Fused ring compounds, pharmaceutical compositions comprising the same and uses thereof

Abstract

The present application relates to the technical field of medicine, and provides a fused ring compound, a pharmaceutical composition containing the same and application, wherein the compound has a structure shown in formula (I) or a tautomer, an entgegen isomer, an enantiomer, a diastereomer or a mixture thereof, a metabolite, a metabolic precursor, an isotopic substitution form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof; the compound provided by the present application can be used for treating cancer caused by KRAS mutation, wherein the cancer caused by KRAS mutation is one or more selected from cancer caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutation, and in particular, the compound can be used as a G12D inhibitor and has high inhibitory activity.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a fused ring compound, a pharmaceutical composition containing the same and application. BACKGROUND

[0002] KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family, and the other two genes of the family are HRAS and NRAS, and the homology between each gene can reach 85%. KRAS is essentially a monomeric G protein, located on both sides of the cell membrane, with GTPase activity, and its encoded protein is composed of 188-189 amino acids, with a molecular weight of 21KD. KRAS plays an important regulatory role in the signal transduction pathway of tumor cell growth and angiogenesis, and under normal circumstances, it can control the path of cell growth; when abnormal, it leads to continuous cell growth and prevents cell self-destruction. When the KRAS gene is mutated, the gene is permanently activated, continuously stimulating cell growth, causing intracellular signal transduction disorder, uncontrolled cell proliferation and cancer.

[0003] KRAS is the most common cancer mutation gene in humans, and about 30% of all cancers are related to the activation of KRAS mutation, including 95% of pancreatic ductal adenocarcinoma (PDAC), 45% of colon cancer and rectal cancer (CRC) and 35% of non-small cell lung cancer (NSCLC) and the like. Due to the problem of protein structure, KRAS was once considered a "non-druggable" target in the field of tumor drug research and development. However, with the in-depth research, researchers found that some specific mutant KRAS proteins can form a site that can interact with drugs, and after binding with small molecule drugs, it can lock KRAS in the inactive KRAS protein-GDP state, play a role in inhibiting the activation of KRAS pathway, and thus initiate the anti-tumor effect. In recent years, a number of KRAS G12C candidate drugs have entered the clinic, among which Amgen's AMG 510 and Mirati Therapeutics' MRTX 849 have progressed the fastest, and the former has been approved for marketing by FDA. But G12C is not the most important KRAS mutation subtype. SUMMARY

[0004] Therefore, the application provides a fused ring compound, a pharmaceutical composition containing the same and application. The provided compound can be used for treating cancer caused by KRAS mutation, wherein the cancer caused by KRAS mutation is one or more selected from cancer caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutation, and the compound can be used as G12D inhibitor, has high inhibitory activity, good bioavailability and can be used for preparing a medicine for preventing and / or treating KRAS G12D mediated disease, and has good application prospect.

[0005] The application provides a compound shown in formula (I), a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, a metabolite, a metabolic precursor, an isotopic substitution form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof:

[0006]

[0007] wherein,

[0008] A1, A2, A3, A4, A5 and A6 are independently selected from C-R4 or nitrogen;

[0009] R1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0010] R2 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;

[0011] R3 is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;

[0012] The substituent R4 in A1, A2, A3, A4, A5 and A6 can be independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted unsaturated cycloalkyl or heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, thiol, amide, sulfonyl, phosphoryl, alkyl oxyphosphoryl, alkyl sulfone, alkyl sulfoxide;

[0013] L1 and L2 are absent or independently selected from -CH=CH-, -N(Ra)-, -N(Ra)-(CRaRb)n-, -O-(CRaRb)n-, -(CRaRb)n-;

[0014] Ra and Rb are independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 heteroalkyl and C3-C6 cycloalkyl.

[0015] Preferably, the compound has a structure shown in formula (II);

[0016]

[0017] wherein,

[0018] R1is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0019] R2is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

[0020] R3is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

[0021] L1is absent or -CH=CH-, -N(Ra)- or -N(Ra)-(CRaRb)n-; L2is -O-(CRaRb)n-, -CH=CH- or -(CRaRb)n-;

[0022] Raand Rbare each independently selected from hydrogen, deuterium, C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl. Preferably, L1is absent or -N(Ra)- or -N(Ra)-(CRaRb)n; L2is -O-(CRaRb)n- or -(CRaRb)n-.

[0023] Preferably, the compound has a structure represented by Formula (III) or Formula (IV);

[0024]

[0025] wherein,

[0026] Ring A is a 4- to 12-membered heterocyclic ring, the heteroatom being N and / or O;

[0027] Ring B is a 4- to 12-membered heterocyclic ring, the heteroatom being N;

[0028] The rings A and B are each independently selected from a saturated or partially saturated monocyclic, annulated, bridged, spirocyclic ring;

[0029] Z is selected from hydrogen or deuterium;

[0030] R1is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0031] R5, R6, R7are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid.

[0032] m1 is selected from an integer from 0 to 6;

[0033] m2 is selected from an integer from 0 to 6.

[0034] Preferably, said halogen is F.

[0035] Preferably, ring B is selected from

[0036]

[0037] wherein,

[0038] X1, X2 are independently selected from hydrogen, deuterium, halogen; Y is selected from hydrogen or deuterium;

[0039] R8, R 20 , R 21 are independently selected from hydrogen, substituted or non-substituted aryl or heteroaryl, substituted or non-substituted alkyl or cycloalkyl, substituted or non-substituted heteroalkyl or heterocycloalkyl;

[0040] R9, R 10 , R 22 are independently selected from hydrogen, substituted or non-substituted alkyl or cycloalkyl, substituted or non-substituted heteroalkyl or heterocycloalkyl, ester, amide, aryl, heteroaryl, acyl guanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein said substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acyl guanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid;

[0041] R 11 is selected from substituted monocyclic heteroalkyl, wherein the heteroatom is nitrogen and / or oxygen.

[0042] Preferably, R9, R 10 are selected from

[0043] Preferably, ring A is selected from

[0044]

[0045] ring C is

[0046] wherein,

[0047] X 3～ X 16 are independently selected from -NR 12 -, -O-, -CO-, -CR 14 R 15 -;

[0048] R 12 , R13 14 15 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid;

[0049] q is selected from an integer from 0 to 3, and when q = 0, the chemical bond is absent.

[0050] Preferably, R1 is selected from

[0051] or

[0052] wherein W1, W3, W5, W8, W9, W 11 12 13 15 16 17 are selected from -NR 12 -, -O-, -CO-, -CR 17 18 -, -SO2-; W2, W4, W6, W7, W 10 14 18 19 20 21 22 23 24 25 26 27 are selected from N atom or R 16 substituted C atom; when W 23 and W 24 are selected from R 16 substituted C atom, the two carbon atoms can be linked by a chemical bond into a saturated or unsaturated 5- or 6-membered ring;

[0053] 12 16 17 18 ​​​​​​​​​​​​​​​​​​​​​​​each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, hydroxyl, alkinyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid.

[0054] Preferably, the compound has any one of the structures of formula (V), formula (VI) and formula (VII).

[0055]

[0056] wherein,

[0057] X1, X2are independently selected from hydrogen, deuterium, halogen; Y is selected from hydrogen or deuterium; Z is selected from hydrogen or deuterium;

[0058] R8, R 20 , R 21 are each independently selected from hydrogen, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl;

[0059] R 22 is selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein the substituents are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid;

[0060] X3is selected from -NR 12 -, -O-, -CO-, -CR 14 R 15 -;

[0061] W 19 , W 20 , W 22 are independently selected from N atom, R 16 substituted C atom.

[0062] Preferably, the compound has the structure of formula (V).

[0063] Preferably, the compound has any one of the structures of formula (VIII), formula (IX) and formula (X).

[0064]

[0065] X1, X2 are independently selected from hydrogen, deuterium, halogen; Y is selected from hydrogen or deuterium; Z is selected from hydrogen or deuterium;

[0066] X3 is selected from -NR 12 -, -O-, -CO-, -CR 14 R 15 -;

[0067] W 19 , W 20 , W 22 are independently selected from N atom, R 16 substituted C atom;

[0068] R 19 is selected from -H, -OH, halogen, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester, amide, aryl, heteroaryl, acyl guanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acyl guanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid;

[0069] R 22 is selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester, amide, aryl, heteroaryl, acyl guanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acyl guanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid;

[0070] m3 is selected from an integer from 0 to 5, and when m3 is equal to or greater than 2, R19 can also be a 4 to 7-membered ring parallel to the benzene ring.

[0071] Preferably, the compound has the structure shown in formula (VIII).

[0072] In a preferred embodiment of the present application, the compound has the structure shown in formula (XI) or formula (XII):

[0073]

[0074] Y is selected from hydrogen or deuterium; Z is selected from hydrogen or deuterium;

[0075] wherein, in general formula XI, R 23Independently selected from -H, -F, -Cl, -CN, -CF3, alkenyl, alkynyl, C 1-3 straight-chain alkyl, C 3-6 Cycloalkyl.

[0076] R 24 Selected from -H, C 1-5 Alkyl or heteroalkyl, -COR 55 R 55 Selected from -H,C 1-10 Straight-chain / branched alkyl, C 1-10 Straight-chain / branched heteroalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups.

[0077] R 25 Selected from -H, -CO(C) 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO-CH2-OCO(C 0-10 Alkyl group), -COO-CH(CH3)-OCO(C 0-10 alkyl).

[0078] K is selected from C or N. When K is N, its corresponding R 29 It does not exist. The R mentioned above... 26 R 27 R 28 R 29 R 30 Independently selected from -H, -OH, halogens, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, phosphate group, monomethyl phosphate group, dimethyl phosphate group, C 1-5 Straight-chain / branched alkyl, C 1-5 Alkoxy, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -S(C 0-10 Alkyl), -OCON(C) 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 aryl, five-membered heteroaryl, six-membered heteroaryl; or R 27 R 28 With R 27 and R 28 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 cycloalkyl, saturated or unsaturated C 3-8 Heterocyclic alkyl groups, saturated or unsaturated cyclic lactones, C 5-6Aryl, bridged cycloalkyl, spirocycloalkyl, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl or amide substitution.

[0079] m4 is selected from integers from 0 to 4.

[0080] In general formula XII, R 31 Independently selected from -F, -Cl, -NH2, -CN, -CF3, -C2F5, -OCF3, alkenyl, alkynyl, C 1-3 Straight-chain / branched alkyl, C 1-3 Straight-chain / branched alkoxy groups, C 3-6 Cycloalkyl, aryl, heteroaryl.

[0081] R 32 Selected from -H, C 1-5 Straight-chain / branched alkyl, C 3-6 Cycloalkyl.

[0082] R 33 Selected from -H, -CO(C) 0-10 alkyl), -COO(C 0-10 Alkyl), -COO-CH2-OCO(C 0-10 Alkyl group), -COO-CH(CH3)-OCO(C 0-10 alkyl).

[0083] The R 34 R 35 R 36 R 37 R 38 Independently selected from -H, -OH, halogens, -NO2, -CN, -CF3, -C2F5, -OCF3, -OCHF2, -OCH2F, C 1-5 Straight-chain / branched alkyl, C 1-5 Alkoxy, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl; or R 35 R 36 With R 35 and R 36 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 cycloalkyl, saturated or unsaturated C 3-8 Heterocyclic alkyl groups, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl or amide substitution.

[0084] m5 is selected from integers from 0 to 4.

[0085] More preferably, the compound has the following structure:

[0086]

[0087]

[0088] Among them, R 39 R 40 Independently selected from -H, -F, -Cl, -CN, alkynyl, C 1-3 Straight-chain alkyl; R 41 R 42 R 43 R 44 Independently selected from -H, -OH, -F, -Cl, -CN, -CF3, -C2F5, -OCF3, monomethylphosphoryl, dimethylphosphoryl, C 1-5 Straight-chain / branched alkyl, C 1-5 Alkoxy, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, -S(C 0-10 Alkyl), -OCON(C) 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 aryl, five-membered heteroaryl, six-membered heteroaryl; or R 42 R 43 With R 42 and R 43 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 cycloalkyl, saturated or unsaturated C 3-8 Heterocyclic alkyl groups, five-membered ring lactones, C 5-6 Aryl, bridged cycloalkyl, spirocycloalkyl, wherein the H in the above groups can be -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 Alkyl or amide substitution.

[0089] R 45 and R 46 Independently selected from -H, -F, -Cl, -NH2, -CN, -CF3, -C2F5, -OCF3, alkynyl, C 1-3 straight-chain alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, aryl, heteroaryl; R 47 R 48 R 49 Independently selected from -H, -F, -Cl, -CN, -CF3, -C2F5; or R 47 R 48 With R 47 and R 48saturated or unsaturated C 3-8 cycloalkyl, saturated or unsaturated C 3-8 heterocycloalkyl, wherein H in the above groups can be replaced by -D, -OH, -F, -CN, -CF3, C 1-3 alkyl.

[0090] wherein R 42 , R 43 and R 42 and R 43 form together with the carbon atom to which they are attached a saturated or unsaturated C 3-8 cycloalkyl, saturated or unsaturated C 3-8 heterocycloalkyl, five-membered ring lactone, C 5-6 aryl, bridged cycloalkyl, spirocycloalkyl include:

[0091]

[0092] wherein K2, K3, K4 are fused to the phenyl ring to form a saturated or unsaturated five-membered ring, K2, K3, K4 are independently selected from C, N, O, S; K5, K6, K7 are independently selected from C, N, O, S; K8 is independently selected from C, N, O, S; R 50 , R 51 , R 52 , R 53 are independently selected from -H, -D, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, m6, m7, m8, m9 are selected from integers from 0 to 6.

[0093] wherein R 47 , R 48 and R 47 and R 48 form together with the carbon atom to which they are attached a saturated or unsaturated C 3-8 cycloalkyl, saturated or unsaturated C 3-8 heterocycloalkyl include:

[0094]

[0095] K9, K 10 , K 11 are independently selected from C, N, O; R 54 are independently selected from -H, -F, -CN, -CF3, -C2F5, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, m10 is selected from integers from 0 to 4.

[0096] Preferably, the structure of formula (I) is selected from:

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] The present application provides a pharmaceutical composition, the active compound of which comprises one or more of a compound according to the above, a tautomer, meso, racemic, enantiomer, diastereomer or mixture thereof, a metabolite, a metabolic precursor, an isotopically substituted form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof.

[0107] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient selected from one or several of a carrier, a diluent or an excipient. Furthermore, the present application does not have a particular limitation on the type of formulation of the pharmaceutical composition, etc.

[0108] The present application provides the use of the above-mentioned compound, a tautomer, meso, racemic, enantiomer, diastereomer or mixture thereof, a metabolite, a metabolic precursor, an isotopically substituted form (such as hydrogen atoms being replaced by deuterium atoms), a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof in the manufacture of a KRAS inhibitor drug.

[0109] Preferably, the above-mentioned compound, a tautomer, meso, racemic, enantiomer, diastereomer or mixture thereof, a metabolite, a metabolic precursor, an isotopically substituted form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof is used in the manufacture of a KRAS G12D mutant drug.

[0110] The present application provides the above-mentioned compound, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic replacement form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal in the preparation of a medicament for treating, alleviating or preventing Noonan syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumor, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal and colon cancer related diseases or disorders.

[0111] In order to more clearly describe the content of the present application, the terms involved are defined as follows:

[0112] The "pharmaceutically acceptable" in the present application refers to any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0113] The pharmaceutically acceptable excipient in the present application is a general term for all additional materials in a drug except the main drug. The excipient should have the following properties: (1) no toxic effect on the human body, little side effect; (2) stable chemical properties, not easily affected by temperature, pH, storage time, etc.; (3) no compatibility contraindication with the main drug, does not affect the efficacy and quality inspection of the main drug; (4) does not interact with the packaging material. The excipient in the present application includes but is not limited to fillers (diluents), lubricants (glidants or anti-adhesion agents), dispersants, humectants, binders, adjusting agents, solubilizers, antioxidants, bacteriostatic agents, emulsifiers, disintegrants, etc. The binder includes syrup, gum arabic, gelatin, sorbitol, tragacanth gum, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.), gelatin syrup, sugar syrup, starch paste or polyvinylpyrrolidone, etc.; the filler includes lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant includes micro-powder silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; the disintegrant includes starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone or microcrystalline cellulose, etc.; the humectant includes sodium dodecyl sulfate, water or alcohol, etc.; the antioxidant includes sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutyl phenyl acid, etc.; the bacteriostatic agent includes 0.5% phenol, 0.3% cresol, 0.5% tertiary butyl alcohol, etc.; the adjusting agent includes hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate and buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; the emulsifier includes polysorbate-80, sorbitan oleate, pluronic F-68, lecithin, soybean phospholipid, etc.; the solubilizer includes Tween-80, bile, glycerol, etc.

[0114] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical.

[0115] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as are known in the art of compounding, including (a) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (b) fillers such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) humectants such as, for example, glycerol; (d) disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders such as, for example, paraffin; (f) absoφtion accelerators such as, for example, quaternary ammonium compounds; (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (h) absorbents such as, for example, kaolin and bentonite clay; and (i) lubricants such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0116] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings and shells known in the art of pharmaceutical formulation. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0117] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof and oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, and the like. The liquid dosage forms can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0118] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0119] Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and the like.

[0120] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0121] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed with a carrier, which can be a sterile powder, a sterile non-fluid, or a sterile fluid.

[0122] The compounds of the present application can also be used in injection formulations. Among them, the injection is selected from liquid injection (water needle), sterile powder for injection (powder needle) or tablet for injection (refers to the tablet made by sterile operation method of medicine, which is dissolved with injection water for subcutaneous or intramuscular injection when used).

[0123] Among them, the injection powder contains at least an excipient in addition to the above-mentioned compound. In the present application, the excipient is a component intentionally added to the drug, which should not have pharmacological properties in the amount used, but the excipient can help the processing, dissolution or dissolution of the drug, the delivery of the drug by targeted drug delivery route or the stability.

[0124] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0125] "Member" refers to the number of skeletal atoms constituting the ring.

[0126] In the present application, "a bond" means only one bond, which can also be understood as "none".

[0127] "Alkyl" refers to an aliphatic hydrocarbon group, which refers to a saturated hydrocarbon group. The alkyl moiety can be a straight chain alkyl group, or a branched chain alkyl group. Typical alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

[0128] C1~Cn used in the present application includes C1~C2, C1~C3... C1~Cn, n is an integer greater than one; the prefix of the substituent group represents the minimum and maximum number of carbon atoms in the substituent group, for example, "C1~C6 alkyl" refers to a straight chain or branched chain alkyl group containing one to six carbon atoms.

[0129] "Heteroalkyl" refers to an alkyl group containing heteroatoms, including alkoxy groups.

[0130] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group can be straight chain or branched.

[0131] "Alkenyl" refers to an aliphatic hydrocarbon group with at least one carbon-carbon double bond.

[0132] "Amido" is a chemical group with the formula -C(O)NHR or -NHC(O)R, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0133] "Sulfonyl" is a chemical group with the formula -S(=O)2R, including sulfonamide groups, where R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, and the like;

[0134] "Phosphoryl" is a chemical group with the formula -P(=O)RR', where R, R' can be independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, amino, and the like;

[0135] "Ester" refers to a chemical group with the formula -COOR, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0136] "Acyi" refers to a chemical group with the formula -C(O)R, where R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

[0137] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent.

[0138] "Heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the ring backbone.

[0139] Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0140] "Ring" refers to any covalently closed structure, including, for example, carbocyclic (e.g., aryl or cycloalkyl), heterocyclic (e.g., heteroaryl or heterocycloalkyl), aromatic (e.g., aryl or heteroaryl), non-aromatic (e.g., cycloalkyl or heterocycloalkyl). The "ring" described herein can be monocyclic or polycyclic, and can be fused, spiro, or bridged.

[0141] Typical cycloalkyl groups include, but are not limited to:

[0142] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0143] Typical heterocycloalkyl groups include, but are not limited to:

[0144]

[0145] "Aryl" refers to a planar ring having a delocalized pi-electron system and containing 4n+2 pi-electrons, where n is an integer. Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, indenyl, and the like.

[0146] Typical heteroaryl groups include, but are not limited to:

[0147]

[0148] "Halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0149] "Deuterium" refers to an isotope of hydrogen, also known as heavy hydrogen, and is represented by the element symbol D or 2 H.

[0150] The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, amino, ester, carbonyl, amido, sulfonyl, phosphoryl, boronic acid, boronate ester, guanidinyl, acylguanidinyl, aryl, heteroaryl, imine groups described herein can be unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, amino, ester, carbonyl, amido, sulfonyl, phosphoryl, boronic acid, boronate ester, guanidinyl, acylguanidinyl, aryl, heteroaryl, imine groups.

[0151] In the above, unless otherwise indicated, the "substituted" means that the referenced group can be substituted with one or more additional groups, each and independently selected from alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, O=, guanidinyl, cyano, nitro, acyl, halogen, haloalkyl, amino, and the like.

[0152] The term "pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are suitable for use as medicaments. The above-mentioned acids and bases are the broadest Lewis acids and bases. Suitable acids for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and the like, and acidic amino acids such as aspartic acid, glutamic acid, and the like.

[0153] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclic group optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

[0154] Most KRAS missense mutations occur in codon 12, resulting in a glycine being changed to another amino acid. KRAS G12D and KRAS G12V mutations are predominant, both of which are found in 90% of pancreatic cancer. Among them, KRAS G12D is also the most common KRAS mutation in colon cancer. Unfortunately, KRAS G12D and KRAS G12V still have no clinical or marketed drugs at present because the amino acid residues at the mutation site are difficult to be combined by chemical methods.

[0155] Mirati Therapeutics reported the first KRAS G12D inhibitor compound MRTX1133 (WO2021041671), which can selectively bind to KRAS G12D mutant protein and highly active inhibit the phosphorylation of downstream ERK. It shows sustained dose-dependent inhibition of KRAS-dependent signals in animal models of pancreatic cancer and colorectal cancer. However, the compound originally planned for clinical trials starting this year has been postponed, and the candidate drug was previously expected to be a traditional oral or intravenous preparation, but Mirati has shifted to a long-acting preparation that requires less infusion volume. Therefore, MRTX1133 may still have some unreported deficiencies, such as toxic side effects. In addition, TAIHO PHARMACEUTICAL CO., LTD. discloses a compound with KRAS G12D inhibitory activity (WO 2021 / 106231), which is still in the early stages of research.

[0156] The development of KRAS inhibitors also has strategies targeting upstream and downstream targets and indirectly targeting KRAS, but these strategies may have bypass activation, inhibit normal KRAS activity, and other problems, and there is little progress in current research.

[0157] Therefore, it is of great clinical significance to find and develop new and efficient KRAS G12D mutation inhibitors.

[0158] Compared with the prior art, the present application has the following detailed description:

[0159] The present application provides a new class of compounds targeting KRAS G12D, which has unexpected excellent activity and pharmacokinetic performance.

[0160] The compound, the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form, the metabolite, the metabolic precursor, the isotopic replacement form, the pharmaceutically acceptable salt, the hydrate, the solvate, the polymorph or the co-crystal of the compound provided by the application can be used for preparing a drug for treating, alleviating or preventing Noonan syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumor, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal and colon cancer related diseases or disorders, which has great development value.

[0161] The compound provided by the application can be used for treating cancer caused by KRAS mutation, and the cancer caused by KRAS mutation is one or more of cancer caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutation.

[0162] The compound provided by the application can effectively block the binding of KRAS G12D protein and SOS1, and the compound provided by the application has obvious improvement in KRAS G12D inhibition activity, liver microsomal stability and rat pharmacokinetics.

[0163] The synthetic method provided by the application is simple in operation and high in yield. DETAILED DESCRIPTION

[0164] In order to enable those skilled in the art to better understand the technical solutions of the application, the application will be further described in detail below with specific examples.

[0165] In the application, the structure of the compound is determined by mass spectrometry (MS) and / or nuclear magnetic resonance (NMR) equipment. 1 The chemical abbreviations have the following meanings:

[0166] DMF: N,N-dimethylformamide

[0167] THF: tetrahydrofuran

[0168] DIPEA: N,N-diisopropylethylamine

[0169] PE: petroleum ether

[0170] EA: ethyl acetate

[0171] DCM: dichloromethane

[0172] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium

[0173] DMSO: dimethyl sulfoxide

[0174] Synthesis of intermediates

[0175] Preparation of Intermediate 1: tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0176]

[0177] Step 1: Synthesis of 2-chloro-3-fluoro-5-iodopyridin-4-amine

[0178] 2-chloro-3-fluoro-4-aminopyridine (14.60 g, 100 mmol) was dissolved in 200 mL of acetonitrile, p-toluenesulfonic acid (0.86 g, 5 mmol) was added at room temperature, and then NIS (24.75 g, 110 mmol) was added portionwise. After the addition was completed, the system was stirred at 70°C overnight. The reaction system was poured into 1000 mL of water, extracted with ethyl acetate, and the organic phase was washed twice with an aqueous solution of sodium sulfite and saturated brine, respectively. After drying and rotary evaporation, purification by FCC (PE / EA = 3 / 1) gave 25.00 g of yellow solid, yield: 92%.

