkyl;

[0108] Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 aryl, 5 to 10 heteroaryl, =O, =CH2, =NH, -C(=O)R 5a -OR 5a -C(=O)OR 5a -NR 5a R 5b and -C(=O)NR 5a R 5b Alternatively, any two of the substituents together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group;

[0109] If it exists, R 5a and R 5b Independently selected from hydrogen and C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0110] D is N or CR 6 ;

[0111] If it exists, R 6 Selected from hydrogen, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, halogen, cyano, -OR 6a and -NR 6a R 6b ;

[0112] If it exists, R 6a and R 6b Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl;

[0113] Indicates a single bond or a double bond;

[0114] Ring B is a 5- to 15-membered heteroaryl or heterocyclic group;

[0115] p is 0, 1, 2, 3, 4, 5 or 6;

[0116] If it exists, each R 2 Independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 aryl and 5 to 10-membered heteroaryl, or two R groups simultaneously connected to any one ring atom. 2 Forms =O or =CH2;

[0117] The heterocyclic group and heteroaryl group each contain one or more heteroatoms selected from N, O, S and P as ring atoms.

[0118] In one embodiment of the present invention, ring A in formula I is selected from C. 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0119] In one specific embodiment of the present invention, ring A in formula I is C 6-10 Aryl.

[0120] In a more specific embodiment of the invention, A in Formula I is selected from phenyl.

[0121] In another specific embodiment of the present invention, ring A in Formula I is a 5- to 10-membered heteroaryl group.

[0122] In another, more specific embodiment of the invention, A in Formula I is selected from thiophene group.

[0123] In one embodiment of the present invention, n in Formula I is 0, 1 or 2, preferably 1 or 2, more preferably 2.

[0124] In one specific embodiment of the present invention, n in formula I is 0, that is, ring A is not affected by R. 1 Substituent substitution.

[0125] In another specific embodiment of the present invention, n in formula I is 1, that is, ring A is surrounded by 1 R. 1 Substituent substitution, and the R 1 The substituent is substituted at any substituted site on ring A.

[0126] In yet another specific embodiment of the present invention, n in formula I is 2, that is, ring A is surrounded by 2 identical or different R. 1 Substituent substitution, and the two Rs 1 Substituents can be substituted independently at any substituted site on ring A.

[0127] In one embodiment of the invention, each R in Formula I... 1 Selected independently from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic groups, amino, halogen, cyano, and nitro groups.

[0128] In one specific embodiment of the present invention, each R in Formula I... 1 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl, amino, halogen, and cyano groups.

[0129] In a more specific embodiment of the invention, each R in Formula I... 1 It is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, naphthyl, amino, fluorine, chlorine, bromine, iodine and cyano.

[0130] In one or even more specific embodiments of the invention, each R in Formula I... 1 It is independently selected from methyl, -CHF2, -CF3, phenyl, amino, fluorine and cyano groups.

[0131] In a further more specific embodiment of the invention, each R in Formula I... 1 It is independently selected from -CHF2, -CF3, amino and fluorine.

[0132] In one embodiment of the invention, R in Formula I 3 Selected from hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0133] In one specific embodiment of the present invention, R in Formula I... 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2 and -CH2CH2CF3.

[0134] In a more specific embodiment of the invention, R in Formula I... 3 It is hydrogen.

[0135] In one embodiment of the invention, R in Formula I... 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a -OR 4a -C(=O)OR 4a -NR 4a R 4b -P(=O)R 4a R 4b and -C(=O)NR 4a R 4b Preferred groups include hydrogen, halogen, cyano, nitro, and C. 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a -C(=O)OR 4a -NR 4a R 4b -P(=O)R 4a R 4b and -C(=O)NR 4a R 4b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: =O, =NH, amino, halogen, C. 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)OC 1-6 alkyl;

[0136] If it exists, R 4a and R 4b Independently selected from hydrogen and C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 alkenyl, -C(=O)-C 3-14 Cycloalkyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic groups, -C(=O)NH-3 to 14-membered heterocyclic groups, -C(=O)-C 6-10 Aryl, -C(=O)-5 to 10-membered heteroaryl and -S(=O) m -C 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: amino, halogen, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups; m is 0, 1 or 2.

[0137] In one specific embodiment of the present invention, R in Formula I... 4 Selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a -OR 4a -NR 4a R 4b and -P(=O)R 4a R 4b Preferred groups include hydrogen, halogen, nitro, and C. 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a -NR 4a R 4b and -P(=O)R 4a R 4b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one substituent; if present, the substituent is selected from the following groups: =O, =NH, amino, halogen, C. 1-6 Alkyl, -OC 1-6 Alkyl groups and -C(=O)-C 1-6 alkyl;

[0138] If it exists, R 4a and R 4b Independently selected from hydrogen and C 1-6Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 alkenyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic groups, -C(=O)-C 6-10 Aryl and -S (=O) m -C 1-6 Alkyl group, wherein the alkyl and alkenyl groups are each optionally substituted with one or more substituents; if present, each substituent is independently selected from the following groups: halogen, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups; m is 0, 1 or 2.

[0139] In a more specific embodiment of the invention, R in Formula I... 4Selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrroloyl (e.g., pyrrolo-1-yl, pyrrolo-2-yl, or pyrrolo-3-yl), imidazole, pyrazole (e.g., 1H-pyrazole-3-yl or 1H-pyrazole-4-yl), furanyl, oxazolyl, isoxazolyl, thiophene (e.g., thiophene-2-yl or thiophene-3-yl), thiazolyl (e.g., thiazolyl-2-yl, thiazolyl-4-yl, or thiazolyl-5-yl), isothiazolyl, dihydropyrroloyl (e.g., 2,5-dihydro-1H... -pyrrolo-3-yl), dihydrofuranyl, dihydrothiophenyl, pyrrolinyl (e.g., pyrrolin-1-yl, pyrrolin-2-yl, or pyrrolin-3-yl), tetrahydrofuranyl, tetrahydrothiophenyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), pyranyl, thioranyl, dihydropyridinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridin-4-yl), piperidinyl (e.g., piperidin-4-yl), dihydropyranyl (e.g., 3,6-dihydro-2H-pyran-4-yl), tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), dihydrothiaranyl (e.g., 3,6-dihydro-2H-thiaran-4-yl), dihydrothiaranyl oxide (e.g., 1-oxo-3,6-dihydro-2H-thiaran-4-yl), dihydrothiaranyl dioxide (e.g., 1,1-dioxo-3,6-dihydro-2H-thiaran-4-yl), imino dihydrothiaranyl oxide (e.g., 1-imino-1-oxo-3,6-dihydro-2H-thiaran-4-yl), 4-yl), tetrahydrothiaranyl (e.g., tetrahydro-2H-thiaran-4-yl), tetrahydrothiaranyl oxide (e.g., 1-oxo-tetrahydro-2H-thiaran-4-yl), tetrahydrothiaranyl dioxide (e.g., 1,1-dioxo-tetrahydro-2H-thiaran-4-yl), imino-tetrahydrothiaranyl oxide (e.g., 1-imino-1-oxo-tetrahydro-2H-thiaran-4-yl), piperazineyl (e.g., piperazine-1-yl), nitrogen-phosphorus hexaneyl oxide (e.g., 4-oxo-1,4-nitrophosphorus hexane-4-yl), 1,4-diazo alkyl groups (e.g., 1,4-diazepines) -1-yl), 3,8-diazabicyclo[3.2.1]octyl (e.g., 3,8-diazabicyclo[3.2.1]oct-3-yl), 2-oxa-6-azaspiro[3.3]heptyl (e.g., 2-oxa-6-azaspiro[3.3]hept-6-yl), morpholinyl (e.g., morpholin-2-yl, morpholin-3-yl or morpholin-4-yl), indoleyl, indazoleyl (e.g., 1H-indazole-3-yl, 1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl or 1H-indazole-7-yl), methoxy, ethoxy, propoxy, formyl, acetyl and propionyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, nitro, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, pyrrololinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrimidinyl, pyridyl, pyranyl, thioranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydrothioranyl oxide, dihydrothioranyl dioxide, imino-dihydrothioranyl oxide, tetrahydrothioranyl oxide, tetrahydrothioranyl dioxide, imino-tetrahydrothioranyl oxide, piperazine, nitrogen-phosphorus hexane, 1,4-diazepine 3,8-diazabicyclo[3.2.1]octyl, 2-oxa-6-azaspiro[3.3]heptyl, morpholinyl, indole, indazole, formyl, acetyl and propionyl;

