Nitrogen-containing heterocyclic compound as well as preparation method, intermediate and application thereof

Abstract

The invention discloses a nitrogen-containing heterocyclic compound as well as a preparation method, an intermediate and application thereof. Specifically, the invention provides a nitrogen-containing heterocyclic compound as shown in a formula (I), a solvate of the nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt of the nitrogen-containing heterocyclic compound or a solvate of the pharmaceutically acceptable salt of the nitrogen-containing heterocyclic compound, the metabolite of the nitrogen-containing heterocyclic compound as shown in the formula (I) has the activity of inhibiting proliferation of Ba / F3 KRAS-G12D cells, AGS cells and Ba / F3 KRAS-G12V cells expressing KRAS G12D and / or KRAS G12V mutant proteins, and the metabolite of the nitrogen-containing heterocyclic compound as shown in the formula (I) has the activity of inhibiting proliferation of the Ba / F3 KRAS-G12V cells expressing KRAS G12D and / or KRAS G12V mutant proteins. The nitrogen-containing heterocyclic ring compound has a relatively good pharmacokinetic property; it is hopeful to treat and / or prevent a variety of diseases mediated by KRAS G12D and / or KRAS G12V.

Description

Nitrogen-containing heterocyclic compound, preparation method thereof, intermediate thereof and application thereof

[0001] This application claims priority from the following documents:

[0002] Chinese patent application 2022110369905, filed on August 25, 2022;

[0003] Chinese patent application No. 202211691981X, filed on December 27, 2022;

[0004] Chinese patent application 2023110289500 with an application date of August 15, 2023.

[0005] This application cites the full text of the above-mentioned Chinese patent application. Technical Field

[0006] The present invention relates to a nitrogen-containing heterocyclic compound, a preparation method thereof, an intermediate thereof and application thereof. Background Art

[0007] RAS proteins are 21kDa guanine trinucleotide phosphate (GTP)-binding proteins located on the cell membrane, composed of 188 or 189 amino acids. The activity of RAS proteins influences cell growth, differentiation, the cytoskeleton, protein trafficking, and secretion. Their activity is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When bound to GDP, RAS proteins are in an "inactive" state. Upon stimulation by specific upstream growth factors, guanine nucleotide exchange factors (GEFs) catalyze the release of GDP from RAS proteins, allowing them to bind to GTP and enter an "activated" state. GTP-bound RAS proteins can activate downstream proteins and signaling pathways. RAS proteins possess weak GTPase activity, hydrolyzing GTP to GDP, thereby transitioning from an active to an inactive state. This hydrolysis process also requires the participation of GTPase-activating proteins (GAPs), which interact with RAS proteins and significantly enhance their ability to hydrolyze GTP to GDP. Any mutation in a RAS protein that affects its GTPase activity, its interaction with GAPs, or its ability to hydrolyze GTP to GDP will result in a prolonged activation of the RAS protein. This prolonged activation of the RAS protein continues to provide growth signals to downstream proteins, leading to continued cell growth and differentiation, and ultimately cancer. The RAS gene family consists of three members: KRAS, NRAS, and HRAS.

[0008] KRAS mutation is the most common oncogenic driver, present in a variety of tumors: lung adenocarcinoma (32%), colorectal cancer (41%), and pancreatic cancer (86%). KRAS mutation is most common with the G12 mutation at codon 12. For example, in KRAS-mutated lung adenocarcinoma, colorectal cancer, and pancreatic cancer, G12 mutations account for 85%, 68%, and 91%, respectively; G12 mutations include G12C, G12D, G12V, G12R and other mutation forms. Among patients with KRAS G12 mutations in lung adenocarcinoma, colorectal cancer, and pancreatic cancer, patients with KRAS G12D mutations accounted for 17%, 45%, and 45%, respectively, and patients with KRAS G12V mutations accounted for 23%, 30%, and 35%, respectively (for example, see Moore, AR et al. Nat Rev Drug Discov 19, 533 (2020)).

[0009] The KRAS G12D inhibitor MRTX1133 developed by Mitati Therapeutics, Inc. has been disclosed in WO2021041671. Its structure is as follows, and preclinical data has been made public.

[0010] Although some progress has been made in this field, there is currently no approved treatment for KRAS G12D and / or KRAS G12V mutations. Therefore, there is still a need to continue to develop effective, stable and safe small molecule KRAS G12D and / or KRAS G12V inhibitors for the treatment of diseases mediated by KRAS G12D and / or KRAS G12V mutations, such as cancer.

[0011] Summary of the Invention

[0012] The technical problem to be solved by the present invention is the problem of the single structure of KRAS G12D and KRAS G12V inhibitors in the prior art. A nitrogen-containing heterocyclic compound, a preparation method thereof, an intermediate thereof and its use are provided. The metabolites of the nitrogen-containing heterocyclic compound have the activity of inhibiting the proliferation of Ba / F3 KRAS-G12D cells, AGS cells and Ba / F3 KRAS-G12V cells expressing KRAS G12D and / or KRAS G12V mutant proteins, and the nitrogen-containing heterocyclic compound has excellent pharmacokinetic properties; it is expected to treat and / or prevent various diseases mediated by KRAS G12D and / or KRAS G12V.

[0013] The present invention solves the above technical problems through the following technical solutions.

[0014] The present invention provides a nitrogen-containing heterocyclic compound as shown in Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0015] Wherein, X is H, deuterium, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O-, -N(R 3 )2, C3-C7 cycloalkyl, halogen, C1-C4 alkyl substituted by one or more halogen, C1-C4 alkyl substituted by one or more deuterium, or C1-C4 alkyl-O-substituted by one or more halogen;

[0016] R 1 -L 1 -OC(=O)-L 2 ;

[0017] L 1 is C1-C4 alkylene or is replaced by one or more L 1a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different;

[0018] Each L 1a is independently deuterium, halogen, -OH, -CN, C1-C6 alkyl-O-, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3;

[0019] L 2 C4-C 20 Alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the C4-C 20 Alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl and 5-10 membered heteroaryl are each optionally substituted by one or more L 2a Substitution; when there are multiple substituents, they are the same or different; the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3;

[0020] Each L 2a are independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O- or C3-C7 cycloalkyl;

[0021] R2 -OH, deuterium, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 alkyl-O-, C1-C6 alkyl-S-, -N(R 3 )2. By one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C1-C6 alkyl-O-, one or more R 2c Substituted C1-C6 alkyl-S-, one or more R 2d Substituted C2-C6 alkenyl, one or more R 2e Substituted C2-C6 alkynyl or one or more R 2f Substituted C3-C7 cycloalkyl; when there are multiple substituents, they may be the same or different;

[0022] Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f Each is independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O-, C3-C7 cycloalkyl,

[0023] Each R 2g and R 2h Each is independently -OH, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C7 cycloalkyl-O-, C3-C7 cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O-, 5-6 membered heteroaryl-O-, -N(R 3 )2. -L 3 -L 4 or -NR 3 -L 5 -C(=O)-OL 6 The heteroatoms in the "4-10 membered heterocycloalkyl" in the 4-10 membered heterocycloalkyl-O-, the "4-10 membered heterocycloalkenyl" in the 4-10 membered heterocycloalkenyl-O-, and the "5-6 membered heteroaryl" in the 5-6 membered heteroaryl-O- are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; when there are multiple substituents, they may be the same or different;

[0024] R 2i is H, halogen, C1-C6 alkyl, -N(R 3)2, 4-10 membered heterocycloalkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, 5-6 membered heteroaryl, 4-10 membered heterocycloalkenyl, C1-C6 alkyl-O-, one or more R 2-b Substituted C1-C6 alkyl, one or more R 2-c Substituted C1-C6 alkyl-O-, one or more R 2-d substituted 4-10 membered heterocycloalkyl, substituted by one or more R 2-e substituted 4-10 membered heterocycloalkenyl, substituted by one or more R 2-f Substituted C3-C7 cycloalkyl, one or more R 2-g Substituted C3-C7 cycloalkenyl, one or more R 2-h Substituted phenyl or one or more R 2-i substituted 5-6 membered heteroaryl; the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, 5-6 membered heteroaryl, substituted by one or more R 2-d The 4-10 membered heterocycloalkyl in the substituted 4-10 membered heterocycloalkyl is replaced by one or more R 2-e The 4-10 membered heterocycloalkenyl in the substituted 4-10 membered heterocycloalkenyl and the 4-10 membered heterocycloalkenyl replaced by one or more R 2-i The heteroatoms in the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they may be the same or different;

[0025] Each R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i are independently deuterium, halogen, -CN, -OH, -N(R 3 )2, C1-C6 alkyl, C2-C4 alkenyl, C1-C4 alkyl-O-, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, or C1-C6 alkyl substituted by one or more halogens; wherein the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, and 5-6 membered heteroaryl are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3;

[0026] Each R 3 are independently H or C1-C6 alkyl;

[0027] Each L 3is independently C1-C4 alkylene or is replaced by one or more L 3a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different;

[0028] Each L 4 is independently C1-C6 alkyl-O-, C3-C7 cycloalkyl-O-, C3-C7 cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O- or 5-6 membered heteroaryl-O-, said C1-C6 alkyl-O-, C3-C7 cycloalkyl-O-, C3-C7 cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O- and 5-6 membered heteroaryl-O- being each optionally substituted by one or more L 4a Substitution; the heteroatoms in the "4-10 membered heterocycloalkyl" in the 4-10 membered heterocycloalkyl-O-, the "4-10 membered heterocycloalkenyl" in the 4-10 membered heterocycloalkenyl-O-, and the "5-6 membered heteroaryl" in the 5-6 membered heteroaryl-O- are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; when there are multiple substituents, they may be the same or different;

[0029] Each L 5 is independently C1-C4 alkylene or is replaced by one or more L 5a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different;

[0030] Each L 6 are independently H, deuterium, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl and 5-10 membered heteroaryl are each optionally substituted by one or more L 6a Substitution; the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they may be the same or different;

[0031] Each L 3a 、L 4a 、L 5a and L 6a Each is independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O- or C3-C7 cycloalkyl;

[0032] Each R 2-a are independently C1-C6 alkyl or -L 7 -N(L 8 )2;

[0033] Each L 7 is independently C1-C4 alkylene or is replaced by one or more L 7a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different;

[0034] Each L 8 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more L 8a Substitution; wherein the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they may be the same or different;

[0035] Each L 7a and L 8a Each is independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O- or C3-C7 cycloalkyl;

[0036] R 4 is C2-C4 alkynyl or C2-C4 alkynyl substituted by one or more deuteriums;

[0037] R 5 and R 6 Each independently is H or deuterium;

[0038] and it meets one, two, three or four of the following conditions:

[0039] (i) X is deuterium, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O-, -N(R 3 )2, C3-C7 cycloalkyl, halogen, C1-C4 alkyl substituted by one or more halogen, C1-C4 alkyl substituted by one or more deuterium, or C1-C4 alkyl-O-substituted by one or more halogen;

[0040] (ii)R 2is deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkyl-O-, C1-C6 alkyl-S-, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -N(R 3 )2. By one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C1-C6 alkyl-O-, one or more R 2c Substituted C1-C6 alkyl-S-, one or more R 2d Substituted C2-C6 alkenyl, one or more R 2e Substituted C2-C6 alkynyl or one or more R 2f Substituted C3-C7 cycloalkyl, R 2i is H, C2-C6 alkyl, halogen, C1-C6 alkyl-O-, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, 5-6 membered heteroaryl, -N(R 3 )2. By one or more R 2-b Substituted C1-C6 alkyl, one or more R 2-c Substituted C1-C6 alkyl-O-, one or more R 2-d substituted 4-10 membered heterocycloalkyl, substituted by one or more R 2-e substituted 4-10 membered heterocycloalkenyl, substituted by one or more R 2-f Substituted C3-C7 cycloalkyl, one or more R 2-g Substituted C3-C7 cycloalkenyl, one or more R 2-h Substituted phenyl or one or more R 2-i substituted 5-6 membered heteroaryl; the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, 5-6 membered heteroaryl, substituted by one or more R 2-d The 4-10 membered heterocycloalkyl in the substituted 4-10 membered heterocycloalkyl is replaced by one or more R 2-e The 4-10 membered heterocycloalkenyl in the substituted 4-10 membered heterocycloalkenyl and the 4-10 membered heterocycloalkenyl replaced by one or more R 2-i The heteroatoms in the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; when there are multiple substituents, they are the same or different; wherein each R 2-b Deuterium, halogen, -CN, -OH, -N(R 3)2, C2-C4 alkenyl, C1-C4 alkyl-O-, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, or C1-C6 alkyl substituted by one or more halogens; wherein the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, and 5-6 membered heteroaryl are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3;

[0041] (iii)R 4 is a C2-C4 alkynyl group substituted by one or more deuteriums;

[0042] (iv)R 5 and R 6 At least one is deuterium.

[0043] In one embodiment, the compound of formula I is not the following compound:

[0044] In one embodiment, X is H or halogen, preferably halogen.

[0045] In one embodiment, R 1 -L 1 -OC(=O)-L 2 .

[0046] In one embodiment, L 1 It is a C1-C4 alkylene group.

[0047] In one embodiment, L 2 C4-C 20 alkyl.

[0048] In one embodiment, R 1 -L 1 -OC(=O)-L 2 ;L 1 is C1-C4 alkylene; L 2 C4-C 20 alkyl.

[0049] In one embodiment, R 2 -OH, or by one or more R 2b Substituted C1-C6 alkyl-O-.

[0050] In one embodiment, R 2i It is C1-C6 alkyl or C1-C6 alkyl-O-.

[0051] In one embodiment, each R 2b Independently Preferably

[0052] In one embodiment, each R 2g and R 2h Each is independently -OH.

[0053] In one embodiment, each R 2-a are independently C1-C6 alkyl.

[0054] In one embodiment, R 2 -OH, or by one or more R 2b Substituted C1-C6 alkyl-O-; R 2i is C1-C6 alkyl or C1-C6 alkyl-O-; each R 2b Independently Preferably Each R 2g and R 2h are each independently -OH; each R 2-a are independently C1-C6 alkyl.

[0055] In one embodiment, R 4 It is a C2-C4 alkynyl group.

