Piperazine compounds and their applications

Abstract

The present invention provides a novel piperazine compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof in the preparation of a drug for preventing and / or treating KRAS G12C mutant tumors.

Description

[0001] The present invention claims priority to the prior application filed with the State Intellectual Property Office of China on November 6, 2020, with patent application number 202011232187.X, entitled “Piperazine compounds and their applications” and the prior application filed with the State Intellectual Property Office of China on February 5, 2021, with patent application number 202110160742.0, entitled “Piperazine compounds and their applications”. The entire contents of the above prior applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a novel piperazine compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and use of the novel piperazine compound as a KRAS G12C inhibitor in preventing or treating related diseases. Background Art

[0003] Ras is the first human proto-oncogene discovered, and it has three family members: Hras, ​​Kras and Nras (Barbacid M, Annu Rev Biochem, 1987; 56: 779-827). RAS, as a small G protein, has GTP hydrolase activity and is located on the inner side of the cytoplasmic membrane. Its activity is regulated by different bindings with GTP / GDP. When it binds to GTP, it is activated (on), and when it binds to GDP, it is in an inactive state (off). Ras GTP kinases are crucial in many signaling networks. They have the function of signal integration and transmit signals to downstream effectors, participate in life activities such as cell movement, cytoskeleton assembly, vesicles and nuclear transport, and then regulate life processes such as cell proliferation, differentiation, aging and apoptosis (Fernandez-Medarde A, et al, Genes Cancer, 2011; 2 (3): 344-58). Therefore, RAS protein is regarded as an important molecular switch protein in cell signaling.

[0004] After being activated, the proto-oncogene Ras becomes an oncogene with carcinogenic activity. There are three ways to activate the Ras gene: point mutation, overexpression, and insertion activation. Among them, the most common way for the Ras gene to be activated is point mutation, and it mainly causes cancer through point mutation. At present, 151 different Ras point mutations have been found, mainly concentrated in mutations of glycine at positions 12 and 13 and glutamine at position 61 (Prior IA, et al, Cancer Res 2012; 72(10): 2457-67). Among the above mutations, the G12 point mutation is the most common, and the G12 mutation is dominant in KRAS and Hras. Among KRAS mutations, 15 different point mutations of G12 have been found, including G12A, G12D, G12F, G12K, G12N, G12S, G12V, G12Y, G12C, G12E, G12I, G12L, G12R, G12T and G12W. Among them, G12D mutation accounts for about 41% of all G12 mutations, G12V accounts for about 28%, and G12C accounts for about 14% (Hobbs GA, et al, Cancer Cell, 2016; 29(3): 251-3).

[0005] Ras mutation is an important cause of the occurrence of many cancers and often appears in the early stage of tumor development. These mutations activate RAS proteins that cause uncontrolled cell growth and proliferation. According to statistics, the five cancers with the highest Ras mutation frequencies are pancreatic ductal adenocarcinoma, colorectal cancer, multiple myeloma, lung cancer, and skin melanoma, with mutation frequencies of 97.7%, 52.2%, 42.6%, 32.2%, and 29.1%, respectively (Albertini AF, et al, Bull Cancer, 2017; 104(7 / 8): 662-74). It is worth noting that among these Ras mutations, the mutation frequency of KRAS is significantly higher than that of the other two mutations. For example, in pancreatic ductal adenocarcinoma, the mutation rate of KRAS is as high as 97.7%, while Nras and Hras are all 0; in colorectal cancer, the mutation rate of KRAS is as high as 44.7% among the 52.2% Ras mutation rate. In the study of non-small cell lung cancer, it was found that Ras mutations mostly occurred at codon 12, with the most common being the G12C point mutation, followed by G12V and G12D (Yoon YK, et al, Mol Carcinog 2010; 49(4):353-62).

[0006] Activating mutations of the KRAS gene are closely related to the occurrence and development of human malignant tumors and tumor recurrence. Genetic and biochemical studies have shown that KRAS-dependent signaling plays an important role in regulating the growth, proliferation, invasion and metastasis of various cancer cells. KRAS is also considered a marker for patient prognosis. In patients with non-small cell lung cancer, patients with KRAS mutations have a shorter survival period than patients with KRAS wild-type, especially those with G12C point mutations (Svaton M, et al, Anticancer Res, 2016; 36(3): 1077-82). Therefore, the scientific community has been committed to finding small molecules that can bind to specific mutant KRAS proteins and inhibit the activation and function of KRAS proteins, thereby preventing the transduction of its downstream signaling pathways and ultimately inhibiting tumor growth.

[0007] In 2013, the Shokat research group of the Howard Hughes Medical Institute first reported KRAS G12C small molecule inhibitors in Nature magazine (Ostrem JM, et al, Nature, 2013, 503(7477): 548-551). These inhibitors can bind to the allosteric binding pocket below the molecular switch II region of the KRAS protein and form a covalent bond with the nearby Cys12, thereby selectively inhibiting the activation of KRAS G12C. Based on the above studies, in 2016, Wellspring reported a new KRAS G12C irreversible covalent inhibitor ARS-853 targeting the allosteric pocket of the KRAS G12C molecular switch region II, which can fix the KRAS protein in an inactive GDP-bound conformation and has selective inhibitory activity against a variety of KRAS G12C mutation-positive tumor cells (Patricelli MP, et al, Cancer Discov, 2016, 6(3):316-329; Lito P, et al, Science, 2016, 351(6273):604-608).