[0140] The phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazole, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrimidinyl, pyridinyl, pyranyl, thioranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydrothioranyl, tetrahydrothioranyl, piperazine, and 1,4-diazolyl The methyl, morpholino, indole, and indazole groups are each optionally substituted by one substituent; if present, the substituent is selected from the following groups: =O, =NH, amino, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, acetyl, and propionyl.

[0141] In one or more specific embodiments of the present invention, R in Formula I... 4Selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyridyl, pyranyl, thioranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydrothioranyl, tetrahydrothioranyl, piperazine, nitric oxide phosphorus hexane, 3,8-diazabicyclo[3.2.1]octyl, 2-oxa-6-azaspiro[3.3]heptyl and morpholinyl;

[0142] The phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, pyrrololinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyridyl, pyranyl, thioranyl, dihydropyridyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, dihydrothioranyl, tetrahydrothioranyl, piperazine, and morpholinyl groups are each optionally substituted by one substituent; if present, the substituent is selected from the following groups: =O, =NH, methyl, ethyl, n-propyl, isopropyl, acetyl, and propionyl.

[0143] In a further more specific embodiment of the invention, R in Formula I... 4 Selected from phenyl, pyrrolyl, furanyl, thiophenyl, pyridyl, pyranyl, thiaranyl, dihydropyridyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, tetrahydrothiaranyl, piperazine, and morpholinyl;

[0144] The phenyl, pyrrolyl, furanyl, thiophenyl, pyridyl, pyranyl, thiaranyl, dihydropyridyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, tetrahydrothiaranyl, piperazineyl, and morpholinyl groups are each optionally substituted by a substituent; if present, the substituent is selected from the following groups: =O, =NH, methyl, ethyl, n-propyl, isopropyl, acetyl, and propionyl.

[0145] In another, more specific embodiment of the invention, R in Formula I 4 -P(=O)R 4a R 4b R 4a and R 4b Independently selected from hydrogen and C 1-6 Alkyl, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups, wherein each of the alkyl, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: amino, halogen, C 3-14 Cycloalkyl groups and 3 to 14-membered heterocyclic groups; preferably, R 4a and R4b Independently selected from hydrogen and C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more substituents; if present, each substituent is independently selected from amino and halogen groups; more preferably, R 4a and R 4b Independently selected from hydrogen and C 1-6 Alkyl; more preferably, R 4a and R 4b It is independently selected from hydrogen and methyl.

[0146] In one embodiment of the invention, R in Formula I... 5 Selected from hydrogen and -OC 1-6 Alkyl group, preferably hydrogen.

[0147] In one embodiment of the invention, R in Formula I... 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, C 1-6 Alkyl, =O, =CH2, =NH, -C(=O)R 5a -OR 5a -C(=O)OR 5a -NR 5a R 5b and -C(=O)NR 5a R 5b ;

[0148] R 5a and R 5b Independently selected from hydrogen and C 1-6 alkyl.

[0149] In a preferred embodiment of the present invention, R in Formula I 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, C 1-6 Alkyl, =O, and =CH2.

[0150] In a more specific embodiment of the invention, R in Formula I... 4 and R 5Together with the atoms to which they are attached, they form 5, 6, 9, 12, 14 or 15-membered heterocyclic groups, preferably 6, 9 or 12-membered heterocyclic groups, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, =O and =CH2.

[0151] In one embodiment of the present invention, D in Formula I is CR 6 R 6 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, halogen, cyano, -OR 6a and -NR 6a R 6b ;

[0152] If it exists, R 6a and R 6b Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 3-6 Cycloalkyl.

[0153] In one specific embodiment of the present invention, D in Formula I is CR 6 R 6 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -OR 6a and -NR 6a R 6b ;

[0154] If it exists, R 6a and R 6b Independently selected from hydrogen and C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0155] In a more specific embodiment of the present invention, D in Formula I is CH.

[0156] In another embodiment of the invention, D in Formula I is N.

[0157] In one embodiment of the present invention, ring B in Formula I is a 5- to 8-membered heteroaryl or heterocyclic group.

[0158] In one specific embodiment of the present invention, ring B in Formula I is a 5- to 8-membered heteroaryl group.

[0159] In a more specific embodiment of the present invention, ring B in Formula I is a 5-membered heteroaryl group.

[0160] In a further specific embodiment of the present invention, ring B in Formula I is a pyrrole ring, an imidazole ring, or a pyrazole ring.

[0161] In one of the most specific embodiments of the present invention, ring B in Formula I is an imidazole ring.

[0162] In one embodiment of the present invention, p in Formula I is 0, 1 or 2, preferably 0 or 1, more preferably 0.

[0163] In one specific embodiment of the present invention, p in formula I is 0, that is, ring B is not affected by R. 2 Substituent substitution.

[0164] In another specific embodiment of the present invention, p in formula I is 1, that is, ring B is surrounded by 1 R. 2 Substituent substitution, and the R 2 The substituent is substituted at any substituted site on ring B.

[0165] In yet another specific embodiment of the invention, p in formula I is 2, that is, ring B is surrounded by two identical or different R. 2 Substituent substitution, and the two Rs 2 Substituents can be substituted independently at any substituted site on ring B.

[0166] In one embodiment of the invention, each R in Formula I... 2 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0167] In one specific embodiment of the present invention, each R in Formula I... 2 Independently selected from hydrogen, halogens and C 1-4 alkyl.

[0168] In a more specific embodiment of the invention, each R in Formula I... 2 It is hydrogen independently.