[0056] In one embodiment, X is H or halogen;

[0057] R 1 -L 1 -OC(=O)-L 2 ;

[0058] L 1 is a C1-C4 alkylene group;

[0059] L 2 C4-C 20 alkyl;

[0060] R 2 -OH, or by one or more R 2b Substituted C1-C6 alkyl-O-;

[0061] R 2i is C1-C6 alkyl or C1-C6 alkyl-O-;

[0062] Each R 2b Independently

[0063] Each R 2g and R 2h each independently -OH;

[0064] Each R 2-a are independently C1-C6 alkyl;

[0065] R 4 is C2-C4 alkynyl or C2-C4 alkynyl substituted by one or more deuteriums;

[0066] R 5 and R 6 Each independently is H or deuterium;

[0067] and it meets one, two, three or four of the following conditions:

[0068] (i) X is halogen;

[0069] (ii)R 2 for or by one or more R 2b Substituted C1-C6 alkyl-O-, R 2i is C2-C6 alkyl or C1-C6 alkyl-O-;

[0070] (iii)R 4 is a C2-C4 alkynyl group substituted by one or more deuteriums;

[0071] (iv)R 5 and R 6 At least one is deuterium.

[0072] In one embodiment, X is halogen;

[0073] R 1 -L 1 -OC(=O)-L 2 ;

[0074] L 1 is a C1-C4 alkylene group;

[0075] L 2 C4-C 20 alkyl;

[0076] R 2 -OH, or by one or more R 2b Substituted C1-C6 alkyl-O-;

[0077] R 2i is C1-C6 alkyl or C1-C6 alkyl-O-;

[0078] Each R 2b Independently

[0079] R4 is a C2-C4 alkynyl group;

[0080] R 5 and R 6 are each independently H or deuterium.

[0081] In one embodiment, in X, the halogen, the halogen in the C1-C4 alkyl substituted by one or more halogens, and the halogen in the C1-C4 alkyl-O- substituted by one or more halogens can each independently be F, Cl, Br or I, such as Cl.

[0082] In one embodiment, in X, the C1-C4 alkyl group, the C1-C4 alkyl group in C1-C4 alkyl-O-, the C1-C4 alkyl group in C1-C4 alkyl substituted by one or more halogens, the C1-C4 alkyl group in C1-C4 alkyl substituted by one or more deuteriums, and the C1-C4 alkyl group in C1-C4 alkyl-O-substituted by one or more halogens may each independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0083] In one embodiment, in X, the C3-C7 cycloalkyl group may be a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0084] In one embodiment, L 1 wherein the C1-C4 alkylene group is replaced by one or more L 1a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups may each independently be -CH2- * 、-CH2CH2- * 、-CH(CH3)- * 、-CH2CH2CH2- * 、-CH2CH(CH3)- * 、-C(CH3)2- * 、-CH2CH2CH2CH2- * 、-CH2CH(CH3)CH2- * 、-CH(CH3)CH2CH2- * or -CH2CH2CH(CH3)- * , such as -CH2- * or -CH(CH3)- * , where the subscript " * " end is preferably connected to "OC(=O)-L 2 "Connected.

[0085] In one embodiment, L 1a wherein the halogen may be F, Cl, Br or I.

[0086] In one embodiment, L 1a In the C1-C6 alkyl-O-, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0087] In one embodiment, L 1a and L 2 In the above, the C3-C7 cycloalkyl groups can each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0088] In one embodiment, L 1a and L 2 In the above, the C3-C7 cycloalkenyl groups can each independently be a cyclopropenyl, a cyclobutenyl, a cyclopentenyl or a cyclohexenyl group.

[0089] In one embodiment, L 1a and L 2 In the above, the 4-10 membered heterocycloalkyl group may be each independently a 3-7 membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0090] In one embodiment, L 1a and L 2 In the above, the 4-10 membered heterocycloalkenyl groups may each independently be a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group.

[0091] In one embodiment, L 1a In the above, the 5-6 membered heteroaryl group may be pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl.

[0092] In one embodiment, L 2 In the C4-C 20 The alkyl group can be C9-C 15 Alkyl groups, such as n-nonyl or n-pentadecyl.

[0093] In one embodiment, L 2 In the above, the C2-C6 alkenyl group may be a C2-C4 alkenyl group, such as a vinyl group.

[0094] In one embodiment, L 2 In the C6-C 10 Aryl may be phenyl or naphthyl.

[0095] In one embodiment, L2 In the above, the 5-10 membered heteroaryl group may be a 5-6 membered heteroaryl group, such as pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridinyl.

[0096] In one embodiment, L 2a and R 2 wherein the halogens are independently F, Cl, Br or I.

[0097] In one embodiment, L 2a In the C1-C4 alkyl group and the C1-C4 alkyl group in C1-C4 alkyl-O-, the C1-C4 alkyl group can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0098] In one embodiment, L 2a In the above, the C3-C7 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0099] In one embodiment, R 2 wherein the C1-C6 alkyl-O- and one or more R 2b The C1-C6 alkyl-O- in the substituted C1-C6 alkyl-O- may each independently be a C1-C4 alkyl-O-, such as CH3-O-, CH3CH2-O-, CH3CH2CH2-O- or CH3CH(CH3)-O-, preferably CH3-O-.

[0100] In one embodiment, R 2 wherein the C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkyl, 2a The C1-C6 alkyl group in the substituted C1-C6 alkyl group and the C1-C6 alkyl group replaced by one or more R 2c The C1-C6 alkyl groups in the substituted C1-C6 alkyl-S- may each independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0101] In one embodiment, R 2 wherein the C2-C6 alkenyl group and one or more R 2d The C2-C6 alkenyl groups in the substituted C2-C6 alkenyl groups may each independently be a C2-C4 alkenyl group, such as a vinyl group, a propenyl group, or an allyl group.

[0102] In one embodiment, R 2 wherein the C2-C6 alkynyl group and one or more R 2e The C2-C6 alkynyl groups in the substituted C2-C6 alkynyl groups may each independently be a C2-C4 alkynyl group, for example, ethynyl.

[0103] In one embodiment, R 2 wherein the C3-C7 cycloalkyl group and one or more R 2f The C3-C7 cycloalkyl groups in the substituted C3-C7 cycloalkyl groups may each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0104] In one embodiment, R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f wherein the halogens are independently F, Cl, Br or I.

[0105] In one embodiment, R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f In the C1-C4 alkyl group and the C1-C4 alkyl group in C1-C4 alkyl-O-, the C1-C4 alkyl group can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0106] In one embodiment, R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f In the above, the C3-C7 cycloalkyl groups can each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0107] In one embodiment, R 2g and R 2h In the C1-C6 alkyl group and the C1-C6 alkyl group in C1-C6 alkyl-O-, each of them can independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0108] In one embodiment, R 2g and R 2h In the C3-C7 cycloalkyl-O-, the C3-C7 cycloalkyl groups can each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0109] In one embodiment, R 2g and R 2h In the C3-C7 cycloalkenyl-O-, the C3-C7 cycloalkenyl groups can each independently be cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

[0110] In one embodiment, R 2g and R 2h In the 4-10 membered heterocycloalkyl-O-, the 4-10 membered heterocycloalkyl group can be each independently a 3-7 membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0111] In one embodiment, R 2g and R 2h In the 4-10 membered heterocycloalkenyl-O-, the 4-10 membered heterocycloalkenyl groups can each independently be a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group.

[0112] In one embodiment, R 2g and R 2h In the 5-6 membered heteroaryl-O-, the 5-6 membered heteroaryl groups can each independently be pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl.

[0113] In one embodiment, R 2i wherein the halogen may be F, Cl, Br or I.

[0114] In one embodiment, R 2i wherein the C1-C6 alkyl group is replaced by one or more R 2-b The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups may each independently be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group, preferably a methyl group or an isopropyl group.

[0115] In one embodiment, R 2i wherein the C1-C6 alkyl-O- and one or more R 2-c The C1-C6 alkyl-O- in the substituted C1-C6 alkyl-O- may each independently be a C1-C4 alkyl-O-, such as CH3-O-, CH3CH2-O-, CH3CH2CH2-O- or CH3CH(CH3)-O-, preferably CH3CH2-O- or CH3CH(CH3)-O-.

[0116] In one embodiment, R 2i wherein the 4-10 membered heterocycloalkyl group and one or more R 2-dThe 4-10 membered heterocycloalkyl groups in the substituted 4-10 membered heterocycloalkyl groups may each independently be a 3-7 membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0117] In one embodiment, R 2i wherein the 4-10 membered heterocycloalkenyl group and one or more R 2-e The 4-10 membered heterocycloalkenyl groups in the substituted 4-10 membered heterocycloalkenyl groups may each independently be a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group.

[0118] In one embodiment, R 2i wherein the C3-C7 cycloalkyl group and one or more R 2-f The C3-C7 cycloalkyl groups in the substituted C3-C7 cycloalkyl groups may each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0119] In one embodiment, R 2i wherein the C3-C7 cycloalkenyl group and one or more R 2-g The C3-C7 cycloalkenyl groups in the substituted C3-C7 cycloalkenyl groups may each independently be a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group.

[0120] In one embodiment, R 2i wherein the 5-6 membered heteroaryl group and one or more R 2-i The 5- to 6-membered heteroaryl groups in the substituted 5- to 6-membered heteroaryl groups may each independently be pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl.

[0121] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the embodiment, the halogen and the halogen in the C1-C6 alkyl group substituted by one or more halogens may each independently be F, Cl, Br or I.

[0122] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R2-g 、R 2-h and R 2-i In the above, the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more halogens may each independently be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.

[0123] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the above, the C2-C4 alkenyl groups may each independently be a vinyl group.

[0124] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the above, the C1-C4 alkyl-O- can be independently CH3-O-, CH3CH2-O-, CH3CH2CH2-O- or CH3CH(CH3)-O-.

[0125] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the above, the C3-C7 cycloalkyl groups can each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0126] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the above, the C3-C7 cycloalkenyl groups can each independently be a cyclopropenyl, a cyclobutenyl, a cyclopentenyl or a cyclohexenyl group.

[0127] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R2-f 、R 2-g 、R 2-h and R 2-i In the above, the 4-10 membered heterocycloalkyl group may be each independently a 3-7 membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0128] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the above, the 4-10 membered heterocycloalkenyl groups may each independently be a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group.

[0129] In one embodiment, R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i In the above, the 5-6 membered heteroaryl groups can each independently be pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl.

[0130] In one embodiment, R 3 In the above, the C1-C6 alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0131] In one embodiment, L 3 wherein the C1-C4 alkylene group is replaced by one or more L 3a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups may each independently be -CH2- ** 、-CH2CH2- ** 、-CH(CH3)- ** 、-CH2CH2CH2- ** 、-CH2CH(CH3)- ** 、-C(CH3)2- ** 、-CH2CH2CH2CH2- ** 、-CH2CH(CH3)CH2- **、-CH(CH3)CH2CH2- ** or -CH2CH2CH(CH3)- ** , where the subscript " ** "The end is preferably with L 4 connected.

[0132] In one embodiment, L 4 In the C1-C6 alkyl-O-, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0133] In one embodiment, L 4 In the C3-C7 cycloalkyl-O-, the C3-C7 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0134] In one embodiment, L 4 In the C3-C7 cycloalkenyl-O-, the C3-C7 cycloalkenyl group may be a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group.

[0135] In one embodiment, L 4 In the 4-10 membered heterocycloalkyl-O-, the 4-10 membered heterocycloalkyl group may be a 3-7 membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0136] In one embodiment, L 4 In the 4-10 membered heterocycloalkenyl-O-, the 4-10 membered heterocycloalkenyl may be a 3-7 membered heterocycloalkenyl, such as a 3-membered heterocycloalkenyl, a 4-membered heterocycloalkenyl, a 5-membered heterocycloalkenyl or a 6-membered heterocycloalkenyl, more preferably a dihydropyrrolyl, a dihydrofuranyl, a dihydropyranyl, a dihydropyridinyl or a tetrahydropyridinyl.

[0137] In one embodiment, L 4 In the 5-6 membered heteroaryl-O-, the 5-6 membered heteroaryl can be pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl.

[0138] In one embodiment, L 5 wherein the C1-C4 alkylene group is replaced by one or more L 5a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups may each independently be -CH2- a 、-CH2CH2- a 、-CH(CH3)- a 、-CH2CH2CH2- a、-CH2CH(CH3)- a 、-C(CH3)2- a 、-CH2CH2CH2CH2- a 、-CH2CH(CH3)CH2- a 、-CH(CH3)CH2CH2- a or -CH2CH2CH(CH3)- a , where the subscript " a " end is preferably connected to "C(=O)-OL 6 "Connected.

[0139] In one embodiment, L 6 and L 8 In the above, the C1-C6 alkyl groups can each independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0140] In one embodiment, L 6 and L 8 In the above, the C3-C7 cycloalkyl groups can each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0141] In one embodiment, L 6 and L 8 In the above, the C3-C7 cycloalkenyl groups can each independently be a cyclopropenyl, a cyclobutenyl, a cyclopentenyl or a cyclohexenyl group.

[0142] In one embodiment, L 6 and L 8 In the above, the 4-10 membered heterocycloalkyl group may be each independently a 3-7 membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0143] In one embodiment, L 6 and L 8 In the above, the 4-10 membered heterocycloalkenyl groups may each independently be a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group.

[0144] In one embodiment, L 6 and L 8 In the C6-C 10 The aryl groups may each independently be phenyl or naphthyl.

[0145] In one embodiment, L 6 and L8 In the above, the 5-10 membered heteroaryl groups may each independently be a 5-6 membered heteroaryl group, for example, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, a thienyl group, a pyrimidinyl group or a pyridinyl group.

[0146] In one embodiment, L 3a 、L 4a 、L 5a 、L 6a 、L 7a and L 8a wherein the halogens are independently F, Cl, Br or I.

[0147] In one embodiment, L 3a 、L 4a 、L 5a 、L 6a 、L 7a and L 8a In the C1-C4 alkyl group and the C1-C4 alkyl group in C1-C4 alkyl-O-, the C1-C4 alkyl group can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0148] In one embodiment, L 3a 、L 4a 、L 5a 、L 6a 、L 7a and L 8a In the above, the C3-C7 cycloalkyl groups can each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0149] In one embodiment, R 2-a In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group, and is preferably an ethyl group.

[0150] In one embodiment, L 7 wherein the C1-C4 alkylene group is replaced by one or more L 7a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups may each independently be -CH2- b 、-CH2CH2- b 、-CH(CH3)- b 、-CH2CH2CH2- b 、-CH2CH(CH3)- b 、-C(CH3)2- b 、-CH2CH2CH2CH2- b 、-CH2CH(CH3)CH2- b 、-CH(CH3)CH2CH2- bor -CH2CH2CH(CH3)- b , where the subscript " b " end is preferably connected with N(L 8 )2 are connected.