[0008] At present, attempts have been made to identify heterocyclic compounds as covalent inhibitors of KRAS G12C, including benzopyrimidones, pyridopyrimidones, and tetrahydropyridopyrimidines (WO2017 / 201161, WO2018 / 119183, WO2018 / 217651, WO2018 / 206539, WO2018 / 143315, WO2017 / 087528, WO2020 / 081282, WO2020 / 178282). All of the above compounds are described as KRAS inhibitors for treating tumors. In view of the huge tumor market and unmet market demand, the development of KRAS G12C inhibitors has huge market prospects. Summary of the invention

[0009] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011]

[0012] in,

[0013] R 1 is selected from aryl or heteroaryl, the aryl or heteroaryl being substituted by one or more amino groups, the aryl or heteroaryl being further optionally substituted by R a replace;

[0014] Every R a independently selected from F, Cl, Br, I, CN, OH, NO2 or optionally R b Substituted with the following groups: C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy;

[0015] R 2 , R 3 independently selected from H, F, Cl, Br, I, CN, OH, NO2 or optionally R b Substituted with the following groups: NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl;

[0016] R 4a , R 4b Selected from H, or R 4a , R 4b co-form = O;

[0017] R 5 Selected from

[0018] Q is selected from C(=O), C(=NR 8 ), NR 9 C(=O), S(=O)2 or NR 9 S(=O)2;

[0019] R 8 , R 9 Independently selected from H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0020] When R 5 Selected from When R 6 , each R 7 Each independently selected from H, F, Cl, Br, I, CN, carboxyl or optionally R c Substituted with the following groups: C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, or R 6 , R 7 Together with the carbon atoms to which they are attached, they form a partially saturated C5-C 10 Cyclic hydrocarbon or 5-10 membered heterocyclic group, the partially saturated C5-C 10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by R c replace;

[0021] When R 5 Selected from When R 7 Selected from H or optionally R c Substituted with the following groups: C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group;

[0022] Every R b , R c independently selected from halogen, CN, OH, =O or optionally replaced by R d Substituted from the following groups: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy or 3-6 membered heterocyclyloxy;

[0023] Every R d Independently selected from halogen, OH, CN, =O, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl.

[0024] In some embodiments, R 1 is selected from phenyl or 5-10 membered heteroaryl, the phenyl or 5-10 membered heteroaryl is substituted by one or more amino groups, the phenyl or 5-10 membered heteroaryl is further optionally substituted by R a replace.

[0025] In some embodiments, R 1is selected from phenyl, 6-membered heteroaryl or 9-membered heteroaryl, wherein the phenyl, 6-membered heteroaryl or 9-membered heteroaryl is substituted by one or more amino groups, and the phenyl, 6-membered heteroaryl or 9-membered heteroaryl is further optionally substituted by R a replace.

[0026] In some embodiments, R 1 is selected from phenyl, pyridyl or benzothiazolyl, wherein the phenyl, pyridyl or benzothiazolyl is substituted by one or more amino groups, and the phenyl, pyridyl or benzothiazolyl is further optionally substituted by R a replace.

[0027] In some embodiments, R 1 Selected from phenyl, The phenyl group, is substituted by one or more amino groups, the phenyl, Further optionally R a replace.

[0028] In some embodiments, R a Selected from F, Cl, Br, I, CN, OH, C3-C6 cycloalkyl or C1-C3 alkyl optionally substituted by halogen.

[0029] In some embodiments, R a is selected from F, Cl, Br, I or C1-C3 alkyl optionally substituted by F.

[0030] In some embodiments, R a is selected from F, Cl, methyl or trifluoromethyl.

[0031] In some embodiments, R 1 Selected from

[0032] In some embodiments, R 1 Selected from

[0033] In some embodiments, R 2 , R 3 independently selected from H, F, Cl, Br, I, CN, OH, NO2 or optionally R b Substituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 3-6 membered heterocyclyloxy, C2-C6 alkenyl, C2-C6 alkynyl.

[0034] In some embodiments, R 2 , R 3Independently selected from F, Cl, Br, I or optionally R b Substituted: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 alkynyl.

[0035] In some embodiments, R 2 Selected from F, Cl, Br, I or optionally R b Substituted: cyclopropyl, C1-C3 alkoxy, C2-C3 alkynyl.

[0036] In some embodiments, R 3 Selected from F, Cl, Br, I or optionally R b Substituted: C1-C3 alkyl, C3-C6 cycloalkyl.

[0037] In some embodiments, R b Selected from halogen, CN, OH, =O or C1-C6 alkyl.

[0038] In some embodiments, R b Selected from halogen.

[0039] In some embodiments, R b Selected from F.

[0040] In some embodiments, R 2 is selected from F, ethynyl, 1-propynyl, cyclopropyl, trifluoromethoxy or difluoromethoxy.

[0041] In some embodiments, R 3 Selected from F, Cl, Br, I, C1-C3 alkyl or C3-C6 cycloalkyl.

[0042] In some embodiments, R 3 Selected from Cl, F, methyl or cyclopropyl.

[0043] In some embodiments, R 5 Selected from

[0044] In some embodiments, R 5 Selected from

[0045] In some embodiments, Q is selected from C(═O) or S(═O) 2 .

[0046] In some embodiments, R 6 , R 7 Each independently selected from H, F, Cl, Br, I, CN or optionally R c Substituted: C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl.

[0047] In some embodiments, R c Selected from halogen, CN, OH, =O or C1-C6 alkyl.

[0048] In some embodiments, R 6 , each R 7 Each is independently selected from H, F, Cl, Br, I, CN, C1-C3 alkyl.

[0049] In some embodiments, R 6 , each R 7 Each is independently selected from H, F, Cl, Br, I.

[0050] In some embodiments, R 6 , each R 7 Each is independently selected from H and F.

[0051] In some embodiments, both R 7 At least one of is selected from H.

[0052] In some embodiments, both R 7 One of them is selected from H, and the other R 7 Selected from H, F, Cl, Br, I, CN or C1-C3 alkyl.

[0053] In some embodiments, R 6 , R 7 are each independently selected from H.

[0054] In some embodiments, R 5 Selected from

[0055] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0056]

[0057]

[0058] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0059]

[0060]

[0061] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0062]

[0063]

[0064] The present invention also provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0065] Furthermore, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a KRAS G12C-related disease.

[0066] Furthermore, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating KRAS G12C-related diseases.

