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

Abstract

The present invention relates to compounds of formula (I) and (II) or pharmaceutically acceptable salts, prodrugs, tautomers or stereoisomers and solvates thereof, which can be used to treat cancer and inflammation in mammals. The present invention also discloses a method for preparing the compounds of formula (I) and (II) and a pharmaceutical composition comprising the compounds.

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 present in 90% of pancreatic cancers, 45% of colon cancers, and 35% of lung cancers. Among the three Ras genes, Kirsten-RAS (KRAS) is the most commonly mutated subtype, accounting for as high as 86%. The other two subtypes, neuroblastoma-RAS (NRAS) and Harvey-RAS (HRAS), have lower mutation rates (11% and 3%). Among KRAS proteins, KRAS-G12D mutations account for 33.4%, KRAS-G12V mutations account for 22.8%, KRAS-G13D mutations account for 12.4%, KRAS-G12C mutations account for 11.3%, KRAS-G12A and KRAS-G12S mutations account for 5.3% and 4.4%, respectively. Among HRAS proteins, the most common mutations are HRAS-G13R (17.8%), HRAS-Q61R (14.0%), and HRAS-G12 (12.3%), while the least common mutation is HRAS-G12S (4.9%). Among NRAS proteins, the most common mutations are NRAS-Q61R (23%), NRAS-Q61K (18%), and NRAS-G12D (12%) (O'Bryan, JP Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol. Res. 2019; 139, 503–511). To date, sotorasib, a drug that directly targets the KRAS-G12C mutation, has been approved by the FDA, and at least five other candidate drugs are in clinical trials. Although some progress has been made in this field, the development of new RAS inhibitors is still needed to meet clinical needs and provide patients with safe and effective treatment options and drugs.

[0007] 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.

[0008] Summary of the Invention

[0009] The present invention provides compounds capable of modulating KRAS, HRAS and / or NRAS protein mutations, 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.

[0010] In one aspect of the present invention, there is provided a compound of formula (I) and (II) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or prodrug thereof, wherein the compound of formula (I) and (II) is:

[0011] in:

[0012] 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 O, S, N and CR 4 ;X 2 Selected from NR 4 , CR 4 and S(O) 0,1,2 R 4 ,

[0013] in,

[0014] 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-, C 3-6 Cycloalkyl;

[0015] 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 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-;

[0016] 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 LbTogether 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;

[0017] 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 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;

[0018] R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R 8 Replace; each R 8independently 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 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、OCH2OC(O)OR 8a , optionally halogen or C 1-12 Alkyl-substituted C3-C6 cycloalkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C3-C6 cycloalkyl, aryl, heteroaryl, aryl or heteroaryl optionally substituted by -OC(O)C(CH3)3, C3-C6 cycloalkyl, aryl, heteroaryl, optionally substituted by halogen 1-12 Alkyl and C 1- 12 Alkoxy-C 1-12 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;

[0019] n 1 is 0, 1, or 2;

[0020] 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;

[0021] where R 6 and R 7 Each is independently hydrogen, halogen, hydroxy, cyano, nitro, C1-6 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-;

[0022] or Q 2 and Q 3 The substituents are connected to form a saturated or partially saturated 5-6 membered aliphatic ring, aromatic ring or aromatic heterocyclic ring.

[0023] In some embodiments, for

[0024] In some embodiments, L is -O-CH2- or -O-.

[0025] 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 R2b ) 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 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 is a tetrahydro-1H-pyrrolizinyl group (e.g., a tetrahydro-1H-pyrrolizin-7-yl group 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.

[0026] In a further preferred embodiment, LR 2 for

[0027] In some embodiments, R in the compounds of formula (I) and (II) 3 for

[0028] a. a monocyclic aryl or heteroaryl group selected from phenyl, pyridyl, pyrimidinyl and pyrazinyl;

[0029] 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,;

[0030] c. a tricyclic aryl or heteroaryl group selected from

[0031] The aryl or heteroaryl group may be optionally substituted by 1 to 3 substituents R 8 Replacement, R 8 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 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、OCH2OC(O)OR 8a , optionally halogen or C 1-12 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C3-C6 cycloalkyl, aryl, heteroaryl, aryl or heteroaryl optionally substituted by -OC(O)C(CH3)3, C3-C6 cycloalkyl, aryl, heteroaryl, optionally substituted by halogen 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 alkyl-.

[0032] In some embodiments, R in the compounds of formula (I) and (II) 3 is naphthalene-1-yl (wherein R 3 As naphthyl, the position of connection with the parent structure is 1), and the 3-position of the naphth-1-yl is unsubstituted or substituted by -OR 8a 、-P(=O)R 8a R 8b or -NR 8a R 8b 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、OCH2OC(O)OR 8a Substituted, where R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2)n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C3-C6 cycloalkyl, aryl, heteroaryl, aryl or heteroaryl optionally substituted by -OC(O)C(CH3)3, C3-C6 cycloalkyl, aryl, heteroaryl, optionally substituted by halogen 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 Alkyl-, preferably the 3-position of the naphth-1-yl is unsubstituted or substituted by -OH or -NH2, -OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、OCH2OC(O)OR 8a and one or two of the 5, 6, 7 and 8 positions of the naphthalene-1-yl group are substituted, wherein the substituents are independently selected from halogen, C 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, optionally substituted by halogen, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 In some preferred embodiments, R in the compounds of formula (I) and (II) 3 is naphthalene-1-yl (wherein R 3As naphthyl, the position of connection with the parent structure is 1), and the 3-position of the naphth-1-yl is unsubstituted or substituted by -OH or -NH2, -OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、OCH2OC(O)OR 8a and at least one of the 7 and 8 positions of the naphthalene-1-yl is substituted, wherein the substituents are independently selected from halogen, C 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-6 Alkyl, C 1-12 Alkyl or C 1-12 Alkoxy, C 1- 12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, optionally substituted by halogen, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 In some preferred embodiments, R in the compounds of formula (I) and (II) 3 is naphthalene-1-yl (wherein R 3 As naphthyl, the position of connection with the parent structure is 1), and the 3-position of the naphth-1-yl is unsubstituted or substituted by -OH or -NH2, -OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、OCH2OC(O)OR 8asubstituted, and at least one of the 7 and 8 positions of the naphthyl group is substituted (for example, both the 7 and 8 positions of the naphthyl group are substituted, the 7 position of the naphthyl group is substituted, or the 8 position of the naphthyl group is substituted), the substituents being independently selected from halogen, C 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-6 Alkyl, C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, optionally substituted by halogen, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 Alkyl-; preferably the substituents are independently selected from F, Cl, methyl, ethyl, isopropyl, trifluoromethyl, ethynyl, -P(=O)(CH3)2 and cyclopropyl.

[0033] In some embodiments, R in the compounds of formula (I) and (II) 3 for

[0034] in,

[0035] X is N or CR 8 , R 8 Preferably selected from hydrogen, fluorine, chlorine, hydroxyl, amino,

[0036] In some embodiments, the compound of formula (I) is

[0037] in:

[0038] for

[0039] LR 2 for

[0040] R 3 for

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

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

[0043] in:

[0044] for

[0045] R 7 is hydrogen, fluorine, chlorine, trifluoroethoxymethyl or cyclopropyloxy, and the remaining variables are as defined for formula (I).

[0046] In some embodiments of Formula (I-1-1), for

[0047] In some embodiments of Formula (I-1-1), LR 2 L is -O-, and R 2 is a tetrahydro-1H-pyrrolizinyl group (e.g., a tetrahydro-1H-pyrrolizin-7-yl group Preferably (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl), wherein R 2 is unsubstituted or substituted by halogen, C 1- 6-alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d In some embodiments of formula (I-1-1), LR 2 for

[0048] In some embodiments of Formula (I-1-1), R 3 for It is optionally substituted by 1 to 3 substituents R 8 Replacement, R 8 are independently selected from: halogen, C optionally substituted by halogen1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、-OCH2OC(O)OR 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, optionally substituted by halogen, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 alkyl-.

[0049] In some embodiments of Formula (I-1-1), R 3 for

[0050] where R 8 Selected from hydrogen, fluorine, chlorine, hydroxyl, amino,

[0051] In some embodiments, the compound of formula (I) is represented by formula (I-2), (I-3), (I-4), (I-5) and (I-6):

[0052] in:

[0053] for

[0054] LR 2 for

[0055] R 6 is hydrogen, fluorine, chlorine or cyano, and the remaining variables are as defined for formula (I).

[0056] In some embodiments, the compound of formula (I) is as follows (I-2-1):

[0057] in,

[0058] for

[0059] L is -O-, and R 2 is a tetrahydro-1H-pyrrolizinyl group (e.g., a tetrahydro-1H-pyrrolizin-7-yl group Preferably (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl), wherein R 2 is unsubstituted or substituted by halogen, C 1-6 Alkyl, -OR 2a and-(CR 2a R 2b ) m -OC(O)NR 2c R 2d One or more substitutions in ;

[0060] R 6 is hydrogen, fluorine, chlorine or cyano,

[0061] R 7 is hydrogen, fluorine, chlorine, trifluoroethoxymethyl or cyclopropyloxy;

[0062] R 3 for It is optionally substituted by 1 to 3 substituents R 8 Replacement, R 8 are independently selected from: halogen, C optionally substituted by halogen 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、-OCH2OC(O)OR 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, optionally substituted by halogen, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 alkyl-.