[0151] In one embodiment, L 8 In the above, the C2-C6 alkenyl group may be a C2-C4 alkenyl group, such as a vinyl group.

[0152] In one embodiment, R 4 wherein the C2-C4 alkynyl group and the C2-C4 alkynyl group substituted by one or more deuteriums may each independently be For example

[0153] In one embodiment, when R 2i When it is a C2-C6 alkyl group, the C2-C6 alkyl group may be ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0154] In a certain embodiment, X is H or Cl.

[0155] In one embodiment, R 1 for

[0156] In one embodiment, R 2 -OH,

[0157] In one embodiment, R 4 for

[0158] In one embodiment, R 5 and R 6 Both are H.

[0159] In one embodiment, R 5 and R 6 All are deuterium.

[0160] In one embodiment, X is H or Cl;

[0161] R 1 for

[0162] R 2 -OH,

[0163] R 4 for

[0164] R 5 and R 6 Each independently is H or deuterium;

[0165] and it meets one, two, three or four of the following conditions:

[0166] (i) X is Cl;

[0167] (ii)R 2 for

[0168] (iii)R 4 for

[0169] (iv)R 5 and R 6 At least one is deuterium.

[0170] In a certain embodiment, X is halogen.

[0171] In one embodiment, R 2 for or by one or more R 2b Substituted C1-C6 alkyl-O-, R 2i It is C1-C6 alkyl-O- or C2-C6 alkyl.

[0172] In one embodiment, R 2 for or by one or more R 2b Substituted C1-C6 alkyl-O-, R 2i is C1-C6 alkyl-O- or C2-C6 alkyl, each R 2b Independently

[0173] Each R 2g and R 2h each independently -OH;

[0174] Each R 2-a are independently C1-C6 alkyl.

[0175] In one embodiment, R 4 is a C2-C4 alkynyl group substituted by one or more deuterium groups.

[0176] In one embodiment, R 5 and R 6 At least one is deuterium.

[0177] In one embodiment, the compound represented by formula I is represented by formula I-1:

[0178] In one embodiment, the compound represented by Formula I is a compound represented by Formula I-2, I-3, or I-4:

[0179] In one embodiment, the compound of formula I is any one of the following structures:

[0180] The present invention also provides a method for preparing the compound as shown in Formula I, which is any one of the following methods:

[0181] Method 1: When R 2 for R 4 for When X is Cl, the details are as follows:

[0182] Among them, P 1 is an amino protecting group, such as Boc, PMB, Bn, Cbz or Fmoc; each P1 may be the same or different; R 9 is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl; R 1 、R 5 and R 6 The definitions of are as above;

[0183] It includes the following steps:

[0184] Step 1: In an organic solvent, a compound represented by Formula SM-1 is subjected to a chlorination reaction with a chlorinating agent to obtain a compound represented by Formula SM-2; the chlorinating agent may be phosphorus oxychloride and / or thionyl chloride;

[0185] Step 2: In an organic solvent, in the presence of a base, the compound represented by Formula SM-2 is subjected to a substitution reaction with the compound represented by Formula SM-11 to obtain the compound represented by Formula SM-3;

[0186] Step 3: In an organic solvent, in the presence of a base, the compound represented by Formula SM-3 is subjected to a substitution reaction with the compound represented by Formula SM-12 to obtain a compound represented by Formula SM-4.

[0187] Step 4: In an organic solvent, in the presence of a base, a palladium catalyst and a phosphine ligand, the compound represented by Formula SM-4 and the compound represented by Formula SM-13 undergo Suzuki reaction to obtain a compound represented by Formula SM-5;

[0188] Step 5: In an organic solvent, in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride or CsF, the compound represented by Formula SM-5 is subjected to a deprotection reaction to obtain a compound represented by Formula SM-6;

[0189] Step 6: In an organic solvent, under the action of an acid, the compound represented by Formula SM-6 is subjected to a deprotection reaction to obtain a compound represented by Formula SM-7;

[0190] Step 7: In an organic solvent, in the presence of a base, the compound of Formula SM-7 is subjected to an amino protection reaction to obtain a compound of Formula SM-8.

[0191] Step 8: In an organic solvent, in the presence of a base, the compound represented by Formula SM-8 and the compound represented by Formula SM-14 undergo a substitution reaction to obtain a compound represented by Formula SM-9.

[0192] Step 9: In an organic solvent, in the presence of an acid, the compound represented by Formula SM-9 is subjected to deprotection and hydrolysis reactions to obtain the compound represented by Formula SM-10.

[0193] Step 10: In an organic solvent, in the presence of a base, react the compound represented by Formula SM-10 with the compound represented by Formula SM-15 to obtain the compound represented by Formula Ia.

[0194] Method 2: When R 2 -OH, R 4 for When X is Cl, the details are as follows:

[0195] Among them, R 1 、R 5 and R 6 The definitions of are as above;

[0196] The method comprises the following steps: reacting a compound represented by Formula SM-7 with a compound represented by Formula SM-15 in an organic solvent in the presence of a base to obtain a compound represented by Formula Ib;

[0197] Method 3: When R 2 for R 7 C1-C 12 Alkyl, R 4 for When X is Cl, the details are as follows:

[0198] Among them, R1 、R 5 and R 6 The definitions of are as above;

[0199] It includes the following steps:

[0200] Step A: In an organic solvent, in the presence of a base, the compound represented by Formula SM-8 and the compound represented by Formula SM-18 undergo a substitution reaction to obtain a compound represented by Formula SM-16;

[0201] Step B: In an organic solvent, under the action of an acid, the compound represented by Formula SM-16 is subjected to a deprotection reaction to obtain a compound represented by Formula SM-17;

[0202] Step C: In an organic solvent, in the presence of a base, the compound represented by Formula SM-17 reacts with the compound represented by Formula SM-15 to obtain the compound represented by Formula Ic;

[0203] Method 4: When R 2 for R 8 C1-C 12 Alkyl, R 4 for When X is Cl, the details are as follows:

[0204] Among them, R 1 、R 5 and R 6 The definitions of are as above;

[0205] The method comprises the following steps: in an organic solvent, in the presence of a base, reacting a compound represented by Formula Ib with a compound represented by Formula SM-19 to obtain a compound represented by Formula Id;

[0206] In Method 1, Method 2, Method 3 and Method 4, the acid in the acidic conditions is an acid conventionally used in similar reactions in the art, and the base in the alkaline conditions is a base conventionally used in similar reactions in the art.

[0207] The present invention also provides a compound as shown in formula SM-17:

[0208] Wherein, the definitions of each substituent are as described above.

[0209] In one embodiment, the compound represented by formula SM-17 is any one of the following compounds:

[0210] The present invention also provides a compound as shown below:

[0211] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of substance A and pharmaceutical excipients; the substance A is the nitrogen-containing heterocyclic compound shown in Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0212] The present invention also provides a use of a substance A in the preparation of a RAS inhibitor, wherein the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0213] In the aforementioned applications, the RAS inhibitors can be used in mammalian organisms; they can also be used in vitro, primarily for experimental purposes, for example, as standard or control samples for comparison, or prepared into kits according to conventional methods in the art to provide rapid detection of the effects of RAS inhibition.

[0214] The present invention also provides a use of a substance A in the preparation of a medicament, wherein the medicament is used to treat and / or prevent RAS-mediated diseases; the RAS-mediated diseases as described above are, for example, cancer; the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; and the substance A is in a therapeutically effective amount.

[0215] The present invention also provides a use of a substance A in the preparation of a medicament, wherein the medicament is used to treat and / or prevent cancer; the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; and the substance A is in a therapeutically effective amount.

[0216] The present invention also provides a method for inhibiting RAS, which comprises administering a therapeutically effective amount of substance A to a patient; the substance A is the nitrogen-containing heterocyclic compound shown in Formula I above, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0217] The present invention also provides a method for treating and / or preventing RAS-mediated diseases, comprising administering a therapeutically effective amount of substance A to a patient; the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0218] The present invention also provides a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of substance A to a patient; the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0219] The RAS described above may be KRAS or a KRAS mutation; for example, KRAS G12D, KRAS G12V.

[0220] The cancer as described above can be selected from one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

[0221] The cancer as described above may be gastric cancer or pancreatic cancer.

[0222] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0223] The term "plurality" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0224] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0225] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0226] The term "solvate" refers to a compound formed by the combination of a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates. Solvates include but are not limited to monohydrates.

[0227] The term "pharmaceutically acceptable salt solvate" refers to a compound formed by combining with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include but are not limited to monohydrochloride monohydrate.

[0228] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0229] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0230] The term "prevent" refers to reducing the risk of developing a disease.

[0231] The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0232] The term "therapeutically effective amount" refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0233] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, the chemical elements are as per the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0234] The expression "a group B substituted by one or more groups A" means that one or more hydrogen atoms in group B are independently replaced by groups A. When multiple groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other.

[0235] The term "halogen" refers to fluorine, chlorine, bromine or iodine, especially Cl.

[0236] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C1-C6 or C4-C 20 , preferably C1-C4 or C9-C 15 ) is a linear or branched, saturated, monovalent hydrocarbon group. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-nonyl, and n-pentadecyl.

[0237] The term "alkylene" means a saturated divalent hydrocarbon radical having the specified number of carbon atoms derived by removing two hydrogen atoms from a saturated straight or branched hydrocarbon radical; that is, one of the hydrogen atoms in an alkyl radical is replaced, and the definition of alkyl is as described above. Examples of alkylene radicals include C1-C4 alkylene, and more preferably -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH(CH3)CH2-, or -CH2CH2CH(CH3)-. * wait.

[0238] In the term "alkyl-O-," the definition of alkyl is as described above. Examples of alkyl-O- include C1-C6 alkyl-O- or C1-C4 alkyl-O-, and further examples include CH3-O-, CH3CH2-O-, CH3CH2CH2-O-, or CH3CH(CH3)-O-. Similarly, in other expressions of the form "Rx-O-" herein, the definition of Rx is as described for the respective corresponding groups. For example, the definition of cycloalkyl in "cycloalkyl-O-" is as described for "cycloalkyl" below.

[0239] In the term "alkyl-S-", alkyl is as defined above. Examples of alkyl-S- include C1-C6 alkyl-S-, and more preferably CH3-S-, CH3CH2-S-, CH3CH2CH2-S-, or CH3CH(CH3)-S-.

[0240] The term "cycloalkyl" refers to a saturated carbocyclic substituent that is attached to the rest of the molecule via a single bond via any suitable carbon atom, such as a C3-C7 cycloalkyl having 3 to 7 carbon atoms, preferably a C3-C6 cycloalkyl having 3 to 6 carbon atoms. In one embodiment, typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0241] The term "cycloalkenyl" means a non-aromatic cyclic hydrocarbon radical having a specified number of carbon atoms, at least one double bond (such as a carbon-carbon double bond), and can be connected to the rest of the molecule by a single bond via any suitable carbon atom. In certain embodiments, "cycloalkenyl" is an unsaturated carbocyclic alkenyl group ("C3-C7 cycloalkenyl") having 3 to 7 ring atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

[0242] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 4-10 members, preferably 3-7 members, more preferably 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). Examples of heterocycloalkyl include, but are not limited to, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazinyl.

[0243] The term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of ring atoms (e.g., 4-10 members, preferably 3-7 members, more preferably 3-membered heterocycloalkenyl, 4-membered heterocycloalkenyl, 5-membered heterocycloalkenyl or 6-membered heterocycloalkenyl), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatom (one or more of N, O and S), which has one or more (e.g., 1, 2 or 3) carbon-carbon sp 2 Double bond, which is not aromatic. Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, or tetrahydropyridinyl.

[0244] The term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic rings, the rings share two atoms and one bond, and each ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0245] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), including monocyclic or polycyclic (e.g., 2 or 3), and aromatic properties. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, pyrimidinyl, pyridyl, benzimidazolyl, benzopyrazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, or quinazolinyl.

[0246] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting solely of carbon and hydrogen atoms, having, for example, 2 to 6 (preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by a single bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl or allyl.

[0247] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting solely of carbon and hydrogen atoms, having, for example, 2 to 6 (preferably 2 to 4) carbon atoms, and linked to the rest of the molecule by a single bond. Examples of alkynyl groups include, but are not limited to

[0248] Those skilled in the art will understand that according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0249] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0250] The reagents and raw materials used in the present invention are commercially available.

[0251] The positive progress of the present invention is that the metabolites of the nitrogen-containing heterocyclic compound have the activity of inhibiting the proliferation of Ba / F3 KRAS-G12D cells, AGS cells, and Ba / F3 KRAS-G12V cells expressing KRAS G12D and / or KRAS G12V mutant proteins, and the nitrogen-containing heterocyclic compound has excellent pharmacokinetic properties; it is expected to treat and / or prevent various diseases mediated by KRAS G12D and / or KRAS G12V. BRIEF DESCRIPTION OF THE DRAWINGS

[0252] Figure 1. Tumor volume change curve in Effect Example 3.

[0253] Figure 2. Body weight change rate curve in Effect Example 3. DETAILED DESCRIPTION

[0254] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Reaction steps in the following examples without specifying specific conditions can be carried out according to conventional methods and conditions in the art, or according to commercial specifications.

[0255] Intermediate 1:

[0256] Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0257] Step 1: 2,6-Dichloro-3-fluoropyridin-4-amine

[0258] 2,6-Dichloropyridin-4-amine (6.52 g, 39.99 mmol, 1 eq) was dissolved in N,N-dimethylformamide (30 mL) and acetonitrile (30 mL). 1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (17 g, 47.99 mmol, 1.2 eq) was added and allowed to react at 80°C for half an hour. LCMS monitored the reaction for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-10%) to afford 2,6-dichloro-3-fluoropyridin-4-amine (4.2 g, 58.03% yield) as a white solid.

[0259] MS m / z:181.1 / 183.1[M+H] +

[0260] Step 2: tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester

[0261] 2,6-Dichloro-3-fluoropyridin-4-amine (4.2 g, 23.21 mmol, 1 eq) was dissolved in dichloromethane (40 mL), and BOC anhydride (10.29 g, 47.15 mmol, 2.03 eq) and 4-dimethylaminopyridine (457.28 mg, 3.74 mmol, 0.16 eq) were added. The mixture was allowed to react at room temperature for 16 hours. LCMS monitored the reaction for completion. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-20%) to afford tert-butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester (7.0 g, 79.13% yield) as a white solid.