[0179] Step 2: Synthesis of methyl 4-amino-6-chloro-5-fluoro-nicotinate

[0180] Into a reaction flask was added 2-chloro-3-fluoro-5-iodopyridin-4-amine (25.00 g, 91.9 mmol), triethylamine (30.30 g, 300 mmol), and 300 mL of methanol. After replacing the nitrogen, Pd(dppf)Cl2(3.66 g, 5 mmol) was added. The reaction mixture was heated to 80°C under a carbon monoxide atmosphere (2 atm) and stirred overnight. After cooling to room temperature, the reaction system was poured into 1000 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by silica gel column chromatography (PE / EA = 3 / 1) to give 14.50 g of yellow solid, yield: 78%.

[0181] Step 3: Synthesis of methyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0182] Into a reaction flask was added 2-chloro-3-fluoro-5-iodopyridin-4-amine (25.00 g, 91.9 mmol), triethylamine (30.30 g, 300 mmol), and 300 mL of methanol. After replacing the nitrogen, Pd(dppf)Cl2(3.66 g, 5 mmol) was added. The reaction mixture was heated to 80°C under a carbon monoxide atmosphere (2 atm) and stirred overnight. After cooling to room temperature, the reaction system was poured into 1000 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by silica gel column chromatography (PE / EA = 3 / 1) to give 14.50 g of yellow solid, yield: 78%.

[0183] Step 4: Synthesis of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol

[0184] To a solution of 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinic acid methyl ester (12.5 g, 31.8 mmol) in 100 mL of methanol was added ammonia / methanol solution (7 M, 20 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction was rotary evaporated and the crude product was purified by FCC (PE / EA = 3 / 1) to give 6.4 g of yellow solid, yield: 94%.

[0185] Step 5: Synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0186] To a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (6.4 g, 29.8 mmol) in 40 mL of phosphorus oxychloride was added DIPEA (19.3 g, 150 mmol) at room temperature. The reaction was stirred at 100 °C for 1 hour. The reaction was rotary evaporated and the crude product was used directly for the next step.

[0187] Step 6: Synthesis of (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0188] To a reaction flask was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (crude from previous step), DIPEA (25.8 g, 200 mmol) and 100 mL of dichloromethane. (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.6 g, 31 mmol) was added at -40 °C. The reaction was stirred at -40 °C for 1 hour. The reaction was poured into 1000 mL of water and extracted with ethyl acetate. The organic phase was dried and rotary evaporated. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give 8.1 g of yellow solid, yield: 64%.

[0189] Step 7: Synthesis of (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0190] To a reaction flask was added (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 1.2 mmol), DIPEA (313 mg, 2.5 mmol), (tetrahydro-1H-pyrazin-7a(5H)-yl)methanol (282 mg, 2.0 mmol) and 5 mL of dioxane, the mixture was stirred at 80 °C overnight. The reaction was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 250 mg of yellow solid, yield: 40%.

[0191] Preparation of Intermediate 2: 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane

[0192]

[0193] Step 1: Synthesis of 1-bromo-3-(methoxymethoxynaphthalene

[0194] To a solution of 4-bromonaphthalen-2-ol (10.0 g, 44.8 mmol), DIPEA (17.4 g, 134.5 mmol) in 100 mL of dichloromethane was added chloromethyl methyl ether (3.6 g, 45.0 mmol) dropwise at 0 °C, after the addition was completed, the mixture was stirred at room temperature for 1 hour. The reaction was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by silica gel column chromatography (PE / EA = 20 / 1) to give 11.5 g of yellow oil, yield: 96%.

[0195] Step 2: Synthesis of 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0196] To a reaction flask was added 1-bromo-3-(methoxymethoxynaphthalene (10.0 g, 37.5 mmol), bis(pinacolato)diboron (10.2 g, 40 mmol), potassium acetate (7.8 g, 80 mmol) and 100 mL of dioxane, after replacing with nitrogen, Pd(dppf)Cl2(1.5 g, 2 mmol) was added. The reaction mixture was heated to 80 °C under nitrogen protection and stirred overnight. After the reaction system was cooled to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by silica gel column chromatography (PE / EA = 10 / 1) to give 10.5 g of white solid, yield: 89%.

[0197] Preparation of Intermediate 3: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)naphthalen- 1 -yl)ethynyl)silane

[0198]

[0199] Step 1 : Synthesis of 8-((triisopropylsilyl)ethynyl)naphthalene- 1,3-diol

[0200] Into a reaction flask was added m-naphthalenediol (10.0 g, 62.5 mmol), (bromoethynyl)triisopropylsilane (19.6 g, 75.0 mmol), potassium acetate (12.3 g, 125.0 mmol) and 100 mL of dioxane, after purging with nitrogen, dichlorobis(4-methylisopropylphenyl)ruthenium(II) (3.8 g, 6.3 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen overnight. After the reaction was cooled to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 50 / 1) to give 11.5 g of yellow oil, yield: 89%.

[0201] Step 2: Synthesis of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- 1 -ol

[0202] Into a reaction flask was added m-naphthalenediol (10.0 g, 62.5 mmol), (bromoethynyl)triisopropylsilane (19.6 g, 75.0 mmol), potassium acetate (12.3 g, 125.0 mmol) and 100 mL of dioxane, after purging with nitrogen, dichlorobis(4-methylisopropylphenyl)ruthenium(II) (3.8 g, 6.3 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen overnight. After the reaction was cooled to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 50 / 1) to give 11.5 g of yellow oil, yield: 89%.

[0203] Step 3: Synthesis of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- 1 -yl trifluoromethanesulfonate

[0204] Into a reaction flask was added m-naphthalenediol (10.0 g, 62.5 mmol), (bromoethynyl)triisopropylsilane (19.6 g, 75.0 mmol), potassium acetate (12.3 g, 125.0 mmol) and 100 mL of dioxane, after purging with nitrogen, dichlorobis(4-methylisopropylphenyl)ruthenium(II) (3.8 g, 6.3 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen overnight. After the reaction was cooled to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 50 / 1) to give 11.5 g of yellow oil, yield: 89%.

[0205] Step 4: Synthesis of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane

[0206] Into a reaction flask was added 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl triflate (4.8 g, 9.3 mmol), bis(pinacolato)diboron (5.0 g, 19.7 mmol), potassium acetate (2.9 g, 29.6 mmol) and 50 mL of dioxane, after replacing nitrogen, Pd(dppf)Cl2(0.7 g, 1 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen protection overnight. After the reaction system was cooled to room temperature, it was poured into 200 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain 2.1 g of white solid, yield: 46%.

[0207] Preparation of intermediate 4: ((2-fluoro-6-(methoxymethoxy)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0208]

[0209] Step 1: Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0210] Into a reaction flask was added 7-fluoro-1,3-naphthalenediol (178 mg, 1.0 mmol), (bromoethynyl)triisopropylsilane (260 mg, 1.0 mmol), potassium acetate (196 mg, 2.0 mmol) and 5 mL of dioxane, after replacing nitrogen, dichlorobis(4-methylisopropylphenyl)ruthenium(II) (60 mg, 0.1 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen protection overnight. After the reaction system was cooled to room temperature, it was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 295 mg of yellow oil, yield: 82%.

[0211] Step 2: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0212] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1,3-diol (295 mg, 0.84 mmol) in dichloromethane (5 mL) was added DIPEA (319 mg, 2.47 mmol) at 0 °C, then MOMCI (67 mg, 0.84 mmol) was added dropwise. After 2 h at 0 °C, the reaction mixture was allowed to warm to room temperature. After the reaction was completed, the system was rotary evaporated, and purified by silica gel column (PE / EA = 20 / 1) to give 210 mg of light yellow solid with a yield of 62%.

[0213] Step 3: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0214] To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (210 mg, 0.52 mmol) in dichloromethane was added DIPEA (194 mg, 1.50 mmol) at -78 °C, then trifluoromethanesulfonic anhydride (169 mg, 0.60 mmol) was added dropwise. After 1 h, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, rotary evaporated, and purified by Prep-TLC (PE / EA = 20 / 1) to give 255 mg of light yellow solid with a yield of 81% for two steps.

[0215] Step 4: Synthesis of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0216] To a reaction flask was added 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (225 mg, 0.42 mmol), pinacol diborane (127 mg, 0.50 mmol), potassium acetate (98 mg, 1.00 mmol) and 5 mL of dioxane, and Pd(dppf)Cl2(15 mg, 0.02 mmol) was added after replacing with nitrogen. The reaction mixture was heated to 100 °C overnight under nitrogen protection. After the reaction mixture was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and purified by Prep-TLC (PE / EA = 20 / 1) to give 140 mg of white solid with a yield of 65%.

[0217] Preparation of Intermediate 5: 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0218]

[0219] Step 1: Synthesis of 4-methoxy-4-oxo-3-(triphenyl-phosphoranylidene) butyric acid

[0220] Triphenylphosphine (52.46 g, 200 mmol) was dissolved in acetonitrile (800 mL), and a solution of maleic anhydride (19.5 g, 200 mmol) in acetonitrile was added dropwise at room temperature. After the dropwise addition was completed in 30 minutes, the reaction was stirred at room temperature for 3 hours. A yellow solid was precipitated, which was filtered. The filter cake was collected and dried under vacuum. Then 800 mL of methanol was added, and the reaction was stirred at room temperature for 16 hours. After the solid was completely dissolved, the reaction was dried under vacuum to obtain 55 g of fluffy yellow solid, with a yield of 84%.

[0221] Step 2: Synthesis of 4-(2-bromo-4,5-difluorophenyl)-3-(methoxycarbonyl)but-3-enoic acid

[0222] 4-methoxy-4-oxo-3-(triphenyl-phosphoranylidene) butyric acid (8.9 g, 22.73 mmol) was dissolved in a mixture of toluene (50 mL) and dichloromethane (10 mL). A solution of 2-bromo-4,5-difluorobenzaldehyde (5 g, 22.73 mmol) in dichloromethane was added dropwise under nitrogen protection. The reaction was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, an aqueous sodium hydroxide solution was slowly added to the system, and stirred for 5 minutes. Ethyl acetate was added for extraction three times. The aqueous phase was collected, and then acidified and extracted with ethyl acetate. The organic phases were combined, washed with an aqueous sodium hydroxide solution, and then the aqueous phase was collected again, acidified and extracted. The obtained organic phase was dried and concentrated under vacuum to obtain 5.5 g of off-white solid, with a yield of 72%.

[0223] Step 3: Synthesis of methyl 4-acetyloxy-8-bromo-5,6-difluoro-2-naphthoate

[0224] In a single-neck flask, 4-(2-bromo-4,5-difluorophenyl)-3-(methoxycarbonyl)but-3-enoic acid (12 g, 35.9 mmol), sodium acetate (3.54 g, 43.2 mmol), and acetic anhydride (120 mL) were added. The reaction was carried out at 140°C for 6 hours. After the reaction was completed, the acetic anhydride in the system was dried under vacuum at 70°C. The black crude product was directly used in the next step after being quickly columned with petroleum ether: ethyl acetate = 1:1.

[0225] Step 4: Synthesis of methyl 8-bromo-5,6-difluoro-4-hydroxy-2-naphthoate

[0226] To the methanol (200 mL) solution of the crude product from the previous step, potassium carbonate (10.9 g, 76.8 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the system was dried under vacuum. The crude product was directly used in the next step.

[0227] Step 5: Synthesis of methyl 4-(benzyloxy)-8-bromo-5,6-difluoro-2-naphthoate

[0228] To the solution of the crude product from the previous step in DMF was added benzyl bromide (8 g, 46.7 mmol) dropwise. After the addition was complete, the reaction was stirred at room temperature for half an hour. After the reaction was complete, water was added to the system, and the product was extracted with ethyl acetate several times. The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated, and the residue was purified on a silica gel column (PE / EA = 50 / 1) to give 9.5 g of a yellow solid in a three-step yield of 65%.

[0229] Step 6: Synthesis of (4-(benzyloxy)-5,6-difluoronaphthalen-2-yl)methanol

[0230] To a solution of methyl 4-(benzyloxy)-8-bromo-5,6-difluoro-2-naphthoate (9.5 g, 23.4 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (1.3 g, 35.2 mmol) at -78 °C under nitrogen protection. After the reaction was carried out at low temperature for 1 hour, the temperature was slowly increased to room temperature, and the reaction was carried out at room temperature overnight. After the reaction was complete, the temperature was decreased to 0 °C, and the system was diluted with tetrahydrofuran. Water (2 mL), 15% sodium hydroxide solution (2 mL), and water (6 mL) were slowly added in sequence, and the temperature was increased to room temperature and stirred for 15 minutes. An appropriate amount of anhydrous sodium sulfate was added, and the system was stirred at room temperature for 15 minutes. After filtration through celite, the filtrate was evaporated to give 7.5 g of a light yellow solid. The crude product was directly used in the next step.

[0231] Step 7: Synthesis of 4-(benzyloxy)-5,6-difluoro-2-naphthaldehyde

[0232] To a solution of (4-(benzyloxy)-5,6-difluoronaphthalen-2-yl)methanol (7.5 g, 25 mmol) in dichloromethane was added manganese dioxide (20 g, 141 mmol), and the reaction was carried out at room temperature overnight. After the reaction was complete, the system was filtered through celite, and the filtrate was evaporated. The residue was purified on a silica gel column (PE / EA = 20 / 1) to give 5.5 g of a white solid in a yield of 73%.

[0233] Step 8: Synthesis of 4-(benzyloxy)-5,6-difluoronaphthalen-2-ol

[0234] To a solution of 4-(benzyloxy)-5,6-difluoro-2-naphthaldehyde (5.4 g, 18.1 mmol) in dichloromethane (54 mL) was added meta-chloroperoxybenzoic acid (11 g, 70 mmol) under nitrogen protection, and the reaction was carried out at room temperature overnight. After the reaction was complete, the system was directly filtered, and the filter cake was washed with a small amount of dichloromethane. The filtrate was evaporated, dissolved in ethyl acetate, and added dropwise to an aqueous sodium carbonate solution. After stirring for 1 hour, the product was extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated. The crude product was directly used in the next step.

[0235] Step 9: Synthesis of 8-(benzyloxy)-l,2-difluoro-6- (methoxymethoxy)naphthalene

[0236] To the solution of the crude product from the previous step in dichloromethane (50 mL) was added DIPEA (4.7 g, 36.4 mmol) at 0 °C, and MOMCI (1.2 g, 14.8 mmol) was added dropwise. After 2 h at 0 °C, the reaction was allowed to warm to room temperature. After the reaction was completed, the system was rotary evaporated, and purified by silica gel column (PE / EA = 20 / 1) to give 540 mg of light yellow solid with 9% yield over two steps.

[0237] Step 10: Synthesis of 7,8-difluoro-3-(methoxymethoxy)naphthalen-l-ol

[0238] To the solution of 8-(benzyloxy)-l,2-difluoro-6- (methoxymethoxy)naphthalene (540 mg, 1.6 mmol) in methanol was added palladium on carbon (10%, 50 mg), and hydrogen was replaced. The reaction was allowed to proceed for 3 h under hydrogen atmosphere. After the reaction was completed, the system was filtered through celite, and the filter cake was washed with methanol. The filtrate was rotary evaporated to give the crude product. No further purification was performed.

[0239] Step 11: Synthesis of 7,8-difluoro-3-(methoxymethoxy)naphthalen-l-yl trifluoromethanesulfonate

[0240] To the solution of the crude product from the previous step in dichloromethane was added DIPEA (645 mg, 5 mmol) at -78 °C, and trifluoromethanesulfonic anhydride (517 mg, 1.83 mmol) was added dropwise. After 1 h, the reaction was quenched with water, and extracted with ethyl acetate. The combined organic phase was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column (PE / EA = 20 / 1) to give 420 mg of light yellow solid with 69% yield over two steps.

[0241] Step 12: Synthesis of 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0242] To a reaction flask was added 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (372 mg, 1.0 mmol), bis(pinacolato)diboron (254 mg, 1.0 mmol), potassium acetate (196 mg, 2.0 mmol) and 5 mL of dioxane, after replaced with nitrogen, Pd(dppf)Cl2(37 mg, 0.05 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen overnight. After the reaction mixture was cooled to room temperature, it was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 20 / 1) to give 240 mg of white solid, yield: 69%.

[0243] Preparation of Intermediate 6: (1R,5S)-3-(7-chloro-8-fluoro-2-(((2S,3aR)-2- fluorohexahydro-pent-3a(lH)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0244]

[0245] To a reaction flask was added (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 1.2 mmol), DIPEA (313 mg, 2.5 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (318 mg, 2.0 mmol) and 5 mL of dioxane, the mixture was stirred at 80 °C overnight. The reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 275 mg of yellow solid, yield: 43%.

[0246] Preparation of Intermediate 7: (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0247]

[0248] Step 1: Synthesis of 7-bromo-8-fluoroquinazoline-2,4-diol

[0249] Into a reaction vial was placed 2-amino-4-bromo-3-fluorobenzoic acid (1.0 g, 4.27 mmol), urea (3.0 g, 50.00 mmol), the reaction was heated to 170 °C and stirred for 4 h. The reaction was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5 / 1) to give 675 mg of the target product in 61% yield.

[0250] Step 2: Synthesis of 7-bromo-2,4-dichloro-8-fluoroquinazoline

[0251] Into a reaction vial was placed 7-bromo-8-fluoroquinazoline-2,4-diol (300 mg, 1.16 mmol), phosphorus oxychloride (1.5 g, 9.80 mmol), and DIEA (650 mg, 5.04 mmol). The reaction was heated to 90 °C and stirred for 3 h. The reaction was cooled to room temperature, and the filtrate was concentrated under reduced pressure to give a crude product, which was used directly in the next step.

[0252] Step 3: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0253] Into a reaction vial was placed the crude product from the previous step, DIEA (650 mg, 5.04 mmol), and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.95 mmol) and 30 mL of anhydrous ethanol. The reaction was heated to 80 °C and stirred for 4 h. The reaction was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 8 / 1) to give 190 mg of the target product in 35% yield over two steps.

[0254] Example 1

[0255] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(difluoro(phenyl)methyl)phenol

[0256]

[0257] Step 1: Synthesis of (3-bromo-5-methoxyphenyl)(phenyl)methanol

[0258] To a solution of 3-bromo-5-methoxybenzaldehyde (2.15 g, 10.0 mmol) in 20 mL of THF was added dropwise phenylmagnesium bromide (1 M, 11 mL, 11.0 mmol) at 0 °C under nitrogen protection. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into 100 mL of water. The organic phase was dried and rotary evaporated. The residue was purified by column chromatography on silica gel (PE / EA = 10 / 1) to give 2.8 g of a light yellow solid in 96% yield.

[0259] Step 2: Synthesis of (3-bromo-5-methoxyphenyl)(phenyl)methanone

[0260] To a solution of (3-bromo-5-methoxyphenyl)(phenyl)methanol (2.8 g, 9.6 mmol) in 50 mL of dichloromethane was added activated manganese dioxide (4.4 g, 50.6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was rotary evaporated. The residue was purified by column chromatography on silica gel (PE / EA = 50 / 1) to give 2.6 g of a light yellow solid in 93% yield.

[0261] Step 3: Synthesis of (3-bromo-5-hydroxyphenyl)(phenyl)methanone

[0262] To a solution of (3-bromo-5-methoxyphenyl)(phenyl)methanol (2.8 g, 9.6 mmol) in 50 mL of dichloromethane was added activated manganese dioxide (4.4 g, 50.6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was rotary evaporated. The residue was purified by column chromatography on silica gel (PE / EA = 50 / 1) to give 2.6 g of a light yellow solid in 93% yield.

[0263] Step 4: Synthesis of (3-bromo-5-((4-methoxybenzyl)oxy)phenyl)(phenyl)methanone

[0264] To a solution of (3-bromo-5-hydroxyphenyl)(phenyl)methanone (277 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in 50 mL of acetonitrile was added dropwise p-methoxybenzyl bromide (241 mg, 1.2 mmol) at 0 °C. The mixture was stirred at room temperature for 5 h. The mixture was filtered and the filtrate was dried to give 370 mg of a yellow solid in 93% yield.

[0265] Step 5: Synthesis of 1-bromo-3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)benzene

[0266] To a reaction flask was added (3-bromo-5-((4-methoxybenzyl)oxy)phenyl)(phenyl)methanone (370 mg, 0.9 mmol) and 1 mL bis(2-methoxyethyl)aminosulfur trifluoride. The reaction mixture was stirred at 80 °C for 2 hours. The reaction was poured into 10 mL ice water and extracted with ethyl acetate. The organic phase was dried and rotary evaporated. Purification by Prep-TLC (PE / EA = 30 / 1) gave 80 mg of yellow solid in 21% yield.

[0267] Step 6: Synthesis of 2-(3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0268] To a reaction flask was added l-bromo-3-(difluoro(phenyl)methyl)-5-((4- methoxybenzyl)oxy)benzene (60 mg, 0.14 mmol), pinacol diborane (38 mg, 0.15 mmol), potassium acetate (29 mg, 0.30 mmol) and 2 mL dioxane. After replacing the nitrogen gas with 10 mg Pd(dppf)Cl2. The reaction mixture was heated to 100 °C for 6 hours under nitrogen protection. After cooling to room temperature, the reaction was poured into 10 mL water and extracted with ethyl acetate. The organic phase was dried and rotary evaporated. Purification by Prep-TLC (PE / EA = 20 / 1) gave 60 mg of yellow solid in 90% yield.

[0269] Step 7: Synthesis of (lR,5S)-3-(7-(3-(difluoro(phenyl)methyl)-5-((4- methoxybenzyl)oxy)phenyl)-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0270] To a reaction vial was added (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (67 mg, 0.13 mmol), 2-(3-(difluoro(phenyl)methyl)-5-((4- methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (60 mg, 0.13 mmol), potassium carbonate (40 mg, 0.29 mmol) and dioxane / water (2 mL / 0.2 mL), 5 mg Pd(dppf)Cl2 was added after purging with nitrogen. The reaction mixture was heated to 100 °C for 6 h under nitrogen. The reaction was cooled to room temperature and poured into 10 mL water, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 17 mg of gray solid, yield: 16%.

[0271] Step 8: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro- 1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(difluoro(phenyl)methyl)phenol

[0272] (1R,5S)-3-(7-(3-(difluoro(phenyl)methyl)-5-((4-methoxybenzyl)oxy)phenyl)-8-fluoro-2- ((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (17 mg, 0.02 mmol) was dissolved in 2 mL ethyl acetate, HCl / EA (4 M, 1 mL) was added at room temperature and stirred for 0.5 h. The reaction was concentrated, 2 mL sodium carbonate aqueous solution was added, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 8 / 1) to give 4 mg of gray solid, yield: 31%.

[0273] LC / MS: m / z = 617.3 [M+H] + .

[0274] Example 2

[0275] 5-ethynyl-4-(8-fluoro-4-((1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)amino)-2- ((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0276]

[0277] Step 1: Synthesis of 4-oxocyclohexane-1,1,3-tricarboxylic acid triethyl ester

[0278] NaH (8.56 g, 357 mmol) was weighed into dry THF (80 mL) and warmed to 40-45 °C. Diethyl malonate (22.85 g, 149 mmol) in THF was added dropwise and the reaction was stirred at this temperature for 15 min. Ethyl acrylate was added dropwise and the reaction was stirred for a further 15 min. The reaction was cooled to room temperature and added to ice water. The pH was adjusted to 3 with concentrated HCl and the mixture was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give a colorless oil (37.6 g, 83%).

[0279] Step 2: Synthesis of 4-oxocyclohexane-1,1-dicarboxylic acid diethyl ester

[0280] Triethyl 4-oxocyclohexane-1,1,3-tricarboxylate (37.6 g, 120 mmol) and sodium chloride (20.97 g, 359 mmol) were added to DMSO (170 mL) and H2O (5 mL) and the reaction was stirred at 160 °C for 1.7 h. The reaction was cooled and added to ice water. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give a colorless oil (21.6 g, 75%).

[0281] Step 3: Synthesis of 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylic acid diethyl ester

[0282] Diethyl 4-oxocyclohexane-1,1-dicarboxylate (21.6 g, 89.2 mmol), ethylene glycol (6.64 g, 107 mmol) and p-toluenesulfonic acid-hydrate (169 mg, 0.89 mmol) were added to toluene (180 mL) and the reaction was stirred at 120 °C for 4 h. The reaction was cooled and added to saturated aqueous NaHCO3solution. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give a light yellow liquid (23.7 g, 93%).

[0283] Step 4: Synthesis of (1,4-dioxaspiro[4.5]decane-8,8-diyl)dimethanol

[0284] Into a three-necked flask, LAH (6.47 g, 166 mmol) was weighed, and anhydrous THF (150 mL) was added. After nitrogen was bubbled through the solution for 10 min, the ice-salt bath was removed, and a solution of diethyl 1,4-dioxaspiro[4.5]decan-8,8-diyl dicarboxylate (23.7 g, 82.8 mmol) in THF (100 mL) was added dropwise. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 5 h. H2O / THF (1:1, 30 mL) was added dropwise to the reaction mixture with ice-water bath cooling. Then 5 N NaOH aqueous solution (8 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM / MeOH (5:1, 250 mL), filtered, and rinsed with DCM / MeOH (5:1). The filtrate was concentrated under reduced pressure to give the product (16.7 g, 99%).

