Heterocyclic compounds as KRAS inhibitors, preparation and therapeutic use thereof

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, tautomers or stereoisomers and solvates thereof, which are useful in the treatment of cancer and inflammation in mammals. The invention also discloses a preparation method of the compound shown in the formula (I) and a pharmaceutical composition containing the compound. # imgabs0 #

Description

Heterocyclic compounds as KRAS inhibitors, and their preparation and therapeutic use Technical Field

[0001] The present invention relates to certain novel heterocyclic compounds or pharmaceutically acceptable salts thereof, which are useful for treating or preventing cancers associated with H-ras, K-ras, or N-ras inhibition. The present invention also relates to pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, as well as intermediates for preparing the compounds, and methods of using the compounds or pharmaceutically acceptable salts thereof to treat cancers associated with H-ras, K-ras, or N-ras inhibition. Background Art

[0002] In 1982, Weinberg and Barbacid first isolated a transforming gene from a human bladder cancer cell line that could cause malignant transformation in NIH 3T3 cells, whereas DNA extracted from normal human tissue had no such effect. Subsequently, Santos and Parada discovered that the transforming gene was not a novel gene but rather the human homolog of the Harvey murine sarcoma virus ras gene, named H2ras. That same year, Krontiris discovered a homolog of the Kirsten murine sarcoma virus gene in human lung cancer cells, named K-ras. Another similar gene, N2ras, was discovered when NIH 3T3 cells were infected with human neuroblastoma DNA. This gene is unrelated to viruses.

[0003] The ras gene is highly conserved throughout evolution and is widely present in various eukaryotic organisms, including mammals, fruit flies, fungi, nematodes, and yeast, suggesting its important physiological function. The mammalian ras gene family consists of three members: H-ras, K-ras, and N-ras. K-ras has two variants, A and B, in its fourth exon. All ras genes share a similar structure, consisting of four exons distributed across approximately 30 kb of DNA. They encode proteins with a relative molecular mass of 21,000, hence the name P21 protein. It has been demonstrated that H-ras is located on the short arm of human chromosome 11 (11p15.1-p15.3), K-ras is located on the short arm of chromosome 12 (12p1.1-pter), and N-ras is located on the short arm of chromosome 1 (1p22-p32). With the exception of a variation in the fourth exon of K-ras, the sequence encoding P21 in each ras gene is evenly distributed across four exons. However, the sequence and size of the introns vary significantly, leading to significant variations in the overall gene. For example, human K-ras is 35 kb long, while N-ras is 3 kb. Due to the presence of two fourth exons, K-ras can be spliced ​​in two different ways, but the mRNA encoding K-ras-B is highly expressed. With the exception of K-ras-B, which contains 188 amino acids, the other two Ras proteins each contain 189 amino acids.

[0004] The Ras (P21) protein, located on the inner cell membrane, plays a crucial role in transmitting cell growth and differentiation signals. It is a guanosine triphosphate (GTP)-binding protein (a coupling factor in cellular signaling), regulating signaling through the interconversion of GTP and guanosine diphosphate (GDP). P21 has a strong affinity for GTP and GDP and possesses weak GTPase activity. Normally, P21 is inactive when bound to GDP. However, when extracellular growth and differentiation factors transmit signals to P21 on the inner cell membrane, this enhances P21's GTP-binding activity, activating the binding and signaling pathway. Because P21 has GTPase activity, it hydrolyzes GTP to GDP. Once bound to GDP, P21 becomes inactive, shutting down the signaling pathway. While P21's GTPase activity is weak, its hydrolysis rate increases 10,000-fold when bound to GTPase-activating protein (GAP), inactivating P21. After P21 binds to GDP, it can activate guanylate-releasing protein (GNRP). GNRP causes P21 to release GDP and bind to GTP. Therefore, through the mutual conversion of GTP and GDP, the opening and closing of the signal system by P21 can be regulated in a controlled manner, completing the process of transmitting growth and differentiation signals into cells.

[0005] More than 1 / 5 of cancer patients have Ras gene mutations, most of which occur at residues G12, G13, and Q61. These mutations lead to GAP protein-mediated failure, and the Ras signal remains in an activated state.

[0006] The RAS gene family is the most commonly mutated gene in human cancer. RAS mutations are found in 90% of pancreatic cancers, 45% of colon cancers, and 35% of lung cancers. Of the three Ras genes, Kirsten-RAS (KRAS) is the most commonly mutated subtype, accounting for 86%. The other two subtypes, neuroblastoma-RAS (NRAS) and Harvey-RAS (HRAS), have lower mutation rates (11% and 3%). The KRAS protein has several mutations. The KRAS-G12C mutation predominates in NSCLC (KRAS-G12C mutations account for approximately 45-50%). On the other hand, the KRAS-G12D mutation (in which glycine at codon -12 is mutated to aspartic acid) is highly prevalent in pancreatic cancer (61%), colon cancer (42%), and NSCLC (22%).

[0007] Research on drugs to treat the KRAS-G12C mutation has yielded exciting results. The clinical results of AMG510 and MRTX849 offer hope to cancer patients. However, there are currently no targeted drugs for the KRAS G12D mutation. At the 32nd International Symposium on Molecular Targets and Cancer Therapeutics, Mirati Therapeutics announced progress on its KRAS-G12D-selective inhibitor, MRTX1133, currently in the preclinical stage. Therefore, the development of new KRAS-G12D inhibitors is urgently needed.

[0008] The present invention designs and synthesizes a series of chemical molecules with strong biological activity of inhibiting ras, and provides a method for treating related cancers by inhibiting H-ras, K-ras or N-ras.

[0009] Summary of the Invention

[0010] The present invention provides compounds capable of modulating G12D mutant KRAS, HRAS and / or NRAS proteins, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof. Methods of using such compounds to treat various diseases or conditions (such as cancer) are also provided.

[0011] In one aspect of the present invention, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or prodrug thereof, wherein the compound of formula (I) is:

[0012] in:

[0013] Y is or -NR a R b , where R a For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl substituted C 1-6 Alkyl, or C 3- 6-cycloalkyl, R b NR c R d -C 1-6 Alkyl-, where NR c R d -C 1-6 The alkyl group in alkyl- is optionally substituted with C 3-6 Cycloalkyl, where R c and R d is hydrogen or C 1-6 alkyl;

[0014] is a 4- to 12-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring or -X 1 (R 1a R 1b )C 1-4 X 2 wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted by one or more R 1 Replace, X 1 Selected from N and CR 4 ;X 2 Selected from NR 4 , CR 4 and S(O) 0,1,2 R 4 ,

[0015] in,

[0016] R 1 Selected from hydrogen, halogen, optionally halogen or hydroxy or -NR 1a R 1b Substituted C 1-6 Alkyl, CN, -OR 1a 、-SR 1a 、-NR 1a R 1b 、-S(O)R 1a 、-S(O)2R1a 、-C(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-C(O)NR 1a R 1b 、-S(O)2N(R 1a R 1b )2 and 5- to 6-membered heteroaryl, wherein R 1a and R 1b are independently hydrogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 Alkyl-, C 3-6环 alkyl;

[0017] R 4 is selected from hydrogen, halogen, C optionally substituted by halogen or hydroxy 1-6 Alkyl, CN, -OR 4a 、-SR 4a 、-S(O)R 4a 、-S(O)2R 4a 、-C(O)R 4a 、-C(O)OR 4a 、-NR 4a C(O)R 4b 、-C(O)NR 4a R 4b and -S(O)2N(R 4a R 4b )2, where R 4a and R 4b Each independently represents hydrogen, 4-6 membered oxacycloalkyl optionally substituted by methyl, dimethyl or isopropyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 alkyl-;

[0018] L is a single bond, -O-, -S-, or -NR La -、-O-(CR La R Lb ) t -、-S-(CR La R Lb ) t -、-NR c -(CR La R Lb ) t -、-(CRLa R Lb ) t -O-、-(CR La R Lb ) t -S-、-(CR La R Lb ) t -NR Lc -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR Lc -or-N Lc C(O)-, where R La 、R Lb and R Lc are each independently selected from hydrogen and C 1-6 Alkyl, or R attached to the same carbon atom La and R Lb Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group, and wherein t is an integer from 1 to 6;

[0019] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, oxo, -OR 2a 、-C(O)R 2a 、-(CR 2a R 2b ) m -OC(O)NR 2c R 2d 、-CO2R 2a 、-CONR 2c R 2d 、-NR 2c R 2d 、C 3- 8 cycloalkyl, C 3-8 Cycloalkyl C 1-6 One or more of alkyl, aryl, heteroaryl and heterocyclic groups are substituted, wherein R 2a 、R2b 、R 2c and R 2d Each is independently hydrogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 Alkyl-, or R attached to the same nitrogen atom 2c and R 2d Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms selected from nitrogen, oxygen, sulfur as ring members, and wherein m is an integer from 1 to 6;

[0020] R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R 8 Replace; each R 8 independently selected from halogen, cyano, oxo, C optionally substituted by halogen, cyano, hydroxyl and deuterated 1-6 alkyl, C2-C6 alkenyl optionally substituted by hydroxy or deuterated, C2-C6 alkynyl optionally substituted by hydroxy or deuterated, -OR 8a 、-SR 8a 、-S(O)2R 8a 、-P(=O)R 8a R 8b 、-NR 8a R 8b 、-C(O)NR 8a R 8b , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein R 8a and R 8b each independently hydrogen, optionally substituted by halogen, C 1-6 Alkyl and C 1-6 Alkoxy-C 1-6 Alkyl-; or two R on the same carbon atom 8 Form a C3-C8 cycloalkyl group; or R on two adjacent carbon atoms 8 Together with the carbon atoms to which they are attached, they form a C3-C8 cycloalkyl group;

[0021] Q 1 , Q 2 and Q 3 Each independently is N or CR 6 , M 1 and M 2 Each independently is N or CR 7 , provided that Q 1 and M1 At least one of them is N;

[0022] where R 6 and R 7 are independently hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl or heterocyclic, -OR 6a 、-C(O)R 6a 、-CO2R 6a 、-CONR 6a R 6b or -NR 6a R 6b , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently replaced by oxo, halogen, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, nitro, cyano and -NR d R e One or more substitutions, wherein R 6a 、R 6b 、R 6c and R 6d Each is independently hydrogen, C 3-6 Alkyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 alkyl-;

[0023] In some embodiments, in some embodiments, for

[0024] where R 4 are independently selected from hydrogen, halogen, C optionally substituted by halogen or hydroxy 1-6 Alkyl, CN, -OR 4a 、-SR 4a 、-S(O)R 4a 、-S(O)2R 4a 、-C(O)R 4a 、-C(O)OR 4a 、-NR 4a C(O)R 4b 、-C(O)NR4a R 4b and -S(O)2N(R 4a R 4b )2, where R 4a and R 4b Each independently represents hydrogen, 4-6 membered oxacycloalkyl optionally substituted by methyl, dimethyl or isopropyl, C 1-6 Alkyl and hydroxy C 1-6 Alkyl; preferably R 4 Each is independently selected from hydrogen, -C(O)CH2OH, -C(O)NH2, -C(O)N(CH3)2, F, Br, Cl, -OH, -SCH3, -S(O)CH3, -S(O)2CH3, -S(O)2N(CH3)2, -S(O)2NH2, CF3 and CN.