[0262] MS m / z:381.1 / 383.1[M+H] +

[0263] 1 H NMR(400MHz,DMSO-d6)δ8.06-8.01(m,1H),1.42(s,18H).

[0264] Step 3: tert-Butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0265] Dissolve tert-butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester (5.84 g, 15.32 mmol, 1 eq) in tetrahydrofuran (30 mL). Add lithium diisopropylamide (2 M, 15.32 mL, 2 eq) dropwise at -78°C and warm to room temperature over 2 hours. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue is purified by column chromatography (ethyl acetate / petroleum ether: 0-20%) to afford tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (5.0 g, 85.62% yield) as a brown solid.

[0266] MS m / z:381.1 / 383.1[M+H] +

[0267] 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H),1.54(s,9H),1.45(s,9H).

[0268] Step 4: 2,6-Dichloro-3-fluoropyridin-4-amine

[0269] Dissolve tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (13 g, 34.10 mmol, 1 eq) in dichloromethane (100 mL), add trifluoroacetic acid (30 mL), and react at room temperature for 16 hours. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated to afford 2,6-dichloro-3-fluoropyridin-4-amine (7.67 g, crude) as a brown solid, which was used directly in the next step.

[0270] MS m / z:225.1[M+H] +

[0271] Step 5: Ethyl-4-amino-2,6-dichloro-5-fluoronicotinate

[0272] Dissolve 2,6-dichloro-3-fluoropyridin-4-amine (7.67 g, 34.09 mmol, 1 eq) in ethanol (100 mL) and add concentrated sulfuric acid (102.35 g, 1.02 mol, 30 eq). React at 80°C for 40 hours. Cool to room temperature, and adjust the pH to 7 with saturated sodium bicarbonate. Extract with ethyl acetate, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the residue via column chromatography (ethyl acetate / petroleum ether: 20-40%) to afford 4-amino-2,6-dichloro-5-fluoronicotine ethyl ester (8.0 g, 92.76% yield) as a brown solid.

[0273] MS m / z:253.1 / 255.1[M+H] +

[0274] Step 6: Nicotine ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)

[0275] Dissolve 4-amino-2,6-dichloro-5-fluoronicotine ethyl ester (1.13 g, 4.47 mmol, 1 eq) in tetrahydrofuran (10 mL) and add trichloroacetyl isocyanate (993.57 mg, 5.27 mmol, 1.18 eq). Allow to react at room temperature for 1 hour. LCMS monitors the reaction for completion. The reaction mixture is concentrated, and the residue is purified by column chromatography (ethyl acetate / petroleum ether: 20-50%) to afford 1.5 g, 76.14% yield, of ethyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester as a white solid.

[0276] MS m / z:441.9 / 443.9[M+H] +

[0277] Step 7: 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol

[0278] Nicotine ethyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido) ester (3.0 g, 6.80 mmol, 1 eq) was dissolved in methanol (40 mL). Ammonia methanol solution (7 M, 2.77 mL, 2.85 eq) was added and allowed to react at room temperature for 2 hours. LCMS monitored the reaction for completion. The reaction solution was concentrated, and the residue was slurried with methyl tert-butyl ether to afford 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.7 g, 100% yield) as a white solid.

[0279] MS m / z:250.1 / 252.1[M+H] +

[0280] Step 8: 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine

[0281] Dissolve 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (12 g, 48.00 mmol, 1 eq) in phosphorus oxychloride (100 mL) and slowly add N,N-diisopropylethylamine (30.71 g, 237.59 mmol, 41.38 mL, 4.95 eq) dropwise. Replace the atmosphere with nitrogen and allow the reaction to proceed at 100°C for 16 hours. Upon completion of the reaction as monitored by LCMS, the reaction solution was concentrated under reduced pressure to yield 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (30 g, crude) as a dark brown oil. This crude product was used directly in the next step.

[0282] MS m / z:288.2 / 290.2[M+H] +

[0283] Step 9: (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0284] Dissolve 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (13.3 g, 27.81 mmol, 1 eq) in dichloromethane (100 mL) and add N,N-diisopropylethylamine (10.78 g, 83.44 mmol, 14.53 mL, 3 eq). Replace the atmosphere with nitrogen and slowly add 8-BOC-3,8-diazabicyclo[3.2.1]octane (5.90 g, 27.81 mmol, 1 eq) at -30°C. Allow to react for half an hour. LCMS monitoring indicates completion of the reaction. The reaction mixture is then slowly added to saturated aqueous ammonium chloride solution for quenching. Extract with dichloromethane, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-16%) to give (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.6 g, two-step yield: 38.74%) as a white solid.

[0285] MS m / z:462.1 / 464.1[M+H] +

[0286] Step 10: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methan-d2-ol

[0287] Dissolve (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid hydrochloride (9.8 g, 46.7 mmol, 1 eq) in tetrahydrofuran (120 mL), and slowly add lithium aluminum hydride (5.7 g, 135.7 mmol, 3 eq) in portions. Allow to react at room temperature for 16 hours. TLC monitors the reaction until complete, and the reaction mixture is quenched by placing it in an ice-water bath. Extract the mixture with ethyl acetate, and wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to yield ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methane-d2-ol (3.6 g, crude) as a yellow oil. This crude product is used directly in the next step.

[0288] MS m / z:162[M+H] +

[0289] Step 11: Tert-butyl (1R, 5S)-3-(5,7-dichloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy-d2)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0290] Dissolve (1R,5S)-tert-butyl 3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.3 g, 13.6 mmol, 1 eq) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methane-d2-ol (2.2 g, 13.6 mmol, 1 eq) in tetrahydrofuran (60 mL), and slowly add lithium tert-butoxide (2.1 g, 27.2 mmol, 2 eq). The reaction was allowed to react at room temperature for 4 hours. LCMS monitored the reaction completion. The reaction solution was slowly poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 40-60%) to obtain tert-butyl (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy-d2)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6 g, yield: 75%) as a yellow solid.

[0291] MS m / z:587[M+H] +

[0292] Step 12: Tert-butyl (1R,5S)-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate

[0293] To the mixture were added tert-butyl (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy-d2)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.1 g, 1.87 mmol, 1 eq), (7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (0.97 g, 2.24 mmol, 1.2 eq). Potassium carbonate (0.77 g, 5.62 mmol, 3 eq), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (175 mg, 0.374 mmol, 0.2 eq) and methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) palladium (II) (313 mg, 0.374 mmol, 0.2 eq) were dissolved in a mixed solvent of toluene (20 mL), water (10 mL) and ethanol (10 mL), the atmosphere was replaced with nitrogen, and the reaction was carried out at 80°C for 16 hours. The reaction solution was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0-50%) to give tert-butyl (1R, 5S)-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (0.5 g, yield: 30%) as a yellow solid.

[0294] MS m / z:937[M+H] +

[0295] Step 13: Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy-d2)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0296] Tert-butyl (1R,5S)-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy-d2)pyridino[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (240 mg, 0.26 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL). Cesium fluoride (389 mg, 2.6 mmol, 10 eq) was added and reacted at room temperature for 1 hour. The reaction solution was filtered and slowly poured into saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration gave tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy-d2)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, crude) as a yellow oil.

[0297] MS m / z:781[M+H] +

[0298] Step 14: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Intermediate A)

[0299] Tert-butyl (1R, 5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy-d2)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.26 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and a hydrochloric acid / dioxane solution (4 M, 3 mL) was added and the reaction was carried out at room temperature for 1 hour. The reaction was complete by LCMS detection. The reaction solution was concentrated and purified by HPLC to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (11 mg) as a white solid.

[0300] MS m / z:637.2[M+H] +

[0301] 1 H NMR(400MHz, DMSO-d6)δ8.20(s,1H),8.00(dd,J=9.2,5.9Hz,1H),7.55–7.21(m,2 H),5.28(d,J=54.8Hz,1H),3.50(s,6H),2.83(q,J=8.3Hz,9H),2.31–1.21(m,6H).

[0302] 19 F NMR(376MHz,DMSO-d6)δ-110.25,-142.14,-172.12.

[0303] HPLC separation conditions:

[0304] Column: Phenomenex C18 80*40mm*3μM; Flow rate: 25mL / min

[0305] Mobile phase A: Water (0.1% formic acid v / v) Mobile phase B: ACN; Gradient: 25%-65% (v / v), 11 min; Detection wavelength: 254 / 214 nm

[0306] Step 15: Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0307] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (1 g, 1.28 mmol), di-tert-butyl dicarbonate (280 mg, 1.28 mmol), and triethylamine (388 mg, 3.84 mmol) were dissolved in tetrahydrofuran (20 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford the product as a yellow solid (530 mg).

[0308] MS m / z:737[M+H] + .

[0309] Intermediate 2:

[0310] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0311] Step 1: 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine

[0312] Dissolve 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (12 g, 48.00 mmol, 1 eq) in phosphorus oxychloride (100 mL) and slowly add N,N-diisopropylethylamine (30.71 g, 237.59 mmol, 41.38 mL, 4.95 eq) dropwise. Replace the atmosphere with nitrogen and allow the reaction to proceed at 100°C for 16 hours. Upon completion of the reaction as monitored by LCMS, the reaction solution was concentrated under reduced pressure to yield 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (30 g, crude) as a dark brown oil. This crude product was used directly in the next step.

[0313] MS m / z:288.2 / 290.2[M+H] +

[0314] Step 2: (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0315] Dissolve 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (13.3 g, 27.81 mmol, 1 eq) in dichloromethane (100 mL) and add N,N-diisopropylethylamine (10.78 g, 83.44 mmol, 14.53 mL, 3 eq). Replace the atmosphere with nitrogen and slowly add 8-BOC-3,8-diazabicyclo[3.2.1]octane (5.90 g, 27.81 mmol, 1 eq) at -30°C. Allow to react for half an hour. LCMS monitoring indicates completion of the reaction. The reaction mixture is then slowly added to saturated aqueous ammonium chloride solution for quenching. Extract with dichloromethane, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-16%) to give (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.6 g, two-step yield: 38.74%) as a white solid.

[0316] MS m / z:462.1 / 464.1[M+H] +

[0317] Step 3: (1R,5S)-tert-Butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0318] Dissolve (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.6 g, 18.59 mmol, 1 eq) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (2.96 g, 18.59 mmol, 1 eq) in dichloromethane (100 mL). Slowly add sodium tert-butoxide (3.57 g, 37.17 mmol, 2 eq). React at room temperature under a nitrogen atmosphere for 1 hour. LCMS monitoring indicates completion of the reaction. The reaction solution is then slowly poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 30-60%) to give (1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9 g, yield: 82.71%) as a yellow solid.

[0319] MS m / z:585.1 / 587.1[M+H] +

[0320] 1 H NMR (400MHz, CDCl3) δ5.35 (br d, J=53.2Hz, 1H), 4.35-4.15 (m, 4H) 3.57-3.20 (m, 4H), 3.08 (br s,1H),2.47-1.95(m,5H),1.89-1.59(m,8H),1.53(s,9H).

[0321] 19 F NMR(376MHz, CDCl3)δ-137.27(s),-172.89(s).

[0322] Step 4: (1R,5S)-tert-Butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0323] To the mixture were added tert-butyl-(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoropiperidin-4-yl)methyl aminoester (5.0 g, 8.54 mmol, 1 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (5.03 g, 9.82 mmol, 1.15 eq). Potassium carbonate (3.54 g, 25.62 mmol, 3 eq), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (797.02 mg, 1.71 mmol, 0.2 eq), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (1.43 g, 1.71 mmol, 0.2 eq) were dissolved in a mixed solvent of toluene (50 mL), water (25 mL), and ethanol (25 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 80°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0-30%) to give (1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, yield: 25%) as a yellow solid.

[0324] MS m / z:935.4 / 937.4[M+H] +

[0325] Step 5: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0326] (1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.36 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and a hydrochloric acid / dioxane solution (4 M, 5 mL, 20 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction was complete as monitored by LCMS, and the reaction solution was concentrated to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (1.2 g, crude) as a yellow solid. The crude product was used directly in the next step.

[0327] MS m / z:791.2 / 793.1[M+H] +

[0328] Step 6: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0329] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (1.2 g crude product, 1.36 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium fluoride (2.30 g, 15.16 mmol, 11.15 eq) was added and allowed to react at room temperature overnight. The reaction was monitored for completion by LCMS, filtered, and the filtrate was separated by HPLC to yield the product (350 mg, 40.53% yield) as a yellow solid.

[0330] MS m / z:635.2[M+H] +

[0331] 19F NMR(376MHz, DMSO-d6)δ-110.26(s),-142.18(s),-172.12(s),172.17(s).

[0332] 1 H NMR (400MHz, DMSO-d6) δ10.22(br s,1H),8.00(dd,J=9.23,5.93Hz,1H),7.49(t,J=9.05Hz,1H),7.42(d,J=2.45Hz,1H),7.26(br s,1H),5.28(br d,J=54Hz,1H),4.18-4.11(m,1H),4.03(dd,J=10.33,3.73Hz,1H),3.87(br s,1H),3.55-3.40(m,4H),3.15-2.96(m,4H),2.88-2.80(m,1H),2.22-1.92(m,4H),1.91-1.70(m,4H),1.56(br s,3H).

[0333] 13 C NMR(101MHz,DMSO-d6)δ163.95,163.53,161.48,154.63,151.57,151.23,148.68, 143.80,143.64,140.35,132.98,132.72,131.25,131.17,125.27,123.69,116.69 ,116.43,112.45,108.66,104.05,103.91,99.13,97.40,91.49,75.75,73.89,72.35,60.37,60.16,56.82,55.24,42.88,42.68,36.04,30.88,27.47,27.32,25.55.

[0334] HPLC separation conditions:

[0335] Column: Boston Prime C18 150*30mm*5μM

[0336] Mobile phase: [Water (NH3H2O ​​+ NH4HCO3) - ACN]; B%: 38% - 68%, 10 min

[0337] Example 1: Compound 1

[0338] (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((phosphocarboxyoxy)methoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0339] Step 1: Chloromethyl (4-nitrophenyl) carbonate

[0340] In a 100 mL reaction flask, dissolve p-nitrophenol (5.0 g, 36.0 mmol, 1.0 eq) in tetrahydrofuran (100 mL). Add triethylamine (4.0 g, 39.6 mmol, 1.1 eq) and chloromethyl chloroformate (5.1 g, 39.6 mmol, 1.1 eq). Stir at room temperature for 1 hour. Monitor the reaction for completion using thin-layer chromatography on silica gel. Filter and concentrate the filtrate. The residue is diluted with ethyl acetate and washed sequentially with 10% sodium bicarbonate solution, dilute hydrochloric acid solution, and saturated brine. Dry over anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain chloromethyl (4-nitrophenyl) carbonate (7.6 g, 92% yield) as a light yellow oil.