[0063] In some embodiments of Formula (I-2-1), R 3 for

[0064] where R 8 Selected from hydrogen, fluorine, chlorine, hydroxyl, amino,

[0065] In some embodiments, Q in the compound of formula (I) 2 and Q 3 The substituents are connected to form a saturated or partially saturated 5-6 membered aliphatic ring or aromatic heterocycle, as shown in formulas (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17) and (I-18):

[0066] in:

[0067] for

[0068] LR 2 Preferably

[0069] The remaining variables are as defined for formula (I).

[0070] In some embodiments, the compound of formula (II) is as shown in formula (II-1):

[0071] in:

[0072] for

[0073] LR 2 for

[0074] R 3 for

[0075] The remaining variables are as defined for formula (II).

[0076] In some embodiments, the compound of formula (II) is as shown in formula (II-1-1):

[0077] in:

[0078] R 3 for

[0079] The remaining variables are as defined for formula (II).

[0080] In some embodiments, the compounds of formula (I) and (II) are

[0081] The present invention relates to pharmaceutical compositions of compounds of formula (I) and (II) or pharmaceutically acceptable salts, prodrugs and solvates thereof.

[0082] Another aspect of the present invention provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with G12KRAS, HRAS, or NRAS mutations (e.g., cancer). Cancers mediated by G12S mutations include pancreatic cancer, lung cancer, colorectal cancer, and the like.

[0083] The compounds of formula (I) and (II) of the present invention have good physicochemical properties and safety and toxicity parameters, and can be used for treating cancer and inflammation in mammals.

[0084] In other embodiments, a method of inhibiting proliferation of a cell population is provided, comprising contacting the cell population with any one of the compounds of structures (I) and (II).

[0085] 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.

[0086] 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

[0087] Unless otherwise indicated, the following definitions are used throughout the disclosure of this invention:

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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 formulae (I) and (II), both as the pure optical isomers and, if appropriate, as mixtures of isomers in varying ratios.

[0092] 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.

[0093] 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. 1-6Examples 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.

[0094] The term "halogen" herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0095] 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.

[0096] 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.

[0097] 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 2-6 Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0098] The term "alkoxy" herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl. Examples of alkoxy groups are C1-6 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.

[0099] 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 wherein 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.

[0100] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0101] a. 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0102] 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

[0103] 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.

[0104] 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.

[0105] The term "heteroaryl" herein refers to a group selected from:

[0106] 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;

[0107] 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

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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).

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] "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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] synthesis

[0124] 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.

[0125] 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.

[0126] Synthesis Example:

[0127] Synthesis of the intermediate 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0128] Step 1: Synthesis of 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene

[0129] Dissolve 1-bromo-3-chloro-2,4-difluorobenzene (5.0 g, 21.98 mmol) and furan (2.99 g, 43.97 mmol) in anhydrous toluene (50 mL). Under a nitrogen atmosphere, cool the reaction solution to -15°C. Then, add n-BuLi (10.6 mL, 26.38 mmol) dropwise. After the addition is complete, slowly warm the reaction mixture to room temperature and stir for 12 hours. After completion, quench the reaction with saturated ammonium chloride and extract with methyl tert-butyl ether. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield a brown oil, which is used directly in the next step (4.3 g, yield: 100%).

[0130] Step 2: Synthesis of 8-chloro-7-fluoronaphthalen-1-ol

[0131] The crude product 8-chloro-7-fluoronaphthalene-1-ol (5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene, 4.3 g, 21.98 mmol) obtained in the previous step was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (8 mL). The mixture was heated to 80°C and stirred for 4 hours. After completion, the reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield a brown oil. The oil was refrigerated for 24 hours to precipitate a solid. The solid was diluted with petroleum ether, filtered, washed with petroleum ether, and dried to yield an off-white solid (1.3 g, yield: 30%). 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.75(dd,J=9.1,5.6Hz,1H),7.44–7.34(m,2H),7.30(d,J=8.7Hz,1H),7.08(d,J=7.1Hz,1H).

[0132] Step 3: Synthesis of 8-chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate

[0133] Dissolve 8-chloro-7-fluoronaphthalen-1-ol (1.0 g, 5.08 mmol) in anhydrous dichloromethane (10 mL). Add DIEA (3.94 g, 30.51 mmol) and molecular sieves (1 g). Stir at room temperature for 10 minutes, then cool to -40°C. Add trifluoromethanesulfonic anhydride (1.86 g, 6.61 mmol) dropwise to the reaction mixture. Stir for 20 minutes, quench with water, extract with dichloromethane, and wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain a yellow solid (1.65 g, yield: 98.8%). 1H NMR (400MHz, CDCl3) δ7.90(d,J=8.1Hz,1H),7.84(dd,J=9.0,5.4Hz,1H),7.59(d,J=7.7Hz,1H),7.51(s,1H),7.44(s,1H).

[0134] Step 4: Synthesis of 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0135] 8-Chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (1.65 g, 5.02 mmol) and pinacol borate (2.53 g, 10.04 mmol) were dissolved in anhydrous DMF (20 mL). Potassium acetate (2.44 g, 24.85 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred under a nitrogen atmosphere for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford an off-white solid (1.25 g, yield: 82%). 1 H NMR (400MHz, CDCl3) δ7.83(t,J=10.4Hz,1H),7.75(dd,J=9.0,5.5Hz,1H),7.70(d,J=6.8Hz,1H),7.50–7.44(m,1H),7.32(t,J=8.7Hz,1H),1.45(s,12H).

[0136] Synthesis of the intermediate 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborolane

[0137] 5-Bromo-1,2,3,4-tetrahydronaphthalene (5.00 g, 23.69 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (12.03 g, 47.37 mmol) were dissolved in anhydrous 1,4-dioxane (50 mL). Potassium acetate (6.97 g, 71.07 mmol) and Pd(dppf)Cl2 (1.73 g, 2.37 mmol) were added. The atmosphere was replaced with nitrogen and the mixture was heated to 100°C with stirring for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a light yellow oil (5.0 g, yield: 82%). 1H NMR (400MHz, CDCl3) δ7.58(d,J=6.9Hz,1H),7.11(s,1H),7.08(d,J=7.3Hz,1H),3.0 3(t,J=5.9Hz,2H),2.77(t,J=5.8Hz,2H),1.78(dd,J=7.1,4.3Hz,4H),1.34(s,12H).

[0138] Synthesis of the intermediate 4-(benzyloxy)-5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0139] Step 1: Synthesis of 2,6-dichloro-3-fluoropyridin-4-amine

[0140] Dissolve 2,6-dichloropyridin-4-amine (5 g, 30.5 mmol) in MeOH / H₂O (50 mL / 10 mL), add selectfluor (11.3 g, 33.5 mmol), and stir at 50°C for 24 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid (2.5 g, yield: 45%).

[0141] Step 2: Synthesis of 3-fluoro-4-[di(tert-butoxycarbonyl)amino]-2,6-dichloropyridine

[0142] Dissolve 2,6-dichloro-3-fluoropyridin-4-amine (2.5 g, 13.8 mmol) in anhydrous THF (25 mL). Add Boc2O (7.53 g, 34.5 mmol) and DMAP (84 mg, 0.7 mmol). Stir and react at 60°C for 12 hours. After completion, concentrate and purify with methanol to obtain a white solid (5.1 g, 97% yield).

[0143] Step 3: Synthesis of tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0144] Dissolve 3-fluoro-4-[di(tert-butoxycarbonyl)amino]-2,6-dichloropyridine (5.1 g, 13.6 mmol) in anhydrous THF (20 mL) and add to a 2M solution of LDA (20.5 mL, 40.9 mmol) in THF (80 mL) at -70°C. Stir the mixture at -70°C for 2 hours. After completion, quench the reaction by pouring it into saturated aqueous ammonium chloride and extracting it with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product (5.2 g, 100%), which is used directly in the next step.

[0145] Step 4: Synthesis of 4-amino-2,6-dichloro-5-fluoronicotinic acid

[0146] Dissolve tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (5.2 g, 13.6 mmol) in 1,4-dioxane (42 mL). Add concentrated hydrochloric acid (13 mL) and stir at room temperature for 18 hours. After completion of the reaction, concentrate the product to obtain a crude product (3 g, 100% yield) that was used directly in the next step.

[0147] Step 5: Synthesis of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one

[0148] Dissolve 4-amino-2,6-dichloro-5-fluoronicotinic acid (3 g, 13.6 mmol) in SOCl₂ (30 mL) and stir at 50°C for 3 hours. After completion, concentrate the solution, dilute with acetone (10 mL), and add it to a solution of NH₄SCN (3.1 g, 40.8 mmol) in acetone (40 mL). Stir at room temperature for 1 hour. After completion, dilute the reaction solution with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product (3.6 g, 100% yield), which is used directly in the next step.

[0149] Step 6: Synthesis of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0150] Dissolve 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (3.6 g, 13.6 mmol) in methanol (272 mL). Add NaOH solution (272 mL, 27.2 mmol, 0.1 M) and MeI (3.9 g, 27.2 mmol). Stir and react at room temperature for 1 hour. After completion, concentrate, dilute with water, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford a yellow solid (1.7 g, 45% yield).

[0151] Step 7: Synthesis of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0152] Dissolve 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (500 mg, 1.79 mmol) in phosphorus oxychloride (50 mL). Add N,N-diethylaniline (400 mg, 2.68 mmol) and heat to 90°C for 12 hours. After completion, cool to room temperature, concentrate to remove excess phosphorus oxychloride, and separate by column chromatography to obtain an off-white solid (500 mg, yield: 93%). MS m / z: 298 [M+H] + .