[0025] In some embodiments, Y is -NR a R b , where R a For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl substituted C 1-6 Alkyl, or C 3-6 Cycloalkyl, R b NR c R d -C 1-6 Alkyl-, where NR c R d -C 1-6 The alkyl group in alkyl- is optionally substituted with C 3- 6-cycloalkyl, where R c and R d is hydrogen or C 1-6 In some embodiments, Y is

[0026] In some embodiments, ring Y is where R 4 Preferably, hydrogen,

[0027] In some embodiments, L is -O-CH2- or -O-.

[0028] In some embodiments, L is -O-CH2-, and R 2 is a heterocyclic group, which is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2cR 2d wherein each variable is as defined in formula (I); preferably the heterocyclic group is unsubstituted or substituted by halogen, C 1-6 Alkyl and -OR 2a More preferably, the heterocyclic group is unsubstituted or substituted by one or two of halogen, methyl and methoxy. In a further embodiment, L is -O-CH2-, and R 2 is a 4- to 8-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur as ring members, or is a 6- to 12-membered bicyclic heterocycle (preferably a bridged bicyclic) containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur as ring members, wherein the monocyclic or bicyclic heterocyclic group is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d wherein each variable is as defined in formula (I); preferably the heterocyclic group is unsubstituted or substituted by halogen, C 1-6 Alkyl and -OR 2a More preferably, the heterocyclic group is unsubstituted or substituted by one or two of halogen, methyl and methoxy. In a further embodiment, L is -O-CH2-, and R 2 is a monocyclic heterocycle which is azetidinyl, pyrrolidinyl or piperidinyl, said ring being unsubstituted or substituted by one or two halogen or C 1-6 In a further embodiment, L is -O-CH2-, and R 2 is a bicyclic heterocycle which is octahydropentalene in which at least one carbon atom is replaced by a nitrogen atom and one of the other carbon atoms is optionally replaced by an oxygen atom; preferably R 2 Tetrahydro-1H-pyrrolizinyl (e.g., tetrahydro-1H-pyrrolizin-7-yl Preferably, (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl), tetrahydro-1H-furopyrrolyl (e.g., tetrahydro-1H-furo[3,4-b]pyrrol-3a-yl) Tetrahydro-1H-furo[3,4-c]pyrrol-3a-yl Tetrahydro-1H-furo[3,4-b]pyrrol-6a-yl ) and octahydrocyclopentapyrrolyl (e.g. octahydrocyclopenta[b]pyrrol-6a-yl Octahydrocyclopenta[c]pyrrol-3a-yl Octahydrocyclopenta[b]pyrrol-3a-yl ); and preferably R 2 is azabicyclo[3.1.0]hexanyl, for example 3-azabicyclo[3.1.0]hexanyl (3-azabicyclo[3.1.0]hexan-1-yl), 2-azabicyclo[3.1.0]hexanyl (2-azabicyclo[3.1.0]hexan-1-yl), wherein the bicyclic heterocycle is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d wherein each variable is as defined in formula (I); preferably the heterocyclic group is unsubstituted or substituted by halogen, C 1-6 Alkyl and -OR 2a More preferably, the heterocyclic group is unsubstituted or substituted by one or two of halogen, methyl and methoxy.

[0029] In a further preferred embodiment, LR 2 for

[0030] In some embodiments, R in the compound of formula (I) 3 for

[0031] a. a monocyclic aryl or heteroaryl group selected from phenyl, pyridyl, pyrimidinyl and pyrazinyl;

[0032] b. a bicyclic aryl or heteroaryl group selected from naphthyl (e.g., naphthalene-1-yl, naphthalene-2-yl, naphthalene-3-yl, naphthalene-4-yl, naphthalene-5-yl, naphthalene-6-yl, naphthalene-7-yl, naphthalene-8-yl), isoquinolinyl (e.g., isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl), tetrahydroisoquinolinyl (e.g., 5-nitro-1-nitro-2-nitro-3-nitro-4-nitro-5-nitro ... , 6,7,8-tetrahydroisoquinolin-1-yl, 5,6,7,8-tetrahydroisoquinolin-3-yl and 5,6,7,8-tetrahydroisoquinolin-4-yl), tetrahydronaphthalene (e.g. 5,6,7,8-tetrahydronaphthalene-1-yl, 5,6,7,8-tetrahydronaphthalene-2-yl, 5,6,7,8-tetrahydronaphthalene-3-yl, 5,6,7,8-tetrahydronaphthalene-4-yl), benzothiazole, benzothiophene,;

[0033] c. a tricyclic aryl or heteroaryl group selected from

[0034] The aryl or heteroaryl group is substituted by 1 to 3 substituents R 8 Replacement, R8 are independently selected from: hydrogen, halogen, C 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen and C 1-6 alkyl.

[0035] In some embodiments, R 3 Selected from

[0036] Where: R 8 Preferably selected from -OH, -NH2, -NH(C=O)CH3, -NH(C=O)CF3,

[0037] In some embodiments, the compound of formula (I) is represented by formula (I-1), (I-2), (I-3), (I-4) and (I-5):

[0038] in

[0039] Y is or -NR a R b , where R a For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl substituted C 1-6 Alkyl, or C 3- 6-cycloalkyl, R b NR c R d -C 1-6 Alkyl-, where NR c R d -C 1-6 The alkyl group in alkyl- is optionally substituted with C 3-6 Cycloalkyl, where R c and R d is hydrogen or C 1-6 alkyl;

[0040] Y is where R 4 Preferably, hydrogen,

[0041] The remaining variables are as defined for formula (I).

[0042] In some embodiments, the compound of formula (I) is as follows:

[0043] where R 4 Preferably, hydrogen,

[0044] LR 2 Preferably

[0045] The remaining variables are as defined for formula (I).

[0046] In some embodiments, the compound of formula (I) is represented by formula (I-2), (I-3), (I-4), (I-5) and (I-6):

[0047] in:

[0048] Y is where R 4 Preferably, hydrogen,

[0049] LR 2 Preferably

[0050] The remaining variables are as defined for formula (I).

[0051] In some embodiments, the compound of formula (I) is as shown in formula (I-2-1):

[0052] Where: R 4 Preferably, hydrogen, R 6 、R 7 Each is independently preferably selected from hydrogen, fluorine, chlorine, bromine, -CN, alkynyl, trifluoromethyl, trifluoroethoxy. The remaining variables are as defined for formula (I).

[0053] In some embodiments, the compound of formula (I) wherein Q 3 CR 6 , and R 6 With R 1 Connect to form a new 7-8 membered heterocycle, as shown in formula (I-7):

[0054] Among them: G 1 and G 2Each is independently a single bond, -O-, -S-, -NR La -、-O-(CR La R Lb ) t -、-S-(CR La R Lb ) t -、-NR c -(CR La R Lb ) t -、-(CR La R Lb ) t -O-、-(CR La R Lb ) t -S-、-(CR La R Lb ) t -NR Lc -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR Lc -or-N Lc C(O)-, where R La 、R Lb and R Lc are each independently selected from hydrogen and C 1-6 alkyl, and wherein t is an integer from 1 to 6. The remaining variables are as defined for formula (I).

[0055] In some embodiments, the compound of formula (I-7) is represented by formula (I-7-1):

[0056] Among them: G 1 and G 2 Each is independently a single bond, -O-, -S-, -NR La -、-O-(CR La R Lb ) t -、-S-(CR La R Lb ) t -、-NR c -(CR La R Lb ) t -、-(CR La R Lb ) t -O-、-(CR La R Lb ) t -S-、-(CR La R Lb ) t-NR Lc -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR Lc -or-N Lc C(O)-, where R La 、R Lb and R Lc are each independently selected from hydrogen and C 1-6 Alkyl, and wherein t is an integer from 1 to 6. Q 2 Preferably N or CR 6 , R 4 Preferably, hydrogen,

[0057] In some embodiments, the compound of formula (I) is

[0058] Other general synthetic methods are provided in the Examples. It will be apparent to one of ordinary skill in the art that compounds of Formula (I) can be prepared according to one or more methods or by other means known in the art. It will be apparent that, in general, when following the general routes described herein, various substituted starting materials and / or protecting groups will be required to obtain the desired compounds. Various substituents may also be added at various points in the synthetic route to prepare the desired compounds.

[0059] The present invention relates to pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts, prodrugs and solvates thereof.

[0060] Another aspect of the present invention provides a method of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with G12K-RAS, H-RAS, or N-RAS mutations (e.g., cancer), comprising administering to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutical compositions of the present invention. Cancers such as pancreatic cancer, lung cancer, and colorectal cancer are mediated by G12D mutations.

[0061] Another aspect of the present invention provides use of a compound or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof in the preparation of a method for treating cancer associated with H-ras, K-ras or N-ras inhibition.

[0062] The compound of formula (I) of the present invention has good physicochemical properties and safety and toxicity parameters, and can be used for treating cancer and inflammation in mammals.

[0063] In other embodiments, there is also provided a method of inhibiting proliferation of a cell population, the method comprising contacting the cell population with any one of the compounds of structure (I).