[0067] Furthermore, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a KRAS G12C-related disease.

[0068] The present invention also relates to a method for treating KRAS G12C-related diseases, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention.

[0069] In a preferred embodiment of the present invention, the KRAS G12C-related diseases include but are not limited to inflammatory diseases, autoimmune diseases or cancer. Definitions and explanations of terms

[0070] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of the present invention, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and coupled with each other. The group definitions and compound structures after such combinations and couplings shall fall within the scope of the description of the present invention.

[0071] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0072] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0073] The term "enantiomer" refers to stereoisomers that are real objects and mirror images of each other and are non-superimposable, and can be simply called enantiomers.

[0074] The term "racemate" refers to an equimolar mixture of an optically active chiral molecule and its enantiomer.

[0075] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms (optical centers) or asymmetric double bonds. Racemates, enantiomers, diastereomers, and geometric isomers are all within the scope of the present invention.

[0076] The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dashed wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. represents the cis-trans configuration of alicyclic compounds. When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, unless specified otherwise, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.

[0077] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention. The compounds containing asymmetric atoms of the present application can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0078] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention includes all tautomeric forms of the compounds.

[0079] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0080] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0081] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0082] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0083] The term "C5-C 10 "Cycloalkyl" is understood to be a saturated or partially saturated non-aromatic monovalent cyclic hydrocarbon radical having 5, 6, 7, 8, 9 or 10 carbon atoms.

[0084] The term "C1-C 10 The term “alkyl” is understood to mean a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; preferably, the “C1-C 10"Alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl", "C1-C6 alkyl" is understood to mean a straight chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, and "C1-C3 alkyl" is understood to mean a straight chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms.

[0085] The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 Alkyl-O-", preferably, "C1-C 10 The "alkoxy group" may include a "C1-C6 alkoxy group" or a "C1-C3 alkoxy group".

[0086] The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring such as decalin. Preferably, "C3-C 10 The term "C3-C6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.

[0087] The term "C3-C 10 "Cycloalkyloxy" can be understood as "C3-C 10 Cycloalkyl-O-", preferably, "C3-C 10 The "cycloalkyloxy" may include a "C3-C6 cycloalkyloxy".

[0088] The term "3-10 membered heterocyclyl" means a saturated or partially saturated monovalent monocyclic, cyclic, spiro or bridged ring containing 1-5, preferably 1-3 heteroatoms selected from N, O, B and S. In particular, "3-10 membered heterocyclyl" includes "5-10 membered heterocyclyl" or "3-6 membered heterocyclyl", and the "3-10 membered heterocyclyl" includes but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 1,3,2-dioxaborolanyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridinyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing nitrogen atoms may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. Optionally, the 3-10-membered heterocyclic group may be a "3-10-membered heterocycloalkyl", meaning a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring containing 1-5 heteroatoms; preferably, "3-10-membered heterocycloalkyl" includes 3-6-membered heterocycloalkyl, and also includes 5-6-membered heterocycloalkyl, etc.

[0089] The term "3-10 membered heterocyclyloxy" may be understood as "3-10 membered heterocyclyl-O-". Preferably, "3-10 membered heterocyclyloxy" includes "3-6 membered heterocyclyloxy".

[0090] The term "aryl" refers to a cyclic aromatic hydrocarbon group. In some embodiments, the aryl group has 6 to 20 carbon atoms (C6-C 20 In some other embodiments, the aryl group includes C6-C 10 Aryl. In other embodiments, the aryl is a C6 aryl. "Aryl" also includes a bicyclic group in which an aromatic ring is fused to a non-aromatic ring or a partially saturated ring. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, indenyl, indanyl, 1,2-dihydronaphthyl and 1,2,3,4-tetrahydronaphthyl.

[0091] The term "C6-C 10The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0092] The term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1-8 heteroatoms independently selected from N, O and S. Heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridinyl, piperazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like.

[0093] The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 10 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S. "6 membered heteroaryl" refers to a group having 6 ring atoms and containing 1-4, preferably 1-3 heteroatoms independently selected from N, O and S. "9 membered heteroaryl" refers to a group having 9 ring atoms and containing 1-6, preferably 1-3 heteroatoms independently selected from N, O and S.

[0094] The term "C2-C 10 "Alkenyl" is understood to be a linear or branched monovalent hydrocarbon radical, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkenyl radical can be divided into "cis" and "trans" orientations (or "E" and "Z" orientations). "C2-C6 alkenyl" is understood to be a linear or branched monovalent hydrocarbon radical, which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. "C2-C6 alkenyl" is understood to be a linear or branched monovalent hydrocarbon radical, which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. 10 Examples of "alkenyl" include, but are not limited to, vinyl (-CH=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methyl-1,3-butadienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, or hex-4-enyl.

[0095] The term "C2-C 10"Alkynyl" is understood to be a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C6 alkynyl" is understood to be a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms. "C2-C6 alkynyl" is understood to be a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms. 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (1-propynyl, -C≡CCH3), prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl or but-3-ynyl. Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (1-propynyl, -C≡CCH3), prop-2-ynyl (propargyl).

[0096] In particular, the term "treatment" means administering the compounds or formulations described herein to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0097] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to such disease state but has not yet been diagnosed as having such disease state;

[0098] (ii) inhibiting a disease or disease state, i.e., arresting its development;

[0099] (iii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0100] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0101] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical preparation, i.e., make the preparation more suitable for direct compression by increasing fluidity and / or adhesion. Examples of typical "pharmaceutically acceptable carriers" suitable for the above-mentioned preparations are: sugars, starches, cellulose and its derivatives, etc., which are commonly used excipients in pharmaceutical preparations.

[0102] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0103] The words “comprise”, “comprise” or “comprises” and their English variations such as comprises or comprising should be construed in an open, non-exclusive sense, ie, “including but not limited to”.