[0153] Step 8: Synthesis of 4-(benzyloxy)-5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0154] Compound 60% NaH (81 mg, 2.01 mmol) was dissolved in anhydrous THF (10 mL). Benzyl alcohol (218 mg, 2.01 mmol) was added under ice-water cooling and the mixture was stirred for 30 minutes under ice-water cooling. A solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500 mg, 1.67 mmol) in THF (1 mL) was added dropwise and the mixture was stirred at 0°C for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid (580 mg, yield: 93%). MS m / z: 371 [M+H] + .

[0155] Synthesis of intermediate 10-(benzyloxy)-5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidine:

[0156] Step 1: Synthesis of 7-chloro-8-fluoro-5-(2-hydroxyethyl)amino-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0157] The compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (200 mg, 0.71 mmol) and 2-aminoethane-1-ol (66 mg, 1.07 mmol) were dissolved in DMA (10 mL). Cesium carbonate (698 mg, 2.14 mmol) was added and the mixture was heated to 100°C with stirring for 48 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (160 mg, yield: 73.5%), which was used directly in the next step. 1HNMR (400MHz, DMSO) δ13.11(s,1H),8.68(t,J=5.0Hz,1H),4.83(s,1H),3.57(s,2H),3.46(t,J=5.4Hz,2H),2.57(s,3H).MS m / z:305.6[M+H] +

[0158] Step 2: Synthesis of 7-chloro-5-((2-chloroethyl)amino)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0159] The compound 7-chloro-8-fluoro-5-(2-hydroxyethyl)amino-2-methylthiopyrido[4,3-d]pyrimidin-4-ol (160 mg, 0.53 mmol) was dissolved in chloroform (6 mL). Thionyl chloride (2 mL) was then added and stirred at 70°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to remove excess thionyl chloride. The resulting residue was diluted with saturated sodium bicarbonate aqueous solution and filtered to collect the solid. The solid was washed with water and dried in vacuo to afford an off-white solid (130 mg, yield: 86.3%). 1 HNMR (400MHz, DMSO) δ9.76 (s, 1H), 4.59 (t, J = 9.6Hz, 2H), 4.01 (t, J = 9.8Hz, 2H), 2.61 (s, 3H).

[0160] Step 3: Synthesis of 5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidin-10-ol

[0161] Dissolve 7-chloro-5-((2-chloroethyl)amino)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (130 mg, 0.402 mmol) in DMF (3 mL), then add DIEA (130 mg, 1.0 mmol) and stir at room temperature for 30 minutes. After completion, dilute the reaction solution with water, adjust the pH to 3-4 with 1M hydrochloric acid, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield a light yellow solid (90 mg, 78% yield). 1 HNMR (400MHz, DMSO) δ4.12 (t, J = 9.6 Hz, 2H), 3.82 (t, J = 9.8 Hz, 2H), 2.36 (s, 3H).

[0162] Step 4: Synthesis of 5-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidin-10-ol:

[0163] The compound 5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidin-10-ol (50 mg, 0.17 mmol), 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 0.35 mmol), sodium carbonate (74 mg, 0.70 mmol), and tetrakistriphenylphosphine palladium (31 mg, 0.026 mmol) were dissolved in 1,4-dioxane / water (5 / 1) (5 mL) and microwave-heated at 125°C for 1 hour under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and the insoluble material was removed by filtration. Preparative TLC (DCM / MeOH = 15 / 1) was used to separate the resulting off-white solid (45 mg, yield: 60%). MS m / z:431[M+H] + .

[0164] Synthesis of the intermediate 10-(benzyloxy)-5-chloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine

[0165] Step 1: Synthesis of 7-chloro-8-fluoro-5-((4-methoxybenzyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0166] Dissolve 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1 g, 3.6 mmol), PMBNH2 (1.5 g, 10.7 mmol), and Cs2CO3 (3.5 g, 10.7 mmol) in DMA (5 mL) and heat to 100°C with stirring for 24 hours. After completion, cool to room temperature, dilute the reaction solution with water, and extract with ethyl acetate. The organic phase is washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield a yellow solid (1.1 g, yield: 81%).

[0167] Step 2: Synthesis of 4,7-dichloro-8-fluoro-N-(4-methoxybenzyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine

[0168] Dissolve 7-chloro-8-fluoro-5-((4-methoxybenzyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.1 g, 2.9 mmol) in 9 ml of POCl₃. Add approximately 1 ml of N,N-diethylaniline at room temperature. Heat the reaction system to 110°C and stir overnight. After the reaction, remove the solvent under reduced pressure to obtain a crude product, which is used directly in the next step (1.2 g, 100% yield).

[0169] Step 3: Synthesis of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine

[0170] The compound 4,7-dichloro-8-fluoro-N-(4-methoxybenzyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine (1.2 g, 2.9 mmol) was dissolved in TFA (10 mL) and stirred at room temperature for 5 hours. After completion, the reaction was concentrated and extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was used directly in the next step (805 mg, yield: 100%).

[0171] Step 4: Synthesis of 5,10-dichloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine

[0172] Dissolve 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine (805 mg, 2.9 mmol) in isopropanol (10 mL) and hydrobromic acid (1 mL). Add 2-chloroacetaldehyde dimethyl acetal (470 mg, 3.77 mmol) and stir at 90°C for 3 hours. After completion, cool to room temperature and concentrate. Extract with DCM and saturated sodium bicarbonate. The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield a yellow solid (610 mg, 70% yield).

[0173] Step 5: Synthesis of 10-(benzyloxy)-5-chloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine

[0174] Compound 60% NaH (95 mg, 2.38 mmol) was dissolved in anhydrous THF (10 mL). Benzyl alcohol (257 mg, 2.38 mmol) was added under ice-water cooling and the mixture was stirred for 30 minutes under ice-water cooling. A solution of 5,10-dichloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine (600 mg, 1.98 mmol) in THF (1 mL) was added dropwise and the mixture was stirred at 0°C for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid (620 mg, yield: 83%). MS m / z: 375 [M+H] + .

[0175] Synthesis of intermediate 1-(benzyloxy)-6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazoline:

[0176] Step 1: Synthesis of compound 4-bromo-5-fluoro-2,3-dihydro-1H-indene

[0177] Dissolve 7-bromo-6-fluoro-2,3-dihydroindanone (4.58 g, 20 mmol) in 100 ml of TFA. Add SiHEt3 (8.4 ml, 50 mmol) at room temperature and stir overnight. After the reaction, remove the solvent under reduced pressure to afford the crude product. Spectroscopic analysis (eluent: petroleum ether / EA 10 / 1) yields a colorless oily liquid (4.1 g, yield: 95%). MS m / z: 215 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ7.14 (m, 1H), 6.80 (t, 1H, J = 1.3Hz), 2.85-2.80 (m, 4H), 2.02-1.92 (m, 2H).

[0178] Step 2: Synthesis of compound 4-bromo-5-fluoro-6-nitro-2,3-dihydro-1H-indene

[0179] Dissolve 4-bromo-5-fluoro-2,3-dihydro-1H-indene (4.1 g, 19 mmol) in 40 ml of concentrated sulfuric acid. Slowly add KNO3 (2.3 g, 22.8 mmol) in an ice-water bath and continue stirring for half an hour. After the reaction is complete, slowly pour the reaction system onto ice. A large amount of solid precipitates. Dissolve the solid in 200 ml of EA and extract the liquid. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain the crude product. The crude product is separated by column chromatography to obtain an off-white solid (3.9 g, yield: 79%). MS m / z: 260 [M+H] + .MS m / z:215[M+H] + . 1 H NMR (400MHz, DMSO-D6) δ7.61(m,1H),2.85-2.80(m,4H),2.02-1.92(m,2H).

[0180] Step 3: Synthesis of compound 7-bromo-6-fluoro-2,3-dihydroindan-5-amine

[0181] The compound 4-bromo-5-fluoro-6-nitro-2,3-dihydro-1H-indene (3.9 g, 15 mmol) was dissolved in 50 ml of glacial acetic acid. Fe powder (1.85 g, 33 mmol) was added at room temperature, and the reaction system was stirred overnight under argon. After the reaction, the reaction system was neutralized with saturated sodium bicarbonate solution and extracted with 500 ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product as a pale yellow solid (2.3 g, yield: 67%). The pale yellow solid was used directly in the next reaction without any further treatment. MS m / z: 230 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ6.33(m,1H),5.32(m,4H)2.85-2.80(m,4H),2.02-1.92(m,2H).

[0182] Step 4: Synthesis of compound 7-bromo-6-fluoro-4-iodo-2,3-dihydroindan-5-amine

[0183] The compound 7-bromo-6-fluoro-2,3-dihydroindan-5-amine (2.3 g, 10 mmol) was dissolved in 20 ml of DMF. NIS (2.7 g, 12 mmol) was added at room temperature. The reaction system was heated to 70°C and stirred overnight. After the reaction was complete, the DMF was removed from the reaction system using an oil pump under reduced pressure. 200 ml of ethyl acetate was then added to dissolve the crude product. The organic phase was washed three times with 100 ml of water and then 100 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain a yellow solid (2.1 g, yield: 60%). MS m / z: 355 [M+H] + .

[0184] Step 5: Synthesis of 5-amino-7-bromo-6-fluoro-2,3-dihydroindane-4-carbonitrile

[0185] The compound 7-bromo-6-fluoro-4-iodo-2,3-dihydroindan-5-amine (2.1 g, 6 mmol), dicyanozinc (914 mg, 7.8 mmol), and 4A molecular sieves (100 mg) were dissolved in 10 ml of DMF. After purging with argon, tetrakistriphenylphosphine palladium (693 mg, 0.6 mmol) was added as a catalyst. After further purging with argon, the reaction system was heated to 100°C and stirred overnight. After completion of the reaction, the solvent was removed from the reaction system under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain an off-yellow solid (581 mg, yield: 38%). MS m / z: 255 [M+H] + .