[0064] Other embodiments relate to pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In further embodiments, the pharmaceutical compositions comprise a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0065] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection. DETAILED DESCRIPTION

[0066] Unless otherwise indicated, the following definitions are used throughout the disclosure of this invention:

[0067] The term "prodrug" refers to any derivative that can be converted into the corresponding active pharmaceutical compound in vivo. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert into the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0068] The term "pharmaceutically acceptable salt", unless otherwise indicated, includes salts of acidic groups (such as, but not limited to, potassium, sodium, magnesium, calcium, etc.) or basic groups (such as, but not limited to, formates, acetates, citrates, tartrates, methanesulfonates, malates or sulfates, hydrochlorides, phosphates, nitrates, carbonates, etc.) which may be present in the compounds of the invention.

[0069] The term "solvate" refers to a complex molecular compound formed in solution when solute molecules or ions attract adjacent solvent molecules through intermolecular forces such as Coulombic forces, van der Waals forces, charge transfer forces, hydrogen bonds, etc. In one embodiment, the solvent is water, i.e., the compounds of the present invention form hydrates.

[0070] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may therefore produce enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R)- or (S)-, or as (D)- or (L)- configurations with respect to the absolute stereochemical configuration of the amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be obtained using chiral synthesis or chiral preparation, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). The present invention provides pure isomers and isomer mixtures, as well as methods for their preparation and use, and compositions comprising them. For the sake of simplicity, they are referred to hereinafter as compounds of the formula (I), both as the pure optical isomers and, if appropriate, as mixtures of isomers in varying ratios.

[0071] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions performed by the reorganization of some bonding electrons.

[0072] The term "alkyl" herein refers to a hydrocarbon group selected from a straight chain saturated hydrocarbon group and a branched chain saturated hydrocarbon group, which contains 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8 or 1 to 6 or 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0073] The term "halogen" herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0074] The term "haloalkyl" herein refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms, such as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Examples of haloalkyl groups include halo C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0075] The term "alkenyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkenyl groups are C 2-6 Alkenyl groups include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0076] The term "alkynyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkynyl groups are C 2-6Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0077] The term "alkoxy" herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl. Examples of alkoxy groups are C 1-6 Alkoxy or C 1-4 Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0078] The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocycles and polycyclic (e.g., bicyclic and tricyclic) groups. For example, cycloalkyl can contain 3 to 12 (e.g., 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms. Even further, for example, cycloalkyl can be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, examples of saturated monocyclic cycloalkyl groups are C 3-8 Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, a cycloalkyl is a monocyclic ring (abbreviated as C 3-6 Cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyls include those having 7 to 12 ring atoms arranged as a bicycle selected from [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, or a bridged bicycle selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyls include those arranged as a bicycle selected from [5,6] and [6,6] ring systems, such as The wavy line indicates the point of attachment. The ring may be saturated or have at least one double bond (ie, partially unsaturated), but is not fully conjugated and is not aromatic as aromatic is defined herein.

[0079] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0080] a. 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0081] b. a bicyclic ring system, such as a 7- to 12-membered bicyclic ring system, in which at least one ring is carbocyclic and aromatic, such as naphthyl; and

[0082] c. tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0083] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a benzene ring. In some embodiments, the aromatic hydrocarbon ring is a benzene ring.

[0084] The term "heteroaryl" herein refers to a group selected from:

[0085] a. a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O) (as one or more ring atoms), the remaining ring atoms being carbon;

[0086] b. a 7- to 12-membered bicyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0087] c. an 11- to 14-membered tricyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0088] In preferred embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group containing one nitrogen atom and 0 or 1 additional heteroatom selected from N, O, and S, including but not limited to pyridyl, isoxazolyl, and oxazolyl.

[0089] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. A nitrogen atom in one or more rings of a heteroaryl group may be oxidized to form an N-oxide.

[0090] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5-6 membered heteroaryl ring, which is a monocyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8-10 membered heteroaryl ring, which is a bicyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0091] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (numbered from the attachment position designated priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, ... yl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3, 4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thiazolyl -2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzophenylthio, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

[0092] The term "heterocyclic" or "heterocycle" or "heterocyclyl" herein refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings containing at least one carbon atom and at least one heteroatom, such as 1 to 4 heteroatoms, further such as 1 to 3 heteroatoms or further such as 1 or 2 heteroatoms, these heteroatoms being selected from nitrogen (N), sulfur (S), oxygen (O), -SO- or -SO2 (as one or more ring atoms).

[0093] In some embodiments, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered monocyclic ring having at least one heteroatom selected from N, O, and S. In some preferred embodiments, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one nitrogen heteroatom. Exemplary heterocyclyl groups are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and azocanyl. In other embodiments, the heterocyclyl group is a 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one nitrogen atom and one additional heteroatom selected from -NH, -O-, -S-, -SO-, or -SO2-. Exemplary heterocyclyl groups are morpholino, morpholinyl, or piperazinyl rings. In some embodiments, the heterocyclyl group is a 7- to 12-membered saturated bicyclic ring containing one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from -NH, -O-, -S-, -SO-, or -SO2-. In some preferred embodiments, the heterocyclyl group is a bicyclic bridged ring or a spirocycle.

[0094] As used herein, "heterocycle" also refers to a 5- to 7-membered heterocyclic ring containing at least one heteroatom selected from N, O, and S, fused to a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that the entire ring structure is non-aromatic. The heterocyclic ring is not a heteroaryl group as defined herein. In a preferred embodiment, the heterocyclic group is a 5- to 6-membered heterocyclic group containing one nitrogen atom and 0 or 1 additional heteroatoms selected from N, O, and S, including but not limited to pyrrolyl, dihydropyridine, morpholino, morpholinyl, and tetrahydropyranyl.

[0095] Examples of heterocycles include, but are not limited to (numbering from the attachment position designated as priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholino, oxiranyl, aziridinyl, thioethanethiol, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thiooxanyl, piperazinyl, homopiperazinyl, homo piperidinyl, azepanyl, oxepinyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepinyl, 1,4-oxathianyl, 1,4-oxathianyl, 1,4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepanyl diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolazinyl, 2-pyrrolazinyl, 3-pyrrolazinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolane, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, 1,1-dioxo-thiomorpholinyl, 3-azabis(1,4-dioxanyl), ...1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, 1,3-dioxolane, cyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, tetrahydro-1H-pyrrolazin-7-yl, tetrahydro-1H-furo[3,4-b]pyrrol-3a-yl, tetrahydro-1H-furo[3,4-c]pyrrol-3a-yl, tetrahydro-1H-furo[3,4-b]pyrrol-6a-yl\octahydrocyclopenta[b]pyrrol-6a-yl, octahydrocyclopenta[c]pyrrol-3a-yl, octahydrocyclopenta[b]pyrrol-3a-yl, 3-azabicyclo[3.1.0]hexan-1-yl or 2-azabicyclo[3.1.0]hexan-1-yl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0096] In some embodiments, the heterocyclyl is a non-aromatic fused bicyclic heterocyclyl, such as the fused bicyclic heterocycles listed above; and such as the non-aromatic fused bicyclic heterocyclyls below.

[0097] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0098] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0099] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to two R, and R in each case has independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds. The term "substituted with one or more ... or less groups" disclosed herein includes, for example, 1 to 5 (such as 1 to 4, further such as 1, 2 or 3) substituents, provided that valence permits.

[0100] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom, or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C1-C6 heteroalkyl; in other embodiments, the heteroalkyl group is C1-C3 heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-SCH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CHNCCH3)-CH 3。 Up to two heteroatoms may be consecutive, for example -CH2-NH-OCH3.

[0101] Unless otherwise indicated, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, etc. moieties described herein may each independently be optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, and thiol.

[0102] synthesis

[0103] Suitable solvents commonly used in organic reactions can be used in each step of the following preparation method of the present invention, for example, but not limited to: aliphatic and aromatic, optional hydrocarbons or halogenated hydrocarbons (such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oil, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene), aliphatic and aromatic, optional alcohols (such as methanol, ethanol, propanol, isopropanol, tert-butyl alcohol), alcohol, ethylene glycol, etc.), ethers (such as diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran and dioxane, etc.), esters (such as methyl acetate or ethyl acetate, etc.), nitriles (such as acetonitrile or propionitrile, etc.), ketones (such as acetone, butanone, etc.), amides (such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, etc.), as well as dimethyl sulfoxide, tetramethylene sulfone, hexamethylphosphoric triamide and N,N-dimethylpropylene urea (DMPU), etc.

[0104] The present invention uses the following abbreviations: DCM represents dichloromethane; CHCl3 represents chloroform; EA represents ethyl acetate; THF represents tetrahydrofuran; MeCN represents acetonitrile; MeOH represents methanol; EtOH represents ethanol; i-PrOH represents isopropanol; PE represents petroleum ether; Toulene represents toluene; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; DMA represents N,N-dimethylacetamide; CDCl3 represents deuterated chloroform; D2O represents heavy water; (CD3)2SO represents deuterated DMSO; CD3O D stands for deuterated methanol; CuI stands for cuprous iodide; DIPEA stands for diisopropylethylamine; TEA stands for triethylamine; K2CO3 stands for potassium carbonate; Cs2CO3 stands for cesium carbonate; Na2CO3 stands for sodium carbonate; NaHCO3 stands for sodium bicarbonate; NaOH stands for sodium hydroxide; KOH stands for potassium hydroxide; LiHMDS stands for lithium hexamethyldisilazide; CDI stands for 1,1'-carbonylimidazole; MS stands for mass spectrometry; NMR stands for nuclear magnetic resonance; TFA stands for trifluoroacetic acid; BINAP stands for (2R,3S)-2,2'-diphenylphosphine-1,2'-diol.1'-binaphthyl; BOC stands for tert-butyloxycarbonyl; Cbz stands for benzyloxycarbonyl; DBU stands for dicyclo-1,5-diaza-5-undecene; DCC stands for 1,3-dicyclohexylcarbodiimide; DCE stands for 1,2-dichloroethane; DMAP stands for 4-dimethylaminopyridine; dppf stands for bis(diphenylphosphino)ferrocene; LiAlH4 stands for lithium aluminum hydride; LDA stands for lithium diisopropylamide; m-CPBA stands for m-chloroperbenzoic acid; MTM stands for dimethyl sulfide; NBS stands for N-bromosuccinimide; NCS stands for N-chlorosuccinimide; NIS stands for N-iodosuccinimide amine; PCC stands for pyridinium dichromate; TBAF stands for tetrabutylammonium fluoride; THP stands for tetrahydropyranyl; TMEDA stands for tetramethylethylenediamine; TMS stands for trimethylsilyl; TMP stands for 2,2,6,6-tetramethylpiperidine; Ts stands for p-toluenesulfonyl; Pd(PPh3)4 stands for tetrakistriphenylphosphine palladium; PdCl2(dppf) stands for 1,1'-bis(diphenylphosphinodiphenylferrocenepalladium dichloride); Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; HOBT stands for 1-hydroxybenzotriazole; HATU stands for 2-(7-benzotriazole oxide)-N,N,N',N'-tetrakis Methyluronium hexafluorophosphate; TBTU represents O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate; Tf2O represents trifluoroacetic anhydride; Pd(OAc)2 represents palladium diacetate; RuPhos represents 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; Pd(PPh3)2Cl2 represents bistriphenylphosphine palladium dichloride; Sphos represents 3,2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; XantPhos represents 4,5-bisdiphenylphosphino-9,9-dimethylxanthene; MeONa represents sodium methoxide; n-BuLi represents n-BuLi. Butyl lithium; t-BuONa stands for sodium tert-butoxide; t-BuOK stands for potassium tert-butoxide; KSCN stands for potassium thiocyanate; CuBr stands for cuprous bromide; NaNO2 stands for sodium nitrite; Urea stands for urea; POCl3 stands for phosphorus oxychloride; BBr3 stands for boron tribromide; NH4Cl stands for ammonium chloride; MeI stands for iodomethane; NMP stands for N-methylpyrrolidone; K3PO4 stands for potassium phosphate; chromatographic separation stands for column chromatography; Ac stands for acetyl; Bn stands for benzyl; Fmoc stands for fluorenylmethyloxycarbonyl; Cy stands for cyclohexyl; Tf stands for trifluoromethanesulfonyl; PDC stands for pyridinium dichromate.