[0169] In one embodiment of the present invention, the structure of the compound of formula I is as shown in formula I':

[0170]

[0171] in:

[0172] X, Y, and Z are independently N or CR 2 ;

[0173] If it exists, each R 2 Independently selected from hydrogen, halogen, C1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 The aryl group and 5 to 10-membered heteroaryl group, wherein each of the heterocyclic group and heteroaryl group comprises one or more, preferably one to five, more preferably one to three heteroatoms selected from N, O, S and P as ring atoms; preferably, each R 2 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, C 6-10 aryl and 5 to 10-membered heteroaryl; more preferably, each R 2 Independently selected from hydrogen, halogens and C 1-4 Alkyl; more preferably, each R 2 Independently hydrogen;

[0174] Rings A, n, R 1 R 3 R 4 R 5 And D is as defined in Equation I.

[0175] In one embodiment of the present invention, X and Y in formula I' are CR 2 When Z is N, the structure of compound I' is as shown in formula I'-1:

[0176]

[0177] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0178] In one specific embodiment of the present invention, the structure of the compound of formula I'-1 is shown as that of formula I'-1A or I'-1B:

[0179]

[0180] Where: n, R 1 R 2 R 3 R 4 R 5 and R 6 As defined in equation I'-1;

[0181] Preferably, R in formula I'-1A 2 R 3 and R 5 All are hydrogen; R in formula I'-1B 2 R3 and R 6 All are hydrogen, preferably R 5 It is also hydrogen.

[0182] In one specific embodiment of the present invention, the structure of the compound of formula I'-1 is shown as that of formula I'-1C, formula I'-1D or formula I'-1E:

[0183]

[0184] Where: n, R 1 R 2 R 3 R 4 R 5 and R 6 As defined in equation I'-1;

[0185] Preferably, R 2 R 3 and R 6 All are hydrogen, preferably R 5 It is also hydrogen.

[0186] In one embodiment of the present invention, X and Z in formula I' are CR 2 When Y is N, the structure of compound I' is as shown in formula I'-2:

[0187]

[0188] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0189] In one embodiment of the present invention, Y and Z in formula I' are CR 2 When X is N, the structure of compound I' is as shown in formula I'-3:

[0190]

[0191] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0192] In one embodiment of the present invention, X in formula I' is CR 2 When Y and Z are N, the structure of compound I' is shown in formula I'-4:

[0193]

[0194] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0195] In one embodiment of the present invention, Y in formula I' is CR 2 When X and Z are N, the structure of compound I' is shown in formula I'-5:

[0196]

[0197] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I';

[0198] Preferably, R 2 R 3 and R 5 Both are hydrogen, with D preferably being CH.

[0199] In one embodiment of the present invention, Z in formula I' is CR 2 When X and Y are N, the structure of compound I' is shown in formula I'-6:

[0200]

[0201] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0202] In one embodiment of the present invention, X, Y, and Z in formula I' are all CR 2 At this point, the structure of compound I' is as shown in formula I'-7:

[0203]

[0204] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0205] In one embodiment of the present invention, X, Y and Z in Formula I' are all N, and the structure of the compound of Formula I' is shown in Formula I'-8:

[0206]

[0207] Where: rings A, n, R 1 R 2 R 3 R 4 R 5 And D is as defined in equation I'.

[0208] In one embodiment of the present invention, formula I, formula I', formula I'-1, formula I'-1A, formula I'-1B, formula I'-2, formula I'-3, formula I'-4, formula I'-5, formula I'-6, formula I'-7 or formula I'-8 for Preferred

[0209] In one embodiment of the present invention, formula I, formula I', formula I'-1, formula I'-1A, formula I'-1B, formula I'-2, formula I'-3, formula I'-4, formula I'-5, formula I'-6, formula I'-7 or formula I'-8 for

[0210] in:

[0211] The ring C is a 5- to 15-membered heterocyclic group;

[0212] q can be 0, 1, 2, 3, 4, 5, or 6;

[0213] If it exists, each R 7 Independently selected from the following groups: halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14-membered heterocyclic groups, C 6-10 aryl, 5 to 10 heteroaryl, =O, =CH2 and =NH, or any two R 7 Together with the atoms they are attached to, they form 5 to 8-membered heterocyclic groups.

[0214] In one specific embodiment of the present invention The ring C in the ring is a 6- to 12-membered heterocyclic group;

[0215] q can be 0, 1, 2, 3, 4, 5, or 6;

[0216] If it exists, each R 7 Independently selected from the following groups: halogen, C 1-4 Alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic groups, C6-10 Aryl, 5 to 10 heteroaryl, =O, =CH2 and =NH.

[0217] In a more specific embodiment of the invention Selected from the following structures:

[0218] Preferably selected from the following structures:

[0219]

[0220] In one embodiment of the present invention, the heterocyclic group and the heteroaryl group each contain 1 to 5 heteroatoms selected from N, O, S and P as ring atoms.

[0221] In another embodiment of the invention, the heterocyclic group and the heteroaryl group each contain 1 to 3 heteroatoms selected from N, O, S and P as ring atoms.

[0222] Specifically, the ethylamino-substituted tricyclic heterocyclic compounds of the present invention include (but are not limited to) the following compounds:

[0223]

[0224]

[0225] [Pharmaceutical Composition]

[0226] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.

[0227] The term "pharmaceuticalally acceptable carrier" refers to a pharmaceutical excipient that is compatible with the active ingredient of a drug and is harmless to the subject, including (but not limited to) one or more of the following: diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odor-correcting agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, and opacifiers.

[0228] The present invention provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof.

[0229] In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0230] [Pharmaceutical Preparations]

[0231] The term "pharmaceutical preparation" refers to a finished drug product prepared in a specific manner and available for use by patients.

[0232] The present invention provides a pharmaceutical formulation made from the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or a combination thereof.

[0233] In one embodiment of the invention, the pharmaceutical preparation is a solid dosage form for oral administration, including (but not limited to) pharmaceutically acceptable capsules, tablets, pills, powders, granules, etc. The solid dosage form may be coated or microencapsulated using a coating or shell material (such as enteric coating or other materials known in the art). The solid dosage form may contain an opaque agent, and the active ingredient therein may be released in a delayed manner into a portion of the digestive tract. Examples of encapsulating components that may be used are polymeric substances and waxes. Additionally, the active ingredient may also be formed into microcapsules with one or more of the aforementioned carriers.

[0234] In another embodiment of the present invention, the above-mentioned pharmaceutical preparation is a liquid dosage form for oral administration, including (but not limited to) pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc.

[0235] In another embodiment of the present invention, the pharmaceutical preparation is a dosage form for parenteral injection, including (but not limited to) physiologically acceptable sterile aqueous or anhydrous water solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.

[0236] In another embodiment of the present invention, the above-mentioned pharmaceutical preparation is a dosage form for local administration, including (but not limited to) ointments, powders, suppositories, drops, sprays, inhalers, etc.

[0237] [Medical Uses]

[0238] Whether it is the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical formulation, all can exhibit inhibitory activity against SOS1. Therefore, the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical formulation, in the preparation of a medicament for the prevention and / or treatment of diseases at least partially mediated by the SOS1 protein.