[0186] Step 6: Synthesis of compound 5-amino-7-bromo-6-fluoro-2,3-dihydro-4-carboxamide

[0187] The compound 5-amino-7-bromo-6-fluoro-2,3-dihydroindane-4-carbonitrile (581 mg, 2.28 mmol) was dissolved in 10 ml of tert-butanol. Potassium tert-butoxide (1.3 g, 11.4 mmol) was added at room temperature, and the reaction system was heated to 70°C and stirred overnight. After completion of the reaction, the solvent was removed from the reaction system under reduced pressure, 50 ml of DCM was added for dissolution, and the separated liquid was washed with 30 ml of water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to produce a white solid (546 mg, yield: 88%). MS m / z: 273 [M+H] + .

[0188] Step 7: Synthesis of 6-bromo-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline-1,3-diol

[0189] Dissolve 5-amino-7-bromo-6-fluoro-2,3-dihydro-4-carboxamide (546 mg, 2 mmol), CDI (1.3 g, 8 mmol), and potassium carbonate (1.1 g, 8 mmol) in 10 ml of DMF. Heat the reaction system to 80°C and stir overnight. After the reaction, add 100 ml of saturated sodium chloride solution and extract with 500 ml of EA. The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a crude product as a white solid. This crude product is used directly in the next reaction without further treatment.

[0190] Step 8: Synthesis of 6-bromo-1,3-dichloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline

[0191] The compound 6-bromo-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline-1,3-diol obtained in the previous step was directly dissolved in phosphorus oxychloride (10 ml). N,N-diethylaniline (1 ml) was added at room temperature. The reaction system was heated under reflux with stirring overnight. After the reaction, the phosphorus oxychloride solvent was removed from the reaction system under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (eluent: DCM) to obtain a yellow solid (510 mg, yield: 76%). MS m / z: 336 [M+H] + .

[0192] Step 9: Synthesis of 1-(benzyloxy)-6-bromo-3-chloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline

[0193] Dissolve NaH (72 mg, 1.79 mmol) in anhydrous THF (10 mL). Add benzyl alcohol (194 mg, 1.79 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. Add dropwise a solution of 6-bromo-1,3-dichloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline (500 mg, 1.49 mmol) in THF (1 mL). Stir and react at 0°C for 1 hour. After completion, quench the reaction with saturated ammonium chloride solution. Extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to yield a white solid (520 mg, yield: 85.7%).

[0194] Step 10: Synthesis of 1-(benzyloxy)-6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazoline

[0195] The compound 1-(benzyloxy)-6-bromo-3-chloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline (0.5 g, 1.23 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.29 g, 1.84 mmol), and cesium carbonate (1.0 g, 3.07 mmol) were dissolved in 1,4-dioxane (8 mL) and heated to 60°C with stirring for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid (0.45 g, yield: 69%).

[0196] Synthesis of the intermediate 9-(benzyloxy)-4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolano[4,5-f]quinazoline

[0197] Step 1: Synthesis of 4-bromo-5-fluorobenzo[d][1,3]dioxazole

[0198] Dissolve 3-bromo-4-fluorobenzene-1,2-diol (1.0 g, 4.83 mmol) in DMA (20 mL), then add cesium carbonate (3.96 g, 12.08 mmol) and diiodomethane (1.42 g, 5.31 mmol). Heat to 60°C and stir for 12 hours. After completion, cool to room temperature, dilute with water, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain an off-white solid (0.82 g, yield: 77.5%).

[0199] Step 2: Synthesis of 4-bromo-5-fluoro-6-nitrobenzo[d][1,3]dioxazole

[0200] Dissolve 4-bromo-5-fluorobenzo[d][1,3]dioxazole (0.82 g, 3.74 mmol) in glacial acetic acid (10 mL). Add potassium nitrate (378 mg, 3.74 mmol) while cooling in an ice-water bath. Continue stirring at the same temperature for 1 hour. After the reaction is complete, pour the reaction solution into ice water and extract with ethyl acetate. The organic phase is washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a light yellow solid (0.8 g, yield: 81%).

[0201] Step 3: Synthesis of 7-bromo-6-fluorobenzo[d][1,3]dioxol-5-amine

[0202] 4-Bromo-5-fluoro-6-nitrobenz[d][1,3]dioxazole (0.8 g, 3.03 mmol) was dissolved in 50 ml of glacial acetic acid. Fe powder (0.38 g, 6.67 mmol) was added at room temperature, and the reaction system was stirred overnight under argon. After completion of the reaction, the system was neutralized with saturated sodium bicarbonate solution and extracted with 50 ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product as a pale yellow solid (0.6 g, yield: 84.6%). The pale yellow solid was used directly in the next reaction without further treatment.

[0203] Step 4: 7-Bromo-6-fluorobenzo[d][1,3]dioxole-5-[di(tert-butoxycarbonyl)]amine

[0204] 7-Bromo-6-fluorobenzo[d][1,3]dioxol-5-amine (0.6 g, 2.56 mmol) was dissolved in anhydrous THF (10 mL). Boc2O (1.4 g, 6.41 mmol) and DMAP (16 mg, 0.13 mmol) were added and stirred at 60°C for 12 hours. After completion, the reaction was concentrated and purified by methanol slurry to obtain a white solid (1.0 g, yield: 89.8%).

[0205] Step 5: Synthesis of tert-butyl 7-bromo-5-(tert-butoxycarbonyl)amino)-6-fluorobenzo[d][1,3]dioxazole-4-carboxylate

[0206] Dissolve 7-bromo-6-fluorobenzo[d][1,3]dioxole-5-[di(tert-butoxycarbonyl)]amine (1.0 g, 2.3 mmol) in anhydrous THF (10 mL) and add to a 2M solution of LDA (2.3 mL, 4.6 mmol) in THF (20 mL) at -70°C. Stir the mixture at -70°C for 2 hours. After completion, quench the reaction by pouring it into saturated aqueous ammonium chloride and extracting it with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product, which is used directly in the next step (1 g, yield: 100%).

[0207] Step 6: Synthesis of 5-amino-7-bromo-6-fluorobenzo[d][1,3]dioxazole-4-carboxylic acid

[0208] Dissolve tert-butyl 7-bromo-5-(tert-butoxycarbonyl)amino)-6-fluorobenzo[d][1,3]dioxazole-4-carboxylate (1 g, 2.3 mmol) in dichloromethane (15 ml). Add trifluoroacetic acid (5 mL) and stir at room temperature for 3 hours. After completion of the reaction, concentrate the reaction mixture to obtain the crude product, which is used directly in the next step.

[0209] Step 7: Synthesis of 4-bromo-5-fluoro-7-mercapto-[1,3]dioxolo[4,5-f]quinazolin-9(8H)-one

[0210] Dissolve 5-amino-7-bromo-6-fluorobenzo[d][1,3]dioxazole-4-carboxylic acid (0.64 g, 2.30 mmol) in SOCl2 (5 mL) and stir at 50°C for 3 hours. After completion, concentrate the solution, dilute with acetone (10 mL), and add it to a solution of NH4SCN (0.53 g, 6.91 mmol) in acetone (10 mL). Stir at room temperature for 1 hour. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product (0.5 g, 68% yield). This was used directly in the next step.

[0211] Step 8: Synthesis of 4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazolin-9(8H)-one

[0212] Dissolve 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (0.5 g, 1.57 mmol) in anhydrous methanol (10 mL). Add 40% sodium methoxide in methanol (1 mL) and MeI (245 mg, 1.72 mmol). Stir and react at room temperature for 1 hour. After completion, concentrate, dilute 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 afford a yellow solid (0.5 g, 95% yield).

[0213] Step 9: Synthesis of 4-bromo-9-chloro-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazoline

[0214] The compound 4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazolin-9(8H)-one was dissolved in phosphorus oxychloride (10 ml). N,N-diethylaniline (1 ml) was added at room temperature. The reaction system was heated under reflux with stirring overnight. After the reaction, the phosphorus oxychloride solvent was removed from the reaction system under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (eluent: DCM) to obtain a yellow solid (510 mg, yield: 96%). MS m / z: 351 [M+H] + .

[0215] Step 10: Synthesis of 9-(benzyloxy)-4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazoline

[0216] Compound NaH (86 mg, 2.13 mmol) was dissolved in anhydrous THF (10 mL). Benzyl alcohol (231 mg, 2.13 mmol) was added under ice-water cooling and the mixture was stirred for 30 minutes. A solution of 4-bromo-9-chloro-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazoline (0.5 g, 1.42 mmol) in THF (1 mL) was added dropwise and the mixture was stirred at 0°C for 1 hour. After completion, the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford a white solid (0.52 g, yield: 86%).

[0217] Step 11: Synthesis of 9-(benzyloxy)-4-bromo-5-fluoro-7-(methylsulfinyl)-[1,3]dioxolano[4,5-f]quinazoline

[0218] Dissolve 9-(benzyloxy)-4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazoline (500 mg, 1.18 mmol) in dichloromethane (10 mL). Add m-chloroperbenzoic acid (360 mg, 1.77 mol) under ice-water cooling. Stir and react for 1 hour under ice-water cooling. After completion, quench the reaction with saturated sodium thiosulfate solution and extract with dichloromethane. The organic phase is washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product, which is used directly in the next step (519 mg, 100% yield).