[0105] Example 1: Synthesis of methyl ((1R,5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate

[0106] Step 1: Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0107] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (512 mg, 1 mmol) was dissolved in 10 mL of dioxane solvent, and a solution of hydrogen chloride in dioxane (2.5 mL, 4 M) was added dropwise. The reaction was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was then added to the reaction. The solution was washed three times with saturated sodium bicarbonate solution (10 × 3 mL), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The crude product was obtained by distillation under reduced pressure at low temperature and was directly used in the next step without further purification. MS: (ESI) m / z = 467.3 [MH] - .

[0108] Step 2: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0109] Tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (551 mg, 1 mmol) and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (468 mg, 1 mmol) were dissolved in a mixed solvent of dioxane and water (8 mL:2 mL). CataCXium Pd G4 (74 mg, 0.1 mmol) and potassium phosphate (636 mg, 3 mmol) were then added. The reaction was replaced with argon three times, and then stirred at 70 degrees Celsius overnight. Afterwards, the temperature was lowered and ammonium chloride solution was added to quench the reaction. Ethyl acetate (20 mL) was extracted, and the resulting organic phase was dried over saturated brine and anhydrous sodium sulfate. The solvent was then removed under reduced pressure, and the resulting crude product was separated by chromatography (dichloromethane: methanol = 100:5). 417 mg of a yellow solid was obtained with a yield of 48.6%. MS: (ESI) m / z = 857.4 [M+H] +

[0110] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidine-7a(5H)-methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0111] Sodium hydride (12 mg, contained in 60% mineral oil, 0.3 mmol) was added to a nitrogen-filled solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (214 mg, 0.25 mmol) in tetrahydrofuran (2 mL) under an ethanol dry ice bath. The reaction was stirred at low temperature for half an hour, after which 2-(chloromethoxy)ethyl acetate (152 mg, 1 mmol) was added. The reaction was stirred in a dry ice ethanol bath for 2 hours, then slowly warmed to room temperature and stirred overnight. The reaction was then quenched with aqueous ammonium chloride. Extraction was performed with ethyl acetate (3 x 3 mL), and the resulting organic phase was dried over saturated brine and anhydrous sodium sulfate. The solvent was then removed under reduced pressure, and the resulting crude product was separated by chromatography to yield 124 mg of the desired yellow product (51% yield). MS: (ESI) m / z = 973.4 [M+H] +

[0112] Step 4: Synthesis of ethyl 2-(((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)methoxy)acetate

[0113] To a solution of tert-butyl (1R,5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolidin-7a(5H)-methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (124 mg, 0.127 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (290 mg, 2.5 mmol). The reaction was stirred at room temperature for 2 hours, after which the solvent and trifluoroacetic acid were removed under reduced pressure. The resulting crude product (115 mg) was used directly in the next step.

[0114] Step 5: Synthesis of ethyl 2-(((6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)methoxy)acetate

[0115] The crude product of ethyl 2-(((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)methoxy)acetate (115 mg) obtained in the previous step was dissolved in tetrahydrofuran (2 mL). 37% aqueous formaldehyde solution (102 mg, 1.27 mmol) was added at 0°C. The mixture was stirred for half an hour, followed by the addition of sodium triacetoxyborohydride (54 mg, 0.254 mmol). The reaction was stirred overnight. After the reaction was complete, the mixture was quenched with ammonium chloride solution and extracted with ethyl acetate (5 mL). The organic phase was dried over saturated brine and then anhydrous sodium sulfate. The organic solvent was then removed by distillation under reduced pressure. The resulting crude product was separated by thin-layer chromatography (dichloromethane:methanol = 100:6) to obtain a white solid (12 mg, 10% yield). MS: (ESI) m / z = 903.1 [M+H] + .

[0116] Step 6: Synthesis of methyl ((1R,5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate

[0117] Ethyl 2-(((6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)methoxy)acetate (35 mg, 0.039 mmol) was dissolved in 2 mL of dichloromethane, followed by the addition of triethylamine (12 mg, 0.12 mmol). The reaction was stirred for 10 minutes, after which acetic anhydride (8 mg, 0.08 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. After completion of the reaction, the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate (5 x 3 mL). The organic phase was dried over saturated brine and anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained crude product was used directly in the next step.

[0118] Step 7: Synthesis of methyl ((1R,5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate

[0119] The methyl ((1R,5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate obtained in the previous step was dissolved in dimethyl sulfoxide (2 mL), followed by the addition of cesium fluoride (12 mg, 0.08 mmol). The reaction was stirred at room temperature for three hours. The dimethyl sulfoxide was then removed under reduced pressure, and the resulting crude product was separated by thin-layer chromatography (dichloromethane:methanol = 100:7) to afford the final product as a light yellow solid (24 mg, 75% yield). MS: (ESI) m / z = 789.2 [M+H] + .

[0120] The preparation method of Example 1 was applied to obtain Examples 2-4

[0121] Example 5: Synthesis of methyl ((1R,5S)-3-(7-(3-(acetoxymethoxy)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate

[0122] Following the synthesis of Example 1, 31 mg of the final product was obtained as a light yellow solid. MS: (ESI) m / z = 745.4 [M+H] +

[0123] The preparation method of Example 1 was applied to obtain Examples 6-10

[0124] Example 11: Synthesis of methyl ((1R,5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate

[0125] Following the synthesis of Example 1, 22 mg of the final product was obtained as a light yellow solid. MS: (ESI) m / z = 715.4 [M+H] +

[0126] The preparation method of Example 11 was applied to obtain Example 12-34

[0127] Example 35: Synthesis of ethyl 2-((((1R,5S)-3-(7-(3-acetoxy-8-vinyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)L-valine

[0128] Step 1: Synthesis of 2-((((1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethan-1-ol

[0129] To the reaction flask, (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane (4.04 g, 20 mmol), ethylene glycol (1.5 g, 24 mmol), toluene (120 mL), and paraformaldehyde (1.5 g, 50 mmol) were added. A water separator and reflux condenser were installed. The mixture was heated in an oil bath at 130°C for 24 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain a dark brown viscous product. Column chromatography (silica gel, methanol:dichloromethane = 1:20) afforded a yellow viscous product (266 mg, 0.96 mmol, yield: 4.8%). MS: (ESI) m / z = 277.3 [M+H] +

[0130] Step 2: Synthesis of 2-((((1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl(tert-butyloxycarbonyl)-L-valine

[0131] To a solution of 2-((((1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethan-1-ol (200 mg, 0.725 mmol), (tert-butyloxycarbonyl)-L-valine (220 mg, 1.01 mmol) and 1-hydroxybenzotriazole (128 mg, 0.95 mmol) in dichloromethane (10 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol) and N,N-diisopropylethylamine ( 0.41 mL, 2.5 mmol). The reaction solution was stirred at room temperature overnight. Dichloromethane (15 mL) was added to dilute the reaction solution. The dichloromethane solution was washed with saturated aqueous ammonium chloride solution (10 mL), saturated aqueous sodium carbonate solution (10 mL), and saturated brine (10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow viscous substance. Column chromatography (silica gel, methanol: dichloromethane = 1:40) was performed to obtain a colorless viscous product (265 mg, 0.558 mmol, yield: 77%). MS: (ESI) m / z = 476.4 [M+H] +

[0132] Step 3: Synthesis of 2-((((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl(tert-butyloxycarbonyl)-L-valine

[0133] To a solution of 2-((((1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl(tert-butoxycarbonyl)-L-valine (238 mg, 0.5 mmol) in methanol (5 mL) was added palladium hydroxide on carbon (100 mg, 0.071 mmol) at room temperature. The hydrogen atmosphere was replaced with a hydrogen balloon, and the mixture was stirred at room temperature for 18 hours. The solid was removed by filtration, and the filtrate was evaporated under reduced pressure to give a white foamy product (200 mg, 0.05 mmol, yield: 100%). This product was used directly in the next reaction. MS: (ESI) m / z = 386.4 [M+H] +

[0134] Step 4: Synthesis of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine

[0135] NaH (594 mg, 14.9 mmol) was added to anhydrous THF (10 mL), and benzyl alcohol (1.6 g, 14.9 mmol) was added under ice-water cooling. The reaction was stirred for 30 minutes under ice-water cooling. A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 9.9 mmol) in THF (3 mL) was added dropwise, and the reaction was stirred at 0°C for 1 hour. After completion of the reaction, the reaction was quenched by the addition of dilute aqueous ammonium chloride (50 mL), and the mixture was extracted with ethyl acetate (50 + 25 mL). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate:petroleum ether = 1:5) to afford a white solid (2.9 g, yield: 90%). MS: (ESI) m / z = 324.1 [M+H] +