[0104] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0105] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0106] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0107] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0108] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0109] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0110] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0111] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0112] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0113] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0114] In all administration methods described herein, the daily dosage of the compound of formula I is 0.01 to 100 mg / kg body weight, preferably 0.05 to 50 mg / kg body weight, more preferably 0.1 to 30 mg / kg body weight, in the form of single or divided doses.

[0115] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments. DETAILED DESCRIPTION

[0116] The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0117] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0118] Example 1

[0119] 1-(9-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-10-chloro-8-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 1)

[0120]

[0121] Step 1: Synthesis of tert-butyl 9-(2-((tert-butyloxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-10-chloro-8-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-carboxylate (Intermediate 1-3)

[0122] The starting material 1-1 (500 mg, 1.15 mmol) and the starting material 1-2 (465.63 mg, 1.49 mmol) were dissolved in 1,4-dioxane and water, and RuPhos (53.55 mg, 114.75 μmol), RuPhos Pd G3 (95.98 mg, 114.75 μmol) and potassium carbonate (317.20 mg, 2.30 mmol) were added. The reaction solution was stirred at 100 ° C for 15 hours under nitrogen protection. The formation of the target product was monitored by LC-MS. The reaction solution was extracted three times with ethyl acetate, the organic layer was washed with saturated brine, and the organic layer was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silicon dioxide, petroleum ether / tetrahydrofuran = 3 / 1) to obtain the title compound (230 mg).

[0123] MS m / z(ESI):=623.5[M+H] + .

[0124] Step 2: Synthesis of 4-(10-chloro-8-fluoro-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-7-fluorobenzo[d]thiazol-2-amine (Intermediate 1-4)

[0125] Dissolve intermediate 1-3 (200 mg, 320.97 μmol) in dichloromethane. Add trifluoroacetic acid (3.08 g, 27.01 mmol) to the reaction solution at 0°C, raise the temperature to 25°C, and stir for 2 hours. LC-MS monitoring shows that all the raw materials have reacted completely and the target product has formed. Adjust the pH value of the reaction solution to 8-9 with saturated sodium bicarbonate aqueous solution. Extract with dichloromethane three times, and concentrate the organic layer to dryness under reduced pressure to obtain the crude title compound (130 mg), which is used directly in the next step without purification.

[0126] MS m / z(ESI):=423.0[M+H] + .

[0127] Step 3: Synthesis of 1-(9-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-10-chloro-8-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 1)

[0128] Dissolve intermediate 1-4 (120 mg, 283.77 μmol) in tetrahydrofuran and water, and add potassium phosphate (150.59 mg, 709.42 μmol). Add a tetrahydrofuran solution of acryloyl chloride (28.25 mg, 312.15 μmol) to the reaction solution at 0°C. Stir the reaction solution at 25°C for 1 hour under nitrogen protection. LC-MS monitoring shows that the raw materials have reacted completely and the target product is formed. The reaction solution was extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure and purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to obtain two racemates (containing one chiral carbon and one chiral axis in the structure, i.e., there are four isomers); a pair of racemates (thin layer chromatography Rf value: 0.54) were successively purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia water]; B%: 35%-35%) and high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [A: water (0.05% ammonia v / v), B: acetonitrile]; B%: 37%-57%, 11 minutes), to obtain compound 1 isomer 1 (11.6 mg, enantiomeric excess 98.4%, RT: 1.979min), to obtain compound 1 isomer 2 (5.5 mg, enantiomeric excess 99.6%, RT: 1.795min); the other racemate (thin layer chromatography Rf value: 0.40) was purified by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia]; B%: 35%-35%) and high performance liquid chromatography (column: YMC-Actus TriartC18150*30mm*5um; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 42%-62%, 11min), to obtain compound 1 isomer 3 (4.6mg, enantiomeric excess 98.9%, RT: 3.528min); to obtain compound 1 isomer 4 (4.2mg, enantiomeric excess 73.3%, RT: 3.895min).

[0129] Compound 1 Isomer 1 1H NMR(400MHz,METHANOL-d4)δ7.20-7.05(m,2H),6.96(t,J=8.9Hz,1H),6.87- 6.71(m,1H),6.25(d,J=16.9Hz,1H),5.79(d,J=10.4Hz,1H),4.43-4.31(m,1H ),4.23-3.98(m,2H),3.96-3.84(m,1H),3.80-3.74(m,1H),3.73-3.63(m,1H) ,3.63-3.46(m,1H),3.25-3.07(m,1H),3.05-2.90(m,2H),2.62-2.47(m,1H).

[0130] MS m / z(ESI):=477.1[M+H] +

[0131] Compound 1 Isomer 2 1 H NMR(400MHz,METHANOL-d4)δ7.20-7.07(m,2H),6.96(t,J=8.9Hz,1H),6.88- 6.68(m,1H),6.25(d,J=17.0Hz,1H),5.79(d,J=10.3Hz,1H),4.45-4.31(m,1H ),4.23-4.00(m,2H),3.93-3.85(m,1H),3.80-3.74(m,1H),3.73-3.65(m,1H ),3.63-3.45(m,1H),3.26-3.08(m,1H),3.05-2.90(m,2H),2.65-2.44(m,1H)

[0132] MS m / z(ESI):=477.1[M+H] +

[0133] Compound 1 Isomer 3 1 H NMR (400MHz, METHANOL-d4) δ7.14-7.10(m,2H),6.95(t,J=8.9Hz,1H),6.86-6.71(m,1H),6.24(d,J=16.6Hz,1H),5.78(d,J=10.6Hz,1H ),4.40-4.26(m,1H),4.18-4.04(m,1H),4.00-3.73(m,4H),3.72-3.46(m,1H),3.44-3.34(m,1H),3.18-2.88(m,2H),2.64-2.45(m,1H)