[0219] Step 12: Synthesis of 9-(benzyloxy)-4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolano[4,5-f]quinazoline

[0220] Dissolve 9-(benzyloxy)-4-bromo-5-fluoro-7-(methylsulfinyl)-[1,3]dioxolano[4,5-f]quinazoline (500 mg, 1.14 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (236 mg, 1.48 mmol) in anhydrous THF (5 mL). Add sodium tert-butoxide (143 mg, 1.48 mmol) under ice-water cooling. Stir at room temperature for 2 hours. After completion, quench the reaction with ice water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford an off-white solid (350 mg, 57% yield).

[0221] Synthesis Example:

[0222] Example 1: Synthesis of (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0223] Step 1: Synthesis of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine

[0224] Dissolve NaH (594 mg, 14.9 mmol) in anhydrous THF (10 mL). Add benzyl alcohol (1.6 g, 14.9 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. Add dropwise a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 9.9 mmol) in THF (1 mL). Stir and react at 0°C for 1 hour. After completion, quench the reaction with saturated ammonium chloride solution. Extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain a white solid (2.9 g, 90% yield).

[0225] Step 2: Synthesis of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0226] 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 dissolved in 1,4-dioxane (15 mL) and heated to 60°C with stirring for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid (2.6 g, yield: 75%).

[0227] Step 3: Synthesis of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidine

[0228] The compound 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (1.2 g, 2.7 mmol), 4,4,5,5-tetramethyl-2-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborolane (1.1 g, 4.0 mmol) and potassium phosphate (1.7 g, 8.1 mmol, 1.5 M) were dissolved in toluene\water = 1\1 (11 ml), and then RuPhos Pd G3 (450 mg, 0.54 mmol) was added. The nitrogen atmosphere was replaced three times and the mixture was heated to 60°C under a nitrogen atmosphere with stirring for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid (1.1 g, yield: 74%).

[0229] Step 4: Synthesis of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol

[0230] The compound 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidine (1.1 g, 2.7 mmol) and Pd / C (0.2 g, 10% wt) were dissolved in methanol (25 ml) and reacted under a hydrogen atmosphere (15 psi) for 3 hours. After completion of the reaction, the mixture was filtered and concentrated to yield a yellow solid (0.5 g, 54% yield).

[0231] Step 5: Synthesis of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate

[0232] 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.43 mmol) and TEA (130 mg, 1.3 mmol) were dissolved in anhydrous DCM (5 mL). TfO (1.6 g, 14.9 mmol) was added under ice-water cooling, and the mixture was stirred under ice-water cooling for 1 hour. After completion of the reaction, the crude product was concentrated to obtain a product that was used directly in the next step (257 mg, 100% yield).

[0233] Step 6: Synthesis of (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0234] The compound 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (257 mg, 0.43 mmol) and TEA (130 mg, 1.3 mmol) were dissolved in DMF (5 mL), and (1R,6R)-8-oxa-3-azabicyclo[4.2.0]octan-7-one trifluoroacetate (207 mg, 0.86 mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a yellow solid. (96 mg, yield: 39%, [M+H] + =576.2).

[0235] Example 2-64 was prepared by the method of Example 1

[0236] Example 65: Synthesis of (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0237] Following the synthesis of Example 1, 2,4,7-trichloropyrido[4,3-d]pyrimidine was used as the starting material to obtain a white solid. (32 mg, [M+H] + =558.2).

[0238] Examples 66-67 were prepared using the method of Example 65.

[0239] Example 68: Synthesis of (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one

[0240] Step 1: Synthesis of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine

[0241] Dissolve NaH (594 mg, 14.9 mmol) in anhydrous THF (10 mL). Add benzyl alcohol (1.6 g, 14.9 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. Add dropwise a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 9.9 mmol) in THF (1 mL). Stir and react at 0°C for 1 hour. After completion, quench the reaction with saturated ammonium chloride solution. Extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain a white solid (2.9 g, 90% yield).

[0242] Step 2: Synthesis of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0243] 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 dissolved in 1,4-dioxane (15 mL) and heated to 60°C with stirring for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid (2.6 g, yield: 75%).

[0244] Step 3: Synthesis of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidine

[0245] The compound 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (1.2 g, 2.7 mmol), 4,4,5,5-tetramethyl-2-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborolane (1.1 g, 4.0 mmol) and potassium phosphate (1.7 g, 8.1 mmol, 1.5 M) were dissolved in toluene\water = 1\1 (11 ml), and then RuPhos Pd G3 (450 mg, 0.54 mmol) was added. The nitrogen atmosphere was replaced three times and the mixture was heated to 60°C under a nitrogen atmosphere with stirring for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid (1.1 g, yield: 74%).

[0246] Step 4: Synthesis of 4-(benzyloxy)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine

[0247] Under a nitrogen atmosphere, sodium hydride (140 mg, 60% purity in mineral oil, 3.6 mmol, 1.2 equiv) was added to a solution of trifluoroethanol (450 mg, 4.5 mmol, 1.5 equiv) in DMF (50 mL) at 0°C. The reaction was stirred for half an hour, followed by the addition of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidine (1.67 g, 3 mmol, 1 equiv). The reaction was slowly warmed to room temperature and stirred for 10 hours. The reaction was then quenched with ammonium chloride solution. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over sodium sulfate. The crude product was then evaporated under reduced pressure. The residue was then separated by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain a brown product (0.6 g, 31% yield). LCMS [ESI, M+1]: 637.

[0248] Step 5: Synthesis of 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyridinyl[4,3-d]pyrimidin-4-ol

[0249] The compound 4-(benzyloxy)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.7 g, 2.7 mmol) and Pd / C (0.2 g, 10% wt) were dissolved in ethyl acetate (25 ml) and reacted under a hydrogen atmosphere (15 psi) for 12 hours. After completion of the reaction, the mixture was filtered and concentrated to afford a yellow solid (0.77 g, 54% yield).

[0250] Step 6: Synthesis of 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate

[0251] 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyridyl[4,3-d]pyrimidin-4-ol (235 mg, 0.43 mmol) and TEA (130 mg, 1.3 mmol) were dissolved in anhydrous DCM (5 mL). Tf2O (1.6 g, 14.9 mmol) was added under ice-water cooling, and the mixture was stirred under ice-water cooling for 1 hour. After completion of the reaction, the crude product was concentrated to obtain a product that was used directly in the next step (292 mg, 100% yield).

[0252] Step 7: Synthesis of (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one

[0253] Compound 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (292 mg, 0.43 mmol) and TEA (130 mg, 1.3 mmol) were dissolved in DMF (5 mL), and (1R,6R)-8-oxa-3-azabicyclo[4.2.0]octan-7-one trifluoroacetate (207 mg, 0.86 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a yellow solid. (109 mg, yield: 39%, [M+H] + =656.3).

[0254] Examples 69-78 were prepared using the method of Example 68.

[0255] Example 79: Synthesis of (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[3,2-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0256] Following the synthesis of Example 1, 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine was used as the starting material to obtain a white solid. (26 mg, [M+H] + =558.2).

[0257] Examples 80-81 were prepared using the method of Example 79.

[0258] Example 82: Synthesis of (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0259] Following the synthesis of Example 1, 2,4,7-trichloropyrido[2,3-d]pyrimidine was used as the starting material to obtain a white solid. (27 mg, [M+H] + =558.2).

[0260] Examples 83-84 were prepared using the method of Example 82.

[0261] Example 85: Synthesis of (1R,6R)-3-(6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0262] Following the synthesis of Example 1, 7-bromo-2,4-dichloro-6-fluoroquinazoline was used as the starting material to obtain a white solid. (35 mg, [M+H] + =575.2).

[0263] Examples 86-87 were prepared using the method of Example 85.

[0264] Example 88: Synthesis of (1R,6R)-3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0265] Following the synthesis of Example 1, 7-bromo-2,4-dichloro-6,8-difluoroquinazoline was used as the starting material to obtain a white solid. (30 mg, [M+H] + =593.2).

[0266] The method of Example 88 was used to prepare the compounds of Examples 89-144.

[0267] Example 145: Synthesis of (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0268] Following the synthesis of Example 1, 7-bromo-2,4-dichloroquinazoline was used as the starting material to obtain a white solid. (25 mg, [M+H] + =557.2).

[0269] Examples 146-152 were prepared using the method of Example 145.

[0270] Example 153: Synthesis of (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0271] Following the synthesis of Example 1, 7-bromo-2,4-dichloro-8-fluoroquinazoline was used as the starting material to obtain a white solid. (41 mg, [M+H] + =575.2).

[0272] The method of Example 153 was used to prepare Examples 154-214

[0273] Example 215: Synthesis of (1R,6R)-3-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0274] Following the synthesis of Example 1, 7-bromo-2,4,6-trichloro-8-fluoroquinazoline was used as the starting material to obtain a white solid. (35 mg, [M+H] + =609.2).

[0275] Examples 216-246 were prepared using the method of Example 215.