[0136] Step 5: Synthesis of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0137] The compound 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 7.7 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.6 g, 11.6 mmol), and cesium carbonate (6.3 g, 19.3 mmol) were added to 1,4-dioxane (15 mL) and stirred at 60°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (methanol:dichloromethane = 1:60) to afford a white solid (2.6 g, yield: 75%). MS: (ESI) m / z = 447.2 [M+H] +

[0138] Step 6: Synthesis of 4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0139] To a reaction flask, 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (350 mg, 0.783 mmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (476 mg, 1.02 mmol), and cesium carbonate (766 mg, 2.35 mmol) were added. The atmosphere was replaced with argon. 1,4-Dioxane (6 mL), purified water (2 mL), and tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were added. The atmosphere was replaced with argon again. The mixture was heated in an oil bath at 100°C for 4 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added for extraction. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated under pressure to yield a brown viscous substance. Column chromatography (silica gel, methanol:dichloromethane = 1:40) afforded the product as a white foam (280 mg, 0.372 mmol, yield: 47%). MS: (ESI) m / z = 753.4 [M+H] +

[0140] Step 7: Synthesis of ethyl 4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-acetate

[0141] A solution of 4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (240 mg, 0.319 mmol) and triethylamine (84 μL, 0.60 mmol) in dichloromethane (3 mL) was cooled in an ice-water bath and acetyl chloride (25 μL, 0.35 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 0.5 hours. Dichloromethane (20 mL) was added for dilution, and the organic phase was washed with water (10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and saturated brine (10 mL). After drying over sodium sulfate, the organic phase was concentrated under reduced pressure to obtain a viscous material. Slurrying with petroleum ether (2 mL) gave a white solid (250 mg). The crude product was used directly in the next reaction. MS: (ESI) m / z = 795.4 [M+H] +

[0142] Step 8: Synthesis of ethyl 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-acetate

[0143] A mixture of ethyl 4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-acetate (200 mg, 0.25 mmol) and trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. Anhydrous dichloromethane (10 mL) was added for dilution, and the mixture was concentrated under reduced pressure to afford a yellow viscous product. Purification by column chromatography (silica gel, methanol:dichloromethane = 1:30) afforded a light yellow solid (115 mg, 0.163 mmol, two-step yield: 65%). MS: (ESI) m / z = 705.4 [M+H] +

[0144] Step 9: Synthesis of 2-(((1R,5S)-3-(7-(3-acetoxy-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl(tert-butoxycarbonyl)-L-valine

[0145] Under ice-water cooling, to a solution of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-acetic acid ethyl ester (100 mg, 0.142 mmol) and triethylamine (40 μL, 0.284 mmol) in anhydrous dichloromethane (2 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (29 μL, 0.17 mmol) in anhydrous dichloromethane (1 mL). Stir for 30 minutes. Concentrate under reduced pressure. The resulting brown viscous material was used directly in the next step.

[0146] The above brown viscous product was dissolved in anhydrous tetrahydrofuran (2 mL) and triethylamine (40 μL, 0.284 mmol) was added. The reaction flask was purged with nitrogen, and the resulting solution was cooled in an ice-water bath. A solution of 2-((((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl(tert-butoxycarbonyl)-L-valine (62 mg, 0.16 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 1 hour. The mixture was extracted with ethyl acetate (25 mL) and water (25 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The organic phases were combined, washed with saturated aqueous ammonium chloride (10 mL) and saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield a brown viscous product. Purification by preparative thin-layer chromatography (methanol:dichloromethane = 1:8) afforded a yellow solid (112 mg, 0.105 mmol, 74% yield). MS: (ESI) m / z = 1072.7 [M+H] +

[0147] Step 10: Synthesis of 2-(((1R,5S)-3-(7-(3-acetoxy-8-vinyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl(tert-butyloxycarbonyl)-L-valine

[0148] To a solution of 2-(((1R,5S)-3-(7-(3-acetoxy-7-fluoro-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl(tert-butoxycarbonyl)-L-valine (112 mg, 0.105 mmol) in anhydrous DMF (1 mL) was added cesium fluoride (38 mg, 0.25 mmol), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (25 mL) was added, and the mixture was washed with water (7 mL*3) and saturated brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a yellow solid (98 mg, 0.105 mmol). MS: (ESI) m / z = 916.5 [M+H] +

[0149] Step 11: Synthesis of ethyl 2-((((1R,5S)-3-(7-(3-acetoxy-8-vinyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)L-valine

[0150] Under ice-water cooling, trifluoroacetic acid (0.4 mL) was added dropwise to a solution of 2-(((1R,5S)-3-(7-(3-acetoxy-8-vinyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethyl(tert-butoxycarbonyl)-L-valine (90 mg, 0.098 mmol) in dichloromethane (2 mL). The mixture was slowly warmed to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure. Dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added for extraction. The organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid. Purification by preparative thin layer chromatography (ammonia methanol solution: dichloromethane = 1:10) gave a light yellow solid (41 mg, 0.050 mmol). MS: (ESI) m / z = 816.5 [M+H] +

[0151] The preparation method of Example 35 was applied to obtain Examples 36-86

[0152] Example 87: Synthesis of the compound acetoxymethyl-3-(3-acetoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl-8-fluoro-2-fluoro-2-fluorotetrahydropyrrolidin-7a(5H)yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0153] Step 1: Synthesis of compound hydroxymethyl acetate:

[0154] Methanol (32g, 1mol) was placed in a 250ml single-necked flask, and acetic anhydride (306.3g, 3mol) was added. After the reaction system was purged with nitrogen, the reaction system was heated to 70°C, and concentrated sulfuric acid (200g, 98% by mass) was slowly added. The reaction system was stirred at 70°C for 7 hours, and the unreacted methanol was removed by vacuum distillation to obtain the acylated product. GC analysis showed that the acylated product content was 98.8%, and the yield was 90.1%.

[0155] Step 2: Synthesis of compound (chloroformyloxy)methyl acetate:

[0156] Hydroxymethyl acetate (80 g, 0.9 mol) was dissolved in 100 ml of ultra-dry DCM. DIEA (150 ml, 0.9 mol) and diphosgene (trichloromethyl chloroformate) (249 g, 1.26 mmol) were added at 0°C. The reaction system was allowed to react in an ice-water bath for 1 hour, then warmed to room temperature and stirred for 2 hours. After the reaction was complete, Et2O was added and the white precipitate was filtered. The filtered organic solvent was washed with 0.2 M HCl solution (500 ml), 0.2 M NaOH solution (500 ml), and H2O, dried over anhydrous Na2SO4, and evaporated to yield the desired product (109 g, 80%).

[0157] Step 3: Synthesis of the compound acetoxymethyl-3-chloro-8-fluoro-2-fluoro-2-fluorotetrahydropyrrolidine-7a-methoxypyridine:

[0158] Dissolve 4-chloro-8-fluoro-2-fluoro-2-thiophene-3-diazabicyclo-3-chloro-8-fluoro-2-fluorotetrahydropyrrolidine-7a-methoxypyridine (9.0 g, 20 mmol) in 100 ml of ultra-dry DCM, and add DIEA (5 ml, 30 mmol). Slowly add (chloroformyloxy)methyl acetate (3.3 g, 22 mmol) in an ice-water bath, and stir the reaction system for 1 hour. After completion of the reaction, as monitored by TLC, the reaction system was diluted with 100 ml of DCM, washed with 100 ml of saturated ammonium chloride, extracted, and separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product, which was then isolated by column chromatography to yield a pale yellow solid powder (10.9 g, 19.2 mmol, yield: 91%).

[0159] Step 4: Synthesis of compound 5-methyl-4-tetra,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-5,6,7,8-tetrahydronaphthalene-2-ol:

[0160] The compound 2-(3-methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (664 mg, 2 mmol) was dissolved in 10 ml of 1,4-dioxane. 2 ml of 4N HCl in dioxane was added at room temperature, and the reaction system was stirred for 2 hours. After completion of the reaction, as monitored by TLC, the solvent was removed from the reaction system under reduced pressure to obtain the crude product. The crude product was dissolved in 50 ml of DCM, washed with saturated sodium bicarbonate solution, and separated by extraction. The organic phase was dried over anhydrous sodium sulfate to obtain a white solid powder (552 mg, 1.92 mmol, yield: 96%).

[0161] Step 5: Synthesis of methyl (5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetate

[0162] The compound 5-methyl-4-tetra,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-5,6,7,8-tetrahydronaphthalene-2-ol (552 mg, 1.92 mmol) was dissolved in 20 ml of ultra-dry dichloromethane, and DIEA (0.53 mml, 3.84 mmol) was added. Then, iodomethyl acetate (420 mg, 2.1 mmol) was slowly added under ice-water bath conditions. The reaction system was stirred for 30 min. After the reaction was completed as monitored by TLC, the reaction system was quenched by adding water, the reaction system was diluted with 20 ml of DCM, and washed with 20 ml of saturated sodium bicarbonate solution to obtain a white solid (656 mg, 1.82 mmol, yield: 94.7%).