[0239] The present invention provides the use of the above-described compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs, or pharmaceutical compositions or pharmaceutical preparations thereof, in the preparation of medicaments for the prevention and / or treatment of cancer.

[0240] The term "cancer" refers to a cellular disorder characterized by uncontrolled or disordered cell proliferation, reduced cell differentiation, inappropriate invasion of surrounding tissues, and / or the ability to establish new growth in ectopic locations. Non-limiting examples of cancer include (but are not limited to) pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cell carcinoma, and sarcoma.

[0241] The present invention also provides the above-described compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels or prodrugs, or pharmaceutical compositions or pharmaceutical preparations thereof, for the prevention and / or treatment of diseases (particularly cancer) mediated at least in part by the SOS1 protein.

[0242] The present invention also provides a method for preventing and / or treating diseases (particularly cancer) mediated at least in part by the SOS1 protein, comprising administering a preventive and / or therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or a pharmaceutical composition or formulation thereof, to an individual in need thereof.

[0243] [Combination therapy]

[0244] The present invention provides a pharmaceutical combination comprising the above-described compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or a pharmaceutical composition or formulation thereof, and at least one additional cancer therapeutic agent.

[0245] The term "cancer therapeutic agent" refers to a pharmaceutical composition or formulation that can effectively control and / or combat cancer. Common cancer therapeutic agents include (but are not limited to) antipurine drugs (e.g., pentostatin), antipyrimidine drugs (e.g., 5-fluorouracil), antifolate drugs (e.g., methotrexate), DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., cyclophosphamide), platinum complexes (e.g., cisplatin, carboplatin), DNA-damaging antibiotics (e.g., mitomycin), topoisomerase inhibitors (e.g., camptothecin), DNA-intercalating drugs that interfere with nucleic acid synthesis (e.g., epirubicin), drugs that block the supply of raw materials (e.g., asparaginase), drugs that interfere with microtubule formation (e.g., paclitaxel), and drugs that interfere with ribosome function (e.g., ...). Harmonyquist, cytokines (e.g., IL-1), thymosin, tumor cell proliferation viruses (e.g., adenovirus ONYX-015), vinblastine alkaloids (e.g., vinorelbine), doxorubicins (e.g., doxorubicin, epirubicin, aclarubicin), tinibs (e.g., imatinib, gefitinib, erlotinib, dasatinib, sunitinib), monoclonal antibodies (e.g., trastuzumab, panitumumab, bevacizumab), bortezomib, calcitriol, capecitabine, amylglutathione, letrozole, reninide, everolimus, fulvestrant, irinotecan, pemetrexed, sirolimus, PD-1, PD-L1, etc.

[0246] In one embodiment of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or the above-mentioned pharmaceutical composition or pharmaceutical formulation, may be administered alone or in combination with other cancer therapeutic agents (or antitumor drugs). This combination therapy can be achieved by administering different cancer therapeutic agents simultaneously, sequentially, or separately.

[0247] The technical solutions of the present invention will be further described below with reference to specific embodiments. Unless otherwise stated, the reagents, materials, instruments, etc. used in the following embodiments can be obtained by conventional commercial means, and the experimental methods used are all conventional methods in the art.

[0248] Example 1: Preparation of Compound 1

[0249] (1) Synthetic route of intermediate 1-1

[0250]

[0251] Under nitrogen protection, compound 1-1a (20.00 g, 106.36 mmol, 1.0 eq.), THF (150 mL), tert-butylsulfinamide (19.31 g, 159.54 mmol, 1.5 eq.), and tetraethyl titanate (74.65 g, 327.26 mmol, 2.0 eq.) were added sequentially to the reaction flask. After the addition was complete, the temperature was raised to 80 °C, and the reaction was stirred for 4 hours. After the reaction system was cooled to room temperature, water (150 mL) was added, followed by extraction with ethyl acetate (150 mL) twice. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 1-1b (28.0 g); MS (ESI+): m / z 292.1 [M+1] + .

[0252] Compound 1-1b (28.00 g, 96.19 mmol, 1.0 eq.), THF (400 mL), and water (6 mL) were added sequentially to the reaction flask. After cooling to -60 to -50 °C, sodium borohydride (6.58 g, 173.14 mmol, 1.8 eq.) was slowly added. After the addition was complete, the temperature was raised to -5 to 0 °C and stirred for 30 minutes. The reaction was quenched by adding water (300 mL), followed by extraction twice with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 1-1c (22.2 g); MS (ESI+): m / z 294.1 [M+1] + .

[0253] Compound 1-1c (22.20 g, 75.76 mmol, 1.0 eq.), dioxane (50 mL), and 4M hydrochloric acid (40 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The pH of the system was adjusted to 8-9 using 1M sodium hydroxide solution, and then extracted twice with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was slurried with petroleum ether to give intermediate 1-1 (10.0 g); MS (ESI+): m / z 190.1 [M+1] + .

[0254] (2) Synthetic route of intermediate 1-2

[0255]

[0256] Compound 1-2a (2.41 g, 10 mmol, 1.0 eq.) and phosphorus oxychloride (20 mL) were added sequentially to the reaction flask. The mixture was then heated to 110 °C and reacted for 5 hours. After concentrating to dryness, ethyl acetate (30 mL) was added, followed by slow addition of 10% sodium bicarbonate solution until the pH reached 8–9. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give intermediate 1-2 (1.6 g); MS (ESI+): m / z 277.9 [M+1] + .

[0257] (3) Synthesis of Compound 1

[0258]

[0259] Intermediate 1-2 (2.77 g, 10 mmol, 1.0 eq.), acetonitrile (10 mL), intermediate 1-1 (1.89 g, 10 mmol, 1.0 eq.), and diisopropylethylamine (2.58 g, 20 mmol, 2.0 eq.) were added sequentially to the reaction flask. After addition, the mixture was stirred at room temperature for 12 h. Water (30 mL) and ethyl acetate (30 mL) were added to the system for extraction three times. The mixture was washed twice with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 1-a (3.1 g); MS (ESI+): m / z 431.0 [M+1] + .

[0260] Compound 1-a (430 mg, 1.0 mmol, 1.0 eq.), acetonitrile (2 mL), and aminoacetaldehyde dimethyl acetal (1 mL) were added sequentially to the reaction flask. After addition, the mixture was stirred in a microwave at 130 °C for 5 h. The mixture was then extracted three times with water (10 mL) and ethyl acetate (10 mL), washed twice with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain compound 1-b (330 mg); MS (ESI+): m / z 500.1 [M+1] + .

[0261] Compound 1-b (330 mg) and acetic acid (3 mL) were added sequentially to the reaction flask. After addition, the mixture was stirred in a microwave oven at 160 °C for 3 h. The mixture was then concentrated to obtain the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give compound 1-c (130 mg). MS (ESI+): m / z 436.1 [M+1] + .

[0262] Under nitrogen protection, compound 1-c (130 mg, 0.30 mmol, 1.0 eq.), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (111 mg, 0.36 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (52 ​​mg, 0.045 mmol, 0.15 eq.), sodium carbonate (79.5 mg, 0.75 mmol, 2.5 eq.), dioxane (4 mL), and water (1 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was heated to 90 °C and stirred for 6 hours. After cooling to room temperature, water (5 mL) and ethyl acetate (5 mL) were added for extraction twice. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 1-d (83 mg); MS (ESI+): m / z 539.1 [M+1] + .