[0285] Step 5: Synthesis of (1,4-dioxaspiro[4.5]decan-8,8-diyl)bis(methylene)bis(4- methylbenzenesulfonate)

[0286] Into a three-necked flask, (1,4-dioxaspiro[4.5]decan-8,8-diyl)dimethanol (16.7 g, 82.6 mmol) was weighed, and pyridine (100 mL) was added. TsCl (34.6 g, 182 mmol) was added with ice-water bath cooling, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 10% citric acid solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was slurried with ethanol to give a white solid (35 g, 83%).

[0287] Step 6: Synthesis of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4- methylbenzenesulfonate)

[0288] Into a three-necked flask, (1,4-dioxaspiro[4.5]decan-8,8-diyl)bis(methylene)bis(4- methylbenzenesulfonate) (35 g, 68.5 mmol) was weighed, and 1 N HCl solution (260 mL) and THF (300 mL) were added. The reaction mixture was stirred at 80°C for 5 h. The reaction mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target product was purified by column chromatography (26.2 g, 82%).

[0289] Step 7: Synthesis of ((4-(1,3-dithian-2-yl)-4-hydroxycyclohexane-1,1-diyl)bis(methylene)bis(4- methylbenzenesulfonate)

[0290] To a reaction flask was added compound 1,3-dithiane (2.1 g, 17.4 mmol), anhydrous THF (40 mL), nitrogen sparge, and dropwise addition of n-butyllithium (2.5 M, 8.5 mL) with dry ice-ethanol bath cooling. After dropwise addition was complete, the reaction was allowed to warm to 0 °C for 1 h. After cooling with a dry ice-ethanol bath, a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (6.5 g, 13.9 mmol) in THF was added dropwise, and the reaction was allowed to warm to room temperature for 1 h. The reaction was quenched by addition to saturated NH4Cl solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (1:1 hexanes:ethyl acetate) to give the title compound (6.77 g, 83%).

[0291] Step 8: Synthesis of (1-(1,3-dithian-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4- methylbenzenesulfonate

[0292] To a reaction flask was added ((4-(1,3-dithian-2-yl)-4-hydroxycyclohexane-1,1- diyl)bis(methylene)bis(4-methylbenzenesulfonate) (6.77 g, 11.5 mmol), NaOH (1.38 g, 34.6 mmol), THF (170 mL), and the reaction was refluxed at 70 °C overnight. The reaction was cooled to room temperature, water was added, and the reaction was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (1:1 hexanes:ethyl acetate) to give the title compound (3.7 g, 77%).

[0293] Step 9: Synthesis of ((1-formyl-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4- methylbenzenesulfonate

[0294] To a reaction flask was added (1-(1,3-dithian-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4- methylbenzenesulfonate (3.7 g, 8.92 mmol), acetonitrile (50 mL), and water (12.5 mL), and NBS (5.56 g, 31.2 mmol) was added with ice water bath cooling. After addition was complete, the reaction was allowed to warm to room temperature for 3 h. The reaction was quenched by addition to saturated NaHCO3 solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was used without further purification.

[0295] Step 10: Synthesis of (1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4- methylbenzenesulfonate

[0296] The above obtained crude product was dissolved in ethanol, NaBH4(508 mg, 13.4 mmol) was added under ice water bath, and the reaction was allowed to warm to room temperature for 1 h. The reaction was quenched by adding saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target product was obtained by column chromatography (2.66 g, 91% yield over two steps).

[0297] Step 11 : Synthesis of (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4- yl)methyl 4-methylbenzenesulfonate

[0298] To a reaction flask was added (1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4- methylbenzenesulfonate (2.56 g, 7.84 mmol), DMAP (287 mg, 2.35 mmol), imidazole (1.06 g, 15.7 mmol) and DMF (15 mL), followed by the addition of TBDPSCl (2.59 g, 9.41 mmol) and allowed to react at room temperature for 0.5 h. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was combined and back-extracted with saturated NaCl solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target product was obtained by column chromatography (4.0 g, 90%).

[0299] Step 12: Synthesis of (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4- yl)methanol

[0300] To a reaction flask was added (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4- yl)methyl 4-methylbenzenesulfonate (4.0 g, 7.08 mmol) and methanol (120 mL), followed by the addition of Mg (1.89 g, 77.9 mmol) under stirring at room temperature. After 30 min, the reaction was exothermic and was allowed to stir overnight. The reaction was quenched by adding saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target product was obtained by column chromatography (2.4 g, 83%).

[0301] Step 13: Synthesis of 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4- carboxylic acid

[0302] To a reaction flask was added (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2- oxabicyclo[2.2.2]octan-4-yl)methanol (2.4 g, 5.85 mmol) and DMF (30 mL), PDC (6.6 g, 17.6 mmol) was added under ice water bath, after addition, it was moved to room temperature and reacted for 2 h. To the reaction flask was added ethyl acetate to dilute the reaction solution, water was added to extract, the organic phase was combined, saturated NaCl solution was used to backwash the organic phase, anhydrous sodium sulfate was used for drying, filtration was performed, and concentration was performed under reduced pressure. Column chromatography purification was performed to obtain the target product (1.99 g, 80%).

[0303] Step 14: Synthesis of 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4-amine

[0304] To a reaction flask was added 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4-carboxylic acid (1.0 g, 2.35 mmol), DPPA (688 mg, 2.50 mmol), 2 mL of tert-butyl alcohol and 10 mL of toluene, the reaction system was stirred at 100°C overnight. After cooling to room temperature, 0.5 mL of concentrated hydrochloric acid was added, and stirring was continued for 10 minutes. The reaction system was poured into 50 mL of water, the pH value was adjusted to basic with sodium carbonate, and the organic phase was dried and rotary evaporated, and then purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 60 mg of yellow oil, yield: 6%.

[0305] Step 15: Synthesis of N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-amine

[0306] 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4-amine (50 mg, 0.13 mmol), 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (33 mg, 0.13 mmol) and DIPEA (39 mg, 0.30 mmol) were dissolved in 2 mL of dichloromethane, and stirred at room temperature for 6 hours. The reaction system was poured into 10 mL of water, dichloromethane was used for extraction, the organic phase was dried and rotary evaporated, and then purified by Prep-TLC (DCM / MeOH = 50 / 1) to obtain 60 mg of yellow solid, yield: 76%.

[0307] Step 16: Synthesis of N-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine

[0308] To a solution of (tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (21 mg, 0.15 mmol) in 2 mL of THF was added NaH (60%, 8 mg, 0.20 mmol) at room temperature. After the resulting reaction mixture was stirred at room temperature for 1 hour, N-(l-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-amine (60 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated to dryness. Purification by Prep-TLC (DCM / MeOH = 20 / 1) gave 33 mg of yellow solid in 46% yield.

[0309] Step 17: Synthesis of N-(l-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl))ethynyl)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine

[0310] To a reaction flask was added N-(l-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]oct-4-yl)-7-chloro-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (33 mg, 0.046 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)silane (25 mg, 0.051 mmol), potassium carbonate (14 mg, 0.100 mmol) and dioxane / water (2 mL / 0.2 mL). After the replacement of nitrogen, 5 mg of Pd(dppf)Cl2was added. The reaction mixture was heated to 100 °C under nitrogen for 6 hours. After the reaction mixture was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated to dryness. Purification by Prep-TLC (DCM / MeOH = 20 / 1) gave 17 mg of gray solid in 35% yield.

[0311] Step 18: Synthesis of (4-((7-(8-ethynyl-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-2-oxabicyclo[2.2.2]oct-l-yl)methanol

[0312] N-(l-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-8- fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl))ethynyl)naphthalen-l-yl)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (10 mg, 0.0095 mmol) was dissolved in 1 mL of DMF, CsF (10 mg) was added at room temperature and stirred overnight. The reaction was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and evaporated, the crude was used directly in the next step.

[0313] Step 19: Synthesis of 5-ethynyl-4-(8-fluoro-4-((l-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)amino)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0314] The crude from previous step was dissolved in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added and stirred for 10 minutes. The reaction was evaporated, purified by Prep-HPLC to give 1 mg of a grey solid, two steps yield: 17%.

[0315] LC / MS: m / z = 610.3 [M+H] + .

[0316] 1 HNMR

[0317] Example 3

[0318] 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(difluoro(phenyl)methyl)phenyl)- 8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0319]

[0320] Step 1: Synthesis of l-bromo-4-(difluoro(phenyl)methyl)benzene

[0321] To a reaction tube was added (4-bromophenyl)(phenyl)methanone (300 mg, 1.15 mmol) and BAST (3 mL), the reaction tube was sealed and heated to 90 °C overnight. The reaction was cooled, poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated under vacuum and purified by silica gel prep. to give 270 mg of product, yield: 83%.

[0322] Step 2: Synthesis of 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0323] Into a reaction flask was added 1-bromo-4-(difluoro(phenyl)methyl)benzene (1.0 g, 3.5 mmol), bis(pinacolato)diboron (1.3 g, 5.1 mmol), potassium acetate (1.0 g, 10.2 mmol) and 15 mL of dioxane, after replaced with nitrogen, Pd(dppf)Cl2(146 mg, 0.2 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen protection for 6 hours. After the reaction system was cooled to room temperature, it was poured into 100 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain 970 mg of white solid, yield: 75%.

[0324] Step 3: Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(difluoro(phenyl)methyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0325] The target product was synthesized by a similar method to Example 1 using the product obtained in the above step and the corresponding intermediate as raw materials.

[0326] LC / MS: m / z = 601.3 [M+H] + .

[0327] Example 4

[0328] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(difluoro(phenyl)methyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0329]

[0330] Step 1: Synthesis of 3-bromo-4,5-difluoro-1H-indole

[0331] Into a reaction flask was added 1-bromo-4-(difluoro(phenyl)methyl)benzene (1.0 g, 3.5 mmol), bis(pinacolato)diboron (1.3 g, 5.1 mmol), potassium acetate (1.0 g, 10.2 mmol) and 15 mL of dioxane, after replaced with nitrogen, Pd(dppf)Cl2(146 mg, 0.2 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen protection for 6 hours. After the reaction system was cooled to room temperature, it was poured into 100 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain 970 mg of white solid, yield: 75%.

[0332] Step 2: Synthesis of 3-bromo-4, 5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-indole

[0333] The product from previous step was dissolved in 5 mL THF, NaH (60%, 120 mg, 3.0 mmol) was added at 0 °C, after stirring at room temperature for 0.5 h, SEM-Cl (367 mg, 2.2 mmol) was added. The reaction was stirred at room temperature for 3 h. The reaction was poured into 50 mL water, extracted with ethyl acetate, the organic phase was dried and concentrated. Purification by column chromatography gave 400 mg colorless oil, two steps yield: 85%.

[0334] Step 3: Synthesis of 4, 5-difluoro-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

[0335] Into a reaction vial was placed 3-bromo-4, 5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole (100 mg, 0.28 mmol), bis(pinacolato)diboron (102 mg, 0.40 mmol), potassium acetate (59 mg, 0.60 mmol) and 3 mL dioxane, after replacing with nitrogen, Pd(dppf)Cl2(7 mg, 0.01 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen for 6 h. After cooling to room temperature, the reaction was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by column chromatography (PE / EA = 5 / 1) to give 20 mg gray solid, yield: 18%.

[0336] Step 4: Synthesis of 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-7-(4, 5-difluoro-1H- indol-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4, 3- d]pyrimidine

[0337] The target product was synthesized by a similar method to Example 1, using the product from the previous step and the corresponding intermediate as starting materials.

[0338] LC / MS: m / z = 550.2 [M+H] + .

[0339] Example 5

[0340] 4-(4-((1R, 5S)-8, 8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4, 3-d]pyrimidin-7-yl)-5- ethynyl naphthalen-2-ol

[0341]

[0342] Step 1: Synthesis of (1R,5S)-3-benzyl-8,8-difluoro-3-azabicyclo[3.2.1]octane

[0343] DAST (300 mg, 1.8 mmol) was added dropwise to a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (250 mg, 1.2 mmol) in 5 mL of dichloromethane at 0 °C. After the addition was completed, the mixture was allowed to warm to room temperature slowly and stirred for 5 h. The mixture was dropped into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 20 / 1) to give 215 mg of the target product as a colorless oily liquid in 78% yield.

[0344] Step 2: Synthesis of (1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octane

[0345] PdOH / C (10%, 20 mg) and 1 mL of methanolic hydrochloric acid solution (4 M) were added to a solution of (1R,5S)-3-benzyl-8,8-difluoro-3-azabicyclo[3.2.1]octane (200 mg, 0.8 mmol) in 5 mL of methanol. The reaction mixture was stirred at room temperature under 2 atm of H2for 4 h. The mixture was filtered and the filtrate was rotary evaporated to give 140 mg of the crude product in 84% yield.

[0346] Step 3: Synthesis of 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl naphthalen-2-ol

[0347] The target product was synthesized by a similar method to Example 2 using the product from the previous step and the corresponding intermediate as the starting materials.

[0348] LC / MS: m / z = 600.3 [M+H] + .

[0349] Example 6

[0350] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-5,8- methenoindolizin-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0351]

[0352] Step 1: Synthesis of 2-(tert-butyl) 3-methyl 2-azabicyclo[2.2.1]heptane-2,3- dicarboxylate

[0353] Into a reaction flask was added 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3- carboxylic acid (5000 mg, 20.7 mmol), potassium carbonate (5726 mg, 41.5 mmol) and 50 mL of DMF, and iodomethane (3535 mg, 24.9 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 6 hours, and TLC showed that the reaction was complete. The system was filtered, the filtrate was collected, 250 mL of water was added, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried, and rotary evaporated. Purification was performed by silica gel column chromatography (PE / EA = 50 / 1 ~ 20 / 1), and 5 g of the target product was obtained with a yield of 94%.

[0354] Step 2: Synthesis of 2-(tert-butyl) 3-methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-2,3- dicarboxylate

[0355] Into a reaction flask was added 2-(tert-butyl) 3-methyl 2-azabicyclo[2.2.1]heptane-2,3- dicarboxylate (1000 mg, 3.9 mmol) and 10 mL of THF. The reaction mixture was cooled to -70°C, and LDA (2M, 2 mL, 4.0 mmol) was added dropwise at -70°C. After the addition was completed, stirring was continued for 1 hour, and 1,3-dibromopropane (1188 mg, 5.9 mmol) was added dropwise. After 10 minutes of stirring after the addition was completed, the system was moved to room temperature and reacted for 2 hours. TLC showed that the reaction was complete. The reaction system was poured into 50 mL of water, and extraction was performed with ethyl acetate. The organic phase was dried and rotary evaporated. Purification was performed by silica gel column chromatography (PE / EA = 20 / 1 ~ 5 / 1), and 1.2 g of the target product was obtained with a yield of 82%.

[0356] Step 3: Synthesis of methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate

[0357] Into a reaction flask was added 2-(tert-butyl) 3-methyl 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1200 mg, 3.2 mmol) and a 1.4-dioxane solution of hydrogen chloride (4M, 12 mL). The reaction mixture was stirred at room temperature for 2 hours, and TLC showed that the reaction was complete. The reaction system was rotary evaporated, and the hydrochloride salt was directly used in the next reaction.

[0358] Step 4: Synthesis of methyl hexahydro-5,8-methanoindolizine-8a(1H)-carboxylate

[0359] To a reaction flask was added 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-3- carboxylic acid methyl ester (the product of Step 3), potassium carbonate (1325 mg, 9.6 mmol) and 10 mL of acetonitrile. The reaction mixture was stirred at room temperature for 4 hours. TLC showed the reaction was complete. The reaction was filtered, the filtrate was dried and concentrated in vacuo and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 611 mg of the desired product. The overall yield for Steps 3 and 4 was 98%.

[0360] Step 5: Synthesis of (hexahydro-5,8-methanoindolizine-8a(lH)-yl)methanol

[0361] To a reaction flask was added 3-(3-bromopropyl)-2-azabicyclo[2.2.1]heptane-3- carboxylic acid methyl ester (the product of Step 3), potassium carbonate (1325 mg, 9.6 mmol) and 10 mL of acetonitrile. The reaction mixture was stirred at room temperature for 4 hours. TLC showed the reaction was complete. The reaction was filtered, the filtrate was dried and concentrated in vacuo and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 611 mg of the desired product. The overall yield for Steps 3 and 4 was 98%.

[0362] Step 6: Synthesis of tert-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-((hexahydro-5,8- methanoindolizine-8a(lH)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate

[0363] To a solution of (hexahydro-5,8-methanoindolizine-8a(lH)-yl)methanol (84 mg, 0.50 mmol) in 2 mL of THF was added NaH (60%, 40 mg, 1.0 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. Then, tert-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (214 mg, 0.50 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 70 mg of yellow solid. The yield was 25%.

[0364] Step 7: Synthesis of tert-butyl (1R, 5S)-3-(8-fluoro-2-((hexahydro-5,8- methenoindolizine-8a(1H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0365] To a reaction vial was added tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-((hexahydro-5,8- methenoindolizine-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (70 mg, 0.13 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (40 mg, 0.13 mmol), potassium carbonate (40 mg, 0.29 mmol) and dioxane / water (2 mL / 0.2 mL), 5 mg Pd(dppf)Cl2 was added after purging with nitrogen. The reaction mixture was heated to 100 °C for 6 h under nitrogen. The reaction mixture was cooled to room temperature and poured into 10 mL water, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 35 mg of gray solid, yield: 39%.

[0366] Step 8: Synthesis of 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-5,8- methenoindolizine-8a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0367] Tert-butyl (1R, 5S)-3-(8-fluoro-2-((hexahydro-5,8-methenoindolizine-8a(1H)-yl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.05 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 M, 1 mL) was added at room temperature and stirred for 0.5 h. The reaction mixture was concentrated, 2 mL of sodium carbonate aqueous solution was added, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 8 / 1) to give 16 mg of gray solid, yield: 57%.

[0368] LC / MS: m / z = 567.3 [M+H] + .

[0369] Example 7

[0370] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-ol

[0371]

[0372] Step 1: Synthesis of 4-bromo-1-((4-methoxybenzyl)oxy)isoquinoline

[0373] Into a reaction flask was added 4-bromo-1-chloroisoquinoline (300 mg, 1.24 mmol), potassium tert-butoxide (279 mg, 2.48 mmol) and (4-methoxyphenyl)methanol (859 mg, 6.22 mmol), the reaction mixture was heated to 80 °C and stirred for 3 hours, TLC showed that the reaction was complete. After the reaction system was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 400 mg of the target product, yield: 94%.

[0374] Step 2: Synthesis of 1-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

[0375] Into a reaction flask was added 4-bromo-1-((4-methoxybenzyl)oxy)isoquinoline (400 mg, 1.17 mmol), bis(pinacolato)diboron (889 mg, 3.51 mmol), potassium acetate (343 mg, 3.51 mmol) and 5 mL of 1,4-dioxane, after replacing with nitrogen, Pd(dppf)Cl2 (170 mg, 0.23 mmol) was added, the reaction mixture was heated to 90 °C and stirred overnight under nitrogen protection. After the reaction system was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 290 mg of the target product, yield: 64%.

[0376] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-ol

[0377] The target product was synthesized by the similar method of Example 1 using the product obtained in the above step and the corresponding intermediate as raw materials.

[0378] LC / MS: m / z = 542.3 [M+H] + .

[0379] Example 8

[0380] 3-((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-yl)oxy)propane-1,2- diol

[0381]

[0382] Step 1: Synthesis of 4-bromo-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isoquinoline

[0383] Into a reaction flask was added 4-bromo-1-chloroisoquinoline (1000 mg, 4.15 mmol), potassium tert-butoxide (929 mg, 8.30 mmol) and acetone glycerol (2.74 g, 20.75 mmol), the reaction mixture was heated to 80 °C and stirred for 3 hours, TLC showed that the reaction was complete. After the reaction system was cooled to room temperature, it was poured into 50 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 700 mg of the target product, yield: 50%.

[0384] Step 2: Synthesis of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2- dioxolan-2-yl)isoquinoline

[0385] Into a reaction flask was added 4-bromo-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isoquinoline (200 mg, 0.59 mmol), bis(pinacolato)diboron (452 mg, 1.78 mmol), potassium acetate (174 mg, 1.78 mmol) and 5 mL of 1,4-dioxane, Pd(dppf)Cl2 (87 mg, 0.12 mmol) was added after replacing nitrogen, the reaction mixture was heated to 90 °C and stirred overnight under nitrogen protection. After the reaction system was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 180 mg of the target product, yield: 79%.

[0386] Step 3: Synthesis of 3-((4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)isoquinolin-1-yl)oxy)propane-1,2- diol

[0387] The target product was synthesized by a similar method to Example 1, using the product from the previous step and the corresponding intermediate as starting materials.

[0388] LC / MS: m / z = 616.3 [M+H] + .

[0389] Example 9

[0390] 4-(8-Fluoro-4-(2-(hydroxymethyl)morpholino)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0391]

[0392] Step 1: Synthesis of (4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)morpholin-2- yl)methanol

[0393] To a reaction flask was added morpholin-2-ylmethanol (59 mg, 0.50 mmol), DIPEA (155 mg, 1.20 mmol) and 5 mL of tetrahydrofuran, a solution of 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (100 mg, 0.40 mmol) in 1.5 mL of tetrahydrofuran was added at -40 °C, the reaction mixture was stirred at -40 °C for 2 hours. The reaction was poured into 15 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (DCM / MeOH = 50 / 1) to give 80 mg of the target product, yield: 60%.

[0394] Step 2: Synthesis of (4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol

[0395] To a solution of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (71 mg, 0.50 mmol) in 2 mL of THF was added NaH (60%, 40 mg, 1.0 mmol) at room temperature, the resulting reaction solution was stirred at room temperature for 1 hour, then (4-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol (80 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 63 mg of yellow solid, yield: 60%.

[0396] Step 3: Synthesis of (4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin- 2-yl)methanol

[0397] To a reaction vial was added (4-(7-chloro-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol (44 mg, 0.10 mmol), 2-(3- (methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (31 mg, 0.10 mmol), potassium carbonate (28 mg, 0.20 mmol) and dioxane / water (2 mL / 0.2 mL), after purging with nitrogen, Pd(dppf)Cl2(7 mg, 0.01 mmol) was added. The reaction mixture was heated to 100 °C for 6 h under nitrogen. After cooling to room temperature, the reaction mixture was poured into 10 mL water, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 25 mg of yellow solid, yield: 42%.

[0398] Step 4: Synthesis of 4-(8-fluoro-4-(2-(hydroxymethyl)morpholino)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol

[0399] To a reaction vial was added (4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin- 2-yl)methanol (25 mg, 0.04 mmol) was dissolved in 2 mL ethyl acetate, after adding HCl / EA (4 M, 1 mL) at room temperature, stirred for 0.5 h. The reaction mixture was concentrated, 2 mL sodium carbonate aqueous solution was added, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 8 / 1) to give 12 mg of gray solid, yield: 52%.

[0400] LC / MS: m / z = 546.2 [M+H] + .

[0401] Example 10

[0402] 1-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-4-ol

[0403]

[0404] Step 1: Synthesis of 6-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2- ((tetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-6- azaspiro[2.5]octane

[0405] To a solution of trimethylsulfoxonium iodide (22 mg, 0.10 mmol) in 1 mL of DMSO was added potassium tert-butoxide (13 mg, 0.12 mmol), after stirring at room temperature for 10 minutes, 1-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrozin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (30 mg, 0.05 mmol, synthesized by a similar method to Example 9) was added, and stirring at room temperature was continued for 20 minutes. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 6 mg of the target product, yield: 20%.

[0406] Step 2: Synthesis of l-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH- pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(hydroxymethyl)piperidin-4- ol

[0407] 6-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrozin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-6-azaspiro[2.5]octane (25 mg, 0.04 mmol) was dissolved in 1 mL of THF and 0.5 mL of water, 0.2 mL of trifluoroacetic acid was added at room temperature, and the reaction was stirred for 1 hour. The reaction mixture was poured into 5 mL of an aqueous sodium carbonate solution, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by Prep-TLC (DCM / MeOH = 8 / 1) to give 6 mg of a gray solid, yield: 25%.

[0408] LC / MS: m / z = 560.3 [M+H] + .

[0409] Example 11

[0410] 4-(Aminomethyl)-l-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrozin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol

[0411]

[0412] Step 1: Synthesis of 4-(aminomethyl)-l-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-ol

[0413] Dissolve 6-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-6- azaspiro[2.5]octane (25 mg, 0.04 mmol) in NH3 / MeOH (7 M, 1 mL), and stir the reaction at 40 °C for 2 h. Dry, and use the crude product in the next step.

[0414] Step 2: Synthesis of 4-(aminomethyl)-l-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-ol

[0415] Dissolve the crude product from the previous step in 2 mL of EA, and add HC1 / EA solution (4 M, 1 mL) at room temperature. Stir the reaction for 0.5 h. Dry the reaction, add 2 mL of aqueous Na2C03solution, extract with ethyl acetate, dry and concentrate the organic phase, and purify by Prep-TLC (DCM / MeOH = 8 / 1) to give 5 mg of a gray solid in 21% yield over two steps.

[0416] LC / MS: m / z = 559.3 [M+H] + .