[0163] Step 6: Synthesis of the compound acetoxymethyl-3-(3-acetoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl-8-fluoro-2-fluoro-2-fluorotetrahydropyrrolidin-7a(5H)yl)methoxypyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0164] The compound 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetic acid methyl ester (112 mg, 0.2 mmol), acetoxymethyl-3-chloro-8-fluoro-2-2-fluoro-2-fluorotetrahydropyrrolidine-7a-methoxypyridine (108 mg, 0.3 mmol), tripotassium phosphate (84 mg, 0.4 mmol), and palladium adamantane (40 mg, 0.02 mmol) were dissolved in a cosolvent of 1,4-dioxane / water (10 ml / 1 ml). After argon replacement, the reaction system was heated to 70°C and stirred for 6 hours. After completion of the reaction, the organic solvent was removed under reduced pressure to obtain the crude product, which was separated by PLC to obtain a white solid (85 mg, 56%). MS: (ESI) m / z = 764.83 [M+H] +

[0165] The preparation method of Example 87 was applied to obtain Examples 88-100

[0166] Example 101: Synthesis of the compound acetoxymethyl (1R, 5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0167] Step 1: Synthesis of acetoxymethyl-3-8-fluoro-2-(2R,7aS)-2-fluorotetrahydropyrrolidine-7a-methoxy-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0168] The compound acetoxymethyl-3-chloro-8-fluoro-2-fluoro-2-fluorotetrahydropyrrolidine-7a-methoxypyridopyrimidine (56 mg, 0.1 mmol) and 5-methyl-4-tetra,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-5,6,7,8-tetrahydronaphthalen-2-ol (56 mg, 0.2 mmol), tripotassium phosphate (42 mg, 0.2 mmol), and palladium adamantane (20 mg, 0.01 mmol) were dissolved in a co-solvent of 1,4-dioxane / water (10 ml / 1 ml). After replacing the argon atmosphere, the reaction system was heated to 70°C and stirred for 6 hours. After completion of the reaction, the organic solvent was removed under reduced pressure to obtain the crude product, which was separated by PLC to obtain a white solid (48 mg, 70%). M / Z: 693.31

[0169] Step 2: Synthesis of the compound acetoxymethyl (1R, 5S)-3-(7-(3-((2-acetoxyethoxy)methoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0170] Acetoxymethyl-3-8-fluoro-2-(2R,7aS)-2-fluorotetrahydropyrrolidine-7a-methoxy-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47 mg, 0.07 mmol) was dissolved in 5 ml of ultra-dry dichloromethane. DIEA (0.1 ml, 0.14 mmol) and 2-(chloromethoxy)ethyl acetate (178 mg, 0.084 mmol) were added in an ice-water bath, and the reaction system was stirred for 2 hours. After completion, the reaction system was quenched by adding 5 ml of saturated ammonium chloride solution, extracted with 50 ml of dichloromethane, and the layers separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by PLC to obtain an off-white solid. (48mg, 85%). MS:(ESI)m / z=809.36[M+H] +

[0171] The preparation method of Example 101 was applied to obtain Examples 102-114

[0172] Example 115: Synthesis of acetoxymethyl (1R,5S)-3-(7-(3-acetoxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0173] Step 1: Chloromethyl (4-nitrophenyl) carbonate

[0174] Dissolve p-nitrophenol (5 g, 35.9 mmol) in THF (150 mL). Add chloromethyl chloroformate (4.9 g, 37.7 mmol) with stirring at 18°C, followed by the dropwise addition of triethylamine (4 g, 39.5 mmol). After reacting for 1 hour, concentrate the mixture and dissolve it in ethyl acetate. The organic phase is washed twice with saturated sodium carbonate and once with 1N hydrochloric acid. Dry the organic phase over anhydrous sodium sulfate and concentrate to yield a crude yellow solid, which is used directly in the next step (7.1 g, yield: 85%).

[0175] Step 2: Synthesis of iodomethyl (4-nitrophenyl) carbonate

[0176] Dissolve chloromethyl (4-nitrophenyl) carbonate (5 g, 21.6 mmol) and sodium iodide (9.7 g, 64.8 mmol) in anhydrous acetone (100 mL) and add The reaction mixture was stirred at 40°C for 15 hours with 2.5 g of molecular sieves. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and saturated aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid (5.9 g, yield: 84%).

[0177] Step 3: Synthesis of methyl (((4-nitrophenoxy)carbonyl)oxy)acetate

[0178] Iodomethyl (4-nitrophenyl) carbonate (5 g, 15.5 mmol) was dissolved in toluene, followed by the addition of AgOAc (3.1 g, 18.6 mmol). The mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography to afford a white solid (3.1 g, 78% yield).

[0179] Step 4: Synthesis of acetoxymethyl (1R,5S)-3-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0180] The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol (1 g, 1.7 mmol) and DIEA (2.2 g, 17.3 mmol) were dissolved in DCM (20 mL). Methyl (((4-nitrophenoxy)carbonyl)oxy)acetate (442 mg, 1.7 mmol) was added with stirring at -40°C and allowed to react for 1 hour. After completion of the reaction, the mixture was concentrated and purified by reverse-phase column chromatography to afford a yellow solid (300 mg, 25% yield).

[0181] Step 5: Synthesis of acetoxymethyl (1R,5S)-3-(7-(3-acetoxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0182] Acetoxymethyl (1R,5S)-3-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.14 mmol) and DIEA (56 mg, 0.43 mmol) were dissolved in DCM (2 mL). Acetyl chloride (14 mg, 0.17 mmol) was added with stirring at 0°C and allowed to react for 1 hour. After completion of the reaction, the mixture was concentrated and separated by preparative TLC (DCM / MeOH (7N NH3) = 10 / 1) to give a pale yellow solid. (65 mg, yield 65%). MS: (ESI) m / z = 735.4 [M+H] +

[0183] The preparation method of Example 115 was applied to obtain Examples 116-142

[0184] Example 143: Synthesis of acetoxymethyl (1R,5S)-3-(7-(3-(diethoxyphosphoryl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0185] Step 1: Synthesis of diethyl chlorophosphate

[0186] Under nitrogen and protected from light by aluminum foil, t-BuOCl (4.7 g, 43.4 mmol) was dissolved in DCM (50 mL). Diethyl phosphate (2 g, 14.5 mmol) was slowly added dropwise. The mixture was stirred at 20°C for 12 hours. After completion of the reaction, the reaction solution was concentrated, diluted with toluene, and concentrated to obtain a crude product, which was used directly in the next step (2.5 g, yield: 100%).

[0187] Step 2: Synthesis of acetoxymethyl (1R,5S)-3-(7-(3-(diethoxyphosphoryl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0188] Acetoxymethyl (1R,5S)-3-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.14 mmol) and TEA (18 mg, 0.18 mmol) were dissolved in DCM (2 mL). Diethyl chlorophosphate (27 mg, 0.16 mmol) was added with stirring at 0°C and allowed to react for 12 hours. After completion of the reaction, the mixture was concentrated and separated by preparative TLC (DCM / MeOH (7N NH3) = 10 / 1) to afford a pale yellow solid (68 mg, 57% yield). MS: (ESI) m / z = 829.4 [M+H] +

[0189] The preparation method of Example 143 was applied to obtain Examples 144-154

[0190] Example 155: Synthesis of methyl ((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetate

[0191] Step 1: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0192] Tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimidin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (167 mg, 0.303 mmol) and 5-methyl-4-tetra,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 0.39 mmol) were dissolved in a mixed solvent of dioxane and water (4 mL:1 mL). CataCXium A Pd G4 (30 mg, 0.04 mmol) and potassium phosphate (191 mg, 0.90 mmol) were added. The reaction was replaced with argon three times, and then stirred at 70°C overnight. The mixture was cooled to room temperature and quenched by adding dilute ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (20 mL), and the resulting organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting crude product was separated by column chromatography (dichloromethane: methanol = 30:1). A yellow solid (117 mg, 0.173 mmol, 57% yield) was obtained. MS: (ESI) m / z = 677.5 [M+H] +

[0193] Step 2: Synthesis of tert-butyl (1R,5S)-3-(7-(3-(acetoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0194] Under ice-water cooling, a solution of bromomethyl acetate (31 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added dropwise to a mixture of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.162 mmol), cesium carbonate (80 mg, 0.244 mmol), and anhydrous tetrahydrofuran (1 mL). The mixture was slowly warmed to room temperature and stirred for 0.5 hour. The reaction solution was directly separated using a preparative thin layer chromatography plate to obtain a yellow solid (79 mg, 0.105 mmol, yield: 65%). MS: (ESI) m / z = 749.5 [M+H] +

[0195] Step 3: Synthesis of methyl ((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetate

[0196] To a solution of tert-butyl (1R,5S)-3-(7-(3-(acetoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.10 mmol) in anhydrous dichloromethane (2 mL) was added dropwise trifluoroacetic acid (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Dichloromethane (10 mL) was added for dilution and the mixture was concentrated under reduced pressure. Extraction was performed with dichloromethane (10 mL) and saturated aqueous sodium carbonate solution (10 mL). After separation, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with saturated brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (triethylamine:methanol:dichloromethane = 1:100:1000) to afford an off-white solid (29 mg, 0.045 mmol, yield: 45%). MS: (ESI) m / z = 649.4 [M+H] +

[0197] The preparation method of Example 155 was applied to obtain Examples 156-274

[0198] Example 275: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalene-2-amine:

[0199] Step 1: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0200] The compound (1R,5S)-3-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydropyrrolazin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 0.36 mmol), 2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (133 mg, 0.40 mmol), potassium phosphate (231 mg, 1.09 mmol) and cataCXium A Pd G4 (40 mg, 0.05 mmol) were dissolved in ethanol / water = 4 / 1 (10 mL), the argon atmosphere was replaced three times, and the reaction was heated to 70°C with stirring for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain an off-white solid (183 mg, yield: 70%).

[0201] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalene-2-ol

[0202] Tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (183 mg, 0.25 mmol) was dissolved in acetonitrile (2 mL). A 4N HCl solution in 1,4-dioxane (2 mL) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford an off-white solid (100 mg, 50% yield). MS m / z:578[M+H] + .

[0203] Step 3: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0204] The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalene-2-ol (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). DIEA (27 mg, 0.21 mmol) and di-tert-butyl dicarbonate (37 mg, 0.17 mmol) were then added and stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by preparative TLC (dichloromethane / methanol = 15 / 1) to obtain an off-white solid. (110 mg, yield: 95%).

[0205] Step 4: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0206] Compound (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.089 mol) was dissolved in dichloromethane (5 mL). Triethylamine (11 mg, 0.107 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (35 mg, 0.098 mmol) were added under ice-water cooling, and the reaction was stirred at room temperature for 6 hours. After the reaction was complete, water was added to dilute the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain an off-white solid (54 mg, yield: 75%). MS m / z: 809.7 [M+H] + .

[0207] Step 5: Synthesis of tert-butyl (1R,5S)-3-(7-(3-((diphenylmethylene)amino)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-azabicyclo[3.2.1]octane-8-carboxylate

[0208] The compound (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (53 mg) was added. A mixture of benzophenone imine (24 mg, 0.131 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.013 mmol), cesium carbonate (64 mg, 0.195 mmol), and tris(dibenzylideneacetone)dipalladium (6 mg, 0.006 mmol) was dissolved in toluene (5 mL). The atmosphere was replaced with argon and the mixture was heated to 100°C with stirring for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, concentrated, and purified by preparative TLC (dichloromethane / methanol = 20 / 1) to afford an off-white solid (30 mg, 55% yield).