[0134] MS m / z(ESI):=477.1[M+H] +

[0135] Compound 1 Isomer 4 1 H NMR (400MHz, METHANOL-d4) δ7.14-7.10(m,2H),6.95(t,J=8.8Hz,1H),6.88-6.71(m,1H),6.24(d,J=16.8Hz,1H),5.78(d,J=10.5Hz,1H ),4.39-4.26(m,1H),4.19-4.04(m,1H),4.01-3.73(m,4H),3.72-3.46(m,1H),3.44-3.35(m,1H),3.19-2.88(m,2H),2.64-2.45(m,1H)

[0136] MS m / z(ESI):=477.1[M+H] +

[0137] Example 2, 1-(9-(2-aminobenzo[d]thiazol-4-yl)-10-chloro-8-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 2)

[0138]

[0139] Step 1: Synthesis of tert-butyl 9-(2-((tert-butyloxycarbonyl)amino)benzo[d]thiazol-4-yl)-10-chloro-8-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-carboxylate (Intermediate 2-2)

[0140] The starting material 1-1 (296.27 mg, 679.96 μmol) and the starting material 2-1 (200 mg, 679.96 μmol, which can be synthesized according to the method reported on page 29 of patent WO 2020081282) were dissolved in 1,4-dioxane and water, and RuPhos (31.73 mg, 68.00 μmol), RuPhos Pd G3 (56.87 mg, 68.00 μmol) and potassium carbonate (187.96 mg, 1.36 mmol) were added. The reaction solution was stirred at 80 ° C for 15 hours under nitrogen protection. LC-MS monitored the formation of the target product. The reaction solution was extracted three times with ethyl acetate, the organic layer was washed with saturated brine, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain the title compound (250 mg).

[0141] MS m / z(ESI):=605.4[M+H] + .

[0142] Step 2: Synthesis of 4-(10-chloro-8-fluoro-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)benzo[d]thiazol-2-amine (Intermediate 2-3)

[0143] Dissolve intermediate 2-2 (280 mg, 462.72 μmol) in dichloromethane and cool to 0°C. Add trifluoroacetic acid (7.70 g, 67.53 mmol) to the reaction solution at 0°C, raise the temperature to 25°C, and stir for 2 hours. LC-MS monitoring shows that all the raw materials have reacted completely and the target product has formed. Adjust the pH value of the reaction solution to 8-9 with saturated sodium bicarbonate aqueous solution. Extract with ethyl acetate three times, and concentrate the organic layer to dryness under reduced pressure to obtain the crude title compound (160 mg), which is directly used in the next step.

[0144] MS m / z(ESI):=405.0[M+H] + .

[0145] Step 3: Synthesis of 1-(9-(2-aminobenzo[d]thiazol-4-yl)-10-chloro-8-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 2)

[0146] The intermediate 2-3 (160 mg, 395.17 μmol) was dissolved in tetrahydrofuran and water, potassium phosphate (209.71 mg, 987.93 μmol) was added, and the temperature was lowered to 0°C. A tetrahydrofuran solution of acryloyl chloride (39.34 mg, 434.69 μmol) was added to the reaction solution at 0°C. The reaction solution was stirred at 25°C for 1 h under nitrogen protection. LC-MS monitored that the raw materials had reacted completely and the target product was formed. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and purified by preparative thin layer chromatography (silica, ethyl acetate / methanol = 50 / 1) to obtain two racemic bodies (the structure contains one chiral carbon and one chiral axis, that is, there are four isomers); a pair of racemic bodies (thin layer chromatography Rf value: 0.47) were purified by supercritical fluid chromatography (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia water]; B%: 60%-60%), to obtain compound 2 isomer 1 (19.2mg, enantiomeric excess>99.9%, RT: 1.419min), to obtain compound 2 isomer 2 (19.3mg, enantiomeric excess>99.9%, RT: 3.709min); the other racemate (thin layer chromatography Rf value: 0.40) was successively purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia water]; B%: 45%-45%) and high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [A: water (0.05% ammonia v / v), B: acetonitrile]; B%: 38%-58%, 11 minutes), to obtain compound 2 isomer 3 (8 mg, enantiomeric excess 99.9%, RT: 2.608 min); to obtain compound 2 isomer 4 (9.8 mg, enantiomeric excess 99.9%, RT: 4.842 min).

[0147] Compound 2 Isomer 1 1H NMR(400MHz,METHANOL-d4)δ7.68(dd,J=1.5,7.6Hz,1H),7.21-7.15(m,1H),7.1 4-7.08(m,2H),6.88-6.72(m,1H),6.27-6.22(m,1H),5.82-5.75(m,1H),4.44-4. 31(m,1H),4.23-3.99(m,2H),3.94-3.91(m,1H),3.80-3.75(m,1H),3.73-3.65(m ,1H),3.62-3.47(m,1H),3.24-3.07(m,1H),3.05-2.91(m,2H),2.64-2.47(m,1H)

[0148] MS m / z(ESI):=459.1[M+H] +

[0149] Compound 2 Isomer 2 1 H NMR(400MHz,METHANOL-d4)δ7.68(dd,J=1.3,7.7Hz,1H),7.20-7.15(m,1H),7.1 5-7.09(m,2H),6.87-6.73(m,1H),6.27-6.22(m,1H),5.82-5.75(m,1H),4.44-4. 31(m,1H),4.23-4.01(m,2H),3.94-3.91(m,1H),3.80-3.75(m,1H),3.74-3.66(m ,1H),3.64-3.47(m,1H),3.22-3.08(m,1H),3.05-2.91(m,2H),2.64-2.48(m,1H)

[0150] MS m / z(ESI):=459.2[M+H] +

[0151] Compound 2 Isomer 3 1H NMR (400MHz, METHANOL-d4) δ7.68 (dd, J=1.3, 7.8Hz, 1H), 7.20-7.14 (m, 1H), 7.13-7.04(m,2H),6.87-6.72(m,1H),6.24(d,J=15.6Hz,1H),5.79-5.75(m,1 H),4.40-4.26(m,1H),4.20-4.05(m,1H),3.98-3.74(m,4H),3.73-3.50(m,1H ),3.48-3.35(m,1H),3.19-3.03(m,1H),2.98-2.92(m,1H),2.59-2.55(m,1H)