[0417] Example 12

[0418] 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-(2- fluoroethyl)-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol

[0419]

[0420] Step 1: Synthesis of 2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester

[0421] To a solution of 2-(tert-butyl) 3-methyl 2-azabicyclo[2.2.1]heptane-2,3- dicarboxylate (1 g, 3.9 mmol) in 10 mL of hydrogen chloride in 1.4-dioxane, the reaction mixture was stirred at room temperature for 2 hours, TLC showed the reaction was complete. The reaction mixture was concentrated to give the hydrochloride salt of the product, which was used directly in the next step.

[0422] Step 2: Synthesis of 2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester

[0423] To a solution of 2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester (the product of Step 2) in 10 mL of acetonitrile, potassium carbonate (1083 mg, 7.8 mmol) was added. After the addition, the reaction mixture was stirred at 60 °C for 24 hours. The reaction mixture was filtered, dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give 407 mg of the target product. The overall yield of two steps was 52%.

[0424] Step 3: Synthesis of (2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptan-3-yl)methanol

[0425] To a reaction flask was added 2-(2-fluoroethyl)-2-azabicyclo[2.2.1]heptane-3- carboxylic acid methyl ester (407 mg, 2.0 mmol) and 5 mL of tetrahydrofuran. The reaction mixture was stirred at -40 °C under nitrogen protection. Lithium aluminum hydride (231 mg, 6.087 mmol) was added portionwise. The stirring was continued for 2 hours. TLC showed the reaction was complete. The reaction mixture was warmed to room temperature. A small amount of THF was added to dilute the reaction mixture. Then 0.4 mL of water was added. The stirring was continued for 10 minutes. Then 15% sodium hydroxide aqueous solution (0.4 mL) was added. The stirring was continued for 10 minutes. Then 1.2 mL of water was added. The stirring was continued for 30 minutes. The reaction mixture was dried over anhydrous sodium sulfate. The mixture was filtered, dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 2 / 1) to give 160 mg of the target product. The yield was 46%.

[0426] Step 4: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-(2- fluoroethyl)-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol

[0427] The target product was synthesized by a similar method to Example 6, using the product from the previous step and the corresponding intermediate as starting materials.

[0428] LC / MS: m / z = 573.3 [M+H] + .

[0429] 1 H NMR (400 MHz, d6-DMSO) δ 9.98 (1H, br s), 9.16 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.42-7.45 (1H, m), 7.22-7.29 (3H, m), 4.52-4.60 (1H, m), 4.43-4.46 (3H, m), 4.17-4.20 (1H, m), 3.93-3.98 (1H, m), 3.61 (1H, s), 3.58 (1H, s), 3.53 (2H, s), 3.25 (1H, s), 2.86-2.88 (1H, m), 2.78-2.82 (1H, m), 2.33-2.36 (1H, m), 2.26-2.27 (1H, m), 1.80-1.88 (1H, m), 1.55-1.70 (6H, m), 1.20-1.33 (4H, m).

[0430] Example 13

[0431] (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)dimethylphosphine oxide

[0432]

[0433] Step 1: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1- yl)-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0434] Into a reaction vial was placed (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (533 mg, 1.0 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (314 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol) and dioxane / water (8 mL / 0.8 mL), after purging with nitrogen, Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added. The reaction mixture was heated to 100 °C for 6 h under nitrogen. After the reaction mixture was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated, and then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 220 mg of gray solid, yield: 32%.

[0435] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0436] Into a reaction vial was placed (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)- 2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (220 mg, 0.32 mmol) and 5 mL of ethyl acetate, after adding HCl / EA (4 M, 2 mL) at room temperature, it was stirred for 0.5 h. The reaction mixture was concentrated, and the crude product was used directly in the next step.

[0437] Step 3: Synthesis of (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0438] Into a reaction vial was placed the crude product from the previous step and 0.5 mL of DIPEA, after adding (Boc)2O (109 mg, 0.5 mmol) at room temperature, it was stirred for 2 h. The reaction mixture was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated, and the crude product was used directly in the next step.

[0439] Step 4: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0440] The crude product from the previous step and 0.5 mL of DIPEA were dissolved in 5 mL of DCM, and triflic anhydride (141 mg, 0.5 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into 20 mL of water, and the organic phase was extracted with ethyl acetate. The organic phase was dried and rotary evaporated. The product was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 85 mg of yellow solid. The overall yield was 34%.

[0441] Step 5: Synthesis of tert-butyl (1R,5S)-3-(7-(3-(dimethylphosphoryl)naphthalen-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0442] To the reaction flask was added tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (77 mg, 0.1 mmol), dimethylphosphine oxide (78 mg, 1 mmol), triethylamine (101 mg, 1 mmol), xantphos (12 mg, 0.02 mmol) and 3 mL of dioxane. After purging with nitrogen, Pd2(dba)3 (9 mg, 0.01 mmol) was added. The reaction mixture was heated to 110 °C under nitrogen for 6 h. After cooling to room temperature, the reaction mixture was poured into 10 mL of water. The organic phase was extracted with ethyl acetate. The organic phase was dried and rotary evaporated. The product was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 17 mg of the target product. The overall yield was 24%.

[0443] Step 6: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-yl)dimethylphosphine oxide

[0444] (1R,5S)-3-(7-(3-(dimethylphosphoryl)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (17 mg, 0.024 mmol) was dissolved in 2 mL ethyl acetate, after adding HCl / EA (4 M, 1 mL) at room temperature, stirring for 0.5 hours. The reaction system was spin-dried, 2 mL sodium carbonate aqueous solution was added, and ethyl acetate was extracted. The organic phase was dried and spin-dried, and then purified by Prep-TLC (DCM / MeOH = 8 / 1) to obtain 8 mg of gray solid, yield: 53%.

[0445] LC / MS: m / z = 601.3 [M+H] + .

[0446] Example 14

[0447] (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0448]

[0449] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (54 mg, 0.1 mmol) and DIPEA (52 mg, 0.4 mmol) were dissolved in 2 mL tetrahydrofuran, and CDI (16 mg, 0.1 mmol) was added at room temperature. The reaction system was stirred at room temperature for 1 hour, then 2,2,2-trifluoroethylamine (50 mg, 0.5 mmol) was added, and the mixture was stirred at 70°C for 6 hours. The reaction system was poured into 10 mL water, and ethyl acetate was extracted. The organic phase was dried and spin-dried, and then purified by TLC (DCM / MeOH = 10 / 1) to obtain 14 mg of the target product as a white solid, yield: 21%.

[0450] LC / MS: m / z = 666.3 [M+H] + .

[0451] 1HNMR (400 MHz, d6-DMSO) δ 9.98 (1H, s), 9.17 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.42-7.44 (2H, m), 7.21-7.29 (3H, m), 4.45-4.55 (4H, m), 4.08 (2H, s), 3.87-3.95 (4H, m), 3.63-3.66 (2H, m), 2.90-2.95 (2H, m), 1.75-1.90 (10H, m), 1.52-1.50 (2H, m).

[0452] Example 15

[0453] 4-(8-Fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((lR,5S)-8-(2,2,2- trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol

[0454]

[0455] To the reaction flask was added 4-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-8- fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (54 mg, 0.1 mmol), potassium carbonate (28 mg, 0.2 mmol) and 2 mL acetonitrile, and then bromo-trifluoroethane (16 mg, 0.1 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, then filtered, and the filtrate was dried by rotary evaporation. Purification by TLC (DCM / MeOH = 8 / 1) gave 5 mg of the target product as a white solid in a yield of 8%.

[0456] LC / MS: m / z = 623.3 [M+H] + .

[0457] 1H NMR (400 MHz, d6-DMSO) δ 9.99 (1H, s), 9.18 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.42-7.46 (1H, m), 7.21-7.29 (3H, m), 4.46-4.50 (2H, m), 4.15-4.17 (2H, m), 3.69-3.72 (2H, m), 3.46 (2H, s), 3.16-3.23 (2H, m), 2.96-3.11 (2H, m), 2.55-2.70 (2H, m), 1.78-2.00 (8H, m), 1.59-1.70 (4H, m).

[0458] Example 16

[0459] 3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-one

[0460]

[0461] Step 1: Synthesis of tert-butyl bis(2-oxoethyl)carbamate

[0462] To a solution of tert-butyl bis(2-hydroxyethyl)carbamate (5.0 g, 24.4 mmol) in 100 mL THF was added PDC (27.5 g, 73.2 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 1000 mL water and extracted with methyl tert-butyl ether. The organic phase was washed with saturated brine for three times, dried, and concentrated to give the crude product which was used directly in the next step.

[0463] Step 2: Synthesis of tert-butyl 9-(4-methoxybenzyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate

[0464] The product from the previous step was dissolved in 50 mL water, and 3-oxopentanedioic acid (3.6 g, 24.8 mmol) and sodium acetate (2.1 g, 25.3 mmol) were added and stirred for 0.5 hour at room temperature. A solution of 4-methoxybenzylamine (3.4 g, 24.8 mmol) in dilute hydrochloric acid (3 M, 8 mL) was added slowly to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and the pH was adjusted to basic with sodium carbonate. The organic phase was extracted with dichloromethane, dried, and concentrated to give 3.0 g of the target product. The yield of the two steps was 17%.

[0465] Step 3: Synthesis of tert-butyl 7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate

[0466] A solution of tert-butyl 9-(4-methoxybenzyl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3- carboxylate (300 mg, 0.83 mmol) in 5 mL of methanol was added 50 mg of 20% palladium on carbon. The reaction was stirred at 45 °C under hydrogen atmosphere for 3 hours. The reaction was filtered and the filtrate was concentrated. The crude was used directly in the next step.

[0467] Step 4: Synthesis of tert-butyl 9-benzyl 3-(tert-butyl) 7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9- dicarboxylate

[0468] The crude from the previous step was dissolved in 5 mL of DCM with 0.5 mL of DIPEA. Cbz-Cl (170 mg, 0.83 mmol) was added at 0 °C and the reaction was stirred at room temperature overnight. The reaction was poured into 20 mL of water and extracted with DCM. The organic phase was dried and concentrated. The crude was purified by Prep-TLC (PE / EA = 2 / 1) to give 200 mg of colorless oil. Yield over two steps: 64%.

[0469] Step 5: Synthesis of benzyl 7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[0470] A solution of tert-butyl 9-benzyl 3-(tert-butyl) 7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9- dicarboxylate (200 mg, 0.53 mmol) in 2 mL of ethyl acetate was added 2 mL of hydrogen chloride in ethyl acetate (4 M) and stirred at room temperature for 1 hour. The reaction was concentrated and the crude was used directly in the next step.

[0471] Step 6: Synthesis of benzyl 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate

[0472] The target product was synthesized by a similar method as in Example 9 using the product from the previous step and the corresponding intermediate as starting materials.

[0473] Step 7: Synthesis of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-one

[0474] A solution of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (10 mg) in 5 mL of methanol was added 5 mg of 10% palladium on carbon. The reaction was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction was filtered and the filtrate was concentrated. The crude product was used directly in the next step.

[0475] Step 8: Synthesis of 3-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-one

[0476] The crude product from the previous step was dissolved in 2 mL of ethyl acetate and stirred at room temperature for 0.5 hours after the addition of HC1 / EA (4 M, 1 mL). The reaction was concentrated, 2 mL of aqueous sodium carbonate was added, and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated, and the product was purified by Prep-TLC (DCM / MeOH = 8 / 1) to give 3 mg of a gray solid. The overall yield was 39%.

[0477] LC / MS: m / z = 569.3 [M+H] + .

[0478] Example 17

[0479] 3-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-ol

[0480]

[0481] Step 1: Synthesis of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-hydroxy-3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester

[0482] To a solution of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (5 mg, 0.0067 mmol) in 1 mL of THF was added sodium borohydride (1 mg). The reaction mixture was stirred at room temperature for 0.5 h, then poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and evaporated to dryness, then purified by Prep-TLC (DCM / MeOH = 30 / 1) to give 4 mg of gray solid, yield: 80%.

[0483] Step 2: Synthesis of 3-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-7-ol

[0484] The target product was synthesized by a similar method to Example 16, using the product from the previous step as the starting material.

[0485] LC / MS: m / z = 571.3 [M+H] + .

[0486] Example 18

[0487] 8-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-3,8-diazaspiro[4.5]decan-2-one

[0488]

[0489] To a solution of 4-(aminomethyl)-l-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol (5 mg, 0.009 mmol) in 1 mL of THF was added CDI (2 mg, 0.012 mmol). The reaction mixture was stirred at room temperature for 0.5 h, then warmed to 60 °C for 2 h. The reaction was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and evaporated to dryness, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 2 mg of gray solid, yield: 38%.

[0490] LC / MS: m / z = 585.3 [M+H] + .

[0491] Example 19

[0492] (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid

[0493]

[0494] Step 1: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid

[0495] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol), potassium acetate (38 mg, 0.39 mmol), pinacol diboronic acid (66 mg, 0.26 mmol) in 5 mL of 1,4-dioxane was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.027 mmol). The reaction mixture was stirred at 90 °C for 2 hours under nitrogen protection. The reaction was poured into 10 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated to give 6 mg of yellow solid, yield: 38%.

[0496] Step 2: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid

[0497] (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-yl)boronic acid (6 mg) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added, and stirring was performed for 1 hour. The reaction system was poured into 10 mL of water, the pH value was adjusted to weak alkaline with sodium bicarbonate, and extraction was performed with ethyl acetate. After drying and rotary evaporation of the organic phase, purification was performed by Prep-TLC (DCM / MeOH = 5 / 1) to obtain 1 mg of a light yellow solid, and the two-step yield was 22%.

[0498] LC / MS: m / z = 569.3 [M+H] + .

[0499] Example 20

[0500] 4-(8-Fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0501]

[0502] Step 1: Synthesis of tert-butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate

[0503] To a reaction bottle were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (250 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol), and 10 mL of dichloromethane, and tert-butyl 2- (hydroxymethyl)piperazine-1-carboxylate (216 mg, 1.0 mmol) was added at -40 °C. After stirring at -40 °C for 1 hour, extraction was performed with ethyl acetate, and the organic phase was dried and rotary evaporated. Purification was performed by silica gel column chromatography (PE / EA = 1 / 1) to obtain 234 mg of a yellow solid, and the yield was 54%.

[0504] Step 2: Synthesis of tert-butyl 4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[0505] To a reaction vial was added (tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (85 mg, 0.60 mmol) and 2 mL of tetrahydrofuran, NaH (60%, 28 mg, 0.70 mmol) was added at 0 °C, the mixture was stirred at room temperature for 1 h. After 4-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-l-carboxylic acid tert-butyl ester (216 mg, 0.50 mmol) was added, the reaction was stirred at room temperature for 2 h. The reaction was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated to dryness, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 170 mg of a gray solid, yield: 63%.

[0506] Step 3: Synthesis of 4-(8-fluoro-7-(3-(methoxymethyl)naphthalen-l-yl)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- (hydroxymethyl)piperazine-l-carboxylic acid tert-butyl ester

[0507] To a reaction vial was added 4-(7-chloro-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-l-carboxylic acid tert-butyl ester (107 mg, 0.20 mmol), 2-(3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (62 mg, 0.20 mmol), potassium carbonate (55 mg, 0.40 mmol) and dioxane / water (2 mL / 0.2 mL), Pd(dppf)Cl2(7 mg, 0.01 mmol) was added after purging with nitrogen. The reaction mixture was heated to 100 °C under nitrogen for 6 h. The reaction was cooled to room temperature, poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated to dryness, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 42 mg of a yellow solid, yield: 30%.

[0508] Step 4: Synthesis of 4-(8-fluoro-4-(3-(hydroxymethyl)piperazin-l-yl)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol

[0509] To a solution of tert-butyl 4-(8-fluoro-7-(3-(methoxymethyl)naphthalen-l-yl)-2- ((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-l- carboxylate (40 mg, 0.058 mmol) in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added and stirred for 10 min. The reaction mixture was poured into 10 mL of water, and the pH was adjusted to weak alkaline with sodium bicarbonate. The organic phase was dried and rotary evaporated, and then purified by Prep-TLC (DCM / MeOH = 5 / 1) to give 19 mg of a gray solid in 59% yield.

[0510] LC / MS: m / z = 545.3 [M+H] + .

[0511] Example 21

[0512] 1-(8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-4-carboxamide

[0513]

[0514] To a solution of l-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro- lH-pyrrolizin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-one (30 mg, 0.05 mmol) in 5 mL of DCM, trimethylsilyl cyanide (15 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 3 h under nitrogen protection. To the reaction mixture, HCl / EA solution (1 mL) was added, and the mixture was stirred at room temperature for another 4 h. The reaction mixture was concentrated at low temperature to dryness, 10 mL of water was added, and the pH was adjusted to alkaline with sodium carbonate solution. The organic phase was extracted with ethyl acetate, dried, and rotary evaporated, and then purified by pre-TLC (DCM / MeOH = 12 / 1) to give 3 mg of a yellow solid in 10% yield.

[0515] LC / MS: m / z = 573.3 [M+H] + .

[0516] 1H NMR (400 MHz, CDC13) δ 9.00 (s, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.38-7.29 (m, 2H), 7.23-7.18 (m, 2H), 4.58-4.45 (m, 3H), 4.30 (dd, J = 3.5, 10.5 Hz, 1H), 4.08 (t, J = 10.1 Hz, 1H), 3.61 (br s, 4H), 3.36 (s, 1H), 2.94 (t, J = 5.0 Hz, 1H), 2.89-2.86 (m, 1H), 2.48-2.44 (m, 2H), 1.87-1.80 (m, 2H), 1.72-1.59 (m, 5H), 1.39-1.29 (m, 3H), 0.90-0.83 (m, 1H).

[0517] Example 22

[0518] 4-(4-(3-amino-1-oxa-8-azaspiro[4.5]dec-8-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0519]

[0520] Step 1: Synthesis of tert-butyl 3-(((benzyloxy)carbonyl)amino)-1-oxa-8- azaspiro[4.5]decane-8-carboxylate

[0521] To a solution of tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (512 mg, 2.0 mmol), DIPEA (774 mg, 6.0 mmol) in 10 mL THF was added benzyl chloroformate (510 mg, 3.0 mmol) in ice bath. After addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was poured into 50 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated to get ~ 700 mg off-white solid, yield: 90%.

[0522] Step 2: Synthesis of benzyl (1-oxa-8-azaspiro[4.5]dec-3-yl)carbamate

[0523] To a vial containing tert-butyl 3-(((benzyloxy)carbonyl)amino)-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (700 mg, 1.79 mmol) was added HCl / EA solution 10 mL, after addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was rotary evaporated to get ~ 590 mg of crude white solid, yield: 100%.

[0524] Step 3: Synthesis of 4-(4-(3-amino-1-oxa-8-azaspiro[4.5]dec-8-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0525] The target product was synthesized by a similar method to Example 16, using the product from the previous step and the corresponding intermediate as starting materials.

[0526] LC / MS: m / z = 585.3 [M+H] + .

[0527] Example 23

[0528] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-phenoxyphenol

[0529]

[0530] Step 1: Synthesis of 3-bromo-4-phenoxybenzaldehyde

[0531] A mixture of 3-bromo-4-fluorobenzaldehyde (203 mg, 1.0 mmol), phenol (113 mg, 1.2 mmol), potassium carbonate (414 mg, 3.0 mmol) in 10 mL of acetonitrile was stirred at 50 °C for 2 hours. After the reaction was completed, it was directly rotary evaporated and purified by column chromatography (PE / EA = 20 / 1) to give 210 mg of light yellow solid in 76% yield.

[0532] Step 2: Synthesis of 3-bromo-4-phenoxyphenol

[0533] To a solution of 3-bromo-4-phenoxybenzaldehyde (210 mg, 0.76 mmol) in 80 mL of DCM was added m-chloroperoxybenzoic acid (262 mg, 1.52 mmol). After the addition was completed, the reaction mixture was stirred at room temperature for 5 hours under nitrogen protection. The reaction solution was added with 30 mL of water and extracted with DCM for three times. The organic phase was dried and concentrated to dryness and purified by pre-TLC to give 70 mg of off-white solid in 35% yield.

[0534] Step 3: Synthesis of 4-phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0535] To a solution of 3-bromo-4-phenoxyphenol (70 mg, 0.26 mmol), potassium acetate (76 mg, 0.78 mmol), bis(pinacolato)diboron (132 mg, 0.52 mmol) in 3 mL of 1,4-dioxane was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (15 mg, 0.02 mmol). The reaction mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness and purified by pre-TLC (PE / EA = 5 / 1) to give 35 mg of light yellow solid, yield: 43%.

[0536] Step 4: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4- phenoxyphenol

[0537] The target product was synthesized by a similar method to Example 1, using the product from the previous step and the corresponding intermediate as the raw materials.

[0538] LC / MS: m / z = 583.3 [M+H] + .

[0539] Example 24

[0540] 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrazin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-[1,1'-biphenyl]-4-ol

[0541]

[0542] Step 1: Synthesis of 2-bromo-4-methoxy-1,1'-biphenyl

[0543] To a solution of 2-bromo-1-iodo-4-methoxybenzene (626 mg, 2.0 mmol), phenylboronic acid (366 mg, 3.0 mmol), potassium carbonate (828 mg, 6.0 mmol) in 10 mL of 1,4-dioxane / water was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (125 mg, 0.17 mmol). After the addition, the reaction mixture was heated to 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness and purified by column chromatography (PE / EA = 15 / 1) to give 350 mg of off-white solid, yield: 67%.

[0544] Step 2: Synthesis of 2-bromo-[l,l'-biphenyl]-4-ol

[0545] 2-bromo-4-methoxy-l,l'-biphenyl (350 mg, 1.33 mmol) was dissolved in HBr / acetic acid solution 5 mL, the reaction mixture was stirred at 100 °C overnight. The reaction was poured into 50 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by column chromatography (PE / EA = 4 / 1) to give 200 mg off-white solid, yield: 60%.

[0546] Step 3: Synthesis of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,l'-biphenyl]-4-ol

[0547] To a solution of 2-bromo-[l,l'-biphenyl]-4-ol (50 mg, 0.20 mmol), potassium acetate (49 mg, 0.50 mmol), pinacol diboron (51 mg, 0.20 mmol) in 3 mL 1,4-dioxane was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (7 mg, 0.01 mmol). The reaction mixture was stirred at 90 °C under nitrogen for 2 hours. The reaction was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (PE / EA = 5 / 1) to give 40 mg of yellowish solid, yield: 68%.

[0548] Step 4: Synthesis of 2-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro- lH-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-[l,l'-biphenyl]-4-ol

[0549] The target product was synthesized by a similar procedure to Example 1, using the product from the previous step and the corresponding intermediate as starting materials.

[0550] LC / MS: m / z = 567.3 [M+H] + .

[0551] Example 25

[0552] 4-(4-(3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-8-fluoro-2-((tetrahydro-lH- pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0553]

[0554] Step 1: Synthesis of 1-(tert-butyl)3-ethyl-4-(benzylamino)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester

[0555] 1-(tert-butyl)-3-ethyl-4-oxopiperidin-1,3-dicarboxylic acid ester (1 g, 3.64 mmol) was dissolved in 10 mL of toluene, and benzylamine (390 mg, 3.64 mmol) was added. The reaction mixture was heated under reflux overnight. The reaction solution was evaporated to dryness, and the crude product was used directly in the next step of the reaction.

[0556] Step 2: Synthesis of 1-(tert-butyl)3-ethyl-4-(benzylamino)piperidine-1,3-dicarboxylic acid ester

[0557] The crude product obtained in the previous step was dissolved in 10 mL of methanol, and Pd / C (10%, 20 mg) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was then filtered, and the filtrate was evaporated to dryness. The crude product was used directly in the next reaction step.

[0558] Step 3: Synthesis of 1-(tert-butyl)3-ethyl-4-(benzyl(2-ethoxy-2-oxoethyl)amino)piperidine-1,3-dicarboxylic acid ester

[0559] The crude product obtained in the previous step was dissolved in 5 mL of acetonitrile, and potassium carbonate (138 mg, 1 mmol) and ethyl bromoacetate (84 mg, 0.5 mmol) were added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The system was poured into 20 mL of water, extracted with ethyl acetate, dried over dryness, and purified by column chromatography (PE / EA = 1 / 1) to give 150 mg of yellow solid. The three-step yield was 9%.

[0560] Step 4: Synthesis of 5-(tert-butyl)3a-ethyl-1-benzyl-3-oxohexahydro-5H-pyrrolo[3,2-c]pyridine-3a,5(4H)-dicarboxylic acid ester

[0561] 1-(tert-butyl)3-ethyl 4-(benzyl(2-ethoxy-2-oxoethyl)amino)piperidine-1,3-dicarboxylic acid ester (150 mg, 0.33 mmol) was dissolved in 5 mL of toluene. Potassium tert-butoxide (98 mg, 1.00 mmol) was added at 0 °C. After stirring at room temperature for 1 hour, the reaction solution was poured into 20 mL of water, extracted with ethyl acetate, dried the organic phase, and then purified by Prep-TLC (PE / EA = 2 / 1) to give 65 mg of yellow solid, yield: 48%.