[0263] Compound 1-d (83 mg, 0.15 mmol, 1.0 eq.), dichloromethane (4 mL), and trifluoroacetic acid (2 mL) were added sequentially to a reaction flask. After addition, the mixture was stirred at room temperature for 3 h, and the crude product was concentrated and directly added to the next step. Tetrahydrofuran (3 mL), triethylamine (45 mg, 0.45 mmol, 3.0 eq.), and acetyl chloride (24 mg, 0.30 mmol, 2.0 eq.) were added sequentially to the crude product. After addition, the mixture was stirred at room temperature for 2 h, and extracted twice with water (10 mL) and ethyl acetate (10 mL). The mixture was washed twice with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain pure compound 1 (8.9 mg); MS (ESI+): m / z 481.2[M+1] + .

[0264] Example 2: Preparation of Compound 2

[0265]

[0266] Compound 2-a (2.58 g, 10 mmol, 1.0 eq.), acetonitrile (10 mL), intermediate 1-1 (1.89 g, 10 mmol, 1.0 eq.), and diisopropylethylamine (2.58 g, 20 mmol, 2.0 eq.) were added sequentially to a reaction flask. After addition, the mixture was heated to 100 °C and stirred for 5 h. After cooling to room temperature, water (30 mL) and ethyl acetate (30 mL) were added to the system for extraction three times. The mixture was washed twice with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 2-b (2.1 g); MS (ESI+): m / z 412.0 [M+1] + .

[0267] Compound 2-c (350 mg) and compound 2 (15.3 mg) were synthesized using the same methods as compounds 1-b and 1-c in Example 1, respectively. The structural confirmation of compound 2 is as follows: MS (ESI+): m / z 417.2 [M+1] + ; 1 HNMR (400MHz, DMSO-d6): δ8.16-8.06(m,2H),7.98(s,1H),7.67(t,J=7.5Hz,1H),7.61(s,1H),7.50(t,J=7.0Hz,1H),7.29(t,J =7.7Hz,1H),7.25(t,J=54.4Hz,1H),7.17(d,J=1.6Hz,1H),5.82-5.75(m,1H),3.99(s,3H),3.97(s,3H),1.63(d,J=7.0Hz,3H).

[0268] Example 3: Preparation of Compound 3

[0269] (1) Synthetic route of intermediate 3-1

[0270]

[0271] Under nitrogen protection, compound 3-1-a (30.00 g, 111.55 mmol, 1.0 eq.), dioxane (300 mL), tributyl(1-ethoxyvinyl)tin (48.34 g, 133.86 mmol, 1.2 eq.), triethylamine (33.86 g, 334.66 mmol, 3 eq.), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (4.06 g, 5.58 mmol, 0.05 eq.) were added sequentially to the reaction flask. After the addition was complete, the temperature was raised to 90 °C, and the reaction was stirred for 12 hours. After the reaction system was cooled to room temperature, it was filtered. The pH of the filtrate was adjusted to 3 with 4M hydrochloric acid, and then water (300 mL) was added. Then ethyl acetate (300 mL) was added and extracted twice. The organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to give compound 3-1-b (25.0 g).

[0272] Under nitrogen protection, compound 3-1-b (25.00 g, 107.28 mmol, 1.0 eq.), tetrahydrofuran (300 mL), tert-butylsulfinamide (19.48 g, 160.92 mmol, 1.5 eq.), and tetraethyl titanate (48.94 g, 214.56 mmol, 2.0 eq.) were added sequentially to the reaction flask. After the addition was complete, the temperature was raised to 80 °C, and the reaction was stirred overnight. After the reaction system was cooled to room temperature, water (300 mL) was added, followed by extraction twice with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give compound 3-1-c (18.40 g); MS (ESI+): m / z 337.0 [M+1] + .

[0273] Compound 3-1-c (18.4.00 g, 54.75 mmol, 1.0 eq.), tetrahydrofuran (300 mL), and water (5 mL) were added sequentially to the reaction flask. After cooling to -70 to -60 °C, sodium borohydride (3.75 g, 98.55 mmol, 1.8 eq.) was slowly added. After the addition was complete, the mixture was stirred at -60 °C for 30 minutes. The reaction was quenched with water (300 mL), and the mixture was extracted twice with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give compound 3-1-d (11.85 g); MS (ESI+): m / z 339.0 [M+1] + .

[0274] Compound 3-1-d (11.85 g, 35.05 mmol, 1.0 eq.), dioxane (50 mL), and 4 M hydrochloric acid (20 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The pH of the system was adjusted to 8-9 using 1 M sodium hydroxide solution, and then extracted twice with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was slurried with petroleum ether to give intermediate 3-1 (7.5 g); MS (ESI+): m / z 235.0 [M+1] + .

[0275] (2) Synthesis of Compound 3

[0276]

[0277] Compound 3-1b (8.5 g) was obtained by following the synthetic method of compound 1-a;

[0278] Compounds 3-1c (7.5 g), 3-1d (4.9 g), 3-1e (230 mg), and 3-1f (205 mg) were obtained by following the synthetic methods of compounds 1-b, 1-c, 1-d, and compound 1, respectively.

[0279] The method for synthesizing compound 3 from compound 3-1f is as follows:

[0280] Compound 3-1f (52.4 mg, 0.1 mmol, 1.0 eq.), ethanol (3 mL), and tin dichloride (38 mg, 0.2 mmol, 2.0 eq.) were added to the reaction flask. After the addition was complete, the mixture was heated to 85 °C and reacted for 2 hours. Then, water (10 mL) was added, and the mixture was extracted twice with ethyl acetate (10 mL). The mixture was washed twice with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain pure compound 3 (7.1 mg); MS (ESI+): m / z 495.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ9.16(s,1H),8.69(s,1H),8.37-8.25(m,2H),8.16-8.04(m,1H),7.54(d,J=2.2Hz,1H),6.90(d,J=1.8Hz,2H),6.73(t,J=1 .8Hz,1H),6.47(s,1H),5.57-5.52(m,3H),4.24-4.18(m,2H),3.78-3.67 (m,2H),2.74-2.62(m,2H),2.09(d,J=15.2Hz,3H),1.64(d,J=7.0Hz,3H).

[0281] Example 4: Preparation of Compound 4

[0282]

[0283] Except for replacing intermediates 1-2 with compounds 3-1a, the conditions were the same as in Example 1, yielding compound 4 (18.6 mg); MS (ESI+): m / z 480.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.54(s,1H),8.28(d,J=7.1Hz,1H),8.16-8.08(m,1H),8.03(d,J=1 .6Hz,1H),7.97-7.93(m,1H),7.69-7.65(m,1H),7.52-7.48(m,1H),7.31(t,J=7.7Hz,1H),7. 25(t,J=54.4Hz,1H),7.17(d,J=1.6Hz,1H),6.41(s,1H),5.82-5.77(m,1H),4.26-4.16(m,2 H), 3.75-3.69 (m, 2H), 2.68 (d, J = 32.5Hz, 2H), 2.09 (d, J = 15.6Hz, 3H), 1.64 (d, J = 7.0Hz, 3H).