[0276] Example 247: Synthesis of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4-((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octan-3-yl)-1,6-naphthyridine-3-carbonitrile

[0277] Step 1: Synthesis of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)-1,6-naphthalene-3-carbonitrile

[0278] To a solution of 2,2,2-trifluoroethanol (11.1 g, 111 mmol, 8.01 mL, 1.20 eq) in toluene (200 mL) at 0°C was added potassium tert-butoxide (26.7 g, 278 mmol, 3.00 eq). The mixture was initially stirred at 10°C for 0.5 h. This mixture was then added to a solution of 2,4,7-trichloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (25.5 g, 92.7 mmol, 1.00 eq) in toluene (200 mL) at -10°C. The mixture was stirred at -10°C to 25°C for 16 h. After monitoring, a mixed solution of potassium tert-butoxide (1.78 g, 18.5 mmol, 0.2 eq) and 2,2,2-trifluoroethanol (1.85 g, 18.5 mmol, 1.33 ml, 0.20 eq) in toluene (20.0 ml) was added at 0°C. The mixture was stirred at 25°C for 30 hours. Upon completion, the mixture was poured onto a silica gel column and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) followed by reverse-phase flash chromatography (water (0.1% formic acid)-acetonitrile) to give 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)-1,6-naphthalene-3-carbonitrile (14.9 g, 47.2% yield) as a yellow solid; LCMS [ESI, M+1]: 340.

[0279] Step 2: Synthesis of 7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrolazin-7a-ylmethoxy-4-(2,2,2-trifluoroethoxy)-1,6-naphthyridine-3-carbonitrile

[0280] A solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)-1,6-naphthalene-3-carbonitrile (21.5 g, 63.3 mmol, 1.00 eq) in 2-methyltetrahydrofuran (200 mL) was added to ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (20.1 g, 126 mmol, 2.00 eq), (15.0 g) and N-ethyl-N-isopropylpropane-2-amine (16.4 g, 126 mmol, 22.0 ml, 2.0 eq) in a 0-5°C 2-methyltetrahydrofuran (200 ml) solution. The mixture was stirred at 0-25°C for 2 hours. After completion, the mixture was filtered and washed with ethyl acetate (100 ml). The filtrate was washed with saturated NH4Cl aqueous solution (300 ml), the organic layer was separated and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure at 40°C. The crude product was ground with acetonitrile (20 ml) at 25°C for 15 minutes and filtered, and the filter cake was dried in vacuo at 40°C to give the title compound (15.4 g, 52.5% yield). Pale yellow solid

[0281] Step 3: Synthesis of 8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)-1,6-naphthyridine-3-carbonitrile

[0282] CataXium G4 Pd (2.3 g, 3.2 mmol, 0.1 eq) and potassium phosphate (20.3 g, 9.6 mmol, 3 eq) were added to a mixed solvent of water and dioxane (water, 100 mL; dioxane, 400 mL) of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)-1,6-naphthyridine-3-carbonitrile (14.8 g, 32.0 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxolane (8.7 g, 32.0 mmol, 1 eq). The reaction was stirred at 70°C under nitrogen for 16 hours. After completion, the filtrate was washed with saturated aqueous NH4Cl (300 mL). The organic layer was separated and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure at 40°C. The product was then purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to yield the yellow title compound (8.7 g, 47.3% yield).

[0283] Step 4: Synthesis of 8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4-(1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octan-3-yl)-1,6-naphthyridine-3-carbonitrile

[0284] Dry N,N-diisopropylethylamine (2.2 g, 30.0 mmol, 3 eq) was added to a solution of 8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4-(2,2,2-trifluoroethoxy)-1,6-naphthyridine-3-carbonitrile (5.7 g, 10 mmol, 1 eq) and (1R,6R)-8-oxo-3-azabicyclo[4.2.0]octan-7-one trifluoroacetate (3.4 g, 15 mmol, 1.5 eq) in DMF (50 mL). The mixture was stirred at 60°C for 5 hours. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. This was then separated by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to afford a brown product (1.8 g, 31% yield). LCMS [ESI, M+1]: 600.

[0285] Examples 248-253 were prepared using the method of Example 247.

[0286] Example 254: Synthesis of 8-fluoro-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4-((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octan-3-yl)quinoline-3-carbonitrile

[0287] Following the synthesis of Example 247, using 7-bromo-2,4-dichloro-8-fluoroquinoline-3-carbonitrile as the starting material, a pale yellow solid (239 mg) was obtained. LCMS [ESI, M+1]: 599.

[0288] Examples 255-266 were prepared using the method of Example 254.

[0289] Example 267: 6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4-((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octan-3-yl)quinoline-3-carbonitrile)

[0290] Following the synthesis of Example 247, using 7-bromo-2,4-dichloro-6,8-difluoroquinoline-3-carbonitrile as the starting material, a pale yellow solid (327 mg) was obtained. LCMS [ESI, M+1]: 617.

[0291] The method of Example 267 was used to prepare the compounds of Examples 268-279.

[0292] Example 280: Synthesis of (1R,6R)-3-(3,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,6-naphthyridin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one

[0293] Step 1: Synthesis of compound 4-acetylamino-6-chloro-5-fluoronicotinic acid:

[0294] Dissolve 4-amino-6-chloro-5-fluoronicotinic acid (1 g, 5.26 mmol) in acetic anhydride (10 mL). Heat the reaction system to 80°C for 5 hours. After completion, remove the organic solvent under reduced pressure to obtain an off-white solid (1.22 g, 100% yield).

[0295] Step 2: Synthesis of compound 4-acetylamino-6-chloro-5-fluorobenzoic acid methyl ester:

[0296] The compound 4-acetylamino-6-chloro-5-fluoronicotinic acid (1.22 g, 5.26 mmol), EDCI (1.2 g, 6.31 mmol), and DMAP (32 mg, 0.26 mmol) were dissolved in dichloromethane (30 mL). Methanol (1 mL) was added and the reaction system was stirred at room temperature for 10 hours. After completion, 20 mL of water was added to quench the reaction. 100 mL of dichloromethane was added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: EA / PET) to obtain a white solid (1.1 g, yield: 86%).

[0297] Step 3: Synthesis of compound 7-chloro-8-fluoro-1,6-naphthyridine-2,4(1H,3H)-dione

[0298] KHMDS (12.4 mL, 12.4 mmol) was added to a single-necked flask under argon protection. The flask was cooled to -78°C and a solution of methyl 4-acetamido-6-chloro-5-fluorobenzoate (1.1 g, 4.52 mmol) in tetrahydrofuran was added. The mixture was warmed to room temperature and reacted for 1 hour. The mixture was then poured into ice water and the pH was adjusted to 2.0 with 6N hydrochloric acid. A white solid precipitated and was filtered and dried to obtain a white solid (725 mg, 75% yield).

[0299] Step 4: Synthesis of compound 7-chloro-8-fluoro-3-nitro-1,6-naphthyridine-2,4(1H,3H)-dione

[0300] Dissolve 7-chloro-8-fluoro-1,6-naphthyridine-2,4(1H,3H)-dione (725 mg, 3.39 mmol) in acetic acid (10 mL). Add concentrated nitric acid (628 mg, 6.78 mmol). Heat to 80°C for 1 hour. Pour into ice water, extract with ethyl acetate, and concentrate to obtain a yellow solid (614 mg, 70% yield).

[0301] Step 5: Synthesis of compound 2,4,7-trichloro-8-fluoro-3-nitro-1,6-naphthyridine:

[0302] Dissolve 7-chloro-8-fluoro-3-nitro-1,6-naphthyridine-2,4(1H,3H)-dione (614 mg, 2.37 mmol) in phosphorus oxychloride (10 mL). Add 1 mL of N,N-diethylbenzylamine. Heat to 100°C and stir overnight. After completion of the reaction, monitor the reaction by TLC. Remove the phosphorus oxychloride under reduced pressure to obtain the crude product. The crude product is purified by column chromatography to obtain a pale yellow solid (561 mg, 80% yield). 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H).

[0303] Step 6: Synthesis of compound 4-(benzyloxy)-2,7-dichloro-8-fluoro-3-nitro-1,6-naphthyridine:

[0304] Dissolve 2,4,7-trichloro-8-fluoro-3-nitro-1,6-naphthyridine (561 mg, 1.90 mmol) in 10 ml of ultra-dry THF. Cool the reaction system to 0°C, then add BnONa (3.2 ml, 1.0 M / THF) dropwise. Stir the resulting mixture at 0°C for 30 minutes. After completion, quench the reaction by adding 10 ml of saturated sodium bicarbonate solution. Extract the mixture with 50 ml of ethyl acetate. After separation, dry the organic phase over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain the crude product. Column chromatography yielded the desired product as a white solid (629 mg, 90%).

[0305] Step 7: Synthesis of compound 4-benzyloxy-7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrolazin-7a-ylmethoxy-3-nitro-1,6-naphthyridine:

[0306] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (406 mg, 2.55 mmol) was dissolved in anhydrous THF (5 mL). 60% NaH (89 mg, 2.22 mmol) was added under ice-water cooling. After stirring for 30 minutes under ice-water cooling, 4-(benzyloxy)-2,7-dichloro-8-fluoro-3-nitro-1,6-naphthyridine (629 mg, 1.70 mmol) was added to the reaction solution and the reaction was stirred overnight. After completion, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (566 mg, yield: 68%).

[0307] Step 8: Synthesis of compound 4-benzyloxy-7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrolazin-7a-ylmethoxy-1,6-naphthyridin-3-amine

[0308] Dissolve 4-benzyloxy-7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrolizin-7a-ylmethoxy-3-nitro-1,6-naphthyridine (566 mg, 1.16 mmol) in ethanol (10 mL). Add water (2 mL), iron powder (324 mg, 5.78 mmol), and acetic acid (131.5 mg, 8.12 mmol). React at room temperature for 2 hours. Filter the iron powder, extract with ethyl acetate, concentrate, and purify by column chromatography to obtain a light yellow solid (427 mg, 80% yield).