[0562] Step 5: Synthesis of tert-butyl 1-benzyl-3-oxooctahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylic acid

[0563] Dissolve 5-(tert-butyl) 3a-ethyl 1-benzyl-3-oxohexahydro-5H-pyrrolo[3,2-c]pyridine- 3a,5(4H)-dicarboxylate (65 mg, 0.16 mmol) in 5 mL of dioxane, add 1 mL of 5M aqueous sodium hydroxide solution, and stir the reaction mixture at reflux overnight. Pour the mixture into 20 mL of water, extract with ethyl acetate, dry the organic phase, and concentrate in vacuo. The crude product is used directly in the next step.

[0564] Step 6: Synthesis of tert-butyl 1-benzyl-3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridine- 5-carboxylate

[0565] Dissolve the crude product from the previous step in 3 mL of dichloromethane, and add DAST (40 mg, 0.24 mmol) at -78 °C. After the addition, stir the reaction mixture at room temperature for 1 hour. Pour the mixture into 20 mL of water, extract with ethyl acetate, dry the organic phase, and concentrate in vacuo. Purify the residue by Prep-TLC (PE / EA = 1 / 1) to give 35 mg of a yellow solid. Yield over two steps: 61%.

[0566] Step 7: Synthesis of 1-benzyl-3,3-difluorooctahydro-1H-pyrrolo[3,2-c]pyridine

[0567] Dissolve tert-butyl 1-benzyl-3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridine-5- carboxylate (35 mg, 0.1 mmol) in 2 mL of dichloromethane, and add 0.2 mL of trifluoroacetic acid. Stir the reaction mixture at room temperature for 1 hour. Concentrate the mixture in vacuo, and use the crude product directly in the next step.

[0568] Step 8: Synthesis of 4-(4-(3,3-difluorooctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-8- fluoro-2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol

[0569] Use the product from the previous step and the corresponding intermediate as starting materials to synthesize the target product by a method similar to that in Example 16.

[0570] LC / MS: m / z = 591.3 [M+H] + .

[0571] Example 26

[0572] 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((3- fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol

[0573]

[0574] Step 1: Synthesis of 2,7-dichloro-4-((lR,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoropyrido[4,3-d]pyrimidine

[0575] To a reaction flask was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (250 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and 10 mL of dichloromethane, and 8,8-difluoro-3-azabicyclo[3.2.1]octane hydrochloride (184 mg, 1.0 mmol) was added at -40 °C. After stirring at -40 °C for 1 h, it was poured into 50 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by silica gel column chromatography (PE / EA = 1 / 1) to give 210 mg of yellow solid, yield: 58%.

[0576] Step 2: Synthesis of (l-(((7-chloro-4-((lR,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol

[0577] To a solution of cyclopropane-l,l-diyl dimethanol (102 mg, 1.0 mmol) in 5 mL of THF was added sodium hydride (100 mg, 2.5 mmol) under ice-bath nitrogen protection. After addition, the reaction mixture was stirred at room temperature for 1 h, and then 2,7-dichloro-4-((lR,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoropyrido[4,3-d]pyrimidine (181 mg, 0.5 mmol) in 2 mL of THF was added to the reaction system under ice-bath. The reaction was stirred at room temperature for another 2 h. The reaction solution was poured into 50 mL of aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by column chromatography (PE / EA = 3 / 1) to give 100 mg of off-white solid, yield: 47%.

[0578] Step 3: Synthesis of (l-(((7-chloro-4-((lR,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl sulfonate

[0579] To (1-(((7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (100 mg, 0.23 mmol), triethylamine (100 mg, 0.92 mmol) in 5 mL DCM was added methanesulfonyl chloride (53 mg, 0.46 mmol), the reaction mixture was stirred at room temperature for 3 hours. The reaction was poured into 30 mL water, extracted with DCM, the organic phase was dried and rotary evaporated to give 90 mg of light yellow oil, yield: 77%.

[0580] Step 4: Synthesis of 7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-((1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidine

[0581] (1-(((7-chloro-4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl sulfonate (90 mg, 0.18 mmol), potassium carbonate (99 mg, 0.72 mmol), 3-fluoropyrrolidine hydrochloride (45 mg, 0.36 mmol) in 4 mL acetonitrile was heated to 70 °C and stirred for 5 hours. The reaction was poured into 20 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, purified by pre-TLC (DCM / MeOH = 30 / 1) to give 20 mg of off-white solid, yield: 22%.

[0582] Step 5: Synthesis of 4-(4-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol

[0583] The target product was synthesized by a similar method to Example 1 using the product from the previous step as the starting material.

[0584] LC / MS: m / z = 608.3 [M+H] + .

[0585] 1H NMR (400 MHz, CDC13) δ 8.94 (s, 1H), 7.66-7.61 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.24-7.17 (m, 3H), 4.61 (d, J = 13.0 Hz, 2H), 4.40 (dd, J = 10.9, 47.7 Hz, 2H), 3.74 (d, J = 13.1 Hz, 2H), 2.88-2.82 (m, 2H), 2.68 (d, J = 11.4 Hz, 1H), 2.554-2.48 (m, 2H), 2.39-2.32 (m, 2H), 2.08-1.97 (m, 2H), 1.89-1.84 (m, 2H), 1.68-1.58 (m, 2H), 1.16-1.01 (m, 2H), 0.69 (s, 2H), 0.51 (s, 2H).

[0586] Example 27

[0587] 4-(4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0588]

[0589] Step 1: Synthesis of 4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0590] To a solution of (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-one (30 mg, 0.05 mmol, synthesized by similar method as Example 9) in 2 mL THF was added 3,3-difluoro-azetidine (9 mg, 0.10 mmol). After the reaction mixture was stirred at room temperature for 0.5 hour, 10 mg of sodium triacetoxyborohydride was added to the reaction solution, and stirring was continued at room temperature for 2 hours. 10 mL of water was added, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, then purified by pre-TLC (DCM / MeOH = 10 / 1) to obtain 22 mg of yellow solid, yield: 65%.

[0591] Step 2: Synthesis of 4-(4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3- azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy) pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0592] To a solution of 4-((1R,5S,8s)-8-(3,3-difluoroazetidin-1-yl)-3-azabicyclo[3.2.1]oct-3-yl)- 8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine (20 mg, 0.030 mmol) in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added and stirred for 10 min. The reaction mixture was poured into 10 mL of water, the pH value was adjusted to weak alkaline with sodium bicarbonate, and the organic phase was dried and rotary evaporated. After purification by Prep-TLC (DCM / MeOH = 10 / 1), 8 mg of gray solid was obtained, yield: 42%.

[0593] LC / MS: m / z = 631.3 [M+H] + .

[0594] Example 28

[0595] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)phenanthren- 2-ol

[0596]

[0597] Step 1: Synthesis of ((2'-bromo-4'-methoxy-[1,1'-biphenyl]-2-yl)ethynyl)trimethylsilane

[0598] To 2-bromo-1-iodoanisole (311 mg, 1.0 mmol), sodium carbonate (216 mg, 2.0 mmol), ((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)trimethylsilane (300 mg, 1.0 mmol) in 5 mL dioxane / water (10 / 1) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol). The reaction mixture was stirred at 90 °C for 2 h under nitrogen. The reaction was poured into 10 mL water, extracted with ethyl acetate, dried and concentrated. The residue was purified by Prep-TLC (PE / EA = 100 / 1) to give 280 mg white solid, yield: 78%.

[0599] Step 2: Synthesis of 2-bromo-2'-ethynyl-4-methoxy-1,1'-biphenyl

[0600] ((2'-Bromo-4'-methoxy-[1,1'-biphenyl]-2-yl)ethynyl)trimethylsilane (280 mg, 0.78 mmol) was dissolved in 5 mL methanol, and 1 g potassium carbonate was added. The reaction mixture was stirred at room temperature for 2 h. Filtration, the filtrate was concentrated to give 230 mg yellow solid, yield: 100%.

[0601] Step 3: Synthesis of 4-bromo-2-methoxyphenanthrene

[0602] 2-bromo-2'-ethynyl-4-methoxy-1,1'-biphenyl (230 mg, 0.80 mmol) was dissolved in 5 mL 1,2-dichloroethane, and 20 mg platinum dichloride was added. The reaction mixture was stirred at 90 °C overnight. The reaction was directly concentrated to give 180 mg white solid, yield: 78%.

[0603] Step 4: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)phenanthren- 2-ol

[0604] The target product was synthesized by the similar procedure of example 1, using the product from the previous step and the corresponding intermediate as starting materials.

[0605] LC / MS: m / z = 609.3 [M+H] + .

[0606] Example 29

[0607] (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)(methyl)phosphinic acid

[0608]

[0609] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(3-(ethoxy(methyl)phosphoryl)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0610] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.039 mmol), diethyl methylphosphonate (14 mg, 0.1 mmol), triethylamine (20 mg, 0.2 mmol) and 5 mg Xantphos in 3 mL of dioxane was added 5 mg Pd2(dba)3. The reaction mixture was stirred at 100 °C under nitrogen for 3 hours. The reaction was poured into 10 mL of water and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 10 mg of yellow solid, yield: 36%.

[0611] Step 2: Synthesis of (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)(methyl)phosphinic acid

[0612] Tert-butyl (1R,5S)-3-(7-(3-(ethoxy(methyl)phosphoryl)naphthalen-1-yl)8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) was dissolved in 2 mL of dioxane, 0.5 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. 1 mL of 4M HCl dioxane solution was added. Stirring was continued for 0.5 hours. The reaction solution was poured into 10 mL of water, and the pH was adjusted to weak alkalinity with sodium carbonate. The organic phase was dried and concentrated under reduced pressure, and the residue was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain 1 mg of a gray solid, yield: 12%.

[0613] LC / MS: m / z = 603.3 [M+H] + .

[0614] Example 30

[0615] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen- 2-ol

[0616]

[0617] Step 1: Synthesis of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid

[0618] To a reaction flask was added 2-amino-4-bromo-3-fluorobenzoic acid (2.34 g, 10.0 mmol), Ag2SO4(3.08 g, 10.0 mmol) and 30 mL of anhydrous ethanol, and a solution of iodine (2.53 g, 10.0 mmol) in ethanol was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. Filtration was performed, and the filtrate was concentrated under reduced pressure. Water was added, and extraction was performed with ethyl acetate. The organic phase was dried and concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 1 / 1) to obtain 1.96 g of the target product, yield: 54%.

[0619] Step 2: Synthesis of 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol

[0620] Into a reaction flask was placed 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (1.2 g, 3.12 mmol), phosphorus oxychloride (2.3 g, 15.00 mmol), the reaction system was heated to 90 °C and stirred for 3 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0621] Step 3: Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline

[0622] Into a reaction flask was placed 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (1.2 g, 3.12 mmol), phosphorus oxychloride (2.3 g, 15.00 mmol), the reaction system was heated to 90 °C and stirred for 3 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0623] Step 4: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0624] Into a reaction flask was placed 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (crude product from previous step), DIEA (1.29 g, 10.00 mmol), tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (678 mg, 3.20 mmol) and 20 mL of anhydrous ethanol, the reaction system was stirred at room temperature for 4 hours. Water was added, extracted with ethyl acetate for 3 times, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 4 / 1) to give 410 mg of the target product, two-step yield: 22%.

[0625] Step 5: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-ylmethoxy)-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0626] To a reaction vial was added tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.20 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (48 mg, 0.30 mmol), cesium carbonate (130 mg, 0.40 mmol) and 1,4-diazabicyclo[2.2.2]octane (22 mg, 0.20 mmol), the reaction vial was purged with nitrogen, anhydrous THF (1 mL) and DMF (1 mL) were added, the reaction vial was again purged with nitrogen and the reaction was stirred at 60 °C for 4 h. The reaction was quenched with water and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried, filtered and concentrated under reduced pressure, the crude product was purified by Prep-TLC (PE / EA = 1 / 1) to give 85 mg of yellow solid, yield: 59%.

[0627] Step 6: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-((trimethylsilyl)ethynyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0628] To a reaction vial was added tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (85 mg, 0.12 mmol), trimethylsilylethynyl (15 mg, 0.15 mmol), triethylamine (30 mg, 0.30 mmol), 5 mg of copper iodide and 2 mL of DMF, 5 mg of Pd(PPh3)Cl2 was added after the reaction vial was purged with nitrogen, the reaction was stirred at 80 °C for 3 h under nitrogen. The reaction was cooled to room temperature, the reaction was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 28 mg of the target product, yield: 35%.

[0629] Step 7: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

[0630] The product from the previous step and the corresponding intermediate were used as starting materials to synthesize the target product by a method similar to Example 2.

[0631] LC / MS: m / z = 618.3 [M+H] + .

[0632] Example 31

[0633] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((5-(3-fluoropropyl)- 2-oxa-5-azabicyclo[2.2.1]heptan-6-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2-ol

[0634]

[0635] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)serine methyl ester

[0636] Into a reaction flask was added (tert-butoxycarbonyl)serine methyl ester (3.0 g, 13.7 mmol), imidazole (2.8 g, 0.41 mmol) and 30 mL of dichloromethane, after the addition of TBDPSCl (3.7 g, 13.7 mmol), the reaction was stirred at room temperature for 3 hours. The reaction was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 10 / 1) to obtain 6.3 g of the target product, yield: 100%.

[0637] Step 2: Synthesis of tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-3-oxopropan-2- yl)carbamate

[0638] N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)serine methyl ester (6.3 g, 13.7 mmol) was dissolved in 100 mL of toluene, and DIBALH (1 M, 14 mL, 14 mmol) was added dropwise at -78°C. The reaction was continued to be stirred at -78°C for 1 hour. The reaction was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.

[0639] Step 3: Synthesis of tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-3-hydroxyhex-5-en-2- yl)carbamate

[0640] The crude product from the previous step was dissolved in 100 mL of tetrahydrofuran and allylmagnesium bromide (1 M, 14 mL, 14 mmol) was added dropwise at -78 °C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5 / 1) to give 2.6 g of the target product. Yield: 40% over two steps.

[0641] Step 4: Synthesis of tert-butyl 2-((((tert-butyldiphenylsilyl)oxy)methyl)-3- hydroxy-5-(iodomethyl)pyrrolidine-1-carboxylate

[0642] To a reaction flask was added tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-3- hydroxyhex-5-en-2-yl)carbamate (1.5 g, 3.2 mmol), 10 mL of aqueous sodium bicarbonate solution (1 M), and 10 mL of ethyl acetate. After the addition of iodine (0.8 g, 3.1 mmol), the reaction was stirred at room temperature for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5 / 1) to give 2.0 g of the target product. Yield: 53%.

[0643] Step 5: Synthesis of tert-butyl 6-((((tert-butyldiphenylsilyl)oxy)methyl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate

[0644] Tert-butyl 2-((((tert-butyldiphenylsilyl)oxy)methyl)-3-hydroxy-5-(iodomethyl)pyrrolidine-1-carboxylate (1.0 g, 1.7 mmol) was dissolved in 10 mL of tetrahydrofuran and potassium tert-butoxide (196 mg, 2.0 mmol) was added at 0 °C. The system was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give 350 mg of the target product. Yield: 44%.

[0645] Step 6: Synthesis of (2-oxa-5-azabicyclo[2.2.1]heptan-6-yl)methanol

[0646] Tert-butyl 6-((((tert-butyldiphenylsilyl)oxy)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate (350 mg, 0.75 mmol) was dissolved in 10 mL of tetrahydrofuran and 200 mg of TBAF was added. The reaction was stirred at room temperature overnight. To the reaction was added 0.5 mL of 6M dilute hydrochloric acid. The stirring was continued at room temperature for 0.5 hours and the reaction system was directly rotary dried. The crude product was obtained.

[0647] Step 7: Synthesis of (5-(3-fluoropropyl)-2-oxa-5-azabicyclo[2.2.1]heptan-6- yl)methanol

[0648] The crude product from the previous step was dissolved in 5 mL of acetonitrile, and 1-fluoro-3-iodopropane (150 mg, 0.8 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added. The resulting mixture was stirred at 80 °C for 6 h. It was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 10 / 1) to give 25 mg of the desired product in 18% yield over two steps.

[0649] Step 8: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((5-(3-fluoropropyl)-2-oxa-5-azabicyclo[2.2.1]heptan-6-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0650] The product from the previous step and the corresponding intermediate were used as starting materials to synthesize the target product by a similar method to Example 6.

[0651] LC / MS: m / z = 625.3 [M+H] + .

[0652] Example 32

[0653] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6,8- trifluoronaphthalen-2-ol

[0654]

[0655] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(5,7,8-trifluoro-3- (methoxymethoxy)naphthalen-1-yl)-1,3,2-dioxaborolane

[0656] It was synthesized by a similar method to Intermediate 5, using 2,4,5-trifluorobenzaldehyde and 4-methoxy-4-oxo-3-(triphenyl-phosphoranylidene)butanoic acid as starting materials.

[0657] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-5,6,8-trifluoronaphthalen-2-ol

[0658] The target product was synthesized by a similar method to Example 6, using the product from the previous step and the corresponding intermediate as starting materials.

[0659] LC / MS: m / z = 613.2 [M+H] + .

[0660] Example 33

[0661] 3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-yl)oxy)methyl)-N-(2,2,2- trifluoroethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide

[0662]

[0663] Step 1: Synthesis of methyl 2-azabicyclo[2.2.1]heptane-3-carboxylate

[0664] Methyl 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (255 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and stirring was performed at room temperature for 0.5 hours. It was spin-dried, and the crude product was directly used in the next step

[0665] Step 2: Synthesis of (2-azabicyclo[2.2.1]heptan-3-yl)-methanol

[0666] Methyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (crude) was dissolved in 5 mL of tetrahydrofuran, lithium aluminum hydride (76 mg, 2.0 mmol) was added at 0°C, and stirring was performed for 1 h. 20 mL of water was added to the reaction system, extraction was performed with ethyl acetate, saturated brine was washed, anhydrous sodium sulfate was dried, filtration was performed, the filtrate was concentrated under reduced pressure, and purification was performed by column chromatography (DCM / MeOH = 20 / 1) to obtain 40 mg of the target product, with a two-step yield of 31%.

[0667] Step 3: Synthesis of 3-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide

[0668] Dissolve 2,2,2-trifluoroethylamine (50 mg, 0.5 mmol) and 0.2 mL of triethylamine in 2 mL of dichloromethane, add p-nitrophenyl chloroformate (100 mg, 0.5 mmol) at 0 °C, stir at room temperature for 1 hour, then add (2-azabicyclo[2.2.1]heptan-3-yl)-methanol (40 mg, 0.3 mmol). Warm the reaction to 60 °C and stir overnight. Add 20 mL of water to the reaction, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM / MeOH = 20 / 1) to give 35 mg of the target product, yield: 44%.

[0669] Step 4: Synthesis of 3-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-yl)oxy)methyl)-N-(2,2,2- trifluoroethyl)-2-azabicyclo[2.2.1]heptane-2-carboxamide

[0670] Use the product from the previous step and the corresponding intermediate as raw materials to synthesize the target product by a method similar to that in Example 6.

[0671] LC / MS: m / z = 688.2 [M+H] + .

[0672] Example 34

[0673] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro- 1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0674]

[0675] Step 1: Synthesis of p-methoxyphenyl magnesium bromide

[0676] Weigh magnesium turnings (4.8 g, 200 mmol) into a flask, add methoxybromobenzene (1 g, 5.3 mmol), 0.2 g of iodine, and 5 mL of tetrahydrofuran. After heating to initiate the reaction, start adding a solution of methoxybromobenzene (17.7 g, 94.7 mmol) in 150 mL of tetrahydrofuran dropwise, maintaining the reaction system in a reflux state. After the addition is complete, continue refluxing for 0.5 hours. The system is used directly in the next step.

[0677] Step 2: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-(4-methoxyphenyl) 5- oxopentanoate

[0678] To a reaction flask was added 1 -(tert-butyl)-2-methyl-5-oxopyrrolidine-1,2-dicarboxylate (24.3 g, 100 mmol) and 250 mL of tetrahydrofuran, the reaction mixture was cooled to -70 °C with a dry ice ethanol bath under nitrogen protection, then p-methoxyphenyl magnesium bromide (reaction liquid from previous step) was added. The reaction was allowed to proceed for 3 h at this temperature. Saturated ammonium chloride solution (500 mL) was added, the organic phase was extracted with ethyl acetate three times, dried and rotary evaporated, then purified by column chromatography (PE / EA = 1 / 1) to give 18.0 g of the target product, yield: 51 %.

[0679] Step 3: Synthesis of methyl 5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

[0680] To a reaction flask was added methyl 2-((tert-butoxycarbonyl)amino)-5-(4- methoxyphenyl) 5-oxopentanoate (18 g, 51.3 mmol), HCl / MeOH (4 M, 100 mL) was added at room temperature, and stirred at room temperature overnight. The reaction system was directly rotary evaporated to give the crude product, which was used without purification.

[0681] Step 4: Synthesis of methyl 5-(4-methoxyphenyl)pyrrole-2-carboxylate

[0682] The crude product from the previous step was dissolved in 200 mL of methanol, sodium borohydride (3.8 g, 100 mmol) was added at 0 °C and stirred for 1 h. The reaction system was rotary evaporated, 5 mL of cold water was added, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated to give the crude product, which was used without purification.

[0683] Step 5: Synthesis of methyl 1 -(3-bromopropyl)-5-(4-methoxyphenyl)pyrrolidine-2- carboxylate

[0684] The crude product from the previous step was dissolved in 200 mL of acetonitrile, potassium carbonate (13.8 g, 100 mmol) and 1,3-dibromopropane (10.1 g, 50 mmol) were added. The reaction was stirred at 60 °C for 6 h. Filtration was performed, the filtrate was rotary evaporated, and purified by column chromatography (DCM / MeOH = 20 / 1) to give 7.9 g of the target product, three-step yield: 44%.

[0685] Step 6: Synthesis of methyl 3-(4-methoxyphenyl)tetrahydro-1 H-pyrrolizin-7a(5H)- carboxylate

[0686] Methyl 1-(3-bromopropyl)-5-(4-methoxyphenyl)pyrrolidine-2-carboxylate (7.9 g, 22.2 mmol) was dissolved in 100 mL of tetrahydrofuran, and LDA (1 M, 25 mL, 25 mmol) was added dropwise at 0 °C. After the addition was completed, the mixture was stirred at 0 °C for 1 h and at room temperature for 1 h. The reaction solution was poured into 300 mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to give 3.6 g of the target product in a yield of 59%.

[0687] Step 7: Synthesis of (3-(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0688] Methyl 3-(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-carboxylate (2.7 g, 10 mmol) was dissolved in 30 mL of tetrahydrofuran, and lithium aluminum hydride (760 mg, 20 mmol) was added at 0 °C and stirred for 1 h. To the reaction mixture was added 100 mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography C (DCM / MeOH = 20 / 1) to give 2.2 g of the target product in a yield of 89%.

[0689] Step 8: Synthesis of (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0690] To a reaction flask was added (3-(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (130 mg, 0.53 mmol) and 5 mL of tetrahydrofuran, and NaH (60%, 64 mg, 1.6 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. After (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (173 mg, 0.40 mmol) was added, the reaction solution was stirred at room temperature for 2 h. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate, dried, and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to give 75 mg of a yellow solid in a yield of 29%.

[0691] Step 9: Synthesis of (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0692] To a reaction vial was added (1R, 5S)-3-(7-chloro-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro)-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.078 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27 mg, 0.078 mmol), potassium carbonate (21 mg, 0.15 mmol) and dioxane / water (2 mL / 0.2 mL), 5 mg Pd(dppf)Cl2 was added after purging with nitrogen. The reaction mixture was heated to 100 °C under nitrogen for 6 h. The reaction was cooled to room temperature and poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by Prep-TLC (DCM / MeOH = 15 / 1) to give 38 mg of gray solid, yield: 58%.

[0693] Step 10: Synthesis of 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0694] (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (38 mg, 0.046 mmol) was dissolved in 2 mL ethyl acetate, HCl / EA (4 M, 0.5 mL) was added, stirred for 10 min. The reaction was poured into 10 mL water, adjusted to weak alkaline with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by Prep-TLC to give 22 mg of gray solid, yield: 71%.

[0695] LC / MS: m / z = 684.3 [M+H] + .

[0696] 1 H NMR (400 MHz, CDC13) δ 8.89 (s, 1H), 7.45-7.39 (m, 1H), 7.27-7.17 (m, 4H), 6.78-6.74 (m, 2H), 4.67-4.60 (m, 1H), 4.47-4.40 (m, 1H), 4.36-4.21 (m, 2H), 3.71-3.58 (m, 7H), 2.91-2.83 (m, 1H), 2.72-2.58 (m, 1H), 2.35-2.25 (m, 1H), 2.13-2.05 (m, 1H), 1.94-1.53 (m, 8H).

[0697] Example 35

[0698] 3-(4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- pyrrolizin-3-yl)phenoxy)propane-1,2-diol

[0699]

[0700] Step 1: Synthesis of 4-(7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)phenol

[0701] (3-(4-methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (247 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethane, 0.2 mL of boron tribromide was added at 0 °C. After stirring at 0 °C for 1 hour, the system was directly rotary evaporated, and the crude product was directly used in the next step reaction.