[0152] MS m / z(ESI):=459.2[M+H] +

[0153] Compound 2 Isomer 4 1 H NMR (400MHz, METHANOL-d4) δ7.68 (dd, J=1.3, 7.8Hz, 1H), 7.22-7.14 (m, 1H), 7.12-7.05(m,2H),6.87-6.69(m,1H),6.24(d,J=15.6Hz,1H),5.79-5.75(m,1 H),4.41-4.24(m,1H),4.20-4.04(m,1H),4.00-3.74(m,4H),3.73-3.48(m,1H ),3.48-3.35(m,1H),3.18-3.02(m,1H),2.98-2.92(m,1H),2.59-2.55(m,1H)

[0154] MS m / z(ESI):=459.2[M+H] +

[0155] Example 3, 1-(9-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-10-chloro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 6)

[0156]

[0157] Step 1: Synthesis of tert-butyl 9-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-10-chloro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-carboxylate (Intermediate 6-3)

[0158] Intermediate 6-1 (300 mg, 658.22 μmol, synthesized according to the method reported in patent WO 2020178282) and intermediate 6-2 (225.99 mg, 724.05 μmol) were dissolved in dioxane (6 mL) and water (1.5 mL), potassium carbonate (272.91 mg, 1.97 mmol) was added, and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl) (2-amino-1,1-biphenyl-2-yl) palladium (II) methanesulfonate (RuPhos Pd G3) (55.05 mg, 65.82 μmol) and RuPhos (30.72 mg, 65.82 μmol) were added under nitrogen atmosphere, and the reaction temperature was raised to 90 ° C and stirred for 3 hours. After the reaction was completed, the temperature was lowered to 25 ° C, water (5 mL) was added, and ethyl acetate (5 mL) was extracted twice, and the organic phases were combined. The organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by column chromatography ( 4g Flash silica gel column, eluent 10-35% ethyl acetate / petroleum ether (ie, the volume ratio of ethyl acetate to petroleum ether is 10:90 to 35:65), gradient, 18 mL / min). The title compound (240 mg) was obtained.

[0159] MS m / z(ESI):=665[M+Na] +

[0160] Step 2: Synthesis of 4-(10-chloro-8-(prop-1-yn-1-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-7-fluorobenzo[d]thiazol-2-amine (Intermediate 6-4)

[0161] Dissolve intermediate 6-3 (240 mg, 373.15 μmol) in dioxane hydrochloride solution (4 M, 2.00 mL) and stir at 25°C for 1 hour. After the reaction is complete, remove the solvent by concentrating under reduced pressure (0.01 MPa) to obtain the crude title compound (195.7 mg).

[0162] MS m / z(ESI):=442.8[M+H] +

[0163] Step 3: Synthesis of 1-(9-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-10-chloro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 6)

[0164] Intermediate 6-4 (195 mg, 440.24 μmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), cooled to 0°C, potassium phosphate (351.73 mg, 1.32 mmol) was added, stirred for 5 minutes, acryloyl chloride (41.84 mg, 462.25 μmol) tetrahydrofuran (558 uL) solution was added, and stirred at 0°C for 1 hour. After the reaction was completed, ethyl acetate (5 mL) was extracted twice, the organic phases were combined, and the organic phases were concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by preparative HPLC (formic acid conditions, column: YMC-ActusTriart C18 150*30mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 35%-55%, 11 minutes). A mixture of two racemic bodies was obtained (the structure contains one chiral carbon and one chiral axis, that is, there are four isomers).

[0165] The mixture of the four isomers was purified by supercritical fluid chromatography (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia water]; B%: 55%-55%) to obtain a mixture of compound 6 isomer 1 and isomer 2, as well as compound 6 isomer 3 (4.1 mg, enantiomeric excess 92.38%, RT: 1.801 min), and compound 6 isomer 4 (4.0 mg, enantiomeric excess 100%, RT: 1.738 min);

[0166] The mixture of isomer 1 and isomer 2 of compound 6 was purified by supercritical fluid chromatography (column: DAICELCHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia water; B%: 55%-55%) and supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [A: carbon dioxide, B: isopropanol solution containing 0.1% ammonia water]; B%: 50%-50%). Compound 6 isomer 1 (2.2 mg, enantiomeric excess 100%, RT: 1.952 min) and compound 6 isomer 2 (2.5 mg, enantiomeric excess 99.7%, RT: 1.866 min) were obtained;

[0167] MS m / z(ESI):=497.2[M+H] +

[0168] Compound 6 Isomer 1 1 H NMR (400MHz, METHANOL-d4) δ7.30 (s, 1H), 7.06 (dd, J = 5.6, 8.4Hz, 1H), 6.98-6.88 ( m,1H),6.78(s,1H),6.25(d,J=17.3Hz,1H),5.78(d,J=9.3Hz,1H),4.41-4.28(m,1H ),4.15-4.11(m,1H),4.11-4.00(m,1H),3.99-3.91(m,1H),3.90-3.81(m,2H),3.80 -3.72(m,1H),3.71-3.57(m,1H),3.20-2.87(m,2H),2.54-2.40(m,1H),1.72(s,3H)

[0169] Compound 6 Isomer 2 1 H NMR(400MHz, METHANOL-d4)δ7.28(s,1H),7.04(dd,J=5.6,8.4Hz,1H),6.95-6.86(m,1H),6.84-6.66(m,1H),6.22(d,J=16.8Hz,1H),5.76(d, J=11.0Hz,1H),4.40-4.27(m,1H),4.13-3.97(m,2H),3.88-3.63(m,4H ),3.54-3.41(m,1H),3.12-2.87(m,2H),2.50-2.40(m,1H),1.70(s,3H)