[0209] Step 6: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalene-2-amine. Tert-butyl 3,8-azabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.0357 mmol) was dissolved in acetonitrile (2 mL) and then added with 4N HCl in 1,4-dioxane (2 mL). The mixture was stirred at room temperature for 6 hours. After completion of the reaction, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford an off-white solid (100 mg, 50% yield). 1 H NMR (400MHz, DMSO) δ9.08 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.28 (d, J = 55.0Hz, 1H), 4. 90(s,2H),4.49(d,J=12.5Hz,1H),4.38(d,J=11.6Hz,1H),4.12(d,J=10.3Hz,1H),4.03 (d,J=10.3Hz,1H),3.68(s,4H),3.02(s,4H),2.83(d,J=6.0Hz,1H),2.67(s,2H),2.05( t,J=26.4Hz,3H),1.73(d,J=30.8Hz,10H),1.54-1.51(m,1H),0.69(d,J=6.9Hz,3H).MS m / z:577[M+H] + .

[0210] The preparation method of Example 275 was applied to obtain Examples 276-303

[0211] Example 304: Synthesis of 4-methoxyphenyl (1R, 5S) -3- (7- (3- ( (ethoxycarbonyl) oxy) -8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolazin-7a (5H) -yl) methoxy) pyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate:

[0212] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(3-((ethoxycarbonyl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0213] To a mixture of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (271 mg, 0.40 mmol), triethylamine (0.22 mL, 1.6 mmol), DMAP (2.4 mg, 0.02 mmol), and dichloromethane (5 mL) was added diethyl pyrocarbonate (0.23 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated by rotary evaporation, and the residue was extracted with water (25 mL) and ethyl acetate (25 mL + 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford a yellow solid (287 mg). The crude product was used directly in the next step.

[0214] Step 2: Synthesis of ethyl 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl carbonate hydrochloride

[0215] Combine acetonitrile (1.5 mL) and a solution of hydrogen chloride in 1,4-dioxane (0.5 mL). Pour the resulting solution into a flask containing tert-butyl (1R,5S)-3-(7-(3-((ethoxycarbonyl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (96 mg). Stir the resulting solution at room temperature for 3 hours. Dilute with ethyl acetate (2 mL) and concentrate by rotary evaporation to yield a yellow solid, which is used directly in the next reaction.

[0216] Step 3: Synthesis of 4-methoxyphenyl (1R, 5S) -3- (7- (3- ( (ethoxycarbonyl) oxy) -8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolazin-7a (5H) -yl) methoxy) pyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0217] To a solution of ethyl 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl carbonate hydrochloride (45 mg, 0.0665 mmol) in dichloromethane (2 mL) was added triethylamine (55 μL, 0.4 mmol) dropwise. The resulting solution was stirred for 2 minutes, and then 4-methoxyphenyl chloroformate (20 μL, 0.133 mmol) was added. The reaction was stirred at room temperature overnight. The solution was directly separated by preparative TLC to yield 4-methoxyphenyl (1R,5S)-3-(7-(3-((ethoxycarbonyl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31 mg, 0.0388 mmol, 58% yield) as a white powder. MS m / z: 799.46 [M+H].

[0218] The preparation method of Example 304 was applied to obtain Examples 305-392

[0219] Example 393: Synthesis of ethyl (5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(3-((isopropyloxycarbonyl)oxy)-8-methyl-5,6,7-8-tetrahydronaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate:

[0220] Step 1: Synthesis of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0221] Dissolve 5,7-dichloro-8-fluoro-2-sulfoxy-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (2.1 g, 6.3 mmol) in DMF (30 mL). Add EtONa (430 mg, 6.3 mmol) dropwise in an ice bath. Stir at room temperature for 10 minutes. Cool again in an ice bath and add iodomethane (0.47 mL, 7.6 mmol) dropwise. Stir at room temperature for 1 hour. After completion of the reaction, dilute the reaction solution with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield a yellow solid (450 mg, yield: 21%). MS: (ESI) m / z = 280.2 [M+H] +

[0222] Step 2: Synthesis of tert-butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0223] Dissolve tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (415 mg, 1.7 mmol) in THF (40 mL). Add NaH (137 mg, 3.4 mmol) portionwise in an ice bath. Stir at room temperature for 30 min. Cool again in an ice bath and add 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (400 mg, 1.4 mmol) all at once. Stir at room temperature for 2 h. After completion of the reaction, quench the reaction with saturated ammonium chloride and extract with DCM. The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford a white solid (420 mg, 61% yield). MS: (ESI) m / z = 486.2 [M+H] +

[0224] Step 3: Synthesis of tert-butyl (5aS,6R,9S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0225] Tert-butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.45 mmol) was dissolved in acetonitrile (20 mL), and PyBOP (471 mg, 0.91 mmol) was added. After cooling in an ice bath, DBU (0.27 mL, 1.8 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction solution was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford a yellow solid (125 mg, yield: 59%). MS: (ESI) m / z = 468.1 [M+H] +

[0226] Step 4: Synthesis of tert-butyl (5aS, 6R, 9S)-1-fluoro-2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-12-(methylthio)-5a, 6,7,8,9,10-hexahydro-5H-4-oxa-3,10a, 11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0227] To the reaction flask were added tert-butyl (5aS,6R,9S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (200 mg, 0.43 mmol), 2-(3-(methoxymethoxy)-8-methyl-5,6,7-8-tetrahydronaphthalen-1-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (199 mg, 0.60 mmol), and potassium carbonate (124 mg, 0.90 mmol). The atmosphere was replaced with argon. THF (2 mL), purified water (0.6 mL), and XPhos-Pd-G2 (34 mg, 0.04 mmol) were added. The atmosphere was replaced with argon again. Heat in a 60°C oil bath for 3 hours. Cool to room temperature, add ethyl acetate and extract with water. The organic phase is washed with saturated brine, dried over sodium sulfate, concentrated, and separated by column chromatography to obtain a yellow solid (170 mg, yield: 62%). MS: (ESI) m / z = 638.2 [M+H] +

[0228] Step 5: Synthesis of tert-butyl (5aS, 6R, 9S)-1-fluoro-2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-12-(methylsulfonyl)-5a, 6,7,8,9,10-hexahydro-5H-4-oxa-3,10a, 11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0229] Tert-butyl (5aS,6R,9S)-1-fluoro-2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (170 mg, 0.27 mmol) was dissolved in DCM (6 mL). m-CPBA (97 mg, 0.56 mmol) was added under ice-cooling. The reaction was allowed to react for 5 min. The reaction solution was then poured into saturated sodium bicarbonate and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. Prep-TLC separation and purification afforded a yellow solid (166 mg, 93% yield). MS: (ESI) m / z = 670.1 [M+H] +

[0230] Step 6: Synthesis of tert-butyl (5aS, 6R, 9S)-1-fluoro-12-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(3-(methoxymethoxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5a, 6,7,8,9,10-hexahydro-5H-4-oxa-3,10a, 11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate

[0231] Compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (38 mg, 0.24 mmol) was dissolved in THF (4 mL), and NaH (19 mg, 0.48 mmol) was added portionwise under ice-bath. The mixture was stirred at room temperature for 30 min. After re-cooling in ice-bath, tert-butyl (5aS,6R,9S)-1-fluoro-2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (160 mg, 0.24 mmol) was added and stirred at room temperature for 12 h. After the reaction was completed, saturated ammonium chloride was added to quench the reaction solution, extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid (125 mg, yield: 70%). MS: (ESI) m / z = 749.2 [M+H] +

[0232] Step 7: Synthesis of 4-((5aS,6R,9S)-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol

[0233] The compound tert-butyl (5aS, 6R, 9S)-1-fluoro-12-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(3-(methoxymethoxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5a, 6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (125 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL) and 4N A solution of HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (80 mg, yield: 79%). MS m / z: 605.1 [M+H] + .

[0234] Step 8: Synthesis of tert-butyl (5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0235] The compound 4-((5aS,6R,9S)-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL). DIEA (21 mg, 0.16 mmol) and di-tert-butyl dicarbonate (29 mg, 0.13 mmol) were then added and stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by preparative TLC to obtain an off-white solid. (90 mg, yield: 96%). MS m / z: 705.1 [M+H] + .

[0236] Step 9: Synthesis of tert-butyl (5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(3-((isopropyloxycarbonyl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate

[0237] The compound tert-butyl (5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (90 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), TEA (26 mg, 0.26 mmol) was added, and isopropyl chloroformate (19 mg, 0.15 mmol) was added dropwise under ice bath, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, water was added to dilute the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by preparative TLC to obtain an off-white solid (89 mg, yield: 88%). MS m / z: 791.1 [M+H] + .

[0238] Step 10: Synthesis of isopropyl 4-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hepten-2-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl carbonate

[0239] The compound tert-butyl (5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(3-((isopropyloxycarbonyl)oxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (89 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL), and a 4N HCl solution in 1,4-dioxane (2 mL) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (65 mg, yield: 84%). MS m / z: 691.1 [M+H] + .

[0240] Step 11: Synthesis of ethyl (5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(3-((isopropyloxycarbonyl)oxy)-8-methyl-5,6,7-8-tetrahydronaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate

[0241] Compound 4-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hepten-2-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl isopropyl carbonate (65 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), TEA (19 mg, 0.19 mmol) was added, and ethyl chloroformate (12 mg, 0.11 mmol) was added dropwise under ice bath, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, water was added to dilute the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by preparative TLC to obtain an off-white solid (59 mg, yield: 82%). MS m / z: 763.1 [M+H] + .

[0242] The preparation method of Example 393 was applied to obtain Examples 394-481

[0243] Cell viability assay:

[0244] 1. Cells

[0245] The cells were cultured in a complete culture medium containing 10% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin in a sterile incubator with a relative humidity of 95% and a CO2 concentration of 5%.

[0246] 2. Reagents: F12K, D-PBS, FBS, penicillin-streptomycin, Tryple, MTT (5 mg / ml)

[0247] Experimental methods

[0248] 1. Compound Preparation

[0249] Weigh an appropriate amount of compound powder into a 1.5 ml centrifuge tube, add the corresponding volume of dimethyl sulfoxide (DMSO) to prepare a 20 mM stock solution, divide the solution into smaller portions, and store in a -20°C refrigerator away from light until use.