[0702] Step 2: Synthesis of (3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methanol

[0703] The crude product of the previous step was dissolved in 5 mL of acetonitrile, potassium carbonate (276 mg, 2.0 mmol) and 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (195 mg, 1.0 mmol) were added. Stirring at 80 °C for 6 hours. Filtration under suction, the filtrate was rotary evaporated, and the crude product was purified by column chromatography to obtain 110 mg of the target product, two-step yield: 32%.

[0704] Step 3: Synthesis of 3-(4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro- 1H-pyrrol-3-yl)phenoxy)propane-1,2-diol

[0705] The target product was synthesized by a similar method to Example 34, using the product from the previous step and the corresponding intermediate as starting materials.

[0706] LC / MS: m / z = 707.3 [M+H] + .

[0707] Example 36

[0708] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((5-(4-fluorophenyl)-1- (3-fluoropropyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen- 2-ol

[0709]

[0710] Step 1: Synthesis of methyl 5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidine-2-carboxylate

[0711] Into a reaction vial was placed methyl 5-(4-fluorophenyl)pyrrolidine-2-carboxylate (223 mg, 1.0 mmol), 1-fluoro-3-iodopropane (188 mg, 1.0 mmol), potassium carbonate (414 mg, 3.0 mmol) and 5 mL of acetonitrile. The mixture was heated to 80 °C and stirred for 6 h. The reaction was cooled to room temperature, filtered, and the crude product was used directly in the next step.

[0712] Step 2: Synthesis of (5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidin-2-yl)-methanol

[0713] Methyl 5-(4-fluorophenyl)-1-(3-fluoropropyl)pyrrolidine-2-carboxylate (crude) was dissolved in 5 mL of tetrahydrofuran, and lithium aluminum hydride (76 mg, 2.0 mmol) was added at 0 °C and stirred for 1 h. 20 mL of water was added to the reaction, and it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 95 mg of the target product in a two-step yield of 37%.

[0714] Step 3: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((5-(4-fluorophenyl)-l-(3-fluoropropyl)pyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0715] The target product was synthesized by a similar method to Example 34, using the product from the previous step and the corresponding intermediate as the raw materials.

[0716] LC / MS: m / z = 691.3 [M+H] + .

[0717] Example 37

[0718] 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-8- cyclopropyl-5,6-difluoronaphthalen-2-ol

[0719]

[0720] Step 1: Synthesis of 4-(benzyloxy)-8-cyclopropyl-5,6-difluoro-2-naphthalenecarboxylic acid methyl ester

[0721] Into a reaction bottle was added 4-(benzyloxy)-8-bromo-5,6-difluoro-2- naphthalenecarboxylic acid methyl ester (407 mg, 1.0 mmol), cyclopropylboronic acid (172 mg, 2.0 mmol), potassium carbonate (414 mg, 3.0 mmol) and dioxane / water (5 mL / 0.5 mL), and after replacement with nitrogen, Pd(dppf)Cl2(37 mg, 0.05 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 3 hours. After the reaction system was cooled to room temperature, it was poured into 30 mL of water, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and then purified by Prep-TLC (PE / EA = 10 / 1) to obtain 295 mg of white solid, yield: 80%.

[0722] Step 2: Synthesis of 2-(5-cyclopropyl-7,8-trifluoro-3-(methoxymethoxy)naphthalen-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0723] The target product was synthesized by a similar method to Intermediate 5, using the product from the previous step as the raw material.

[0724] Step 3: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-8-cyclopropyl-5,6-difluoronaphthalen-l-ol

[0725] The target product was synthesized by a similar method to Example 6, using the product from the previous step and the corresponding intermediate as starting materials.

[0726] LC / MS: m / z = 635.3 [M+H] + .

[0727] Example 38

[0728] (lR,5S,Z)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2. l]octan-8-one O-methyl oxime

[0729]

[0730] (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-l-yl)-2-((tetrahydro-lH- pyrrolizin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2. l]octan-8- one (30 mg, 0.05 mmol) was dissolved in 2 mL of ethanol, 0.1 mL of pyridine and methoxyamine hydrochloride (9 mg, 0.10 mmol) were added. The reaction mixture was stirred at room temperature overnight, the reaction solution was rotary evaporated and purified by pre-TLC (DCM / MeOH = 10 / 1) to give 8 mg of white solid, yield: 25%.

[0731] LC / MS: m / z = 637.3 [M+H] + .

[0732] Example 39

[0733] N-(4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)methanesulfonamide

[0734]

[0735] Step 1 : Synthesis of tert-butyl (1R,5S)-3-(7-(3-aminonaphthalen-1-yl)8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0736] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.039 mmol), benzophenone imine (18 mg, 0.1 mmol), cesium carbonate (66 mg, 0.2 mmol) and 5 mg of RuPhos in 3 mL of dioxane was added 5 mg of Pd2(dba)3 under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 hours under nitrogen atmosphere. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated under vacuum and purified by Prep-TLC (DCM / MeOH = 20 / 1). The product was dissolved in 5 mL of methanol and 10 mg of Pd / C (10%) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 15 mg of yellow solid in 60% yield.

[0737] Step 2: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methylsulfonamido)naphthalen-1- yl)2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0738] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methylsulfonamido)naphthalen-1- yl)2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (15 mg, 0.023 mmol) and triethylamine (10 mg, 0.1 mmol) in 2 mL of dichloromethane was added methanesulfonyl chloride (4 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 10 mL of water and extracted with dichloromethane. The organic phase was dried and concentrated under vacuum and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 10 mg of yellow solid in 59% yield.

[0739] Step 3: Synthesis of N-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl) methanesulfonamide

[0740] To the reaction flask was added tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methylsulfonamido)naphthalen- 1-yl)-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) dissolved in EA (0.5 mL), followed by hydrochloric acid-ethyl acetate solution (1.5 mL) and allowed to react at room temperature for 1 hour. The reaction was spun down and the pH was adjusted to basic with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by thin layer silica gel plate (DCM / MeOH = 7 / 1) to give the title compound 3 mg, white solid, yield: 35%.

[0741] LC / MS: m / z = 618.3 [M+H] + .

[0742] Example 40

[0743] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrazin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0744]

[0745] To the reaction flask was added tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methylsulfonamido)naphthalen- 1-yl)-2-((tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) dissolved in EA (0.5 mL), followed by hydrochloric acid-ethyl acetate solution (1.5 mL) and allowed to react at room temperature for 1 hour. The reaction was spun down and the pH was adjusted to basic with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by thin layer silica gel plate (DCM / MeOH = 7 / 1) to give the title compound 3 mg, white solid, yield: 35%.

[0746] LC / MS: m / z = 618.3 [M+H]+ .

[0747] Example 41

[0748] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)- yl)methoxy)quinolin-6-yl)propanenitrile

[0749]

[0750] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-6-((E)-2-cyanoethenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0751] To a reaction vial was added tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-iodoquinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (166 mg, 0.23 mmol), triethylamine (50 mg, 0.50 mmol), acrylonitrile (2.8 g, 20 mmol) and 5 mL DMF. After purging with nitrogen, 5 mg of tris(o-tolyl)phosphine and 5 mg of palladium acetate were added. The reaction was heated to 80 °C with stirring overnight under a nitrogen atmosphere. The reaction was cooled to room temperature and the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 76 mg of the target product in 51% yield.

[0752] Step 2: Synthesis of tert-butyl (1R,5S)-3-(6-((E)-2-cyanoethenyl)-7-(7,8-difluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin- 7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0753] To a reaction flask was added tert-butyl (1R,5S)-3-(7-bromo-6-((E)-2- cyanoethenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)- yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (76 mg, 0.12 mmol), cesium carbonate (65 mg, 0.2 mmol), 2-(7,8-difluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53 mg, 0.15 mmol) and 2 mL dioxane / water (10 / 1). After purging with nitrogen, 5 mg Pd(dppf)Cl2was added. The reaction was heated to 90 °C with stirring under nitrogen for 2 hours. The reaction was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by Prep-TLC (DCM / MeOH = 15 / 1) to give 17 mg of the target product, yield: 18%.

[0754] Step 3: Synthesis of tert-butyl (1R,5S)-3-(6-(2-cyanoethyl)-7-(7,8-difluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0755] To a solution of tert-butyl (1R,5S)-3-(6-((E)-2-cyanoethenyl)-7-(7,8-difluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (17 mg, 0.021 mmol) in tetrahydrofuran was added lithium triethylborohydride (1 min THF, 0.1 mL) at 0 °C. Stirring was continued at 0 °C for 10 minutes. The reaction was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to give the crude product.

[0756] Step 4: Synthesis of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8- difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolin-7a(5H)-yl)methoxy)quinolin-6-yl)propanenitrile

[0757] The crude product from previous step was dissolved in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added and stirred for 10 min. The reaction mixture was poured into 10 mL of water, neutralized to weak basicity with sodium carbonate, extracted with ethyl acetate, dried and concentrated under reduced pressure, and purified by Prep-TLC to give 3 mg of gray solid, yield: 21% over two steps.

[0758] LC / MS: m / z = 647.3 [M+H] + .

[0759] Example 42

[0760] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5,6- difluoronaphthalen-2-ol

[0761]

[0762] Step 1: Synthesis of methyl 3-(4-amino-6-chloro-5-fluoropyridin-3-yl)propanoate

[0763] To a reaction flask was added 2-chloro-3-fluoro-5-iodopyridin-4-amine (272 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), methyl propiolate (168 mg, 0.2 mmol), copper iodide (19 mg, 0.1 mmol) and 2 mL of tetrahydrofuran. After purging with nitrogen, Pd(PPh3)Cl2(35 mg, 0.05 mmol) was added. The reaction mixture was heated to 70 °C under nitrogen and stirred for 4 hours. The reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 40 mg of the target product, yield: 18%.

[0764] Step 2: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-hydroxy-1,6- naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0765] To a reaction vial was added 3-(4-amino-6-chloro-5-fluoropyridin-3-yl)propan-1-ol methyl ester (40 mg, 0.18 mmol), 100 mg lithium chloride, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (42 mg, 0.20 mmol) and 2 mL tert-butanol. The reaction was heated to 120 °C with stirring for 2 days. The reaction was cooled to room temperature and poured into water. The reaction was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 20 mg of the desired product in 28% yield.

[0766] Step 3: Synthesis of (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0767] To a reaction vial was added (1R,5S)-3-(7-chloro-8-fluoro-2-hydroxy-1,6-naphthyridin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 0.049 mmol), cesium carbonate (33 mg, 0.2 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18 mg, 0.05 mmol) and 2 mL dioxane / water (10 / 1). After purging with nitrogen, 3 mg Pd(dppf)Cl2was added. The reaction was heated to 90 °C with stirring for 2 hours under nitrogen. The reaction was cooled to room temperature and poured into water. The reaction was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to give 10 mg of the desired product in 34% yield.

[0768] Step 4: Synthesis of (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-1,6-naphthyridin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0769] To a reaction vial was added (1R,5S)-3-(7-(7,8-difluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (10 mg, 0.017 mmol), silver carbonate (28 mg, 0.1 mmol), (2R,7aS)-7a-(chloromethyl)-2-fluorohexahydro-1H- pyrrolizine (4 mg, 0.02 mmol) and 2 mL DMF. The reaction was heated to 80 °C under nitrogen for 4 h. The reaction was cooled to room temperature and poured into water. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give the crude product.

[0770] Step 5: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5,6- difluoronaphthalen-2-ol

[0771] The crude product from the previous step was dissolved in 2 mL ethyl acetate and HCl / EA (4 M, 0.5 mL) was added. The reaction was stirred for 10 min. The reaction was poured into 10 mL water and the pH was adjusted to weakly basic with sodium carbonate. The reaction mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The crude product was purified by Prep-TLC to give 0.5 mg of a gray solid. Two step yield: 5%.

[0772] LC / MS: m / z = 594.2 [M+H] + .

[0773] Example 43

[0774] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5,6- difluoronaphthalen-2-ol

[0775]

[0776] Step 1: Synthesis of 5-bromo-1,3-dihydroisobenzofuran-1-ol

[0777] 5-Bromoisobenzofuran-1(3H)-one (213 mg, 1.0 mmol) was dissolved in 5 mL tetrahydrofuran and DIBALH (1 M, 1 mL, 1 mmol) was added dropwise at -70 °C. The reaction was stirred at -70 °C for 2 h. The reaction was poured into 10 mL water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The crude product was used directly in the next step.

[0778] Step 2: Synthesis of 5-bromo-l,3-dihydroisobenzofuran

[0779] The crude product from previous step was dissolved in 5 mL of dichloromethane, 0.2 mL of trifluoroacetic acid and 0.2 mL of triethylsilane were added. The reaction mixture was stirred at room temperature overnight. After the reaction mixture was cooled to room temperature, it was poured into 20 mL of water and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by Prep-TLC (PE / EA = 2 / 1) to give 110 mg of the target product in 55% yield over two steps.

[0780] Step 3: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(l,3- dihydroisobenzofuran-5-yl)tetrahydro-lH-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0781] The above product and corresponding intermediates were used as starting materials to synthesize the following products by the same method as in Example 34.

[0782] LC / MS: m / z = 659.3 [M+H] + .

[0783] Example 44

[0784] 4-(7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3- hydroxynaphthalen-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-lH-pyrrolizin-3- yl)benzonitrile

[0785]

[0786] Step 1: Synthesis of (3-(4-bromophenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

[0787] The above product and corresponding intermediates were used as starting materials to synthesize the following products by the same method as in Example 34.

[0788] Step 2: Synthesis of 4-(7a-(hydroxymethyl)hexahydro-lH-pyrrolizin-3-yl)- benzonitrile

[0789] Into a reaction vial was added (3-(4-bromophenyl)tetrahydro-1H-pyrrozine-7a(5H)-yl)methanol (295 mg, 1.0 mmol), cuprous cyanide (445 mg, 5.0 mmol), 0.5 mL of pyridine and 5 mL of DMSO. The reaction mixture was heated to 130 °C under nitrogen for 1 h. After cooling to room temperature, the reaction mixture was poured into 20 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 2 / 1) to give 160 mg of white solid in 66% yield.

[0790] Step 3: Synthesis of 4-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrozin-3- yl)benzonitrile

[0791] The above product and the corresponding intermediates were synthesized by the same method as in Example 34.

[0792] LC / MS: m / z = 642.3 [M+H] + .

[0793] Example 45

[0794] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl) tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol

[0795] Example 46

[0796] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4-(tetrahydro-2H-pyran-4-yl) phenyl)tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol

[0797]

[0798] Step 1: Synthesis of (3-(4-(3,6-dihydro-2H-pyran-4-yl)-phenyl)tetrahydro-1H-pyrrozine-7a(5H)- yl)methanol

[0799] Into a reaction vial was placed 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 2-((3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)- 8-fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50 mg, 0.07 mmol), 2-(3,6- dihydro-2H-pyran-4-yl)acetonitrile (12 mg, 0.07 mmol), potassium carbonate (19 mg, 0.14 mmol) and dioxane / water (1 mL / 0.1 mL). After being purged with nitrogen, Pd(dppf)Cl2(3 mg, 0.003 mmol) was added. The reaction mixture was heated to 100 °C for 6 h under nitrogen. After being cooled to room temperature, the reaction mixture was poured into 20 mL water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 20 mg of yellow solid, yield: 36%.

[0800] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4-(3,6- dihydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0801] The above product and the corresponding intermediates were synthesized by the same method as in Example 34.

[0802] LC / MS: m / z = 699.3 [M+H] + .

[0803] 1 H NMR (400 MHz, CDC13) δ 8.92 (s, 1H), 7.64-7.58 (m, 1H), 7.48-7.42 (m, 1H), 7.25-7.04 (m, 8H), 5.95 (s, 1H), 4.55-4.42 (m, 2H), 4.30-4.12 (m, 4H), 3.81-3.56 (m, 5H), 3.22 (s, 2H), 2.86-2.76 (m, 1H), 2.65-2.54 (m, 1H), 2.37 (s, 2H), 2.28-2.21 (m, 1H), 2.21-2.04 (m, 1H), 1.96-1.54 (m, 10H).

[0804] Step 3: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4- (tetrahydro-2H-pyran-4-yl)phenyl)tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0805] To a solution of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4- (3,6-dihydro-2H-pyran-4-yl)phenyl)tetrahydro-lH-pyrrol-7a(5H)-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (10 mg, 0.014 mmol) in 3 mL of methanol, 5 mg of Pd / C (10%) was added, and the reaction system was stirred at room temperature under a hydrogen atmosphere for 6 hours. Filtration was performed under suction, and the filtrate was rotary evaporated to dryness to obtain 8 mg of a gray solid, with a yield of 80%.

[0806] LC / MS: m / z = 701.3 [M+H] + .

[0807] Example 47

[0808] 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4- methoxyphenyl)tetrahydro-lH-pyrrol-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol

[0809]

[0810] Step 1: Synthesis of (3-(4-methoxyphenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methane-d2-ol

[0811] Methyl 3-(4-methoxyphenyl)tetrahydro-lH-pyrrolizin-7a(5H)-carboxylate (138 mg, 0.5 mmol) was dissolved in 2 mL of tetrahydrofuran, and deuterated lithium aluminum hydride (42 mg, 1.0 mmol) was added at 0°C and stirred for 1 h. 10 mL of water was added to the reaction system, which was extracted with ethyl acetate three times. The organic phase was dried and rotary evaporated to dryness, and then purified by column chromatography (PE / EA = 5 / 1) to obtain 75 mg of the target product, with a yield of 60%.

[0812] Step 2: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2- fluoro-5-(4-methoxyphenyl)tetrahydro-lH-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0813] The target product was synthesized by a method similar to that in Example 34, using the product obtained in the above step and the corresponding intermediate as raw materials.

[0814] LC / MS: m / z = 649.3 [M+H] + .

[0815] 1 H NMR (400 MHz, CDC13) δ 8.96 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.21-7.12 (m, 5H), 6.72 (d, J = 8.4 Hz, 2H), 4.54 (d, J = 12.0 Hz, 2H), 3.67-3.55 (m, 5H), 3.26 (s, 3H), 2.95-2.85 (m, 1H), 2.77-2.67 (m, 1H), 2.35-2.25 (m, 1H), 2.13-2.05 (m, 1H), 1.99-1.70 (m, 10H).

[0816] Example 48

[0817] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(4- methoxyphenyl)tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol

[0818]

[0819] Step 1: Synthesis of 1-(tert-butyl) 2-methyl (4R)-2-(3-(tert-butoxy)-3-oxopropyl)-4- fluoropyrrolidine-1,2-dicarboxylate

[0820] To a reaction flask was added 1-(tert-butyl) 2-methyl (4R)-4-fluoropyrrolidine-1,2- dicarboxylate (3 g, 12.15 mmol), HMPA (2.8 g, 15.80 mmol) and 30 mL of tetrahydrofuran, the reaction mixture was cooled to -70 °C with a dry ice ethanol bath under nitrogen protection, then LiHMDS (1 M, 15.8 mL) was added and after 30 min of reaction at this temperature, a solution of tert-butyl 3-bromopropionate (2.5 g, 12.15 mmol) in tetrahydrofuran (3 mL) was added, and stirred at -70 °C for 4 hours. Saturated ammonium chloride solution (20 mL) was added, extracted with ethyl acetate for 3 times, the organic phase was dried and rotary evaporated, then purified by column chromatography (PE / EA = 5 / 1) to obtain 3.29 g of the target product, yield: 72%.

[0821] Step 2: Synthesis of 3-((4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propanoic acid

[0822] To a reaction flask was added 1 -(tert-butyl) 2-methyl (4R)-2-(3-(tert-butoxy)-3- oxopropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (3.29 g, 8.75 mmol) and 25 mL of dichloromethane, followed by trifluoroacetic acid (25 mL) and stirred at room temperature overnight. The system was directly spin dried to give the crude trifluoroacetate salt of 3-((4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-2-yl)propanoic acid (4.05 g), which was used without purification.

[0823] Step 3: Synthesis of 3-((4R)-1 -(tert-butoxycarbonyl)-4-fluoro-2- (methoxycarbonyl)pyrrolidin-2-yl)propanoic acid

[0824] To a reaction flask was added the crude trifluoroacetate salt of 3-((4R)-4-fluoro-2- (methoxycarbonyl)pyrrolidin-2-yl)propanoic acid (4.05 g, 12.15 mmol), triethylamine (6.14 g, 60.75 mmol) and 40 mL of methanol, and the pH was tested with pH paper until it was greater than 7, then (Boc)20 (3.45 g, 15.80 mmol) was added and stirred at room temperature for 1 h. The system was directly spin dried to give the crude product (3.88 g), which was used without purification.

[0825] Step 4: Synthesis of 1 -(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(methoxy(methyl)amino)- 3-oxopropyl)pyrrolidine-1,2-dicarboxylate

[0826] To a reaction flask was added the crude 3-((4R)-1 -(tert-butoxycarbonyl)-4-fluoro-2- (methoxycarbonyl)pyrrolidin-2-yl)propanoic acid (3.88 g, 12.15 mmol), N,O- dimethylhydroxylamine hydrochloride, HATU (6 g, 15.80 mmol), triethylamine (6.14 g, 60.75 mmol) and 40 mL of N,N-dimethylformamide, and stirred at room temperature overnight. The system was directly poured into 400 mL of water, and extracted with ethyl acetate three times, and the organic phase was dried and spin dried before being purified by column chromatography (PE / EA = 5 / 1) to give 291 mg of the target product, with a total yield of 6.6% over four steps.

[0827] Step 5: Synthesis of 1 -(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(4-methoxyphenyl)-3- oxopropyl)pyrrolidine-1,2-dicarboxylate

[0828] To a reaction flask was added 1-(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(methoxy(methyl)amino)-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (291 mg, 0.8 mmol) and 4 mL of tetrahydrofuran, the reaction mixture was cooled to -70 °C with a dry ice ethanol bath under nitrogen protection, then (4-methoxyphenyl)magnesium bromide (1 M, 1.6 mL) was added and reacted at this temperature for 3 h. Saturated ammonium chloride solution (4 mL) was added, extracted with ethyl acetate for 3 times, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (PE / EA = 1 / 1) to obtain 235 mg of the target product, yield: 72%.

[0829] Step 6: Synthesis of methyl (6R)-6-fluoro-3-(4-methoxyphenyl)-6,7-dihydro-1H-pyrrolizine-7a(5H)-carboxylate

[0830] To a reaction flask was added 1-(tert-butyl) 2-methyl (4R)-4-fluoro-2-(3-(methoxy(methyl)amino)-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (291 mg, 0.8 mmol) and 4 mL of tetrahydrofuran, the reaction mixture was cooled to -70 °C with a dry ice ethanol bath under nitrogen protection, then (4-methoxyphenyl)magnesium bromide (1 M, 1.6 mL) was added and reacted at this temperature for 3 h. Saturated ammonium chloride solution (4 mL) was added, extracted with ethyl acetate for 3 times, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (PE / EA = 1 / 1) to obtain 235 mg of the target product, yield: 72%.

[0831] Step 7: Synthesis of methyl (2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate

[0832] The crude methyl (6R)-6-fluoro-3-(4-methoxyphenyl)-6,7-dihydro-1H-pyrrolizine-7a(5H)-carboxylate (167 mg, 0.57 mmol) was dissolved in 5 mL of methanol, sodium borohydride (32 mg, 0.86 mmol) was added at 0 °C and stirred for 1 h. The reaction system was rotary evaporated, 5 mL of cold water was added, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (PE / EA = 1 / 1) to obtain 120 mg of white liquid, yield: 72%.

[0833] Step 8: Synthesis of ((2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol

[0834] Methyl (2R)-2-fluoro-5-(4-methoxyphenyl)tetrahydro-lH-pyrrolizine-7a(5H)- carboxylate (120 mg, 0.41 mmol) was dissolved in 1 mL of tetrahydrofuran, lithium aluminum hydride (24 mg, 0.62 mmol) was added at 0 °C and stirred for 1 h. To the reaction was added 24 mg of water, 24 mg of 15% sodium hydroxide solution and 72 mg of water, then a small amount of anhydrous sodium sulfate was added to dry, filtered and rotary evaporated to give about 110 mg of the crude product of the target product without purification.

[0835] Step 9: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2- fluoro-5-(4-methoxyphenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0836] The target product was synthesized by a similar method to Example 34 using the product from the previous step and the corresponding intermediate as starting materials.

[0837] LC / MS: m / z = 665.3 [M+H] + .

[0838] 1 HNMR (400 MHz, CDC13) δ 9.07 (s, 1H), 7.72-7.59 (m, 2H), 7.42-7.28 (m, 6H), 6.82 (d, J = 8.2 Hz, 2H), 5.41 (d, J = 53.6 Hz, 1H), 4.66-4.52 (m, 2H), 4.45-4.33 (m, 2H), 3.77 (s, 3H), 3.74-3.58 (m, 4H), 3.39-3.31 (m, 1H), 2.94-2.80 (m, 1H), 2.70-2.61 (m, 1H), 2.45-2.39 (m, 1H), 2.26-2.20 (m, 1H), 2.04-1.51 (m, 8H).