[0170] Compound 6 Isomer 3 1 H NMR(400MHz,METHANOL-d4)δ7.33(s,1H),7.15-7.03(m,1H),6.98-6.88(m,1H), 6.78(dd,J=10.8,16.3Hz,1H),6.24(d,J=17.0Hz,1H),5.78(d,J=10.0Hz,1H),4. 50-4.32(m,1H),4.27-4.05(m,1H),4.04-3.88(m,2H),3.81-3.64(m,2H),3.61-3 .41(m,1H),3.31-3.07(m,1H),3.04-2.82(m,2H),2.64-2.44(m,1H),1.70(s,3H)

[0171] Compound 6 Isomer 4 1 H NMR (400MHz, METHANOL-d4) δ7.31 (s, 1H), 7.07 (dd, J=5.6, 8.4Hz, 1H), 6.91 (t, J= 8.9Hz,1H),6.84-6.68(m,1H),6.22(d,J=16.6Hz,1H),5.77(d,J=10.5Hz,1H),4. 43-4.28(m,1H),4.25-4.03(m,1H),4.02-3.83(m,2H),3.78-3.62(m,2H),3.58-3 .46(m,1H),3.27-3.09(m,1H),3.09-2.80(m,2H),2.63-2.43(m,1H),1.71(s,3H)

[0172] Example 4, 1-(9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-10-chloro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 7)

[0173]

[0174] Step 1: Synthesis of tert-butyl 10-chloro-8-(prop-1-yn-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-carboxylate (Intermediate 7-1)

[0175] The reactant 6-1 (440 mg, 965.39 μmol) was dissolved in tetrahydrofuran, and n-butyl lithium (2.5 M, 579.24 μL 1.45 mmol) was added at -78 ° C. After the reaction solution was stirred at -78 ° C for 30 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (359.23 mg, 1.93 mmol) was added dropwise thereto, and the reaction solution was stirred at -78 ° C for 30 minutes. LC-MS monitoring showed that all the raw materials had reacted completely. Saturated aqueous ammonium chloride solution was added to the reaction solution at -10 ° C, and the reaction solution was extracted with ethyl acetate three times. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by thin layer chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (80 mg).

[0176] MS m / z(ESI):=502.9[M+H]+ .

[0177] Step 2: Synthesis of tert-butyl 9-(6-(di(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-10-chloro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-carboxylate (Intermediate 7-3)

[0178] Intermediate 7-1 (120 mg, 238.65 μmol) and intermediate 7-2 (120 mg, 238.65 μmol) were dissolved in dioxane / water, and potassium carbonate (98.95 mg, 715.94 μmol), dicyclohexyl (2,6-diisopropoxy-[1,1-biphenyl]-2-yl) phosphine (Ruphos) (11.14 mg, 23.86 μmol), (2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl) (2-amino-1,1-biphenyl-2-yl) palladium (II) methanesulfonate (RuPhos Pd G3) (19.96 mg, 23.86 μmol) were added. The reaction solution was stirred at 100 ° C for 3 hours under nitrogen protection. LC-MS monitoring showed that all the raw materials had reacted completely. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by thin layer chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to give a crude product of the title compound (110 mg).

[0179] MS m / z(ESI):=791.3[M+H] + .

[0180] Step 3: Synthesis of 6-(10-chloro-8-(prop-1-yn-1-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 7-4)

[0181] The intermediate 7-3 (110 mg, 139.01 μmol) was dissolved in trifluoroacetic acid, and the reaction solution was stirred at 50°C for 12 hours. LC-MS monitoring showed that all the raw materials had reacted completely and the target product was formed. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product of the title compound (62 mg).

[0182] MS m / z(ESI):=451.1[M+H] +

[0183] Step 4: Synthesis of 1-(9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-10-chloro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one (Compound 7)

[0184] Dissolve the intermediate 7-4 (62 mg, 137.51 μmol) in tetrahydrofuran and add triethylamine (27.83 mg, 275.02 μmol). Add acryloyl chloride (12.45 mg, 137.51 μmol) dropwise to the reaction solution at 0°C. After the addition, stir the reaction solution at 0°C for 20 minutes. LC-MS monitoring showed that all the raw materials had reacted completely and the target product was formed. The reaction solution was concentrated to dryness under reduced pressure and the residue was purified by thin layer chromatography (silica, dichloromethane / methanol = 10 / 1) to obtain two racemic isomers (the structure contains one chiral carbon and one chiral axis, that is, there are four isomers). A pair of racemates (TLC Rf value: 0.77, dichloromethane: methanol = 10:1) were separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia]; B%: 45%-45%) and then purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [A: water (0.05% ammonia v / v), B: acetonitrile]; B%: 40%-60%, 11 minutes) to obtain compound 7 isomer 1 (2.1 mg, enantiomeric excess 100%, RT: 3.709 min); compound 7 isomer 2 (1.5 mg, enantiomeric excess 100%, RT: 4.575 min). Another racemic compound (TLC Rf value: 0.66, dichloromethane: methanol = 10:1) was purified by supercritical fluid chromatography (column: DAICELCHIRALPAK IC (250mm*30mm, 10um); mobile phase: [A: carbon dioxide, B: ethanol solution containing 0.1% ammonia water]; B%: 35%-35%) to obtain compound 7 isomer 3 (6.7 mg, enantiomeric excess 99.92%, RT: 4.424 min) and compound 7 isomer 4 (7.0 mg, enantiomeric excess 98.77%, RT: 5.028 min).