[0341] Step 2: Iodomethyl (4-nitrophenyl) carbonate

[0342] In a 100 mL reaction flask, dissolve chloromethyl (4-nitrophenyl) carbonate (7.6 g, 32.9 mmol, 1.0 eq) in acetone (20 mL). Add sodium iodide (5.9 g, 39.5 mmol, 1.2 eq). Warm to 50°C and stir for 16 hours. Monitor the reaction on a silica gel plate for thin-layer chromatography (TLC). No new spots are observed. Filter and concentrate the filtrate. The residue is diluted with ether and washed sequentially with 10% sodium sulfite solution, water, and saturated brine, then dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to afford iodomethyl (4-nitrophenyl) carbonate (8.1 g, 76% yield) as a light yellow oil.

[0343] Step 3: (((4-nitrophenoxy)carbonyl)oxy)methyl palmitate

[0344] In a 100 mL reaction flask, dissolve iodomethyl (4-nitrophenyl) carbonate (5.0 g, 15.5 mmol, 1.0 eq) in toluene (30 mL). Add silver carbonate (2.6 g, 9.3 mmol, 0.6 eq) and palmitic acid (4.0 g, 15.5 mmol, 1.0 eq). Heat to 80°C and stir for 2 hours. Monitor the reaction on a silica gel plate for a new spot. Filter, concentrate the filtrate, and purify the residue on a silica gel column (ethyl acetate / petroleum ether: 1-5%) to afford (((4-nitrophenoxy)carbonyl)oxy)methyl palmitate (5.5 g, 79% yield) as a white solid.

[0345] 1 H NMR(400MHz, CDCl3) δ8.29(d,J=9.2Hz,2H),7.41(d,J=9.2Hz,2H),5.88(s,2H),2.4 2(t,J=7.5Hz,2H),1.66(q,J=7.2Hz,2H),1.27-1.25(m,24H),0.88(t,J=6.7Hz,3H).

[0346] Step 4: Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0347] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (1 g, 1.28 mmol), di-tert-butyl dicarbonate (280 mg, 1.28 mmol), and triethylamine (388 mg, 3.84 mmol) were dissolved in tetrahydrofuran (20 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford the product as a yellow solid (530 mg).

[0348] MS m / z:735[M+H] + .

[0349] Step 5: tert-Butyl (1R,5S)-3-(5-chloro-7-(3-(((di-tert-butoxyphosphoryl)oxy)methoxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0350] Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530 mg, 0.72 mmol), cesium carbonate (708 mg, 2.16 mmol), and di-tert-butyl (chloromethyl) phosphate (371 mg, 1.44 mmol) were dissolved in tetrahydrofuran (20 mL) and stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the product as a yellow liquid (500 mg).

[0351] MS m / z:957[M+H] +

[0352] Step 6: ((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl)oxy)methyl dihydrogen phosphate

[0353] Tert-butyl (1R,5S)-3-(5-chloro-7-(3-(((di-tert-butoxyphosphoryl)oxy)methoxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), and methanesulfonic acid (69 mg, 0.72 mmol) was added. The reaction was stirred at room temperature for 0.5 hour. The reaction was quenched by the addition of triethylamine, and the reaction solution was concentrated under reduced pressure. The residue was used directly in the next step as a yellow oil (280 mg).

[0354] MS m / z:745[M+H]+

[0355] Step 7: (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((phosphooxy)methoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0356] In a 50 mL reaction vial, ((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl)oxy)methyl dihydrogen phosphate (20 mg, 0.03 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL). Triethylamine (9 mg, 0.09 mmol, 3.0 eq) and (((4-nitrophenoxy)carbonyl)oxy)methyl palmitate (14 mg, 0.03 mmol, 1.0 eq) were added. The mixture was heated to 60°C and stirred for 30 minutes. The reaction was monitored for completion by LCMS. The reaction solution was concentrated and separated and purified by preparative high performance liquid chromatography to give (palmitoyl < hexadecanoyl > oxy)methyl (1R, 5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((phosphocarboxyloxy)methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.01 mg, yield: 4%) as a white solid.

[0357] MS m / z:529[M / 2+H] +

[0358] 1H NMR (400MHz, DMSO-d6) δ8.06(dd,J=9.2,5.8Hz,1H),7.83(d,J=2.6Hz,1H),7.53(t,J=9.1Hz,1H),7.41 (s,1H),5.75(s,2H),5.57(d,J=9.9Hz,2H),5.31(d,J=54.2Hz,1H),4.38-4.32(m,1H),4.22-4.16(m,1 H),3.98(s,2H),3.57(s,1H),3.27-3.06(m,6H),2.88(d,J=7.5Hz,2H),2.35(t,J=7.3Hz,2H),2.11(t, J=29.6Hz,4H),1.84(d,J=22.2Hz,6H),1.58-1.43(m,2H),1.22(d,J=13.5Hz,24H),0.91-0.61(m,3H).

[0359] HPLC separation conditions:

[0360] Column:SunFire Prep C18 OBD TM 5μm, 19*250mm column; flow rate: 25mL / min

[0361] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v); Detection wavelength: 254 / 214 nm

[0362] Example 2: Compound 2

[0363] (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(isobutyloxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0364] Step 1: tert-Butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(isobutyloxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0365] In a 100 mL reaction vial, tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL). Triethylamine (26 mg, 0.26 mmol, 2.0 eq) and isobutyryl chloride (17 mg, 0.16 mmol, 1.2 eq) were added under ice-cooling and the mixture was stirred at room temperature for 30 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product of tert-butyl (1R, 5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(isobutoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (108 mg) as a yellow solid.

[0366] MS m / z:807[M+H] +

[0367] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isobutyrate

[0368] In a 100 mL reaction vial, tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(isobutyloxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (108 mg, 0.13 mmol, 1.0 eq) was dissolved in 1,4-dioxane hydrochloric acid (4 mL) and stirred at room temperature for 1 hour. The reaction was monitored for completion by LCMS. Concentration gave crude 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isobutyrate (95 mg) as a yellow solid.

[0369] MS m / z:707[M+H] +

[0370] Step 3: (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(isobutyloxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0371] In a 100 mL reaction vial, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isobutyrate (95 mg, 0.13 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL). Triethylamine (39 mg, 0.39 mmol, 3.0 eq) and (((4-nitrophenoxy)carbonyl)oxy)methyl palmitate (59 mg, 0.13 mmol, 1.0 eq) were added. The mixture was heated to 60°C and stirred for 30 minutes. The reaction was monitored by thin-layer chromatography on silica gel to detect a new spot. The reaction solution was concentrated and separated and purified by preparative high performance liquid chromatography to give (palmitoyl < hexadecanoyl > oxy)methyl (1R, 5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-(isobutyloxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28.9 mg, yield: 22%) as a white solid.

[0372] MS m / z:1019[M+H] +

[0373] 1 H NMR (400MHz, DMSO-d6) δ8.24(dd,J=9.2,5.9Hz,1H),8.04(d,J=2.5Hz,1H),7.67(t,J=9.0Hz,1H),7.56(s,1H),5.75(s,2H),5.41(d,J=54.8Hz,1H),4. 39(s,1H),4.10(s,1H),3.70(s,1H),3.24-2.67(m,6H),2.36(t,J=7.3Hz,4 H),1.80(s,9H),1.72-1.38(m,4H),1.40-1.01(m,30H),0.88-0.70(m,3H).

[0374] HPLC separation conditions:

[0375] Column:SunFire Prep C18 OBD TM 5μm, 19*250mm column; flow rate: 25mL / min

[0376] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v); Detection wavelength: 254 / 214 nm

[0377] Example 3: Compound 3

[0378] (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((isopropoxycarbonyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0379] Step 1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0380] In a 100 mL reaction vial, tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol, 1.0 eq) was dissolved in 1,4-dioxane hydrochloric acid solution (4 mL) and stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. Concentration gave crude 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (86 mg) as a yellow solid.

[0381] MS m / z:637.2[M+H] +

[0382] Step 2: (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0383] In a 100 mL reaction vial, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (86 mg, 0.13 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL). Triethylamine (39 mg, 0.39 mmol, 3.0 eq) and (((4-nitrophenoxy)carbonyl)oxy)methyl palmitate (59 mg, 0.13 mmol, 1.0 eq) were added. The mixture was heated to 60°C and stirred for 30 minutes. The reaction was monitored by LCMS, and a small amount of starting material remained. The product was concentrated to give crude (palmitoyl<hexadecanoyl>oxy)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (123 mg) as a yellow solid.

[0384] MS m / z:949[M+H] +

[0385] Step 3: (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((isopropoxycarbonyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0386] In a 100 mL reaction vial, (palmitoyl<hexadecanoyl>oxy)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.13 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL). Triethylamine (26 mg, 0.26 mmol, 2.0 eq) and isopropyl chloroformate (18 mg, 0.15 mmol, 1.1 eq) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction was monitored for completion by LCMS. The mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by preparative high-performance liquid chromatography to obtain (palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((isopropoxycarbonyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.65 mg, 7% yield) as a white solid.

[0387] MS m / z:518[M / 2+H] +

[0388] 1 H NMR (400MHz, DMSO-d6) δ8.24(dd,J=9.2,5.8Hz,1H),8.14(d,J=2.6Hz,1H),7.69(t,J=9.0Hz,2H) ,5.75(s,2H),5.27(d,J=53.9Hz,1H),4.92(p,J=6.2Hz,1H),4.39(s,1H),4.10(s,1H),3.68(s,1 H),3.17-2.93(m,4H),2.82(q,J=8.3Hz,2H),2.36(t,J=7.3Hz,2H),2.15-1.92(m,4H),1.88-1.6 8(m,6H),1.52(q,J=7.4Hz,4H),1.34(d,J=6.3Hz,6H),1.28-1.08(m,24H),0.83(t,J=6.8Hz,3H).

[0389] HPLC separation conditions:

[0390] Column:SunFire Prep C18 OBDTM 5μm, 19*250mm column; flow rate: 25mL / min

[0391] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v); Detection wavelength: 254 / 214 nm

[0392] Example 4: Compound 4

[0393] (Decyloxyl)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0394] Step 1: Chloromethyl (4-nitrophenyl) carbonate

[0395] In a 100 mL reaction flask, dissolve p-nitrophenol (5.0 g, 36.0 mmol, 1.0 eq) in tetrahydrofuran (100 mL). Add triethylamine (4.0 g, 39.6 mmol, 1.1 eq) and chloromethyl chloroformate (5.1 g, 39.6 mmol, 1.1 eq). Stir at room temperature for 1 hour. Monitor the reaction for completion using thin-layer chromatography on silica gel. Filter and concentrate the filtrate. The residue is diluted with ethyl acetate and washed sequentially with 10% sodium bicarbonate solution, dilute hydrochloric acid solution, and saturated brine. Dry over anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain chloromethyl (4-nitrophenyl) carbonate (7.6 g, 92% yield) as a light yellow oil.

[0396] Step 2: Iodomethyl (4-nitrophenyl) carbonate

[0397] In a 100 mL reaction flask, dissolve chloromethyl (4-nitrophenyl) carbonate (7.6 g, 32.9 mmol, 1.0 eq) in acetone (20 mL). Add sodium iodide (5.9 g, 39.5 mmol, 1.2 eq). Warm to 50°C and stir for 16 hours. Monitor the reaction on a silica gel plate for thin-layer chromatography (TLC). No new spots are observed. Filter and concentrate the filtrate. The residue is diluted with ether and washed sequentially with 10% sodium sulfite solution, water, and saturated brine, then dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to afford iodomethyl (4-nitrophenyl) carbonate (8.1 g, 76% yield) as a light yellow oil.

[0398] Step 3: (((4-nitrophenoxy)carbonyl)oxy)methyldecanoate

[0399] In a 100 mL reaction flask, dissolve iodomethyl (4-nitrophenyl) carbonate (5.0 g, 15.5 mmol, 1.0 eq) in toluene (30 mL). Add silver carbonate (2.6 g, 9.3 mmol, 0.6 eq) and decanoic acid (2.7 g, 15.5 mmol, 1.0 eq). Heat to 80°C and stir for 2 hours. Monitor the reaction on a silica gel plate for a new spot. Filter, concentrate the filtrate, and purify the residue on a silica gel column (ethyl acetate / petroleum ether: 1-10%) to obtain (((4-nitrophenoxy)carbonyl)oxy)methyldecanoate (4.2 g, 74% yield) as a colorless oil.

[0400] 1 H NMR(400MHz, CDCl3) δ8.29(d,J=9.2Hz,2H),7.41(d,J=9.2Hz,2H),5.89(s,2H), 2.42(t,J=7.5Hz,2H),1.93-1.48(m,2H),1.42-1.14(m,12H),1.04-0.70(m,3H).

[0401] Step 4: (Decyloyloxy)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0402] In a 50 mL reaction vial, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (86 mg, 0.13 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL). Triethylamine (39 mg, 0.39 mmol, 3.0 eq) and (((4-nitrophenoxy)carbonyl)oxy)methyldecanoate (48 mg, 0.13 mmol, 1.0 eq) were added. The mixture was heated to 60°C and stirred for 30 minutes. The reaction was monitored for completion by LCMS. The reaction solution was concentrated and separated and purified by preparative high performance liquid chromatography to give (decyloxo)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.35 mg, yield: 7%) as a white solid.

[0403] MS m / z:865[M+H] +

[0404] 1 H NMR (400MHz, DMSO-d6) δ8.00(dd,J=9.2,5.9Hz,1H),7.49(t,J=9.0Hz,1H),7.42(d,J=2. 6Hz,1H),7.25(s,1H),5.75(s,2H),5.29(d,J=54.2Hz,1H),4.39-4.37(m,1H),3.96(s,1H ),3.68(s,1H),3.12-3.05(m,4H),2.85(s,2H),2.36(t,J=7.3Hz,2H),2.21-1.97(m,4H), 1.83(d,J=35.6Hz,6H),1.52(q,J=7.1Hz,4H),1.23(d,J=8.7Hz,12H),0.95-0.68(m,3H).