[0839] Example 49

[0840] 8-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-6,8-difluoro-2-((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-7-yl)quinolin-6-ol

[0841]

[0842] Step 1: Synthesis of 8-bromo-6-methoxyquinoline

[0843] To a reaction flask was added compound 6-methoxyquinolin-8-amine (5.0 g, 28.70 mmol) dissolved in 40% HBr (50 mL) and the reaction was cooled to 0 °C. A solution of sodium nitrite (2.57 g, 37.31 mmol) in water (10 mL) was prepared and then added dropwise to the reaction at 0 °C for 30 min. To another reaction flask was added cuprous bromide (4.94 g, 34.44 mmol) and 40% HBr (50 mL) and the solution from the previous reaction was added dropwise to this reaction at room temperature for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE / EA = 7 / 1) to give the title compound 3.56 g as a white solid in 52% yield.

[0844] Step 2: Synthesis of 8-bromoquinolin-6-ol

[0845] To a three-necked flask was added compound 8-bromo-6-methoxyquinoline (3.0 g, 12.60 mmol) and the reaction was protected with nitrogen. The reaction was then cooled to -78 °C and 2.0 M boron tribromide (25.2 mL, 50.4 mmol) was added dropwise. The reaction was stirred at -78 °C for 1 h and then allowed to warm to room temperature for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE / EA = 3 / 1) to give the title compound 2.40 g as a white solid in 85% yield.

[0846] Step 3: Synthesis of 8-bromo-6-(methoxymethoxy)quinoline

[0847] To a three-necked flask was added 8-bromoquinolin-6-ol (2.25 g, 10.04 mmol) and the reaction was protected with nitrogen. Dry tetrahydrofuran (30 mL) was added and the reaction was cooled in an ice water bath. Sodium hydride (803 mg, 20.08 mmol) was added in portions and the reaction was stirred for 30 min. Chloromethyl methyl ether (970 mg, 12.05 mmol) was then added dropwise and the reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE / EA = 2 / 1) to give the title compound 2.15 g as a white solid in 80% yield.

[0848] Step 4: Synthesis of 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline

[0849] Into a three-necked flask was placed 8-bromo-6-(methoxymethoxy)quinoline (300 mg, 1.12 mmol), bis(pinacolato)diboron (569 mg, 2.24 mmol), potassium acetate (220 mg, 2.24 mmol) and Pd(dppf)Cl2(81 mg, 0.11 mmol), then nitrogen protection, 1,4-dioxane (3 mL) and water (0.3 mL) were added, and then nitrogen was replaced. The reaction was stirred at 80 °C for 4 h. The reaction was quenched by water, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was separated and purified by Prep-TLC (PE / EA = 1 / 1) to give the title compound 170 mg, white solid, yield: 48%.

[0850] Step 5: Synthesis of 3-bromo-2,4-difluoro-6-iodoaniline

[0851] Into a reaction flask was placed 3-bromo-2,4-difluoroaniline (3.3 g, 15.87 mmol), Ag2SO4(4.9 g, 15.87 mmol) and 30 mL of anhydrous ethanol, and an iodine (4.03 g, 15.87 mmol) ethanol solution was slowly added dropwise. The reaction mixture was stirred at room temperature for 4 h. After filtration, the filtrate was concentrated, water was added, and then extracted with ethyl acetate. The organic phase was dried and rotary evaporated, and then purified by column (PE / EA = 50 / 1) to give 2.7 g of the target product, yield: 52%.

[0852] Step 6: Synthesis of 2-amino-4-bromo-3,5-difluorobenzoic acid

[0853] Into a reaction flask was placed 3-bromo-2,4-difluoro-6-iodoaniline (2.7 g, 8.08 mmol), K2CO3(2.8 g, 20 mmol), DMF (30 mL) and 30 mL of water, and then Pd(dppf)Cl2(293 mg, 0.4 mmol) was added. The reaction system was protected by carbon monoxide gas and heated to 90 °C for stirring overnight. The reaction system was cooled to room temperature, and then the reaction solution was poured into water. The aqueous phase was extracted with ethyl acetate, and then the pH was adjusted to weakly acidic with dilute hydrochloric acid. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified by column (DCM / MeOH = 20 / 1) to give 1.0 g of the target product, yield: 49%.

[0854] Step 7: Synthesis of 7-bromo-6,8-difluoroquinazoline-2,4-diol

[0855] To a reaction flask was added 2-amino-4-bromo-3,5-difluorobenzoic acid (1.0 g, 3.98 mmol), urea (2.4 g, 39.84 mmol), the reaction system was heated to 170 °C and stirred for 4 h. The reaction system was cooled to room temperature, water was added, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column (PE / EA = 5 / 1) to give 650 mg of the target product, yield: 59%.

[0856] Step 8: Synthesis of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline

[0857] To a reaction flask was added 7-bromo-6,8-difluoroquinazoline-2,4-diol (300 mg, 1.09 mmol), phosphorus oxychloride (1.67 g, 10.86 mmol), DIEA (630 mg, 4.91 mmol), the reaction system was heated to 90 °C and stirred for 3 h. The reaction system was cooled to room temperature, concentrated under reduced pressure to give a crude product, which was directly used in the next step.

[0858] Step 9: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0859] To a reaction flask was added 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (300 mg, 0.95 mmol), DIEA (630 mg, 4.91 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (201 mg, 0.95 mmol) and 30 mL of anhydrous ethanol, the reaction system was heated to 80 °C and stirred for 4 h. The reaction system was cooled to room temperature, water was added, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by Prep-TLC (PE / EA = 8 / 1) to give 35 mg of the target product, two-step yield: 6%.

[0860] Step 10: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0861] To a reaction vial was added tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.10 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (24 mg, 0.15 mmol), cesium carbonate (65 mg, 0.20 mmol) and 1,4-diazabicyclo[2.2.2]octane (11 mg, 0.10 mmol), then nitrogen was purged, anhydrous THF (1 mL) and DMF (1 mL) were added, nitrogen was purged again, the reaction was stirred at 60 °C for 4 h. The reaction was quenched by water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, the crude product was separated and purified by Prep-TLC (PE / EA = 2 / 1) to give the title compound 22 mg, yellow solid, yield: 36%.

[0862] Step 11: Synthesis of tert-butyl (1R,5S)-3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(6-(methoxymethoxy)quinolin-8-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0863] To a reaction vial was added tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.033 mmol), 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (16 mg, 0.050 mmol), cesium carbonate (22 mg, 0.066 mmol) and Pd(dppf)Cl2(3 mg, 0.0033 mmol), then nitrogen was purged, 1,4-dioxane (1 mL) and water (0.1 mL) were added, nitrogen was purged again, the reaction was stirred at 100 °C for 2 h. The reaction was quenched by water, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, the crude product was separated and purified by Prep-TLC (PE / EA = 1 / 1) to give the title compound 10 mg, yellow solid, yield: 43%.

[0864] Step 12: Synthesis of 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-6,8- difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-7- yl)quinolin-6-ol

[0865] To the reaction flask was added tert-butyl (1R,5S)-3-(6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(6-(methoxymethoxy)quinolin-8- yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) dissolved in EA (0.5 mL), then hydrochloric acid-ethyl acetate solution (1.5 mL), and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give the title compound 5 mg, white solid, yield: 62%.

[0866] LC / MS: m / z = 577.3 [M+H] + .

[0867] 1 H NMR (400 MHz, CDC13) δ 8.62-8.59 (m, 1H), 7.99-7.95 (m, 1H), 7.55 (dd, J = 2.1, 43.2 Hz, 1H), 7.31-7.29 (m, 2H), 7.17-7.15 (m, 1H), 5.22 (dd, J = 20.4, 54.4 Hz, 1H), 4.50-4.41 (m, 1H), 4.24-4.15 (m, 3H), 3.59-3.53 (m, 3H), 3.41-2.93 (m, 5H), 2.44-1.63 (m, 10H).

[0868] Example 50

[0869] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0870]

[0871] Step 1: Synthesis of 2,4,7-trichloropyrido[2,3-d]pyrimidine

[0872] To a reaction flask was added 7-chloropyrido[2,3-d]pyrimidine-2,4-diol (200 mg, 1.01 mmol), DIPEA (774 mg, 6.00 mmol) and 3 mL of toluene, and phosphorus oxychloride (459 mg, 3.00 mmol) was added. After stirring at 110 °C for 4 h, the reaction was concentrated and the crude material was used directly in the next step.

[0873] Step 2: Synthesis of (1R,5S)-tert-butyl 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0874] To a reaction flask was added (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (106 mg, 0.50 mmol), DIPEA (774 mg, 6.00 mmol) and 5 mL of DCM. The crude material from the previous step was added at 0 °C. After stirring for 1 h, the reaction was poured into 20 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated, and purified by Prep-TLC (EA / PE = 2 / 1) to give 205 mg of a white solid in 49% yield over two steps.

[0875] Step 3: Synthesis of (1R,5S)-tert-butyl 3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0876] To a reaction flask was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (80 mg, 0.50 mmol) and 2 mL of tetrahydrofuran, and NaH (60%, 20 mg, 0.50 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. After addition of (1R,5S)-tert-butyl 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.49 mmol), the reaction was stirred at room temperature for 2 h. The reaction was poured into 10 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated, and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 120 mg of a white solid in 46% yield.

[0877] Step 4: Synthesis of (1R,5S)-tert-butyl 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0878] To a reaction vial was added (1R,5S)-3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrazin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (53 mg, 0.10 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31 mg, 0.10 mmol), potassium carbonate (28 mg, 0.20 mmol) and dioxane / water (2 mL / 0.2 mL), after purging with nitrogen, Pd(dppf)Cl2(7 mg, 0.01 mmol) was added. The reaction mixture was heated to 100 °C for 6 h under nitrogen. After cooling to room temperature, the reaction mixture was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 23 mg of yellow solid, yield: 34%.

[0879] Step 5: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0880] (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (23 mg, 0.034 mmol) was dissolved in 2 mL ethyl acetate, HCl / EA (4 M, 0.5 mL) was added, and stirred for 10 min. The reaction mixture was poured into 10 mL water, adjusted to weak alkaline with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by Prep-TLC (DCM / MeOH = 5 / 1) to give 13 mg of yellow solid, two-step yield: 72%.

[0881] LC / MS: m / z = 541.3 [M+H] + .

[0882] 1HNMR (400 MHz, CDC13) δ 8.30 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.33-7.29 (m, 1H), 7.17-7.14 (m, 2H), 6.73 (d, J = 8.8 Hz, 1H), 5.16 (d, J = 53.9 Hz, 1H), 4.29-4.18 (m, 4H), 3.52-3.43 (m, 4H), 3.23-2.88 (m, 4H), 2.10-1.66 (m, 10H).

[0883] Example 51

[0884] 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)isoquinoline-4-carbonitrile

[0885]

[0886] Step 1: Synthesis of tert-butyl (1R,5S)-3-(3,6-dichloroisoquinolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0887] Into a reaction vial was placed 1,3,6-trichloroisoquinoline (100 mg, 0.43 mmol), DIPEA (129 mg, 1.00 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (106 mg, 0.50 mmol) and 3 mL NMP. After stirring at 100 °C for 4 h, it was poured into 20 mL water, a solid precipitated, suction filtered, and the filter cake was dried under vacuum to give 150 mg of white solid in 85% yield.

[0888] Step 2: Synthesis of tert-butyl (1R,5S)-3-(3-chloro-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0889] To a reaction flask was added (1R,5S)-3-(3,6-dichloroisoquinolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.37 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (126 mg, 0.40 mmol), potassium carbonate (138 mg, 1.0 mmol) and dioxane / water (4 mL / 0.4 mL), after purging with nitrogen, Pd(dppf)Cl2(15 mg, 0.02 mmol) was added. The reaction mixture was heated to 100 °C under nitrogen for 6 h. After cooling to room temperature, the reaction mixture was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 135 mg of white solid, yield: 66%.

[0890] Step 3: Synthesis of (1R,5S)-3-(3-chloro-4-iodo-6-(3-(methoxymethoxy)naphthalen-1- yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0891] (1R,5S)-3-(3-chloro-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg, 0.2 mmol) was dissolved in 3 mL acetonitrile, NIS (54 mg, 0.24 mmol) was added at 0 °C, stirred at room temperature for 2 h. The reaction mixture was concentrated, purified by Prep-TLC (PE / EA = 2 / 1) to give 130 mg of white solid, yield: 95%

[0892] Step 4: Synthesis of (1R,5S)-3-(3-chloro-4-cyano-6-(3-(methoxymethoxy)naphthalen-1- yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0893] To a reaction flask was added (1R,5S)-3-(3-chloro-4-iodo-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (130 mg, 0.19 mmol), cuprous cyanide (43 mg, 0.48 mmol), 0.1 mL pyridine and 1 mL DMSO, the reaction mixture was heated to 130 °C under nitrogen for 1 h. After cooling to room temperature, the reaction mixture was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and concentrated, then purified by Prep-TLC (PE / EA = 2 / 1) to give 77 mg of white solid, yield: 69%.

[0894] Step 5: Synthesis of (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[0895] To the reaction flask was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (13 mg, 0.082 mmol) and 2 mL tetrahydrofuran, NaH (60%, 4 mg, 0.10 mmoL) was added at 0 °C, the mixture was stirred at room temperature for 1 hour. After (1R,5S)-3-(3-chloro-4-cyano-6-(3- (methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40 mg, 0.068 mmol) was added, the reaction was stirred at room temperature for 2 hours. The reaction was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (DCM / MeOH = 20 / 1) to give 18 mg white solid, yield: 37%.

[0896] Step 6: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)isoquinoline-4-carbonitrile

[0897] (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3- (methoxymethoxy)naphthalen-1-yl)isoquinolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (18 mg, 0.025 mmol) was dissolved in 2 mL ethyl acetate, HCl / EA (4 M, 0.5 mL) was added, stirred for 10 minutes. The reaction was poured into 10 mL water, adjusted to weak alkaline with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (DCM / MeOH = 5 / 1) to give 12 mg gray solid, yield: 84%.

[0898] LC / MS: m / z = 564.3 [M+H] + .

[0899] 1H NMR (400 MHz, CDC13) δ 7.87-7.83 (m, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.31-7.27 (m, 1H), 7.14-7.07 (m, 2H), 7.00 (s, 1H), 5.36 (d, J = 51.8 Hz, 1H), 4.44-4.31 (m, 2H), 4.22-4.15 (m, 2H), 3.78-3.31 (m, 6H), 3.22-3.05 (m, 2H), 2.53-1.92 (m, 10H).

[0900] Example 52

[0901] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4- methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0902]

[0903] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4- methoxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0904] To a reaction flask was added (3-(4-methoxyphenyl)tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methanol (130 mg, 0.53 mmol) and 5 mL of tetrahydrofuran, NaH (60%, 64 mg, 1.6 mmol) was added at 0 °C, the mixture was stirred at room temperature for 1 hour. After the addition of tert-butyl (1R,5S)-3-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (173 mg, 0.40 mmol), the reaction was stirred at room temperature for 2 hours. The reaction was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (DCM / MeOH = 15 / 1) to give 75 mg of yellow solid, yield: 29%.

[0905] Step 2: Synthesis of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(4-methoxyphenyl)tetrahydro-1H- pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester

[0906] To a reaction vial was added (1R,5S)-3-(7-chloro-8-fluoro-2-((3-(4- methoxyphenyl)tetrahydro)-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.078 mmol), ((2-fluoro- 6-(methoxymethoxy)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (40 mg, 0.078 mmol), potassium carbonate (21 mg, 0.15 mmol) and dioxane / water (2 mL / 0.2 mL), 5 mg Pd(dppf)Cl2 was added after purging with nitrogen. The reaction mixture was heated to 100 °C with stirring under nitrogen for 6 hours. The reaction was cooled to room temperature and poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by Prep-TLC (DCM / MeOH = 15 / 1) to give 31 mg of gray solid, yield: 40%.

[0907] Step 3: Synthesis of (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-((3-(4-methoxyphenyl))tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0908] (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((trisopropylsilyl)ethynyl)naphthalen- 1-yl)-2-((3-(4-methoxyphenyl)tetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (30 mg, 0.030 mmol) was dissolved in 1 mL DMF, CsF (10 mg) was added at room temperature and stirred overnight. The reaction was poured into 10 mL water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was used directly in the next step.

[0909] Step 4: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(4- methoxyphenyl)tetrahydro-lH-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol

[0910] The crude product from previous step was dissolved in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added and stirred for 10 min. The reaction was poured into 10 mL of water, Na2C03 was added to make it weakly basic, and the product was extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by Prep-TLC to give 12 mg of a gray solid, 38% yield over two steps.

[0911] LC / MS: m / z = 689.3 [M+H] + .

[0912] 1 HNMR (400 MHz, CDC13) δ 8.85 (s, 1H), 7.71-7.62 (m, 1H), 7.29-7.10 (m, 4H), 6.78-6.69 (m, 2H), 4.59-4.43 (m, 2H), 4.31-4.20 (m, 2H), 3.56-3.35 (m, 5H), 3.25 (s, 3H), 3.23-3.19 (m, 1H), 2.95-2.84 (m, 1H), 2.79-2.71 (m, 1H), 2.35-2.24 (m, 1H), 2.11-2.02 (m, 1H), 1.99-1.64 (m, 10H).

[0913] The compounds of Examples 53-140 were prepared according to procedures analogous to those described in the above examples using commercially available corresponding reagents as starting materials.

[0914] Table 1

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929] Example 138

[0930] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((3S,7aR)-3-(4- fluorophenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 5,6-difluoronaphthalen-2-ol

[0931]

[0932] The starting material drawn in the synthetic route was used as a raw material, the desired isomer was separated, and the target product was synthesized by a method similar to that of Example 34.

[0933] LC / MS: m / z = 671.3 [M+H] + .

[0934] 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.34-7.28 (m, 3H), 7.21-7.16 (m, 2H), 7.06 (br s, 1H), 7.02-6.87 (m, 2H), 4.65-4.56 (m, 1H), 4.41-4.35 (m, 1H), 4.30-4.21 (m, 2H), 3.76-3.37 (m, 6H), 2.85-2.81 (m, 1H), 2.61-2.59 (m, 1H), 2.30-2.29 (m, 1H), 2.13-2.11 (m, 1H), 1.98-1.81 (m, 4H), 1.76-1.61 (m, 5H).

[0935] Example 139

[0936] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((3R,7aS)-3-(4- fluorophenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 5,6-difluoronaphthalen-2-ol

[0937]

[0938] The starting material drawn in the synthetic route was used as a raw material, and the target product was synthesized by a method similar to that of Example 34.

[0939] LC / MS: m / z = 671.3 [M+H] + .

[0940] 1 H NMR (400 MHz, CDC13) δ 8.92 (s, 1H), 7.33-7.31 (m, 3H), 7.20-7.16 (m, 2H), 7.05 (br s, 1H), 6.95-6.87 (m, 2H), 4.39-4.08 (m, 5H), 3.66-3.52 (m, 5H), 2.90-2.82 (m, 1H), 2.62-2.54 (m, 1H), 2.34-2.29 (m, 1H), 2.17-2.11 (m, 1H), 1.93-1.81 (m, 4H), 1.75-1.56 (m, 5H).

[0941] Example 140

[0942] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)- 5,6-difluoronaphthalen-2-ol (Trans racemate)

[0943]

[0944] Step 1, Step 2 The starting material drawn in the synthetic route was used as a raw material, and the desired intermediate was synthesized by a method similar to that of Example 34.

[0945] Step 3: Synthesis of methyl 2-(3-chloropropyl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)- 3,4-dihydro-2H-pyrrole-2-carboxylate

[0946] Methyl 5-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-3,4-dihydro-2H-pyrrole-2- carboxylate (5.0 g, 17.66 mmol) and l-bromo-3-chloropropane (5.56 g, 35.32 mmol) were dissolved in 10 mL DMF and 40 mL THF, sodium hydride (1.06 g, 26.49 mmol) was added portionwise under ice bath, and the mixture was stirred at room temperature for 1-2 h. The reaction mixture was poured into 100 mL saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was purified by column chromatography (PE\EA=8\l) to give 4.1 g of a white solid, yield: 64.6%.

[0947] Step 4: Synthesis of methyl 3-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)tetrahydro-lH- pyrrolizin-7a(5H)-carboxylate (Trans racemate)

[0948] The product from the previous step (4.1 g, 11.40 mmol) was dissolved in 40 mL methanol, and acetic acid (1.03 g, 17.1 mL) was added. NaBH3CN (1.07 g, 17.1 mL) was added portionwise under ice bath, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, 100 mL water was added, and the mixture was adjusted to weak alkalinity with sodium carbonate. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (PE\EA=5\l) to give 1.8 g of a yellowish oil (cis isomer), and 1.5 g of a white solid (trans isomer), total yield: 88.9%.

[0949] The target product was synthesized by a method similar to that of Example 34, using the trans isomer as the starting material.

[0950] LC / MS: m / z = 733.2 [M+H] + .

[0951] 1H NMR (400 MHz, CDC13) δ 10.29 (br s, 1H), 9.12 (s, 1H), 7.76-7.73 (m, 1H), 7.61-7.54 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.25 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 4.50-4.40 (m, 2H), 4.30-4.27 (m, 1H), 4.23-4.18 (m, 2H), 3.65-3.56 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.17 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.51 (m, 7H).

[0952] Example 141 (Trans isomer 1), Example 142 (Trans isomer 2)

[0953] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0954]

[0955] Step 1: Synthesis of (3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl (S)-2-phenylpropanoate

[0956] To a reaction flask was added (3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (trans racemate, 297 mg, 1.0 mmol), (S)-2-phenylpropanoic acid (180 mg, 1.2 mmol), DMAP (12 mg, 0.1 mmol) and 5 mL of dichloromethane, EDCI (288 mg, 1.5 mmol) was added portionwise at room temperature, the mixture was stirred at room temperature overnight. The reaction was poured into 20 mL of water, extracted with dichloromethane, the organic phase was dried and evaporated to dryness and purified by column chromatography (DCM / MeOH = 50 / 1) to give the upper spot (TLC spot 1) 120 mg as a yellowish solid; the lower spot (TLC spot 2) 130 mg as a yellowish solid. Total yield: 58%.

[0957] Step 2: Synthesis of (3-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)tetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol

[0958] (S)-2-phenylpropanoic acid (3-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)tetrahydro-lH- pyrrolizin-7a(5H)-yl)methyl ester (TLC spot 1, 120 mg, 0.28 mmol) was dissolved in MeOH / H20 (3 mL / 0.3 mL), NaOH (40 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was backwashed once with 1 M aqueous NaOH, dried, and concentrated to give 85 mg of the target product (Trans isomer 1) in 100% yield.

[0959] Step 3: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-2-((3-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0960] The above product (Trans isomer 1) was used as a starting material to obtain the target product (i.e., Example 141, Trans isomer 1) by a similar method to Example 34.

[0961] LC / MS: m / z = 733.3 [M+H] + .

[0962] 1 H NMR (400 MHz, CDC13) δ 10.29 (br s, 1H), 9.12 (s, 1H), 7.76-7.73 (m, 1H), 7.61-7.54 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.25 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 4.50-4.40 (m, 2H), 4.30-4.27 (m, 1H), 4.23-4.18 (m, 2H), 3.65-3.56 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.17 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.51 (m, 7H).

[0963] Using the product of Step 1 (TLC spot 2) as the starting material, the same procedure as described in Example 142, Trans isomer 2 was obtained.

[0964] LC / MS: m / z = 733.3 [M+H] + .

[0965] 1 H NMR (400 MHz, CDC13) δ 10.29 (br s, 1H), 9.12 (s, 1H), 7.76-7.73 (m, 1H), 7.61-7.54 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.25 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 4.50-4.40 (m, 2H), 4.30-4.27 (m, 1H), 4.23-4.18 (m, 2H), 3.65-3.56 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.17 (m, 1H), 2.15-2.05 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.51 (m, 7H).

[0966] Example 143

[0967] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((5'-(4- (trifluoromethoxy)phenyl)dihydro-1 'H,3 'H-spiro[cyclopropane-1,2'-pyrrolizine]- 7a'(5'H)-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0968]

[0969] Using the product of Step 1 (TLC spot 2) as the starting material, the same procedure as described in Example 142, Trans isomer 2 was obtained.

[0970] LC / MS: m / z = 727.3 [M+H] + .

[0971] Example 144

[0972] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-fluoro-3-(4- (trifluoromethoxy)phenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0973]

[0974] Step 1: Synthesis of 1-(tert-butyl) 2-methyl 4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate

[0975] To a reaction flask was added 1-(tert-butyl) 2-methyl-4-hydroxy-5-oxopyrrolidine-1,2- dicarboxylate (2.59 g, 10.0 mmol) and 25 mL of dichloromethane, DAST (2.4 g, 15.0 mmol) was added at 0 °C, the mixture was stirred at room temperature for 4 hours. The reaction was poured into 100 mL of water, extracted with dichloromethane, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE\EA = 5\1) to give 1.7 g of colorless oil, yield: 65%.

[0976] Step 2: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-fluoro-3-(4- (trifluoromethoxy)phenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[0977] The above product was used as raw material for the synthesis of the target product by a method similar to that in Example 34.

[0978] LC / MS: m / z = 719.3 [M+H] + .