[0284] Examples 5, 8, 10, 12-14 and 18-19: Preparation of compounds 5, 8, 10, 12-14 and 18-19

[0285] Compounds 5, 8, 10, 12-14 and 18-19 were synthesized following procedures substantially similar to those in Example 3 (see Table 1).

[0286] Table 1. Structural and mass spectrometric data of compounds 5, 8, 10, 12-14 and 18-19

[0287]

[0288]

[0289] Example 6: Preparation of Compound 6

[0290]

[0291] Compound 3 (50 mg, 0.10 mmol, 1.0 eq.), 10% palladium on carbon (15 mg), and methanol / tetrahydrofuran (1 mL / 5 mL) were added to the reaction flask. The mixture was purged with hydrogen three times, heated to 30 °C under a hydrogen atmosphere, and reacted for 5 h. The reaction system was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by reversed-phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain compound 6 (15.3 mg); MS (ESI+): m / z 497.1 [M+1] + .

[0292] Example 7: Preparation of Compound 7

[0293]

[0294] Except for replacing N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, the other conditions were the same as those for the synthesis of compounds 1-d in Example 1, yielding compound 7-1a (185 mg); compound 7 (21.3 mg) was obtained by referring to the synthesis method of compound 3 in Example 3; MS (ESI+): m / z 454.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.53(d,J=1.8Hz,1H),8.39(d,J=7.2Hz,1H),8.17-8. 12(m,1H),8.09(d,J=1.8Hz,1H),7.99-7.97(m,1H),7.24(d,J=1.7Hz,1H),6.88 (d,J=5.2Hz,2H),6.71-6.69(m,1H),6.51-6.50(m,1H),5.54-5.49(m,3H),4.3 2-4.30(m,2H),3.91(t,J=5.4Hz,2H),2.74-2.54(m,2H),1.60(d,J=7.0Hz,3H).

[0295] Example 9: Preparation of Compound 9

[0296]

[0297] Compound 9-1a (105 mg) was obtained by referring to the synthesis method of compound 3 in Example 3.

[0298] Compound 9-1a (58 mg, 0.15 mmol, 1.0 eq.), dichloromethane (4 mL), and trifluoroacetic acid (2 mL) were added sequentially to a reaction flask. After addition, the mixture was stirred at room temperature for 3 h. The crude product was concentrated, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (25 mL * 3), separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography (DCM / MeOH = 50 / 1, v / v) to give compound 9 (35 mg); MS (ESI+): m / z 453.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.53(d,J=1.8Hz,1H),8.39(d,J=7.2Hz,1H),8.17-8.12( m,1H),8.09(d,J=1.8Hz,1H),7.99-7.97(m,1H),7.24(d,J=1.7Hz,1H),6.88(d,J= 5.2Hz,2H),6.71-6.69(m,1H),6.53-6.51(m,1H),5.57-5.54(m,3H),4.36-4.34(m ,2H),3.91(t,J=5.4Hz,2H),3.12(s,1H),2.74-2.54(m,2H),1.60(d,J=7.0Hz,3H).

[0299] Example 11: Preparation of Compound 11

[0300]

[0301] Except for replacing N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester with phenylboronic acid, the other conditions were the same as those for the synthesis of compounds 1-d in Example 1, yielding compound 11-1a (88.6 mg); compound 11 (18.8 mg) was obtained by referring to the synthesis method of compound 3 in Example 3; MS (ESI+): m / z 448.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ8.88(s,1H),8.57(d,J=7.5Hz,1H),8.28-8.21(m,2H),8.15(d,J=9.0Hz,1H),7.90(d,J=7.6Hz,2H) ,7.58-7.55(m,2H),7.46(d,J=7.5Hz,1H),7.29(s,1H),6.90(s,2H),6.71(s,1H),5.54-5.50(m,3H),1.61(d,J=7.0Hz,3H).

[0302] Example 15: Preparation of Compound 15

[0303]

[0304] Except for replacing N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester with thiophene-3-boronic acid, the other conditions were the same as those for the synthesis of compounds 1-d in Example 1, yielding compound 15-1a (78.6 mg). Compound 15 (13.4 mg) was obtained by referring to the synthesis method of compound 3 in Example 3; MS (ESI+): m / z 454.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.93(s,1H),8.78(s,1H),8.41-8.31(m,1H),8.32-8.22(m,2H),8.15(s,1H),7.86-7.84(m ,1H),7.79-7.77(m,1H),7.42(s,1H),6.90(d,J=4.6Hz,2H),6.72(s,1H),5.56-5.52(m,3H),1.64(d,J=7.0Hz,3H).

[0305] Examples 16-17: Preparation of compounds 16-17

[0306]

[0307] Compound 8 (400 mg, 0.85 mmol, 1.0 eq.), dichloromethane (10 mL), and m-chloroperoxybenzoic acid (146 mg, 0.85 mmol, 1.0 eq.) were added to a reaction flask. The reaction was carried out at room temperature for 2 h. The reaction system was quenched with sodium sulfite aqueous solution (50 mL), and extracted three times with dichloromethane (50 mL). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1, v / v) to give compound 16-a (210 mg); MS (ESI+): m / z 486.2 [M+1]+ .

[0308] Compound 16-a (210 mg, 0.43 mmol, 1.0 eq.), rhodium dimeracetate (8 mg, 0.017 mmol, 0.04 eq.), diethyl iodophenyl ester (208 mg, 0.43 mmol, 1.5 eq.), trifluoroacetamide (97 mg, 0.43 mmol, 2.0 eq.), magnesium oxide (69 mg, 1.72 mmol, 4.0 eq.), and dichloromethane (4 mL) were added to a reaction flask, and the mixture was reacted at room temperature under nitrogen protection for 24 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 50:1, v / v) to give compound 16-b (155 mg); MS (ESI+): m / z 597.1 [M+1] + .

[0309] Compound 16-b (155 mg, 0.26 mmol, 1.0 eq.), potassium carbonate (180 mg, 1.30 mmol, 5.0 eq.), and methanol (3 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 2 h. The reaction system was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by reversed-phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain compound 16 (60 mg); MS (ESI+): m / z 501.1 [M+1] + .

[0310] Compound 16 (40 mg, 0.08 mmol, 1.0 eq.), dichloromethane (2 mL), and triethylamine (16 mg, 0.16 mmol, 2.0 eq.) were added to a reaction flask. Acetyl chloride (7 mg, 0.10 mmol, 1.2 eq.) was added dropwise under nitrogen protection in an ice bath. After the addition was complete, the mixture was brought to room temperature and reacted for 1 h. The reaction mixture was evaporated to dryness to obtain the crude product, which was then purified by reversed-phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 17 (13 mg); MS (ESI+): m / z 543.1 [M+1] + .