[0250] 2. Tumor Cell Culture

[0251] The cells were inoculated into a cell culture flask, an appropriate amount of complete culture medium was added, and the cells were cultured in a sterile incubator. When the cell confluence reached more than 80%, subculture was performed.

[0252] 3. MTT / MTS Assay for Cell Proliferation in Vitro

[0253] Adherent cells in the logarithmic growth phase were trypsinized or suspended cells were collected by centrifugation and counted. 90 μl of the cell suspension was seeded into a 96-well plate at a seeding density of 1000 cells / well. After 24 hours, 10 μl / well of the compound diluted in culture medium at 10-fold the final concentration was added. A control well containing the same volume of 5% DMSO was used, resulting in a final DMSO concentration of 0.5%. Three days after drug treatment, cell viability was assessed using MTT assays. The assay was performed as follows: 10 μl of MTT was added to each well and the plate was incubated in an incubator for another 4 hours. The supernatant was discarded, and 150 μl of DMSO was added to dissolve the crystalline formazan. The absorbance at 490 nM was measured using a microplate reader. Alternatively, 10 μl of MTS was added to each well and the plate was incubated in an incubator for 4 hours. The absorbance at 490 nM was measured directly using a microplate reader. Dose-response curves were generated and IC50 values ​​were calculated using GraphPad Prism 6 software.

[0254] Activity data IC of compound of formula (I) 50 The values ​​are shown in Table 1:

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein the compound of formula (I) is: in: Y is or -NR a R b , where R a For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl substituted C 1-6 Alkyl, or C 3- 6-cycloalkyl, R b NR c R d -C 1-6 Alkyl-, where NR c R d -C 1-6 The alkyl group in alkyl- is optionally substituted with C 3-6 Cycloalkyl, where R c and R d is hydrogen or C 1-6 alkyl; is a 4- to 12-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted with one or more R 1 Replace, X 1 Selected from N and CR 4 ;X 2 Selected from NR 4 , CR 4 and S(O) 0,1,2 R 4 , in, R 1 Selected from hydrogen, halogen, optionally halogen or hydroxy or -NR 1a R 1b Substituted C 1-6 Alkyl, CN, -OR 1a 、-SR 1a 、-NR 1a R 1b 、-S(O)R 1a 、-S(O)2R 1a 、-C(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-C(O)NR 1a R 1b 、-S(O)2N(R 1a R 1b )2 and 5- to 6-membered heteroaryl, wherein R 1a and R 1b are independently hydrogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 Alkyl- or C 3-6 Cycloalkyl; R 4 is selected from hydrogen, halogen, C optionally substituted by halogen or hydroxy 1-6 Alkyl, CN, -OR 4a 、-SR 4a 、-S(O)R 4a 、-S(O)2R 4a 、-C(O)R 4a 、-C(O)OR 4a 、-NR 4a C(O)R 4b 、-C(O)NR 4a R 4b and -S(O)2N(R 4a R 4b )2, where R 4a and R 4b Each independently represents hydrogen, 4-6 membered oxacycloalkyl optionally substituted by methyl, dimethyl or isopropyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 alkyl-; L is a single bond, -O-, -S-, or -NR La -、-O-(CR La R Lb ) t -、-S-(CR La R Lb ) t -、-NR c -(CR La R Lb ) t -、-(CR La R Lb ) t -O-、-(CR La R Lb ) t -S-、-(CR La R Lb ) t -NR Lc -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR Lc -or-N Lc C(O)-, where R La 、R Lb and R Lc are each independently selected from hydrogen and C 1-6 Alkyl, or R attached to the same carbon atom La and R Lb Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group, and wherein t is an integer from 1 to 6; R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, oxo, -OR 2a 、-C(O)R 2a 、-(CR 2a R 2b ) m -OC(O)NR 2c R 2d 、-CO2R 2a 、-CONR 2c R 2d 、-NR 2c R 2d 、C 3- 8 cycloalkyl, C 3-8 Cycloalkyl C 1-6 One or more of alkyl, aryl, heteroaryl and heterocyclic groups are substituted, wherein R 2a 、R 2b 、R 2c and R 2d Each is independently hydrogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl-, or R attached to the same nitrogen atom 2c and R 2d Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms selected from nitrogen, oxygen, sulfur as ring members, and wherein m is an integer from 1 to 6; R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R 8 Replace; each R 8 alone is selected from halogen, cyano, oxo, C optionally substituted by halogen, cyano, hydroxyl and deuterated 1-6 alkyl, C2-C6 alkenyl optionally substituted by hydroxy or deuterated, C2-C6 alkynyl optionally substituted by hydroxy or deuterated, -OR 8a 、-SR 8a 、-S(O)2R 8a 、-P(=O)R 8a R 8b 、-NR 8a R 8b 、-C(O)NR 8a R 8b , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein R 8a and R 8b each independently hydrogen, optionally substituted by halogen, C 1-6 Alkyl and C 1-6 Alkoxy-C 1-6 Alkyl-; or two R on the same carbon atom 8 Form a C3-C8 cycloalkyl group; or R on two adjacent carbon atoms 8 Together with the carbon atoms to which they are attached, they form a C3-C8 cycloalkyl group; Q 1 , Q 2 and Q 3 Each independently is N or CR 6 , M 1 and M 2 Each independently is N or CR 7 , provided that Q 1 and M 1 At least one of them is N; where R 6 and R 7 are independently hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl or heterocyclic, -OR 6a 、-C(O)R 6a 、-CO2R 6a 、-CONR 6a R 6b or -NR 6a R 6b , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted by oxo, halogen, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, nitro, cyano and -NR d R e One or more substitutions, wherein R 6a 、R 6b 、R 6c and R 6d Each is independently hydrogen, C 3-6 Alkyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 alkyl-. or Q 3 CR 6 , and R 6 With R 1 Connect to form a new 7-8 membered heterocyclic ring.

2. The compound of claim 1, wherein Y is where R 4 are independently selected from hydrogen, halogen, C optionally substituted by halogen or hydroxy 1-6 Alkyl, CN, -OR 4a 、-SR 4a 、-S(O)R 4a 、-S(O)2R 4a 、-C(O)R 4a 、-C(O)OR 4a 、-NR 4a C(O)R 4b 、-C(O)NR 4a R 4b and -S(O)2N(R 4a R 4b )2, where R 4a and R 4b Each independently represents hydrogen, 4-6 membered oxacycloalkyl optionally substituted by methyl, dimethyl or isopropyl, C 1-6 Alkyl or hydroxy C 1-6 Alkyl; preferably R 4 Each is independently selected from hydrogen, -C(O)CH2OH, -C(O)NH2, -C(O)N(CH3)2, F, Br, Cl, -OH, -SCH3, -S(O)CH3, -S(O)2CH3, -S(O)2N(CH3)2, -S(O)2NH2, CF3 or CN.

3. The compound of claim 1, wherein Y is R 4 Preferably, hydrogen, 4. The compound of any one of claims 1 to 3, wherein L is -O-CH2- or -O-.

5. The compound of claim 1, wherein L is -O-CH2-, and R 2 is a heterocyclic group, which is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d wherein each variable is as defined in formula (I); preferably the heterocyclic group is unsubstituted or substituted by halogen, C 1-6 Alkyl and -OR 2a More preferably, the heterocyclic group is unsubstituted or substituted by one or two of halogen, methyl and methoxy.

6. The compound of any one of claims 1 to 5, wherein L is -O-CH2-, and R 2 is a 4- to 8-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur as ring members, or is a 6- to 12-membered bicyclic heterocycle containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur as ring members, said monocyclic or bicyclic heterocyclic group being unsubstituted or replaced by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d wherein each variable is as defined in formula (I).

7. The compound of claim 6, wherein the heterocyclic group is unsubstituted or substituted by halogen, C 1-6 Alkyl and -OR 2a More preferably, the heterocyclic group is unsubstituted or substituted by one or two of halogen, methyl and methoxy.

8. The compound of claim 6, wherein L is -O-CH2-, and R 2 is a monocyclic heterocycle which is azetidinyl, pyrrolidinyl or piperidinyl, said ring being unsubstituted or substituted by one or two halogen or C 1-6 Alkyl substituted; or L is -O-CH2-, and R 2 is a bicyclic heterocycle which is octahydropentalene, wherein at least one carbon atom is replaced by a nitrogen atom and one of the other carbon atoms is optionally replaced by an oxygen atom.

9. The compound of claim 6, wherein L is -O-CH2-, and R 2 is a bicyclic heterocycle which is tetrahydro-1H-pyrrolazinyl, tetrahydro-1H-furopyrrolyl, octahydrocyclopentapyrrolyl, azabicyclo[3.1.0]hexane, wherein said group is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d wherein each variable is as defined in formula (I); preferably halogen, C 1-6 Alkyl and -OR 2a More preferably, it is substituted by one or two of halogen, methyl and methoxy.

10. The compound of claim 9, wherein the bicyclic heterocycle is tetrahydro-1H-pyrrolazin-7-yl, tetrahydro-1H-furo[3,4-b]pyrrol-3a-yl, tetrahydro-1H-furo[3,4-c]pyrrol-3a-yl, tetrahydro-1H-furo[3,4-b]pyrrol-6a-yl, octahydrocyclopenta[b]pyrrol-6a-yl, octahydrocyclopenta[c]pyrrol-3a-yl, octahydrocyclopenta[b]pyrrol-3a-yl, 3-azabicyclo[3.1.0]hexan-1-yl or 2-azabicyclo[3.1.0]hexan-1-yl, wherein the group is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d wherein each variable is as defined in formula (I); preferably halogen, C 1-6 Alkyl and -OR 2a More preferably, it is substituted by one or two of halogen, methyl and methoxy.

11. The compound of claim 1, wherein LR 2 for 12. The compound of claim 1, wherein R 3 for , R 8 Preferably selected from -OH, -NH2, -NH(C=O)CH3, -NH(C=O)CF3, 13. The compound of claim 1, wherein the compound is a specific compound disclosed herein.

14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof.

15. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof in the preparation of a drug for treating cancer associated with H-ras, K-ras or N-ras inhibition.

16. The use according to claim 15, wherein the cancer is a cancer mediated by G12D mutation.

17. The use according to claim 16, wherein the cancer is lung cancer, colorectal cancer or pancreatic cancer.

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