[0309] Step 9: Synthesis of compound 4-benzyloxy-7-chloro-3,8-difluoro-2-fluorotetrahydro-1H-pyrrolazin-7a-ylmethoxy-1,6-naphthyridine:

[0310] The compound 4-benzyloxy-7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrolizin-7a-ylmethoxy-1,6-naphthyridin-3-amine (427 mg, 0.928 mmol) was dissolved in hydrogen fluoride pyridine (5 mL). Sodium nitrite (88 mg, 1.21 mmol) was added under ice-cooling. The reaction system was heated to 80°C for 10 hours. After completion, water was added to quench the reaction. Extraction was performed with 100 ml of ethyl acetate, the layers were separated, dried, and the solvent removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain a light yellow solid (355 mg, yield: 66.7%).

[0311] Step 10: Synthesis of compound 4-benzyloxy-3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-methyl-5,6,8-tetrahydronaphthalen-1-yl)-1,6-naphthyridine

[0312] The compound 4-benzyloxy-7-chloro-3,8-difluoro-2-2-fluorotetrahydro-1H-pyrrolazin-7a-ylmethoxy-1,6-naphthyridine (355 mg, 0.62 mmol), 4,4,5,5-tetramethyl-2-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborolane (219 mg, 0.81 mmol), cesium carbonate (401.5 mg, 1.24 mmol), and Pd(PPh3)4 (70 mg, 0.06 mmol) were dissolved in 1,4-dioxane / water = 5 / 1 (30 mL). The atmosphere was replaced with nitrogen. The reaction system was heated to 100°C under a nitrogen atmosphere and stirred for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by PLC to obtain an off-white solid. (259 mg, yield: 73%).

[0313] Step 11: Synthesis of compound 3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,6-naphthalen-4-ol

[0314] The compound (4-benzyloxy-3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy-7-(8-methyl-5,6,8-tetrahydronaphthalen-1-yl)-1,6-naphthyridine (259 mg, 0.45 mmol) was dissolved in 10 ml of methanol. Palladium on carbon (10% wt, 50 mg) was added. The reaction system was purged with hydrogen and stirred at room temperature for 5 hours. After completion of the reaction, the reaction system was filtered through celite and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by PLC to obtain a yellow solid (87 mg, 40%).

[0315] Step 12: Synthesis of compound 3-(3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0316] A solution of compound 3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-1,6-naphthalen-4-ol (87 mg, 0.18 mmol) in dichloromethane (5 mL) was cooled to 0°C. Triethylamine (77 μL, 0.54 mmol) and trifluoromethanesulfonic anhydride (62 μL, 0.36 mmol) were added sequentially via syringe. The reaction was continued at 0°C for 1 hour. After the starting material was completely converted to the trimethylamine adduct, the solvent was removed from the reaction system under reduced pressure to obtain the crude product. DMF (2 mL) and triethylamine (77 μL, 0.54 mmol) were added to the crude product to obtain a brown solution. 8-Oxa-3-azabicyclo[4.2.0]octan-7-one trifluoroacetate (81 mg, 0.36 mmol) was added as a solid. The reaction was stirred at room temperature for 1 hour, and then the reaction mixture was diluted with 2.0 mL of acetonitrile:water + 5% formic acid (1:1). The solvent was removed under reduced pressure to obtain the crude product, which was separated by column chromatography to yield the desired product as a yellow powder (48 mg, 45%). MS m / z: 593.27 [M+H] + .

[0317] Examples 281-291 were prepared using the method of Example 280.

[0318] Example 292: Synthesis of Compound 3-(3,6,8-trifluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane-7-one:

[0319] Following the synthesis of Example 280, using 2-amino-4-bromo-3,5-difluorobenzoic acid as the starting material, a light yellow solid (52 mg) was obtained. MS m / z: 610.26 [M+H]+

[0320] The method of Example 292 was used to prepare the compounds of Examples 293-312.

[0321] Example 313: Synthesis of Compound 3-(3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane-7-one:

[0322] Following the synthesis of Example 280, using 2-amino-4-bromo-3-fluorobenzoic acid as the starting material, a pale yellow solid (220 mg) was obtained. MS m / z: 592.27 [M+H] +

[0323] Examples 314-333 were prepared using the method of Example 313.

[0324] Example 334: Synthesis of (1R, 6R)-3-(4-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-[1,3]dioxolano[4,5-f]quinazolin-9-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one:

[0325] Referring to the synthesis of Example 1, the intermediate 9-(benzyloxy)-4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolano[4,5-f]quinazoline was used as the starting material to obtain the target compound as a white solid. (10 mg, [M+H] + =663.2).

[0326] The method of Example 334 was used to prepare the compounds of Examples 335-342.

[0327] Example 343: Synthesis of (1R,6R)-3-(6-(8-(1R,6R)-3-(4-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one:

[0328] Referring to the synthesis of Example 1, the intermediate 1-(benzyloxy)-6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazoline was used as the starting material to obtain the target compound as a white solid. (10 mg, [M+H] + =659.3).

[0329] The method of Example 343 was used to prepare the compounds of Examples 344-348.

[0330] Example 349: Synthesis of (1R,6R)-3-(5-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidin-10-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0331] Referring to the synthesis of Example 1, the intermediate 10-(benzyloxy)-5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidine was used as the starting material to obtain the target compound as an off-white solid. (15 mg, [M+H] + =651.2).

[0332] The method of Example 349 was used to prepare the compounds of Examples 350-356.

[0333] Example 357: Synthesis of (1R,6R)-3-(5-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidin-10-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0334] Referring to the synthesis of Example 1, the intermediate 10-(benzyloxy)-5-chloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine was used as the starting material to obtain the target compound as an off-white solid. (15 mg, [M+H] + =649.2).

[0335] Examples 358-366 were prepared using the method of Example 357.

[0336] Example 367: Synthesis of (1R,6R)-3-(6-(8-chloro-7-fluoronaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)imidazo[1',5':1,2]pyrido[4,3-d]pyrimidin-1-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one

[0337] Referring to the synthesis of Example 1, the intermediate 4-(benzyloxy)-5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine was used as the starting material to obtain the target compound as an off-white solid. (15 mg, [M+H] + =649.2).

[0338] Examples 368-373 were prepared using the method of Example 367.

[0339] Example 374: Synthesis of (1R,6R)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one

[0340] Step 1: Synthesis of ethyl 1-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-3-oxopiperidine-4-carboxylate

[0341] Ethyl 3-oxopiperidine-4-carboxylate (1.71 g, 10 mmol), 8-bromo-1-methyl-1,2,3,4-tetrahydronaphthalene (3.38 g, 15 mmol), and cesium carbonate (8.15 g, 25 mmol) were dissolved in 50 ml of anhydrous toluene. After purging with argon, XantPhos (1 g, 2 mmol) and Pd2(dba)3 (2 g, 2 mmol) catalysts were added, and the purging with argon was continued. The reaction system was heated to 100°C and stirred overnight. After completion of the reaction, the system was cooled to room temperature and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain an off-white solid (2.14 g, yield: 68%).

[0342] Step 2: Synthesis of compound 7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-2-methylthio-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

[0343] Ethyl 1-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-3-oxopiperidine-4-carboxylate (2.14 g, 6.8 mmol) was dissolved in anhydrous methanol (30 ml). 30% sodium methoxide solution (3.67 g, 20.4 mmol) and thiourea (0.78 g, 10.2 mmol) were added. The reaction system was heated to 80°C and stirred for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature. Methyl iodide (0.53 ml, 10.2 mmol) was added dropwise to the reaction system. Stirring was continued for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude product. 20 ml of water was added to the crude product, and the pH was adjusted to 6-7 with dilute hydrochloric acid. A large amount of solid precipitated, which was filtered to obtain a white solid (2.2 g, yield: 95%).

[0344] Step 3: Synthesis of compound 4-benzyloxy-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-2-methylthio-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0345] The compound 7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-2-methylthio-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (2.2 g, 6.46 mmol) was dissolved in 30 ml of ultra-dry THF. The reaction system was cooled to 0°C, and BnONa (11 ml, 1.0 M / THF) was added dropwise. The resulting mixture was stirred at 0°C for 30 minutes. After completion, the reaction system was quenched by the addition of 30 ml of saturated sodium bicarbonate solution, followed by extraction with 100 ml of ethyl acetate. After separation, 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 column chromatography to obtain a white solid (2.5 g, 90%).

[0346] Step 4: Synthesis of 4-benzyloxy-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0347] The compound 4-benzyloxy-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-2-methylthio-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (2.5 g, 5.8 mmol) was dissolved in 50 ml of dichloromethane, and 85% m-chloroperbenzoic acid (1.4 g, 6.96 mmol) was added under ice-water bath conditions. Stirring was continued under ice-water bath conditions for 30 min. After the reaction was completed, 5 ml of saturated sodium thiosulfate solution was added to quench the reaction, and then 100 ml of dichloromethane was added for extraction. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product (2.6 g, yield; 100%).

[0348] Step 5: Synthesis of compound 4-benzyloxy-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0349] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.2 g, 7.54 mmol) was dissolved in anhydrous THF (5 mL). 60% NaH (279 mg, 6.96 mmol) was added under ice-water cooling. After stirring for 30 minutes under ice-water cooling, 4-(benzyloxy)-2,7-dichloro-8-fluoro-3-nitro-1,6-naphthyridine (2.6 g, 5.8 mmol) was added to the reaction solution and the reaction was stirred overnight. After completion, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (2.2 g, yield: 71%).