[0311] Example 20: Preparation of Compound 20

[0312]

[0313] Under nitrogen protection, compounds 3-1d (100 mg, 0.22 mmol, 1.0 eq.), 2-oxa-6-azaspiro[3,3]heptane (32 mg, 0.33 mmol, 1.5 eq.), Pd2(dba)3 (50 mg, 0.055 mmol, 0.25 eq.), xantphos (64 mg, 0.11 mmol, 0.5 eq.), cesium carbonate (215 mg, 0.66 mmol, 3.0 eq.), and toluene (4 mL) were added sequentially to the reaction flask. The reaction was carried out in a microwave oven (110 °C, 2 h). After cooling to room temperature, water (5 mL) was added to the system, followed by extraction twice with ethyl acetate (20 mL). The organic phases were combined and washed once with water (10 mL) and once with saturated sodium chloride aqueous solution (10 mL). The organic phases were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by reversed-phase column chromatography (Shim-pack GIS C18 20*250mm, 5μm; 0.01% formic acid-water / acetonitrile) to give compound 20-a (31.5 mg); MS (ESI+): m / z 499.2 [M+1] + .

[0314] Compound 20-a (31.5 mg, 0.063 mmol, 1.0 eq.), ethanol (3 mL), and tin dichloride (24 mg, 0.126 mmol, 2.0 eq.) were added to the reaction flask. After the addition was complete, the mixture was heated to 85 °C and reacted for 2 h. Then, water (10 mL) and ethyl acetate (10 mL) were added, followed by extraction twice. The mixture was washed twice with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain pure compound 20 (7.3 mg); MS (ESI+): m / z 469.2 [M+1] + .

[0315] Examples 21-23: Preparation of compounds 21-23

[0316] Compounds 21-23 were synthesized following a procedure substantially similar to that in Example 20 (see Table 2).

[0317] Table 2. Structural and mass spectrometric data of compounds 21-23

[0318]

[0319]

[0320] Example 24: Preparation of compound 24

[0321]

[0322] Except for replacing intermediate 1-1 with intermediate 3-1, the other conditions were the same as in Example 2, yielding compound 24-c (530 mg); MS (ESI+): m / z 412.0 [M+1] + .

[0323] Compound 24-c (500 mg, 1.0 eq.) and HBr aqueous solution (20 mL) were added to the reaction flask. The mixture was purged with nitrogen three times, and the mixture was heated to reflux at 24-c under a nitrogen atmosphere until the reaction was complete. After cooling to room temperature, the crude product was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 80 / 1, v / v) to give compound 24-d (230 mg); MS (ESI+): m / z 434.1 [M+1] + .

[0324] Compound 24-d (150 mg, 1.0 eq.), 1,2-dibromoethane (1.5 eq.), sodium carbonate (3.0 eq.), and glycerol (2 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and heated to 120 °C under a nitrogen atmosphere. After compound 24-d reacted completely, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (25 mL * 3). The organic phases were combined, concentrated under reduced pressure to obtain the crude product, and purified by column chromatography (DCM / MeOH = 150 / 1, v / v) to give compound 24-e (120 mg); MS (ESI+): m / z 460.1 [M+1] + .

[0325] Compound 24 (35.4 mg) was obtained by following the synthetic method of compound 3 in Example 3; MS (ESI+): m / z 430.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ8.41-8.31(m,1H),8.15(s,1H),7.81(s,1H),7.79-7.77(m,1H),7.62(s,1 H), 6.90 (d, J = 4.6Hz, 2H), 6.72 (s, 1H), 5.56-5.52 (m, 3H), 4.32-4.29 (m, 4H), 1.64 (d, J = 7.0Hz, 3H).

[0326] Example 25: Preparation of Compound 25

[0327]

[0328] Except for replacing 1,2-dibromoethane with 1,2-bis(2-bromoethoxy)ethane, the conditions were the same as in Example 24, yielding compound 25 (8.5 mg); MS (ESI+): m / z 518.2 [M+1]+ ; 1 H NMR (400MHz, DMSO-d6): δ8.41-8.31(m,1H),8.15(s,1H),7.81(s,1H),7.79-7.77(m,1H),7.62(s,1H),6.90(d,J=4.6H z,2H),6.72(s,1H),5.56-5.52(m,3H),4.22-4.19(m,4H),4.05-3.95(m,4H),3.78-3.65(m,4H),1.64(d,J=7.0Hz,3H).

[0329] Example 26: Preparation of Compound 26

[0330]

[0331] Except for replacing 2-oxa-6-azaspiro[3,3]heptane with dimethylphosphine oxide, the conditions were the same as in Example 20, yielding compound 26 (11.9 mg); MS (ESI+): m / z 448.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ9.91(d,J=7.6Hz,1H),9.34-9.25(m,1H),8.51-8.49(m,2H),8.41-8.36(m,1H),7.73(d,J=2.5Hz,1H) ,7.01-6.82(m,2H),6.76-6.74(m,1H),5.66-5.47(m,3H),1.84(d,J=3.1Hz,3H),1.81(d,J=3.1Hz,3H),1.67(d,J=7.1Hz,3H).

[0332] Example 27: Preparation of Compound 27

[0333]

[0334] Except for replacing 2-oxa-6-azaspiro[3,3]heptane with 1-benzyl-1,4-azaphosphine 4-oxide, the other conditions were the same as those for the synthesis of compound 20-a in Example 20, yielding compound 27-a (350 mg); MS (ESI+): m / z 609.2 [M+1] + .

[0335] Compound 27-a (200 mg, 1.0 eq.), TMSI (2.0 eq.), and acetonitrile (5 mL) were added to the reaction flask. The mixture was purged with nitrogen three times, and the temperature was raised to 60 °C under a nitrogen atmosphere until 27-a reacted completely. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (DCM / MeOH = 100 / 1) to give compound 27-b (109 mg); MS (ESI+): m / z 519.1 [M+1] + .

[0336] Compound 27-b (109 mg, 1.0 eq.), triethylamine (2.0 eq.), and dichloromethane (5 mL) were added to a reaction flask. The reaction system was cooled to 0 °C, and acetyl chloride (1.5 eq.) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (DCM / MeOH = 150 / 1, v / v) to give compound 27-c (95 mg); MS (ESI+): m / z 519.1 [M+1] + .

[0337] Compound 27 (35.0 mg) was obtained by following the synthetic method of compound 3 in Example 3; MS (ESI+): m / z 531.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ9.91(d,J=7.6Hz,1H),9.34-9.25(m,1H),8.51-8.49(m,2H),8.41-8.36(m,1H),7.73(d,J=2.5Hz,1H),7.01 -6.82(m,2H),6.76-6.74(m,1H),5.66-5.47(m,3H),3.21-2.95(m,2H),2.64-2.44(m,2H),2.21-2.06(m,7H),1.67(d,J=7.1Hz,3H).

[0338] Experimental Example 1: KRAS-G12C / SOS1 Inhibitory Activity Test

[0339] The inhibitory effect of the compounds of this invention on KRAS-G12C / SOS1 was evaluated by detecting the inhibition rate on KRAS-G12C / SOS1 using the Binding Assay method. The compound was tested at a concentration of 500 nM, using single-concentration, duplicate-well assays.