[0405] HPLC separation conditions:

[0406] Column:SunFire Prep C18 OBD TM 5μm, 19*250mm column; flow rate: 25mL / min

[0407] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v), Detection wavelength: 254 / 214 nm

[0408] Example 5: Compound 5

[0409] (Palmitoyloxy)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0410] Step 1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0411] Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.14 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL). A solution of 1,4-dioxane in hydrochloric acid (4 M, 0.5 mL) was added dropwise and stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The product was concentrated to give the product (100 mg) as a yellow solid.

[0412] MS m / z:637.2[M+H] +

[0413] Step 2: (Palmitoyloxy)methyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0414] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (100 mg, 0.136 mmol), methyl ((4-nitrophenoxy)carbonyl)oxy)palmitate (61 mg, 0.13 mmol) and triethylamine (41 mg, 0.41 mmol) were dissolved in acetonitrile (10 mL) and stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then prepared using an efficient preparative liquid chromatography system. The product was lyophilized to obtain a white solid (38 mg).

[0415] 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.00(dd,J=9.2,5.9Hz,1H),7.56–7.40(m ,2H),7.24(s,1H),5.75(s,2H),5.32(d,J=54.3Hz,1H),4.36(d,J=23.0Hz,2H), 3.95(s,2H),3.08–2.90(m,4H),2.36(t,J=7.3Hz,3H),2.24–1.99(m,4H),1.81( s,6H),1.50(dt,J=21.3,6.9Hz,4H),1.24–1.19(m,24H),0.84(d,J=8.6Hz,3H).

[0416] 19 F NMR(377MHz,DMSO-d6)δ-110.24,-141.62,-172.21.

[0417] MS m / z:949[M+H] +

[0418] HPLC separation conditions:

[0419] Column:SunFire Prep C18 OBD TM 5μm, 19*250mm column; flow rate: 25mL / min

[0420] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v); Detection wavelength: 254 / 214 nm

[0421] Example 6: Compound 6

[0422] (Palmitoyloxy)methyl (1R,5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0423] Step 1: Tert-butyl (1R,5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0424] Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL). Triethylamine (26 mg, 0.26 mmol, 2.0 eq) and acetyl chloride (13 mg, 0.16 mmol, 1.2 eq) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction was monitored for completion by LCMS. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl (1R, 5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-5-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazine-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, yield: 98%) as a yellow solid.

[0425] MS m / z:779[M+H] +

[0426] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl acetate

[0427] Tert-butyl (1R,5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.11 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL). A 1,4-dioxane hydrochloric acid solution (4 M, 0.2 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored for completion by LCMS. Concentration gave 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl acetate (75 mg) as a yellow solid.

[0428] MS m / z:679[M+H] +

[0429] Step 3: (Palmitoyloxy)methyl (1R,5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0430] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridino[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl acetate (75 mg, 0.13 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL), and triethylamine (39 mg, 0.39 mmol, 3.0 eq) and (((4-nitrophenoxy)carbonyl)oxy)methyl palmitate (59 mg, 0.13 mmol, 1.0 eq) were added. The mixture was heated to 60°C and stirred for 30 minutes. The reaction solution was concentrated and separated and purified by HPLC preparative chromatography to give (palmitoyloxy)methyl (1R, 5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-5-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, yield: 27%) as a white solid.

[0431] 1 H NMR (400MHz, DMSO-d6) δ8.24 (dd, J=9.2, 5.9Hz, 1H), 8.03 (d, J=2.4Hz, 1H), 7.6 7(t,J=9.0Hz,1H),7.58(s,1H),5.76(s,2H),5.45(d,J=53.6Hz,1H),4.36(d,J =28.8Hz, 3H), 4.10 (s, 1H), 3.13 (m, 5H), 2.35 (d, J = 7.9Hz, 8H), 1.94 (d, J = 107. 0Hz, 6H), 1.52 (q, J = 7.1Hz, 3H), 1.21 (d, J = 9.7Hz, 26H), 0.84 (t, J = 6.7Hz, 3H).

[0432] 19 F NMR(377MHz,DMSO-d6)δ-105.67,-141.07,-172.54.

[0433] MS m / z:991[M+H] +

[0434] HPLC separation conditions:

[0435] Column:SunFire Prep C18 OBD TM 5μm, 19*250mm column; flow rate: 25mL / min

[0436] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v); Detection wavelength: 254 / 214 nm

[0437] Example 7: Compound 7

[0438] 1-(Palmitoyloxy)ethyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0439] Step 1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0440] Tert-butyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.07 mmol, 1.0 eq) was dissolved in acetonitrile (3 mL). A solution of 1,4-dioxane in hydrochloric acid (4 M, 0.5 mL) was added dropwise and stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. Concentration afforded the product (50 mg) as a yellow solid.

[0441] MS m / z:637.2[M+H] +

[0442] Step 2: 1-(Palmitoyloxy)ethyl (1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0443] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy-d2)pyridino[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50 mg, 0.07 mmol), ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)palmitate (30 mg, 0.07 mmol) and triethylamine (21 mg, 0.21 mmol) were dissolved in acetonitrile (10 mL) and stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then prepared using an efficient preparative liquid chromatography system. The product was lyophilized to obtain the product as a white solid (10 mg).

[0444] 1 H NMR (400MHz, DMSO-d6) δ8.27(dd,J=9.3,5.9Hz,1H),8.20–8.01(m,1H),7.70(q,J=8.4,7.8Hz,2H),6.77(q,J=5.4Hz,1H),5.32(d,J=53.5H z,1H),4.12(s,6H),2.89(s,7H),2.43–2.31(m,3H),1.86(s,6H),1.53(dd,J=17.2,6.5Hz,6H),1.24–1.15(m,24H),0.84(t,J=6.8Hz,3H).

[0445] 19 F NMR(377MHz,DMSO-d6)δ-105.13,-141.00,-172.22.

[0446] MS m / z: 963 [M+H] +

[0447] HPLC separation conditions:

[0448] Column:SunFire Prep C18 OBD TM 5μm, 19*250mm column; flow rate: 25mL / min

[0449] Mobile phase A: Water (0.1% formic acid, v / v) Mobile phase B: ACN; Gradient: 20%-60% (v / v); Detection wavelength: 254 / 214 nm

[0450] Example 8: Compound 8

[0451] (Palmitoyl<hexadecanoyl>oxy)methyl(1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-((isopropoxycarbonyl)oxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0452] Compound 8 was prepared by the method of steps 2 and 3 of Example 3 using 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as the starting material.

[0453] MS m / z:1033.30[M+H] +

[0454] 1 H NMR(400MHz,Chloroform-d)δ7.90(dd,J=9.1,5.7Hz,1H),7.82(m,1H),7.56(m,1H),7.36 (m,1H),5.83(s,2H),5.38–5.17(m,1H),5.01(p,J=6.3Hz,1H),4.43(m,2H),4.30–4.16(m, 2H),3.72(m,2H),3.32–3.10(m,3H),3.03–2.93(m,1H),2.85(m,1H),2.38(t,J=7.5Hz,2H ),2.34–2.08(m,3H),1.90(m,6H),1.65(m,2H),1.45–1.17(m,33H),0.87(t,J=6.8Hz,3H).

[0455] Effect Example 1 Whole Blood Stability Test

[0456] 1. Sample Preparation

[0457] a) Prepare human and rat whole blood;

[0458] b) Prepare a 10 mM stock solution of the compound in DMSO, take 10 μL and add 990 μL of 50% methanol solution to obtain a 100 μM working solution of the compound;

[0459] c) Add 10 μL of 100 μM compound working solution to 990 μL of whole blood to obtain a 1 μM incubation sample;

[0460] d) Incubate the sample in a water bath at 37°C for 0, 5, 30, 60, 120, 180, 240, and 300 minutes, respectively, and terminate the reaction with pre-cooled internal standard acetonitrile;

[0461] e) centrifuging the terminated sample at 12,000 rpm for 10 minutes;

[0462] f) The supernatant was transferred to a 96-well plate, and the sample was mixed with purified water (v / v=1:1).

[0463] 2. Determine the residual concentration of the compound after incubation and the peak time of the metabolite by LC-MS / MS

[0464] LC-MS / MS assay conditions:

[0465] Mobile phase A: 0.1% formic acid in water;

[0466] Mobile phase B: 0.1% formic acid in acetonitrile;

[0467] Column: ACQUITY UPLC BEH C18 1.7 μm 2.1*50 mm Column;

[0468] Flow rate: 0.50mL / min.

[0469] LC-MS / MS results:

[0470] Metabolites of compounds 3, 4, 5, and 6 peak time: 0.70 min; MS m / z: 637.2 [M+H] + .

[0471] The stability results of the compounds after incubation are shown in the following table:

[0472] Note: T 1 / 2 represents the elimination half-life.

[0473] The results showed that the compounds of the present invention exhibited good stability in the whole blood stability test of humans and rats; compounds 3, 4, 5, and 6 produced the same active product, namely intermediate A, during the whole blood incubation process.

[0474] Effect Example 2 Proliferation Inhibitory Activity on Ba / F3 KRAS-G12D, Ba / F3 KRAS-G12V Stable Cell Lines and AGS Tumor Cell Lines Containing KRAS G12D Mutations

[0475] Used to determine the in vitro proliferation inhibitory activity of compounds on mouse primary B cells Ba / F3 stably expressing KRAS G12D / V mutant protein, Ba / F3 KRAS-G12D and Ba / F3 KRAS-G12V cells, and gastric cancer AGS cells expressing KRAS G12D mutant protein.

[0476] Cell sources: Ba / F3 KRAS-G12D and Ba / F3 KRAS-G12V were purchased from Kangyuan Broad Biotechnology (Beijing) Co., Ltd., with catalog numbers KC-1259 and KC-1261, respectively; AGS was purchased from Shanghai Baili Biotechnology Co., Ltd.

[0477] Logarithmically growing cells were seeded in 96-well plates (8,000, 8,000, and 4,000 cells / well, respectively, for Ba / F3 KRAS-G12D, Ba / F3 KRAS-G12V, and AGS cells, 90 μl / well). After incubation at 37°C, 5% CO₂ for one day, a serial dilution of the test compound (Intermediate A) was added. Specifically, a 10 mM stock solution of the compound, previously dissolved in DMSO, was diluted four-fold to a total of 10 concentrations. This solution was then diluted to 10-fold the target concentration in culture medium in a separate 96-well plate. Then, 10 μl / well of the compound solution was added to the 96-well plate seeded with cells to achieve the target concentrations (10,000, 2,500, 625, 156, 39, 10, 2.5, 0.6, 0.15, and 0.04 nM). Three replicates were performed for each concentration, and a blank control was included. After culturing for 72 h at 37°C and 5% CO2, 50 μl of 2.0 reagent (luciferase ATP bioluminescence detection reagent, purchased from Promega, catalog number G9243), shake for 2 minutes, incubate at room temperature for 8 minutes, and then measure the fluorescence intensity (light collection time is 100ms). The inhibition rate of cell proliferation at each concentration of compound was calculated as follows: cell proliferation inhibition rate (%) = [(luminescence intensity 72 hours control group containing cell culture medium - luminescence intensity)] 72小时化合物组 ) / (luminescence intensity of the control group containing cell culture medium at 72 hours – luminescence intensity 72小时无细胞 培养基对照组 )] × 100%. The data were analyzed using GraphPad Prism 8.3 software, and the dose-effect curve was fitted using nonlinear S-curve regression to obtain the data, from which the IC 50 The results are shown in the table below.

[0478] The test results showed that intermediate A had good proliferation inhibitory activity against Ba / F3 KRAS-G12D, Ba / F3 KRAS-G12V and AGS cells containing KRAS G12D / V mutations.

[0479] Effect Example 3 Antitumor Effect of Test Compounds in Human Pancreatic Cancer HPAC Subcutaneous Xenograft Model

[0480] This experiment is used to evaluate the anti-tumor effect of the compound of the present invention in a BALB / c female nude mouse animal model of subcutaneous xenograft of human pancreatic cancer HPAC (with KRAS G12D mutation).

[0481] Experimental animals: BALB / c nude mice, female, 7-8 weeks (age of mice at the time of tumor cell inoculation), weighing 16.8-21.1 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. Shanghai Branch.

[0482] Animal modeling and random grouping: HPAC cells were cultured and expanded to 15 T225cm2 culture flasks. The cells were collected, resuspended in serum-free medium RPMI-1640, counted, and added with matrigel at a ratio of 1:1. 5×10 6 0.1 mL was inoculated subcutaneously in the right anterior region of BALB / c nude mice. When the average tumor volume reached approximately 230 mm 3 At 4 hr, the mice were randomly divided into two experimental groups according to tumor size, with 5 mice in each group. The day of grouping was defined as day 0, or D0.

[0483] Experimental plan: BALB / c nude mice were subcutaneously inoculated with HPAC cells to establish a cell line xenograft tumor model. The experiment was divided into a compound 3 (20 mg / kg) group and a vehicle group, with 5 mice in each group, and the drugs were administered by intraperitoneal injection at a volume of 10 μL / g. The vehicle group was given an equal amount of vehicle (10% dimethylacetamide + 5% polyethylene glycol (15)-hydroxystearate + 85% saline) twice daily for 4 weeks. Throughout the experiment, the tumor size and body weight of the mice were measured twice a week to observe any toxic reactions.

[0484] The calculation formula for tumor volume (TV) is: TV = 1 / 2 × a × b × b, where a and b represent the length and width of the tumor, respectively.

[0485] Body weight change rate (%) = (body weight / body weight on D0 - 1) × 100%.

[0486] After measurement and calculation, the mouse tumor volume results are shown in the following table:

[0487] After measurement and calculation, the weight change rate of mice is shown in the following table:

[0488] The tumor volume change curves of the two experimental groups are shown in Figure 1, and the body weight change rate curves are shown in Figure 2.

[0489] The results showed that in the human pancreatic cancer HPAC subcutaneous xenograft BALB / c female nude mouse animal model, the compounds of the present invention (especially compound 3) exhibited good anti-tumor effects and had little effect on the body weight of nude mice, showing good safety.