[0185] MS m / z(ESI):=505.1[M+H] +

[0186] Compound 7 Isomer 1 1H NMR(400MHz,METHANOL-d4)δ7.29(s,1H),6.89-6.73(m,1H),6.55(s,1H),6 .25(d,J=17.9Hz,1H),5.79(d,J=10.1Hz,1H),4.48-4.36(m,1H),4.31-4.12 (m,1H),4.00-3.90(m,2H),3.77-3.64(m,2H),3.55-3.45(m,0.5H),3.25-3. 15(m,0.5H),3.02-2.84(m,3H),2.60-2.50(m,1H),2.44(s,3H),1.80(s,3H)

[0187] Compound 7 Isomer 2 1 H NMR(400MHz,METHANOL-d4)δ7.29(s,1H),6.91-6.72(m,1H),6.55(s,1H),6 .24(d,J=16.8Hz,1H),5.79(d,J=10.8Hz,1H),4.50-4.42(m,1H),4.32-4.13 (m,1H),4.00-3.95(m,2H),3.77-3.64(m,2H),3.51-3.49(m,0.5H),3.20-3. 11(m,0.5H),3.05-2.83(m,3H),2.60-2.50(m,1H),2.44(s,3H),1.80(s,3H)

[0188] Compound 7 Isomer 3 1 H NMR(400MHz,METHANOL-d4)δ7.28(s,1H),6.89-6.72(m,1H),6.55(s,1H),6. 24(d,J=16.9Hz,1H),5.78(d,J=10.6Hz,1H),4.44-4.31(m,1H),4.10-4.06( m,1H),4.02-3.80(m,2H),3.78-3.68(m,2H),3.67-3.63(m,0.5H),3.62-3.5 6(m,0.5H),3.27-2.84(m,3H),2.60-2.50(m,1H),2.44(s,3H),1.80(s,3H).

[0189] Compound 7 Isomer 4 1H NMR(400MHz,METHANOL-d4)δ7.16(s,1H),6.75-6.60(m,1H),6.43(s,1H),6. 12(d,J=17.0Hz,1H),5.66(d,J=10.9Hz,1H),4.33-4.18(m,1H),4.10-3.90( m,1H),3.89-3.72(m,2H),3.66-3.57(m,2H),3.53-3.50(m,0.5H),3.15-3.1 1(m,0.5H),3.05-2.70(m,3H),2.50-2.42(m,1H),2.31(s,3H),1.68(s,3H).

[0190] Test example: Human non-small cell lung cancer H358 cell proliferation inhibition test

[0191] Brief introduction of test principle:

[0192] KRAS mutation is a driving factor for abnormal proliferation of various tumor cells, among which KRAS-G12C mutation is more common in non-small cell lung cancer and pancreatic cancer. In vitro, human non-small cell lung cancer H358 carrying KRAS-G12C mutation was used as a cell model to detect the inhibitory activity of KRAS-G12C inhibitor on cell proliferation. Experimental method reference: Janes MR et al, Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor, Cell 2018 Jan 25; 172(3): 578-589.

[0193] Experimental materials and instruments:

[0194] NCI-H358 cells were purchased from ATCC (USA).

[0195] 384-well plates were purchased from Corning (USA).

[0196] RPMI-1640 medium was purchased from Gibco (USA).

[0197] DMEM culture medium was purchased from Gibco (USA)

[0198] FBS was purchased from Gibco (USA).

[0199] Horse serum was purchased from Gibco (USA).

[0200] Penicillin-streptomycin was purchased from Invitrogen (USA).

[0201] 1640 complete medium: RPMI1640 medium + 10% FBS + 1% Penicillin-streptomycin.

[0202] DMEM complete medium: DMEM+10% FBS+2.5% horse serum+1% Penicillin-streptomycin.

[0203] Celltiter Glo assay kit (2D-CTG reagent) was purchased from Promega (USA).

[0204] Echo 550 Liquid Handler (Labcyte, USA).

[0205] Plate reader: Envision (PerkinElmer, USA).

[0206] Experimental methods:

[0207] On the first day, H358 cells were collected, counted, and cell density was adjusted. 40 μL of the cell suspension was inoculated into a 384-well plate (containing 800 cells / well) and placed in a 37°C, 5% CO2 incubator for overnight culture. On the second day, compound dilution and cell treatment were performed. The compound stock solution of 10 mM was diluted with DMSO to 200*final concentration (for example, if the final concentration of the compound is 1 μM, first dilute 10 mM to 200 μM, take 2 μL to 98 μL DMSO, mix well, and take 40 μL 200 μM to the source plate). Using the ECHO550 gradient dilution program, the compound was added to the cell culture plate inoculated on the first day with gradient concentration changes (200 nL / well, each concentration of the test compound). The cell culture plate was placed in a 37°C, 5% CO2 incubator for 3 days. On the fifth day, the cell culture plate was removed and 2D-CTG reagent was added at 20 μL / well, and incubated at room temperature for 20 min. The luminescence signal was read in Envision.

[0208] Data Analysis:

[0209] Cell proliferation inhibition rate % = (Average_DMSO-Sample) / (Average_DMSO-Ratio_PositiveControl) x 100%. 100% inhibition is defined as the cell proliferation inhibition level under the treatment of 1 μM positive compound (2-((S)-1-acryloyl-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile). XLfit was used for data analysis and processing. The concentration-effect curve was fitted with a nonlinear four-parameter curve, and the IC of the compound was calculated. 50 :

[0210] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0211] X: Log of cpd concentration

[0212] Y:Percent inhibition (%inh)

[0213] Test results:

[0214] Under the conditions of this experiment, the test compound has significant inhibitory activity on the proliferation of human non-small cell lung cancer H358 cells with KRAS G12C mutation. The binding activity of the test compound to KRAS G12C protein is shown in Table 1.

[0215] Table 1

[0216]

[0217]

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R 1 Selected from R 2 , R 3 independently selected from F, Cl, Br, I or C2-C 10 Alkynyl; R 4a , R 4b are independently selected from H; R 5 Selected from 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 , R 3 Independently selected from F, Cl, Br, I or C2-C6 alkynyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 is selected from F, ethynyl or 1-propynyl.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 3 is selected from F, Cl, Br or I.

5. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

6. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

7. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for preventing or treating cancer with KRAS G12C mutation.

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