[0340] 1.1 Experimental Materials

[0341] 1.1.1 Reagents and Consumables

[0342] Reagent Name Supplier KRAS G12C / SOS Binding kit Cisbio DMSO Sigm 384-well white plate PerkinElmer

[0343] 1.1.1 Instruments

[0344] Centrifuge (Manufacturer: Eppendorf, Model: 5430)

[0345] Microplate reader (Manufacturer: Perkin Elmer, Model: Envision)

[0346] Echo 550 (Manufacturer: Labcyte, Model: Echo 550)

[0347] 1.2 Kinase Response Process

[0348] (1) Preparation of the compound: The test compound was prepared at a concentration of 500 nM and diluted 200 times to a final concentration of 100% DMSO in a 384-well plate. 50 nl of the 200-fold final concentration of the compound was transferred to the target 384-well plate using an Echo 550 dispenser. 50 nl of 100% DMSO was added to each of the negative and positive control wells.

[0349] (2) Prepare a Tag1-SOS1 solution with a final concentration of 4 times using dilution buffer.

[0350] (3) Add 2.5 μl of Tag1-SOS1 solution with a final concentration of 4 to the 384-well plate.

[0351] (4) Prepare a Tag2-KRAS-G12C solution with a final concentration of 4 times using dilution buffer.

[0352] (5) Add 2.5 μl of Tag2-KRAS-G12C solution at 4 times the final concentration to the compound well and the positive control well, respectively; add 2.5 μl of dilution buffer to the negative control well.

[0353] (6) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 15 minutes.

[0354] (7) Prepare a final concentration of Anti-Tag1-TB3+ solution and a final concentration of Anti-Tag2-XL665 solution using detection buffer. After mixing the two solutions, add 5 μl of Mix solution to each well.

[0355] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 120 minutes.

[0356] (9) Use an Envision microplate reader to read and record Em665 / 620.

[0357] 1.3 Data Analysis

[0358] 1.3.1 Formula for calculating inhibition rate

[0359]

[0360] Wherein: Min signal represents the average absorbance of pure DMSO wells; Max signal represents the average absorbance of the mixture of enzyme, substrate, detection reagent, and DMSO wells; Compound signal represents the average absorbance of the sample wells.

[0361] 1.3.2 Fitting the dose-response curve

[0362] Using the log value of compound concentration as the X-axis and the percentage inhibition rate as the Y-axis, the dose-response curve was fitted using the log(inhibitor) vs. response-variable slope of the analysis software GrapHPadPrism 5 to obtain the IC50 value of each compound on enzyme activity.

[0363] The fitting formula is: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0364] Where: Top represents the top platform, and the standard for the Top of the curve is generally between 80% and 120%; Bottom represents the bottom platform, and the Bottom of the curve is generally between -20% and 20%.

[0365] In vitro inhibitory activity test results (in terms of inhibition rate and IC50) 50 express)

[0366]

[0367]

[0368] The compounds of this invention exhibit excellent in vitro inhibitory activity against KRAS-G12C / SOS1, enabling them to function as small-molecule SOS1 inhibitors. They inhibit cell proliferation and angiogenesis, demonstrating good anti-tumor activity and showing promising efficacy in treating neoplastic diseases in mammals (including humans).

[0369] Although the invention has been described through specific embodiments above, it should not be construed as being limited thereto. Rather, the invention covers the general aspects previously disclosed and may be modified and implemented in various ways without departing from the spirit and scope of the invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in: Ring A is phenyl; n is 2; Each R 1 Independently selected from -CHF2, -CF3, amino, and fluorine; R 3 It is hydrogen; R 4 The compound is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyridyl, pyranyl, thioranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiophenyl, tetrahydrothiophenyl, piperazine, nitric oxide phosphorus hexane, 3,8-diazabicyclo[3.2.1]octyl, 2-oxa-6-azaspiro[3.3]heptyl and morpholinyl, wherein the phenyl and naphthyl groups are... Pyrrole, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, dihydropyrrole, dihydrofuranyl, dihydrothiophenyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyridyl, pyranyl, thioranyl, dihydropyridyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, dihydrothioranyl, tetrahydrothioranyl, piperazine, and morpholinyl are each optionally substituted by one substituent; if present, the substituent is selected from the following groups: =O, =NH, methyl, ethyl, n-propyl, isopropyl, acetyl, and propionyl; or, R 4 -P(=O)R 4a R 4b , where R 4a and R 4b Independently selected from hydrogen and C 1-6 alkyl; R 5 It is hydrogen; Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each substituent is independently selected from the following groups: halogen, C 1-6 Alkyl groups, =O, and =CH2; D stands for CH; Indicates a single key; Ring B is an imidazole ring; p is 0, 1, 2, 3, 4, 5 or 6; If it exists, each R 2 Independently hydrogen; The heterocyclic group contains one or more heteroatoms selected from N, O, S and P as ring atoms.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4 The group is selected from phenyl, pyrrolyl, furanyl, thiophenyl, pyridyl, pyranyl, thiaranyl, dihydropyridyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, tetrahydrothiaranyl, piperazineyl, and morpholinyl, wherein each of the phenyl, pyrrolyl, furanyl, thiophenyl, pyridyl, pyranyl, thiaranyl, dihydropyridyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, tetrahydrothiaranyl, piperazineyl, and morpholinyl groups is optionally substituted by one substituent; if present, the substituent is selected from the following groups: =O, =NH, methyl, ethyl, n-propyl, isopropyl, acetyl, and propionyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4a and R 4b It is independently selected from hydrogen and methyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4 and R 5 Together with the atoms to which they are attached, they form 5, 6, 9, 12, 14 or 15-membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, =O and =CH2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4 and R 5 Together with the atoms to which they are attached, they form a 6, 9, or 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, =O, and =CH2.

6. A compound of formula I'-1 or a pharmaceutically acceptable salt thereof, in: Rings A, n, R 1 R 2 R 3 R 4 R 5 And D as defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that, for .

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that, for , in: The ring C is a 5- to 15-membered heterocyclic group; q can be 0, 1, 2, 3, 4, 5, or 6; If it exists, each R 7 Independently selected from the following groups: halogen, C 1-6 Alkyl, =O, and =CH2.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, characterized in that, The ring C is a 6- to 12-membered heterocyclic group; q can be 0, 1, 2, 3, 4, 5, or 6; If it exists, each R 7 Independently selected from the following groups: halogen, C 1-4 Alkyl, =O, and =CH2.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following structures: , , , , and .

11. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following structures: , and .

12. The following compounds or their pharmaceutically acceptable salts: 。 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, characterized in that, The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

15. A pharmaceutical preparation made from a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 or 14.

16. Use of the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13 or 14, or the pharmaceutical formulation of claim 15, in the preparation of a medicament for the prevention and / or treatment of diseases at least partially mediated by the SOS1 protein.

17. The use according to claim 16, characterized in that, The diseases mediated at least in part by the SOS1 protein are cancers.

18. The use according to claim 17, characterized in that, The cancers mentioned are selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

19. A pharmaceutical combination comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 or 14, or a pharmaceutical formulation according to claim 15, and at least one additional cancer therapeutic agent.

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