[0350] Step 6: Synthesis of compound 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

[0351] The compound 4-benzyloxy-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)-(4-methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (2.2 g, 4.1 mmol) was dissolved in 30 ml of methanol. Palladium on carbon (10% wt, 200 mg) was added. The reaction system was purged with hydrogen and stirred at room temperature for 5 h. After completion of the reaction, the reaction system was filtered through celite and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by PLC to obtain a yellow solid (926 mg, 50%).

[0352] Step 7: Synthesis of compound 2-fluorotetrahydro-1H-pyrrolazine-7-methoxy-7-(8-methyl-5,7,7-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octan-7-one

[0353] A solution of 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (926 mg, 2.05 mmol) in dichloromethane (20 mL) was cooled to 0°C. Triethylamine (876 μL, 6.15 mmol) and trifluoromethanesulfonic anhydride (706 μL, 4.1 mmol) were added sequentially via syringe. The reaction was continued at 0°C for 1 hour. After the starting material was completely converted to the trimethylamine adduct, the solvent was removed from the reaction system under reduced pressure to obtain the crude product. DMF (10 mL) and triethylamine (876 μL, 6.15 mmol) were added to the crude product to obtain a brown solution. 8-Oxa-3-azabicyclo[4.2.0]octan-7-one trifluoroacetate (922 mg, 4.1 mmol) was added as a solid. The reaction was stirred at room temperature for 1 hour, and then the reaction mixture was diluted with 2.0 mL of acetonitrile:water + 5% formic acid (1:1). The solvent was removed under reduced pressure to obtain the crude product, which was separated by column chromatography to yield the desired product as a yellow powder (460 mg, 40%). MS m / z: 562.31 [M+H]+

[0354] The method of Example 374 was used to prepare the compounds of Examples 375-403.

[0355] Example 404: Synthesis of Compound (1R,6R)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxy-1-naphthyl)-6,7-dihydro-5H-pyrano[3,4-d]pyrimidin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one

[0356] Following the synthesis of Example 373, using ethyl 4-oxopyrrolidine-3-carboxylate as the starting material, a pale yellow solid (19 mg) was obtained. MS m / z: 574.2 [M+H] +

[0357] Examples 405-411 were prepared using the method of Example 404.

[0358] Example 412: Synthesis of ethyl (4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbonate

[0359] Step 1: Synthesis of ethyl (4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbonate. Under ice-water cooling, to (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxy- To a solution of 8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octan-7-one (18 mg, 0.030 mmol) and TEA (8.4 μL) in dichloromethane (0.5 mL) was added dropwise a solution of ethyl chloroformate (6.5 mg, 0.060 mmol) in dichloromethane (0.5 mL). After the addition was complete, the ice-water bath was removed and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly separated by preparative TLC (ethyl acetate:petroleum ether = 2:1) to obtain the desired product (15 mg, yield: 77%, [M+H] + =663.6).

[0360] Example 413-498 was prepared by the method of Example 412, and the acylating agent was an acyl chloride or a chloroformate.

[0361] Example 499: Synthesis of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,6R)-7-oxo-8-oxa-3-azabicyclo[4.2.0]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl(2-methoxyethyl)carbamate

[0362] Step 1: Synthesis of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,6R)-7-oxo-8-oxa-3-azabicyclo[4.2.0]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl(4-nitrophenyl)carbonate

[0363] The compound (1R,6R)-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)-8-oxa-3-azabicyclo[4.2.0]octan-7-one (200 mg, 0.34 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). DIEA (88 mg, 0.68 mmol) and di(p-nitrobenzene) carbonate (309 mg, 1.01 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 ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was used directly in the next step.

[0364] Step 2: Synthesis of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,6R)-7-oxo-8-oxa-3-azabicyclo[4.2.0]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl(2-methoxyethyl)carbamate

[0365] The compound 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,6R)-7-oxo-8-oxa-3-azabicyclo[4.2.0]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl(4-nitrophenyl)carbonate (50 mg, 0.066 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (13 mg, 0.132 mmol) and 2-methoxyethane-1-amine (6 mg, 0.086 mmol) were then added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by preparative TLC to obtain an off-white solid. (20 mg, yield: 43%, [M+H] + =693.3).

[0366] Example 500: Synthesis of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(1-oxo-2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ylmethylcarbamate

[0367] The compound 7-(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)-2-oxa-7-azaspiro[3.5]nonan-1-one (50 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), and then DIEA (1 ml) and methylcarbamoyl chloride (16 mg, 0.16 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The product was separated and purified by preparative TLC to obtain an off-white solid. (45 mg, yield: 82%, [M+H] + =663.3)

[0368] The preparation method of Example 499 or 500 was used to prepare the compounds of Examples 501-544.

[0369] Cell viability assay:

[0370] BaF3 cell culture:

[0371] Ba / F3 cells were cultured in RPMI 1640 supplemented with 10% heat-inactivated FBS and 10 ng / ml recombinant mouse IL-3. When the cell confluence reached more than 80%, subculture was performed.

[0372] CTG assay for BaF3 cell proliferation in vitro:

[0373] Trypsinize adherent cells in the logarithmic growth phase or collect suspended cells by centrifugation, count them, and inoculate 90 μl of cell suspension into a 96-well plate at a cell seeding density of 1000 cells / well.

[0374] After 24 hours, 10 μl / well of a 9-point series of compound diluted 3-fold was added. The wells to which the same volume of 5% DMSO was added served as controls, with a final DMSO concentration of 0.5%.

[0375] After 3 days of drug treatment, cell viability was assessed using MTT / MTS assays. The specific method was as follows: a 96-well plate was equilibrated to room temperature, and 100 μl of diluted CTG reagent (1:4 CTG reagent / PBS) was added to each well. The plate was placed on an orbital shaker for 30 minutes, and chemiluminescence was recorded using a multi-function microplate reader (EnVision, PE).

[0376] GraphPad Prism 8 software was used to generate dose-effect curves and calculate IC 50 .

[0377] Activity data IC of compounds of formula (I) and (II) 50 The values ​​are shown in Table 1:

[0378] ++++<500nm; 500nM<+++<1000nM; 1000nM<++<2000nM; +>2000nM.

Claims

1. A compound of formula (I) or (II) or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein the compound of formula (I) and (II) is: in: 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 , 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-, 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 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-; 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 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; 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 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、-OCH2OC(O)OR 8a , optionally halogen or C 1-12 Alkyl-substituted C3-C6 cycloalkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, aryl, heteroaryl, aryl or heteroaryl optionally substituted with -OC(O)C(CH3)3, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 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; n 1 is 0, 1, or 2; 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 is N; where R 6 and R 7 Each is independently hydrogen, halogen, hydroxy, cyano, nitro, C1-6 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 2 and Q 3 The substituents are connected to form a saturated or partially saturated 5-6 membered aliphatic ring, aromatic ring or aromatic heterocyclic ring.

2. The compound of claim 1, wherein for 3. The compound of any one of claims 1-2, wherein L is -O-CH2- or -O-.

4. 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.

5. The compound of any one of claims 1 to 4, 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).

6. The compound of claim 5, 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.

7. 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.

8. The compound of claim 5, 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.

9. The compound of claim 8, 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.

10. The compound of claim 1, wherein LR 2 for 11. The compound of claim 1, wherein R 3 for a. a monocyclic aryl or heteroaryl group selected from phenyl, pyridyl, pyrimidinyl and pyrazinyl; 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), tetrahydroisoquinoline, quinoline (e.g., 5,6,7,8-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); c. a tricyclic aryl or heteroaryl group selected from The aryl or heteroaryl group may be optionally substituted by 1 to 3 substituents R 8 Replacement, R 8 are independently selected from: halogen, C optionally substituted by halogen 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、-OCH2OC(O)OR 8a , optionally halogen or C 1-6 Alkyl-substituted C3-C6 cycloalkyl, wherein R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, optionally substituted by halogen, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 alkyl-.

12. The compound of claim 11, wherein R 3 is naphthalene-1-yl, wherein the 3-position of the naphthalene-1-yl is unsubstituted or substituted by -OR 8a 、-P(=O)R 8a R 8b or -NR 8a R 8b 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 8a 、-OCH2OC(O)OR 8a Substituted, where R 8a and R 8b Each independently hydrogen, -(CH2) m (OCH2CH2) n -OCH3 (wherein m is 0, 1 or 2; n is 1 to 5), C 1-12 Alkyl or C 1-12 Alkoxy, C 1-12 Alkoxy-C 1-12 Alkyl-, C 3-6 Cycloalkyl, aryl, heteroaryl, aryl or heteroaryl optionally substituted with -OC(O)C(CH3)3, C 1-12 Alkyl and C 1-12 Alkoxy-C 1-12 alkyl-.

13. The compound of claim 12, wherein one or two of the 5, 6, 7, and 8 positions of the naphthalene-1-yl group are substituted, and the substituents are independently selected from halogen, C 1-6 Alkyl, C2-C6 alkynyl, -P(=O)R 8a R 8b 、-NR 8a R 8b 、-OR 8a 、-SR 8a 、-OC(O)NR 8a R 8b 、-OC(O)OR 8a 、-OC(O)R 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.

14. The compound of claim 1, wherein R 3 for in, R 8 Preferably selected from hydrogen, fluorine, chlorine, hydroxyl, amino, 15. The compound of claim 1, wherein the compound is a specific compound disclosed herein.

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof.

17. Use of a compound according to any one of claims 1 to 16 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.

18. The use according to claim 17, wherein the cancer is a cancer mediated by G12S or G12D mutations.

19. The use of claim 18, wherein the cancer is lung cancer, colorectal cancer or pancreatic cancer.

Images