[0490] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A nitrogen-containing heterocyclic compound as represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, X is H, deuterium, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O-, -N(R 3 )2, C3-C7 cycloalkyl, halogen, C1-C4 alkyl substituted by one or more halogen, C1-C4 alkyl substituted by one or more deuterium, or C1-C4 alkyl-O-substituted by one or more halogen; R 1 -L 1 -OC(=O)-L 2 ; L 1 is C1-C4 alkylene or is replaced by one or more L 1a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different; Each L 1a is independently deuterium, halogen, -OH, -CN, C1-C6 alkyl-O-, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; L 2 C4-C 20 Alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the C4-C 20 Alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl and 5-10 membered heteroaryl are each optionally substituted by one or more L 2a Substitution; when there are multiple substituents, they are the same or different; the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; Each L 2a are independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O- or C3-C7 cycloalkyl; R 2 -OH, deuterium, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 alkyl-O-, C1-C6 alkyl-S-, -N(R 3 )2. By one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C1-C6 alkyl-O-, one or more R 2c Substituted C1-C6 alkyl-S-, one or more R 2d Substituted C2-C6 alkenyl, one or more R 2e Substituted C2-C6 alkynyl or one or more R 2f Substituted C3-C7 cycloalkyl; when there are multiple substituents, they may be the same or different; Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f are independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl -O-, C3-C7 cycloalkyl, Each R 2g and R 2h Each is independently -OH, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C7 cycloalkyl-O-, C3-C7 cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O-, 5-6 membered heteroaryl-O-, -N(R 3 )2. -L 3 -L 4 or -NR 3 -L 5 -C(=O)-OL 6 The heteroatoms in the "4-10 membered heterocycloalkyl" in the 4-10 membered heterocycloalkyl-O-, the "4-10 membered heterocycloalkenyl" in the 4-10 membered heterocycloalkenyl-O-, and the "5-6 membered heteroaryl" in the 5-6 membered heteroaryl-O- are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; when there are multiple substituents, they may be the same or different; R 2i is H, halogen, C1-C6 alkyl, -N(R 3 )2, 4-10 membered heterocycloalkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, 5-6 membered heteroaryl, 4-10 membered heterocycloalkenyl, C1-C6 alkyl-O-, one or more R 2-b Substituted C1-C6 alkyl, one or more R 2-c Substituted C1-C6 alkyl-O-, one or more R 2-d substituted 4-10 membered heterocycloalkyl, substituted by one or more R 2-e substituted 4-10 membered heterocycloalkenyl, substituted by one or more R 2-f Substituted C3-C7 cycloalkyl, one or more R 2-g Substituted C3-C7 cycloalkenyl, one or more R 2-h Substituted phenyl or one or more R 2-i substituted 5-6 membered heteroaryl; the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, 5-6 membered heteroaryl, substituted by one or more R 2-d The 4-10 membered heterocycloalkyl in the substituted 4-10 membered heterocycloalkyl is replaced by one or more R 2-e The 4-10 membered heterocycloalkenyl in the substituted 4-10 membered heterocycloalkenyl and the 4-10 membered heterocycloalkenyl replaced by one or more R 2-i The heteroatoms in the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they may be the same or different; Each R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i are independently deuterium, halogen, -CN, -OH, -N(R 3 )2, C1-C6 alkyl, C2-C4 alkenyl, C1-C4 alkyl-O-, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, or C1-C6 alkyl substituted by one or more halogens; wherein the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, and 5-6 membered heteroaryl are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; Each R 3 are independently H or C1-C6 alkyl; Each L 3 is independently C1-C4 alkylene or is replaced by one or more L 3a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different; Each L 4 is independently C1-C6 alkyl-O-, C3-C7 cycloalkyl-O-, C3-C7 cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O- or 5-6 membered heteroaryl-O-, said C1-C6 alkyl-O-, C3-C7 cycloalkyl-O-, C3-C7 cycloalkenyl-O-, 4-10 membered heterocycloalkyl-O-, 4-10 membered heterocycloalkenyl-O-, phenyl-O- and 5-6 membered heteroaryl-O- being each optionally substituted by one or more L 4a Substitution; the heteroatoms in the "4-10 membered heterocycloalkyl" in the 4-10 membered heterocycloalkyl-O-, the "4-10 membered heterocycloalkenyl" in the 4-10 membered heterocycloalkenyl-O-, and the "5-6 membered heteroaryl" in the 5-6 membered heteroaryl-O- are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; when there are multiple substituents, they may be the same or different; Each L 5 is independently C1-C4 alkylene or is replaced by one or more L 5a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different; Each L 6 are independently H, deuterium, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered hetero Cycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl and 5-10 membered heteroaryl are each optionally substituted by one or more L 6a Substitution; the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they may be the same or different; Each L 3a 、L 4a 、L 5a and L 6a Each is independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O- or C3-C7 cycloalkyl; Each R 2-a are independently C1-C6 alkyl or -L 7 -N(L 8 )2; Each L 7 is independently C1-C4 alkylene or is replaced by one or more L 7a Substituted C1-C4 alkylene; when there are multiple substituents, they may be the same or different; Each L 8 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more L 8a Substitution; wherein the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl and 5-10 membered heteroaryl are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they may be the same or different; Each L 7a and L 8a Each is independently deuterium, halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O- or C3-C7 cycloalkyl; R 4 is C2-C4 alkynyl or C2-C4 alkynyl substituted by one or more deuteriums; R 5 and R 6 Each independently is H or deuterium; and it meets one, two, three or four of the following conditions: (i) X is deuterium, -CN, -OH, C1-C4 alkyl, C1-C4 alkyl-O-, -N(R 3 )2, C3-C7 cycloalkyl, halogen, C1-C4 alkyl substituted by one or more halogen, C1-C4 alkyl substituted by one or more deuterium, or C1-C4 alkyl-O-substituted by one or more halogen; (ii)R 2 is deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkyl-O-, C1-C6 alkyl-S-, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -N(R 3 )2. By one or more R 2a Substituted C1-C6 alkyl, one or more R 2b Substituted C1-C6 alkyl-O-, one or more R 2c Substituted C1-C6 alkyl-S-, one or more R 2d Substituted C2-C6 alkenyl, one or more R 2e Substituted C2-C6 alkynyl or one or more R 2f Substituted C3-C7 cycloalkyl, R 2i is H, C2-C6 alkyl, halogen, C1-C6 alkyl-O-, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, 5-6 membered heteroaryl, -N(R 3 )2. By one or more R 2-b Substituted C1-C6 alkyl, one or more R 2-c Substituted C1-C6 alkyl-O-, one or more R 2-d substituted 4-10 membered heterocycloalkyl, substituted by one or more R 2-e substituted 4-10 membered heterocycloalkenyl, substituted by one or more R 2-f Substituted C3-C7 cycloalkyl, one or more R 2-g Substituted C3-C7 cycloalkenyl, one or more R 2-h Substituted phenyl or one or more R 2-i substituted 5-6 membered heteroaryl; the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, 5-6 membered heteroaryl, substituted by one or more R 2-d The 4-10 membered heterocycloalkyl in the substituted 4-10 membered heterocycloalkyl is replaced by one or more R 2-e The 4-10 membered heterocycloalkenyl in the substituted 4-10 membered heterocycloalkenyl and the 4-10 membered heterocycloalkenyl replaced by one or more R 2-i The heteroatom in the 5-6 membered heteroaryl in the substituted 5-6 membered heteroaryl The substituents are each independently selected from one or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; when there are multiple substituents, they are the same or different; wherein each R 2-b are independently deuterium, halogen, -CN, -OH, -N(R 3 )2, C2-C4 alkenyl, C1-C4 alkyl-O-, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, or C1-C6 alkyl substituted by one or more halogens; wherein the heteroatoms in the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, and 5-6 membered heteroaryl are each independently selected from one or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3; (iii)R 4 is a C2-C4 alkynyl group substituted by one or more deuteriums; (iv)R 5 and R 6 At least one is deuterium.

2. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein: The nitrogen-containing heterocyclic compound shown in Formula I is not the following compound:

3. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 and 2, wherein: It meets one or more of the following conditions: (1) X is H or halogen, preferably halogen; (2)R 1 -L 1 -OC(=O)-L 2 , L 1 is C1-C4 alkylene, L 2 C4-C 20 alkyl; (3)R 2 -OH, or by one or more R 2b Substituted C1-C6 alkyl-O-; R 2i is C1-C6 alkyl or C1-C6 alkyl-O-; Each R 2b Independently Preferably Each R 2g and R 2h each independently -OH; Each R 2-a are independently C1-C6 alkyl; (4)R 4 It is a C2-C4 alkynyl group.

4. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 3, wherein: X is H or halogen; R 1 -L 1 -OC(=O)-L 2 ; L 1 is a C1-C4 alkylene group; L 2 C4-C 20 alkyl; R 2 -OH, or by one or more R 2b Substituted C1-C6 alkyl-O-; R 2i is C1-C6 alkyl or C1-C6 alkyl-O-; Each R 2b Independently Each R 2g and R 2h each independently -OH; Each R 2-a are independently C1-C6 alkyl; R 4 is C2-C4 alkynyl or C2-C4 alkynyl substituted by one or more deuteriums; R 5 and R 6 Each independently is H or deuterium; and it meets one, two, three or four of the following conditions: (i) X is halogen; (ii)R 2 for or by one or more R 2b Substituted C1-C6 alkyl-O-, R 2i is C2-C6 alkyl or C1-C6 alkyl-O-; (iii)R 4 is a C2-C4 alkynyl group substituted by one or more deuteriums; (iv)R 5 and R 6 At least one is deuterium.

5. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 and 2, wherein: It meets one or more of the following conditions: (1) In X, the halogen, the halogen in the C1-C4 alkyl group substituted by one or more halogens, and the halogen in the C1-C4 alkyl-O- group substituted by one or more halogens are each independently F, Cl, Br, or I, such as Cl; (2) In X, the C1-C4 alkyl group, the C1-C4 alkyl group in C1-C4 alkyl-O-, the C1-C4 alkyl group in C1-C4 alkyl substituted by one or more halogens, the C1-C4 alkyl group in C1-C4 alkyl substituted by one or more deuteriums, and the C1-C4 alkyl group in C1-C4 alkyl-O-substituted by one or more halogens are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (3) In X, the C3-C7 cycloalkyl group is a C3-C6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (4)L 1 wherein the C1-C4 alkylene group is replaced by one or more L 1a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups are each independently -CH2- * 、-CH2CH2- * 、-CH(CH3)- * 、-CH2CH2CH2- * 、-CH2CH(CH3)- * 、-C(CH3)2- * 、-CH2CH2CH2CH2- * 、-CH2CH(CH3)CH2- * 、-CH(CH3)CH2CH2- * or -CH2CH2CH(CH3)- * , such as -CH2- * or -CH(CH3)- * , among which the bid * " end preferably with "OC(=O)-L 2 ” connected; (5)L 1a wherein the halogen is F, Cl, Br or I; (6)L 1a wherein the C1-C6 alkyl in the C1-C6 alkyl-O- is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (7)L 1a and L 2 wherein the C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8)L 1a and L 2 wherein the C3-C7 cycloalkenyl groups are each independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (9)L 1a and L 2 wherein the 4-10 membered heterocycloalkyl groups are each independently 3-7 membered heterocycloalkyl groups, such as 3-membered heterocycloalkyl groups, 4-membered heterocycloalkyl groups, 5-membered heterocycloalkyl groups or 6-membered heterocycloalkyl groups, and more preferably oxetanyl groups, azetidinyl groups, tetrahydropyrrolyl groups, tetrahydrofuranyl groups, piperidinyl groups, morpholinyl groups or piperazinyl groups; (10)L 1a and L 2 wherein the 4-10 membered heterocycloalkenyl groups are each independently a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group; (11)L 1a wherein the 5-6 membered heteroaryl group is pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl; (12)L 2 In the C4-C 20 The alkyl group is C9-C 15 Alkyl groups, such as n-nonyl or n-pentadecyl; (13)L 2 In the above, the C2-C6 alkenyl group is a C2-C4 alkenyl group, such as vinyl; (14)L 2 In the C6-C 10 Aryl is phenyl or naphthyl; (15)L 2 wherein the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, such as pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl; (16)L 2a and R 2 wherein the halogen is independently F, Cl, Br or I; (17)L 2a wherein the C1-C4 alkyl group and the C1-C4 alkyl group in the C1-C4 alkyl-O- are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (18)L 2a wherein the C3-C7 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (19)R 2 wherein the C1-C6 alkyl-O- and one or more R 2b The C1-C6 alkyl-O- in the substituted C1-C6 alkyl-O- is each independently a C1-C4 alkyl-O-, such as CH3-O-, CH3CH2-O-, CH3CH2CH2-O- or CH3CH(CH3)-O-, preferably CH3-O-; (20)R 2 wherein the C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkyl, 2a The C1-C6 alkyl group in the substituted C1-C6 alkyl group and the C1-C6 alkyl group replaced by one or more R 2c The C1-C6 alkyl groups in the substituted C1-C6 alkyl-S- are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (21)R 2 wherein the C2-C6 alkenyl group and one or more R 2d The C2-C6 alkenyl groups in the substituted C2-C6 alkenyl groups are each independently C2-C4 alkenyl, such as ethenyl, propenyl or allyl; (22)R 2 wherein the C2-C6 alkynyl group and one or more R 2e The C2-C6 alkynyl groups in the substituted C2-C6 alkynyl groups are each independently C2-C4 alkynyl, such as ethynyl; (23)R 2 wherein the C3-C7 cycloalkyl group and one or more R 2f The C3-C7 cycloalkyl groups in the substituted C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (24)R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f wherein the halogen is independently F, Cl, Br or I; (25)R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f wherein the C1-C4 alkyl group and the C1-C4 alkyl group in the C1-C4 alkyl-O- are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (26)R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f wherein the C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (27)R 2g and R 2h wherein the C1-C6 alkyl group and the C1-C6 alkyl group in the C1-C6 alkyl-O- are each independently a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; (28)R 2g and R 2h In the C3-C7 cycloalkyl-O-, the C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (29)R 2g and R 2h wherein the C3-C7 cycloalkenyl in the C3-C7 cycloalkenyl-O- is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (30)R 2g and R 2h , the 4-10 membered heterocycloalkyl in the 4-10 membered heterocycloalkyl-O- is each independently a 3-7 membered heterocycloalkyl, such as a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl, more preferably an oxetanyl, an azetidinyl, a tetrahydropyrrolyl, a tetrahydrofuranyl, a piperidinyl, a morpholinyl or a piperazinyl; (31)R 2g and R 2h , the 4-10 membered heterocycloalkenyl in the 4-10 membered heterocycloalkenyl-O- is each independently a 3-7 membered heterocycloalkenyl, such as a 3-membered heterocycloalkenyl, a 4-membered heterocycloalkenyl, a 5-membered heterocycloalkenyl or a 6-membered heterocycloalkenyl, more preferably a dihydropyrrolyl, a dihydrofuranyl, a dihydropyranyl, a dihydropyridinyl or a tetrahydropyridinyl; (32)R 2g and R 2h , wherein the 5-6 membered heteroaryl in the 5-6 membered heteroaryl-O- is independently pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl; (33)R 2i wherein the halogen is F, Cl, Br or I; (34)R 2i wherein the C1-C6 alkyl group is replaced by one or more R 2-b The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are each independently a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group, preferably a methyl group or an isopropyl group; (35)R 2i wherein the C1-C6 alkyl-O- and one or more R 2-c The C1-C6 alkyl-O- in the substituted C1-C6 alkyl-O- is each independently a C1-C4 alkyl-O-, such as CH3-O-, CH3CH2-O-, CH3CH2CH2-O- or CH3CH(CH3)-O-, preferably CH3CH2-O- or CH3CH(CH3)-O-; (36)R 2i wherein the 4-10 membered heterocycloalkyl group and one or more R 2-d The 4-10-membered heterocycloalkyl group in the substituted 4-10-membered heterocycloalkyl group is each independently a 3-7-membered heterocycloalkyl group, such as a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group, and more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group; (37)R 2i wherein the 4-10 membered heterocycloalkenyl group and one or more R 2-e The 4-10-membered heterocycloalkenyl groups in the substituted 4-10-membered heterocycloalkenyl groups are each independently a 3-7-membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group; (38)R 2i wherein the C3-C7 cycloalkyl group and one or more R 2-f The C3-C7 cycloalkyl groups in the substituted C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (39)R 2i wherein the C3-C7 cycloalkenyl group and one or more R 2-g The C3-C7 cycloalkenyl groups in the substituted C3-C7 cycloalkenyl groups are each independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (40)R 2i wherein the 5-6 membered heteroaryl group and one or more R 2-i The 5-6 membered heteroaryl in the substituted 5-6 membered heteroaryl is each independently pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl; (41)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the halogen and the halogen in the C1-C6 alkyl group substituted by one or more halogens are each independently F, Cl, Br or I; (42)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more halogens are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (43)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the C2-C4 alkenyl groups are each independently vinyl; (44)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the C1-C4 alkyl-O- is independently CH3-O-, CH3CH2-O-, CH3CH2CH2-O- or CH3CH(CH3)-O-; (45)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (46)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the C3-C7 cycloalkenyl groups are each independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (47)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the 4-10 membered heterocycloalkyl groups are each independently 3-7 membered heterocycloalkyl groups, such as 3-membered heterocycloalkyl groups, 4-membered heterocycloalkyl groups, 5-membered heterocycloalkyl groups or 6-membered heterocycloalkyl groups, and more preferably oxetanyl groups, azetidinyl groups, tetrahydropyrrolyl groups, tetrahydrofuranyl groups, piperidinyl groups, morpholinyl groups or piperazinyl groups; (48)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the 4-10 membered heterocycloalkenyl groups are each independently a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group; (49)R 2-b 、R 2-c 、R 2-d 、R 2-e 、R 2-f 、R 2-g 、R 2-h and R 2-i wherein the 5-6 membered heteroaryl groups are each independently pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl; (50)R 3 wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (51)L 3 wherein the C1-C4 alkylene group is replaced by one or more L 3a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups are each independently -CH2- ** 、-CH2CH2- ** 、-CH(CH3)- ** 、-CH2CH2CH2- ** 、-CH2CH(CH3)- ** 、-C(CH3)2- ** 、-CH2CH2CH2CH2- ** 、-CH2CH(CH3)CH2- ** 、-CH(CH3)CH2CH2- ** or -CH2CH2CH(CH3)- ** , among which the bid ** "The end is preferably with L 4 connected; (52)L 4 wherein the C1-C6 alkyl in the C1-C6 alkyl-O- is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (53)L 4 In the C3-C7 cycloalkyl-O-, the C3-C7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (54)L 4 wherein the C3-C7 cycloalkenyl in the C3-C7 cycloalkenyl-O- is cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (55)L 4 wherein the 4-10 membered heterocycloalkyl in the 4-10 membered heterocycloalkyl-O- is a 3-7 membered heterocycloalkyl, such as a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl, and more preferably an oxetanyl, an azetidinyl, a tetrahydropyrrolyl, a tetrahydrofuranyl, a piperidinyl, a morpholinyl or a piperazinyl; (56)L 4 wherein the 4-10 membered heterocycloalkenyl-O- is a 3-7 membered heterocycloalkenyl, such as a 3-membered heterocycloalkenyl, a 4-membered heterocycloalkenyl, a 5-membered heterocycloalkenyl or a 6-membered heterocycloalkenyl, more preferably a dihydropyrrolyl, a dihydrofuranyl, a dihydropyranyl, dihydropyridinyl or tetrahydropyridinyl; (57)L 4 wherein the 5-6 membered heteroaryl in the 5-6 membered heteroaryl-O- is pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridyl; (58)L 5 wherein the C1-C4 alkylene group is replaced by one or more L 5a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups are each independently -CH2- a 、-CH2CH2- a 、-CH(CH3)- a 、-CH2CH2CH2- a 、-CH2CH(CH3)- a 、-C(CH3)2- a 、-CH2CH2CH2CH2- a 、-CH2CH(CH3)CH2- a 、-CH(CH3)CH2CH2- a or -CH2CH2CH(CH3)- a , among which the bid a " end is preferably connected with "C(=O)-OL 6 ” connected; (59)L 6 and L 8 wherein the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (60)L 6 and L 8 wherein the C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (61)L 6 and L 8 wherein the C3-C7 cycloalkenyl groups are each independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (62)L 6 and L 8 wherein the 4-10 membered heterocycloalkyl groups are each independently 3-7 membered heterocycloalkyl groups, such as 3-membered heterocycloalkyl groups, 4-membered heterocycloalkyl groups, 5-membered heterocycloalkyl groups or 6-membered heterocycloalkyl groups, and more preferably oxetanyl groups, azetidinyl groups, tetrahydropyrrolyl groups, tetrahydrofuranyl groups, piperidinyl groups, morpholinyl groups or piperazinyl groups; (63)L 6 and L 8 wherein the 4-10 membered heterocycloalkenyl groups are each independently a 3-7 membered heterocycloalkenyl group, such as a 3-membered heterocycloalkenyl group, a 4-membered heterocycloalkenyl group, a 5-membered heterocycloalkenyl group or a 6-membered heterocycloalkenyl group, and more preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydropyridinyl group or a tetrahydropyridinyl group; (64)L 6 and L 8 In the C6-C 10 each aryl group is independently phenyl or naphthyl; (65)L 6 and L 8 wherein the 5-10 membered heteroaryl groups are each independently a 5-6 membered heteroaryl group, for example, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyrimidinyl or pyridinyl; (66)L 3a 、L 4a 、L 5a 、L 6a 、L 7a and L 8a wherein the halogen is independently F, Cl, Br or I; (67)L 3a 、L 4a 、L 5a 、L 6a 、L 7a and L 8a wherein the C1-C4 alkyl group and the C1-C4 alkyl group in the C1-C4 alkyl-O- are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (68)L 3a 、L 4a 、L 5a 、L 6a 、L 7a and L 8a wherein the C3-C7 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (69)R 2-a wherein the C1-C6 alkyl group is a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group, preferably an ethyl group; (70)L 7 wherein the C1-C4 alkylene group is replaced by one or more L 7a The C1-C4 alkylene groups in the substituted C1-C4 alkylene groups are each independently -CH2- b 、-CH2CH2- b 、-CH(CH3)- b 、-CH2CH2CH2- b 、-CH2CH(CH3)- b 、-C(CH3)2- b 、-CH2CH2CH2CH2- b 、-CH2CH(CH3)CH2- b 、-CH(CH3)CH2CH2- b or -CH2CH2CH(CH3)- b , among which the bid b " end is preferably connected with N(L 8 )2 connected; (71)L 8 In the above, the C2-C6 alkenyl group is a C2-C4 alkenyl group, such as vinyl; (72)R 4 wherein the C2-C4 alkynyl group and the C2-C4 alkynyl group substituted by one or more deuteriums are each independently For example (73) When R 2i When it is a C2-C6 alkyl group, the C2-C6 alkyl group is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

6. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 5, wherein: It meets one or more of the following conditions: (1) X is H or Cl; (2)R 1 for (3)R 2 -OH, (4)R 4 for (5)R 5 and R 6 Both H or R 5 and R 6 All are deuterium.

7. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 6, wherein: X is H or Cl; R 1 for R 2 -OH, R 4 for R 5 and R 6 Each independently is H or deuterium; and it meets one, two, three or four of the following conditions: (i) X is Cl; (ii)R 2 for (iii)R 4 for (iv)R 5 and R 6 At least one is deuterium.

8. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 and 2, wherein: It is any of the following: (1) X is a halogen; (2)R 2 for or by one or more R 2b Substituted C1-C6 alkyl-O-, R 2i is C1-C6 alkyl-O- or C2-C6 alkyl; preferably, each R 2b Independently Each R 2g and R 2h are each independently -OH; each R 2-a are independently C1-C6 alkyl; (3)R 4 is a C2-C4 alkynyl group substituted by one or more deuteriums; (4)R 5 and R 6 At least one is deuterium.

9. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 and 2, characterized in that The compound represented by formula I is a compound represented by formula I-1: Preferably, the compound represented by formula I is a compound represented by formula I-2, I-3, or I-4:

10. The nitrogen-containing heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 and 2, characterized in that The compound shown in formula I is any one of the following structures:

11. A method for preparing a compound of formula I according to at least one of claims 1 to 10, characterized in that: It is any of the following methods: Method 1: When R 2 for R 4 for When X is Cl, the details are as follows: Among them, P 1 is an amino protecting group, such as Boc, PMB, Bn, Cbz or Fmoc; each P1 is the same or different; R 9 is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl; R 1 、R 5 and R 6 The definitions are as described in at least one of claims 1 to 10; It includes the following steps: Step 1: In an organic solvent, a compound represented by Formula SM-1 is subjected to a chlorination reaction with a chlorinating agent to obtain a compound represented by Formula SM-2; the chlorinating agent is preferably phosphorus oxychloride and / or thionyl chloride; Step 2: In an organic solvent, in the presence of a base, the compound represented by Formula SM-2 is subjected to a substitution reaction with the compound represented by Formula SM-11 to obtain the compound represented by Formula SM-3; Step 3: In an organic solvent, in the presence of a base, the compound represented by Formula SM-3 is subjected to a substitution reaction with the compound represented by Formula SM-12 to obtain a compound represented by Formula SM-4. Step 4: In an organic solvent, in the presence of a base, a palladium catalyst, and a phosphine ligand, the compound represented by Formula SM-4 and the compound represented by Formula SM-13 undergo Suzuki reaction to obtain a compound represented by Formula SM-5; Step 5: In an organic solvent, in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride or CsF, the compound represented by Formula SM-5 is subjected to a deprotection reaction to obtain a compound represented by Formula SM-6; Step 6: In an organic solvent, under the action of an acid, the compound represented by Formula SM-6 is subjected to a deprotection reaction to obtain a compound represented by Formula SM-7; Step 7: In an organic solvent, in the presence of a base, the compound of Formula SM-7 is subjected to an amino protection reaction to obtain a compound of Formula SM-8. Step 8: In an organic solvent, in the presence of a base, the compound represented by Formula SM-8 and the compound represented by Formula SM-14 undergo a substitution reaction to obtain a compound represented by Formula SM-9. Step 9: In an organic solvent, in the presence of an acid, the compound represented by Formula SM-9 is subjected to deprotection and hydrolysis reactions to obtain the compound represented by Formula SM-10. Step 10: In an organic solvent, in the presence of a base, react the compound represented by Formula SM-10 with the compound represented by Formula SM-15 to obtain the compound represented by Formula Ia. Method 2: When R 2 -OH, R 4 for When X is Cl, the details are as follows: Among them, R 1 、R 5 and R 6 The definitions are as described in at least one of claims 1 to 10; The method comprises the following steps: reacting a compound represented by Formula SM-7 with a compound represented by Formula SM-15 in an organic solvent in the presence of a base to obtain a compound represented by Formula Ib; Method 3: When R 2 for R 7 C1-C 12 Alkyl, R 4 for When X is Cl, the details are as follows: Among them, R 1 、R 5 and R 6 The definitions are as described in at least one of claims 1 to 10; It includes the following steps: Step A: In an organic solvent, in the presence of a base, the compound represented by Formula SM-8 and the compound represented by Formula SM-18 undergo a substitution reaction to obtain a compound represented by Formula SM-16; Step B: In an organic solvent, under the action of an acid, the compound represented by Formula SM-16 is subjected to a deprotection reaction to obtain a compound represented by Formula SM-17; Step C: In an organic solvent, in the presence of a base, the compound represented by Formula SM-17 reacts with the compound represented by Formula SM-15 to obtain the compound represented by Formula Ic; Method 4: When R 2 for R 8 C1-C 12 Alkyl, R 4 for When X is Cl, the details are as follows: Among them, R 1 、R 5 and R 6 The definitions are as described in at least one of claims 1 to 10; The method comprises the following steps: in an organic solvent, under the action of a base, a compound represented by Formula Ib and a compound represented by Formula SM-19 undergo a substitution reaction to obtain a compound represented by Formula Id.

12. A compound represented by formula SM-17: in, R 5 and R 6 As defined in at least one of claims 1 to 10, R 7 The definition of is as described in claim 11.

13. A compound as shown below:

14. A pharmaceutical composition comprising a therapeutically effective amount of a substance A and a pharmaceutical excipient; the substance A is a nitrogen-containing heterocyclic compound of Formula I according to at least one of claims 1 to 10, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

15. Use of a substance A in the preparation of a RAS inhibitor, wherein the substance A is a nitrogen-containing heterocyclic compound of Formula I according to at least one of claims 1 to 10, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; The RAS inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes; The RAS may be KRAS or a KRAS mutation; for example, KRAS G12D, KRAS G12V.

16. Use of substance A in preparing a medicine, characterized in that: The substance A is a nitrogen-containing heterocyclic compound as shown in Formula I according to at least one of claims 1 to 10, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; The substance A is in a therapeutically effective amount; The drug can be used to treat and / or prevent RAS-mediated diseases; or, the drug can be used to treat and / or prevent cancer.

17. The use according to claim 16, characterized in that The application meets one or more of the following conditions: (1) The RAS is KRAS or a KRAS mutation; for example, KRAS G12D, KRAS G12V; (2) The RAS-mediated disease is cancer; (3) The cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, One or more of pancreatic cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma; for example, gastric cancer or pancreatic cancer.

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