[0979] 1 H NMR (400 MHz, CDC13) δ 9.01 (s, 1H), 7.65-7.55 (m, 2H), 7.47 (d, 2H, J = 8.4 Hz), 7.37-7.30 (m, 4H), 7.23-7.15 (m, 4H), 5.19 (s, 0.5H), 5.07 (s, 0.5H), 4.47-4.32 (m, 4H), 3.98 (s, 0.5H), 3.91 (s, 0.5H), 3.65-3.47 (m, 4H), 3.04-2.98 (m, 1H), 2.78-2.70 (m, 1H), 2.56-2.50 (m, 1H), 2.17-2.12 (m, 1H), 1.99-1.87 (m, 3H), 1.76-1.60 (m, 5H).

[0980] Example 145

[0981] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(4,4-difluorocinnolin-6- yl)tetrahydro-1H-pyrrozal-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)- 5,6-difluoronaphthalen-2-ol

[0982]

[0983] Step 1: Synthesis of 7-bromo-1,1-difluoro-2,3-dihydrochromene

[0984] Into a reaction flask was added 6-bromo-4-dihydrochromenone (5.0 g, 22.03 mmol) and 20 mL BAST, the mixture was stirred at 70 °C overnight. The reaction was poured into 200 mL ice water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE\EA=8\1) to give a yellow oil 2.1 g, yield: 38.2%.

[0985] The above intermediate was used as raw material, and the target product was synthesized by a method similar to Example 34.

[0986] LC / MS: m / z = 745.3 [M+H] + .

[0987] Example 146

[0988] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(1,1-dimethyl-1,3- dihydroisochromen-5-yl)tetrahydro-1H-pyrrozal-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0989]

[0990] Step 1: Synthesis of 2-(4-bromo-2-(hydroxymethyl)phenyl)propan-2-ol

[0991] Into a three-necked reaction flask was added 5-bromobenzofuran-1(3H)-one (6.4 g, 30.00 mmol) and 50 mL tetrahydrofuran, methyl magnesium bromide (60 mL, 120.00 mmol) was added at 0 °C, the mixture was heated to reflux and reacted overnight. The reaction was poured into 200 mL saturated ammonium chloride, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE\EA=2\1) to give a yellow solid 2.5 g, yield: 34%.

[0992] Step 2: Synthesis of 5-bromo-1,1-dimethyl-1,3-dihydroisochromene

[0993] To a reaction flask was added 2-(4-bromo-2-(hydroxymethyl)phenyl)propan-2-ol (2.5 g, 10.20 mmol) and 20 mL of toluene, phosphoric acid (1.5 g, 15.30 mmol) was added at room temperature, the reaction was heated to 80 °C and stirred for 2 hours. The reaction system was cooled to room temperature and poured into 50 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE\EA = 10\1) to obtain a white solid 1.5 g, yield: 65.2%.

[0994] The above intermediate was used as raw material, and the target product was synthesized by a method similar to Example 34.

[0995] LC / MS: m / z = 723.3 [M+H] + .

[0996] Example 147

[0997] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(4-(difluoro(tetrahydro- 2H-pyran-4-yl)methyl)phenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[0998]

[0999] Step 1: Synthesis of (4-bromophenyl)(tetrahydro-2H-pyran-4-yl)methanone

[1000] To a reaction flask was added 1,4-dibromobenzene (5.0 g, 21.2 mmol) and 30 mL of tetrahydrofuran, n-BuLi (2.5 M, 8.5 mL, 21.2 mmol) was added at -78 °C, and stirred at -78 °C for 1 hour. N-methoxy-N-methyltetrahydro-2H-pyran-4- carboxamide (4.41 g, 25.44 mmol) was added, and stirred at -78 °C for another 1 hour. The reaction solution was poured into 100 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE\EA = 3\1) to obtain a white solid 4.5 g, yield: 79.8%.

[1001] Step 2: Synthesis of 4-((4-bromophenyl) difluoromethyl)tetrahydro-2H-pyran

[1002] Into a reaction flask was placed (4-bromophenyl)(tetrahydro-2H-pyran-4- yl)methanone (4.5 g, 16.72 mmol) and 20 mL of BAST, the mixture was stirred at 70 °C overnight. The reaction was poured into 200 mL of ice water, extracted with ethyl acetate, the organic phase was dried and concentrated to dryness, the crude product was purified by column chromatography (PE\EA = 8\1) to give 3.1 g of a yellowish oil, yield: 63.7%

[1003] The above intermediate was used as the raw material to synthesize the target product by a method similar to that in Example 34.

[1004] LC / MS: m / z = 787.3 [M+H] + .

[1005] Example 148

[1006] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(1,3-dihydroisochromen-5-yl- 1,1,3,3-d4)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[1007]

[1008] Step 1: Synthesis of (4-bromo-1,2-phenylene)bis(methane-d2-ol)

[1009] Into a reaction flask was placed 4-bromophthalic acid dimethyl ester (5.0 g, 18.32 mmol) and 50 mL of tetrahydrofuran, LiAlD4(1.04 g, 27.47 mmol) was added at 0 °C, the mixture was stirred at 0 °C for 1 hour. After the reaction was completed, 1 mL of water, 1 mL of 15% sodium hydroxide aqueous solution were added dropwise to the system under ice bath, stirred for 5 minutes, then 3 mL of water was added. An appropriate amount of anhydrous magnesium sulfate was added, stirred at room temperature for 15 minutes, the system was filtered, the filtrate was concentrated to dryness to give 3.5 g of a white solid, yield: 86%.

[1010] Step 2: Synthesis of 5-bromo-1,3-dihydroisochromene-1,1,3,3-d4

[1011] Into a reaction flask was placed (4-bromo-1,2-phenylene)bis(methane-d2-ol) (3.5 g, 15.84 mmol) and 30 mL of toluene, phosphoric acid (2.33 g, 23.76 mmol) was added at room temperature, the reaction was heated to 80 °C and stirred for 2 hours. After the reaction system was cooled to room temperature, it was poured into 80 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated to dryness, the crude product was purified by column chromatography (PE\EA = 10\1) to give 2.3 g of a white solid, yield: 72%.

[1012] The above intermediate was used as the raw material, and the target product was synthesized by a method similar to that in Example 34.

[1013] LC / MS: m / z = 663.3 [M+H] + .

[1014] Example 149

[1015] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,1,3,3-tetramethyl- 1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[1016]

[1017] The starting material drawn in the synthetic route was used as the raw material, and the target product was synthesized by a method similar to that in Example 34 and Example 146.

[1018] LC / MS: m / z = 715.4 [M+H] + .

[1019] Example 150

[1020] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,1,3,3-tetramethyl- 1,3-dihydroisobenzofuran-5-yl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol

[1021]

[1022] Step 1: Synthesis of 5-bromo-2,3-dihydro-1H-inden-2-ol

[1023] Into a reaction flask was added 5-bromo-1,3-dihydro-2H-inden-2-one (5.0 g, 23.70 mmol) and 30 mL of methanol, and NaBH4(1.08 g, 28.44 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to quench the reaction, and the system was concentrated to remove methanol. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness to obtain 4.6 g of white solid, with a yield of 92%.

[1024] Step 2: Synthesis of 5-bromo-2-methoxy-2,3-dihydro-1H-indene

[1025] Into a reaction flask was placed 5-bromo-2,3-dihydro-lH-inden-2-ol (4.6 g, 21.60 mmol), potassium carbonate (8.94 g, 64.79 mmol) and DMF (50 mL), and iodomethane (6.13 g, 43.20 mmol) was added at room temperature. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 hours. After the reaction system was cooled to room temperature, it was poured into 10 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE\EA=5\1) to obtain 2.8 g of colorless oil, yield: 57.1%.

[1026] The above intermediate was used as raw material, and the target product was synthesized by a method similar to that in Example 34.

[1027] LC / MS: m / z = 687.3 [M+H] + .

[1028] Example 151

[1029] 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(l,3-dihydroisochromen-5-yl- 1,1-d2)tetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7- yl)-5,6-difluoronaphthalen-2-ol

[1030]

[1031] The starting material drawn in the synthetic route was used as raw material, and the target product was synthesized by a method similar to that in Example 34 and Example 148.

[1032] LC / MS: m / z = 687.3 [M+H] + .

[1033] 1 H NMR (400 MHz, CDC13) δ 9.13 (s, 1H), 8.03 (s, 1H), 8.00-7.97 (m, 1H), 7.79-7.73 (m, 1H), 7.57 (d, 1H, J = 6.0 Hz), 7.35-7.32 (m, 2H), 7.05-6.97 (m, 2H), 4.44-4.4 (m, 2H), 4.32-4.18 (m, 2H), 3.76-3.45 (m, 12H), 2.76-2.74 (m, 1H), 2.17-2.11 (m, 2H), 1.88-1.57 (m, 6H).

[1034] Example 152

[1035] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(2-fluoro-2,3-dihydro-1H-inden-5-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol

[1036]

[1037] Step 1: Synthesis of 5-bromo-2-fluoro-2,3-dihydro-1H-indene

[1038] 5-Bromo-2,3-dihydro-1H-inden-2-ol (3.0 g, 14.08 mmol) and 25 mL of dichloromethane were added to a reaction flask. DAST (3.4 g, 21.13 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 100 mL of water, extracted with dichloromethane, dried over an evaporator, and purified by column chromatography (PE / EA = 5 / 1) to give 1.2 g of a colorless oil, yield: 39.6%.

[1039] The target product was synthesized using the above intermediate as a raw material through a method similar to that in Example 34.

[1040] LC / MS: m / z = 675.3 [M+H] + .

[1041] Example 153

[1042] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,2,3,4-tetrahydro-1,4-epoxynaphthyl-6-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthyl-2-ol

[1043]

[1044] Step 1: Synthesis of 6-bromo-1,4-dihydro-1,4-epoxynaphthalene

[1045] Weigh 50 g (0.20 mol) of 1,4-dibromo-2-fluorobenzene and 40 g (0.59 mol) of furan and dissolve them in 150 mL of toluene. Purge the solution three times with nitrogen, cool to -30 °C, and slowly add n-butyllithium (80 mL, 2.5 M) dropwise. After the addition is complete, heat to room temperature and stir for 0.5 hours. Pour the reaction mixture into a saturated aqueous solution of ammonium chloride, extract twice with ethyl acetate, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure to dryness, and purify by column chromatography (PE / EA = 10:1) to obtain 30 g of a colorless oil, yield: 68%.

[1046] Step two: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-(1,4-dihydro-1,4- naphthoquinone-6-yl)-5-oxopentanoate

[1047] Compound 6-bromo-1,4-dihydro-1,4-naphthoquinone (30 g, 0.13 mol) was dissolved in tetrahydrofuran (150 mL) and replaced with nitrogen for 3 times. The temperature was reduced to -78 °C and n-butyllithium (54 mL, 2.5 M) was slowly added dropwise. After the dropwise addition was completed, the mixture was stirred at -78 °C for 0.5 h and was ready for use.

[1048] Compound Boc-L-pyroglutamic acid methyl ester (33 g, 0.13 mol) was dissolved in tetrahydrofuran (330 mL) and replaced with nitrogen for 3 times. The temperature was reduced to -78 °C and the above reaction solution was slowly added dropwise while controlling the temperature to be less than -55 °C. After the dropwise addition was completed, the mixture was stirred at -78 °C for 0.5 h. The reaction was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate twice. The combined organic phase was washed with saturated brine once and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave 60 g of a yellowish oil as a crude product.

[1049] Step three: Synthesis of methyl 5-(1,4-dihydro-1,4-naphthoquinone-6-yl)-3,4-dihydro-2H- pyrrole-2-carboxylate

[1050] The crude product from the previous step was dissolved in dichloromethane (60 mL) and trifluoroacetic acid (60 mL) was slowly added under ice water bath conditions. After the addition was completed, the temperature was increased to room temperature and the mixture was stirred for 1 h. The mixture was concentrated under reduced pressure and the pH was adjusted to 7-8 with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate three times and the combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 3:1) gave 11 g of a yellowish oil as a product with a yield of 30% (two steps).

[1051] Step four: Synthesis of methyl 2-(3-chloropropyl)-5-(1,4-dihydro-1,4-naphthoquinone-6-yl)- 3,4-dihydro-2H-pyrrole-2-carboxylate

[1052] Methyl 3-(1,4-dihydro-1,4-oxonaphthalen-6-yl)tetrahydro-1 H-pyrrolizin-7a(5H)- carboxylate (3.5 g, 11.2 mmol) was dissolved in glacial acetic acid (18 mL), purged with nitrogen for 3 times, added palladium on carbon 10% (1.0 g), purged with hydrogen for 3 times and stirred at room temperature for 1 hour under hydrogen balloon, the reaction system was filtered with celite, concentrated to dryness, adjusted to alkaline with sodium bicarbonate aqueous solution, extracted with ethyl acetate for 3 times, combined the organic phase, washed with saturated brine for 1 time, dried over anhydrous sodium sulfate. Filtered, concentrated to dryness, purified by reverse phase separation to get light yellow oil 1.6 g, yield: 46%.

[1053] Step five: synthesis of methyl 3-(1,4-dihydro-1,4-oxonaphthalen-6-yl)tetrahydro-1 H- pyrrolizin-7a(5H)-carboxylate

[1054] Methyl 2-(3-chloropropyl)-5-(1,4-dihydro-1,4-oxonaphthalen-6-yl)-3,4-dihydro-2H- pyrrole-2-carboxylate (3.7 g, 10.7 mmol) was dissolved in methanol (37 mL), added glacial acetic acid (965 mg, 16.0 mmol) and sodium cyanoborohydride (1.0 g, 16.0 mmol) in sequence, stirred at room temperature for 1 hour, quenched with sodium bicarbonate aqueous solution, concentrated to remove most of the methanol under reduced pressure, the crude product was extracted with water and ethyl acetate for 3 times, combined the organic phase, washed with saturated brine for 1 time, dried over anhydrous sodium sulfate. Filtered, concentrated to dryness, purified by column chromatography (PE / EA = 1 :1) to collect the point to get colorless oil 1.6 g, yield: 50%.

[1055] Step six: synthesis of methyl 3-(1,2,3,4-tetrahydro-1,4-oxonaphthalen-6-yl)tetrahydro-1 H- pyrrolizin-7a(5H)-carboxylate

[1056] Methyl 3-(1,4-dihydro-1,4-oxonaphthalen-6-yl)tetrahydro-1 H-pyrrolizin-7a(5H)- carboxylate (3.5 g, 11.2 mmol) was dissolved in glacial acetic acid (18 mL), purged with nitrogen for 3 times, added palladium on carbon 10% (1.0 g), purged with hydrogen for 3 times and stirred at room temperature for 1 hour under hydrogen balloon, the reaction system was filtered with celite, concentrated to dryness, adjusted to alkaline with sodium bicarbonate aqueous solution, extracted with ethyl acetate for 3 times, combined the organic phase, washed with saturated brine for 1 time, dried over anhydrous sodium sulfate. Filtered, concentrated to dryness, purified by reverse phase separation to get light yellow oil 1.6 g, yield: 46%.

[1057] Step 4: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(l,2,3,4-tetrahydro-l,4-oxonaphthyridin-6-yl)tetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[1058] The above product was used as raw material to synthesize the target product by a similar method to Example 34.

[1059] LC / MS: m / z = 721.3 [M+H] + .

[1060] 1 H NMR (400 MHz, CDC13) δ 10.27 (s, 1H), 9.13 (s, 1H), 7.77-7.73 (m, 1H), 7.61-7.55 (m, 1H), 7.40 (s, 1H), 7.28-7.21 (m, 2H), 7.11-7.04 (m, 2H), 5.32-5.22 (m, 2H), 4.45-4.18 (m, 5H), 3.74-3.71 (m, 1H), 3.65-3.56 (m, 4H), 2.77-2.74 (m, 1H), 2.18-2.08 (m, 2H), 1.91-1.66 (m, 14H).

[1061] Example 154

[1062] 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(spiro[cyclopropane-l,4'-isochroman]-6'-yl)tetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[1063]

[1064] Step 1: Synthesis of (l-(3-bromophenyl)cyclopropyl)methanol

[1065] To a reaction flask was added l-(3-bromophenyl)cyclopropane-l-carboxylic acid (4.82 g, 20.00 mmol) and 20 mL of tetrahydrofuran, BH3-THF (1 M, 30 mL) was added at 0 °C, the mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of methanol. The system was concentrated to dryness to give a crude product which was used directly in the next step.

[1066] Step 2: Synthesis of l-bromo-3-(l-((methoxymethoxy)methyl)cyclopropyl)benzene

[1067] The above crude product was dissolved in 30 mL of dichloromethane, TEA (6.06 g, 60.00 mmol) was added at room temperature, and MOMOCl (2.42 g, 30.00 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 8 hours under nitrogen protection. After the reaction system was cooled to room temperature, it was poured into 100 mL of water, extracted with dichloromethane, and the organic phase was washed twice with dilute hydrochloric acid, dried and rotary evaporated to obtain a crude product which was directly used in the next step.

[1068] Step 3: Synthesis of 6'-bromospiro[cyclopropane-l,4'-isochroman]

[1069] The crude product obtained in step 2 was dissolved in 30 mL of DCM, and TMSOTf (13.33 g, 60.00 mmol) was added at 0 °C, and stirred for 2 hours. The reaction was directly rotary evaporated, and the crude product was purified by column chromatography (PE\EA=5\1) to obtain 1.8 g of yellowish oil, yield: 37.5% (3 steps).

[1070] The above intermediate was used as raw material, and the target product was synthesized by a method similar to that in Example 34.

[1071] LC / MS: m / z = 735.3 [M+H] + .

[1072] Example 155

[1073] 5-(7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-lH- pyrrozin-3-yl)isobenzo furan-l(3H)-one

[1074]

[1075] Step 1: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-(l-oxo-l,3- dihydroisobenzofuran-5-yl)pentanoate

[1076] Into a reaction flask was added 5-bromobenzofuran-l(3H)-one (2.1 g, 10.0 mmol), l-(tert-butyl) 2-methyl 5-oxopyrrolidine-l,2-dicarboxylate (2.4 g, 10.0 mmol), and 20 mL of super dry tetrahydrofuran, and n-butyllithium (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise at 0 °C. After the addition was completed, it was stirred at 0 °C for 1 hour. The reaction solution was poured into 100 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and rotary evaporated, and purified by column chromatography (PE / EA=5 / 1) to obtain 160 mg of yellow solid, yield: 4%.

[1077] Step 2: Synthesis of 5-(7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8- difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro- 1H-pyrrozin-3-yl)isobenzo furan-1(3H)-one

[1078] The above product of last step was used as raw material, the target product was synthesized by similar method with example 34.

[1079] LC / MS: m / z = 709.3 [M+H] + .

[1080] Example 156

[1081] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(3,3-dimethyl-1,3-dihydroisobenzofuran- 5-yl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2-ol

[1082]

[1083] The starting material drawn in the synthetic route was used as raw material, the target product was synthesized by similar method with example 34, example 146 and example 154.

[1084] LC / MS: m / z = 723.3 [M+H] + .

[1085] 1 H NMR (400 MHz, CDC13) δ 10.28 (br s, 1H), 9.12 (s, 1H), 7.77-7.73 (m, 1H), 7.61-7.55 (m, 1H), 7.30 (s, 1H), 7.25-7.21 (m, 2H), 7.16 (1H, d, J = 2.8 Hz), 7.07-7.04 (m, 1H), 4.88 (s, 2H), 4.49-4.31 (m, 3H), 4.25-4.18 (m, 1H), 3.79-3.74 (m, 1H), 3.65-3.55 (m, 4H), 2.78 (br s, 1H), 2.56-2.50 (m, 1H), 2.18-2.10 (m, 2H), 1.92-1.80 (m, 4H), 1.79-1.63 (m, 6H), 1.34 (s, 6H).

[1086] Example 157

[1087] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(1,3,4,5-tetrahydrobenzo[c]oxepin-7-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[1088]

[1089] The starting material drawn in the synthetic route was used as the raw material, and the target product was synthesized by a method similar to that in Example 34 and Example 154.

[1090] LC / MS: m / z = 723.3 [M+H] +

[1091] Example 158

[1092] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl-3d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

[1093]

[1094] Step 1: Synthesis of methyl 5-(4-fluorophenyl)pyrrolidine-2-carboxylate-5-d

[1095] Into a reaction flask was added methyl 5-(4-fluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (2.21 g, 10.00 mmol) and 20 mL of methanol, and acetic acid (0.9 g, 15.00 mmol) and NaBD3CN (0.99 g, 15.00 mmol) were added at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water, and the pH was adjusted to about 9 with sodium carbonate. The organic phase was dried and rotary evaporated to obtain a crude product which was directly used in the next reaction.

[1096] The above intermediate was used as the raw material, and the target product was synthesized by a method similar to that in Example 34.

[1097] LC / MS: m / z = 672.3 [M+H] + .

[1098] Example 159

[1099] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4-fluorophenyl)-3- methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2-ol (Trans racemate)

[1100]

[1101] Step 1: Synthesis of (E)-ethyl 3-(4-fluorophenyl)but-2-enoate

[1102] To a reaction flask was added ethyl 2-(dimethoxyphosphoryl)acetate (14.7 g, 75.0 mmol) and 50 mL of tetrahydrofuran, NaH (60%, 3.2 g, 80 mmol) was added portionwise at 0 °C, the mixture was stirred at room temperature for 1 hour. After the addition of 4-fluoroacetophenone (7.0 g, 50.7 mmol), the reaction was stirred at room temperature for 16 hours. The reaction was poured into 200 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated to give the crude product which was used directly in the next step.

[1103] Step 2: Synthesis of (E)-3-(4-fluorophenyl)but-2-en-1-ol

[1104] The above crude product was dissolved in 50 mL of tetrahydrofuran, LiAlH4(1.91 g, 50.0 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, 1.9 mL of water, 1.9 mL of 15% aqueous sodium hydroxide solution was added dropwise to the system under ice bath, stirred for 5 minutes, then 5.7 mL of water was added. The appropriate amount of anhydrous magnesium sulfate was added, stirred at room temperature for 15 minutes, the system was filtered, the filtrate was concentrated to dryness, the crude product was purified by column chromatography (PE\EA=2\1) to give 3.5 g of white solid, yield: 42.2% (2 steps).

[1105] Step 3: Synthesis of (E)-1-(4-bromobut-2-en-2-yl)-4-fluorobenzene

[1106] (E)-3-(4-fluorophenyl)but-2-en-1-ol (3.5 g, 21.06 mmol) was dissolved in 30 mL of ether, protected by nitrogen, phosphorus tribromide (6.84 g, 25.27 mmol) was added under ice bath, the reaction was stirred at room temperature for 15 minutes, the reaction system was added to 100 mL of ice water, extracted with petroleum ether, the organic phase was dried and concentrated to dryness, the crude product was used directly in the next step.

[1107] Step 4: Synthesis of 1-(tert-butyl) 2-methyl (E)-2-(3-(4-fluorophenyl)but-2-en-1-yl)pyrrolidine- 1,2-dicarboxylate

[1108] Boc-L-proline methyl ester (4.13 g, 18.00 mmol) was dissolved in 40 mL of dry tetrahydrofuran, and LDA (2 M, 13.5 mL, 27.00 mmol) was added dropwise at -78 °C under nitrogen protection. After stirring for 30 min, the crude product from Step 3 was dissolved in 10 mL of tetrahydrofuran and added dropwise to the reaction system at -78 °C. The reaction was stirred for another 2 h. The reaction system was directly poured into saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness to obtain the crude product, which was directly used in the next step.

[1109] Step 5: Synthesis of (E)-methyl 2-(3-(4-fluorophenyl)but-2-en-1-yl)pyrrolidine-2- carboxylate

[1110] The crude product from Step 4 was dissolved in 40 mL of ethyl acetate hydrochloric acid solution, and stirred at room temperature for 1 h. The reaction system was directly concentrated to dryness, and then water was added. The aqueous phase was first extracted with ethyl acetate twice, and then the aqueous phase was adjusted to basic with sodium carbonate. The organic phase was extracted with ethyl acetate, and then dried and concentrated to dryness to obtain 1.5 g of pure product, with a yield of 30% (2 steps).

[1111] Step 6: Synthesis of methyl 3-(4-fluorophenyl)-2-iodo-3-methyltetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate

[1112] (E)-methyl 2-(3-(4-fluorophenyl)but-2-en-1-yl)pyrrolidine-2-carboxylate (1.5 g, 5.41 mmol) was dissolved in 20 mL of ethyl acetate, and elemental iodine (1.98 g, 8.11 mmol) was added at 0 °C. After the addition was completed, the reaction was stirred at room temperature for 2 h. The reaction system was directly poured into water, and extracted with ethyl acetate. The organic phase was washed with appropriate amount of aqueous sodium bisulfite solution twice, dried, and concentrated to dryness to obtain the crude product, which was directly used in the next step.

[1113] Step 7: Synthesis of methyl 3-(4-fluorophenyl)-3-methyltetrahydro-1H-pyrrolizine-7a(5H)- carboxylate

[1114] The crude product from Step 6 was dissolved in 20 mL of toluene, and tri-n-butyltin hydride (3.15 g, 10.82 mmol) and AIBN (88 mg, 0.54 mmol) were added at room temperature. The reaction was heated to 80 °C for 2 h. The reaction system was directly poured into water, and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness, and the crude product was purified by column chromatography (PE\EA = 8\1) to elute ~0.6 g of the cis intermediate as a yellowish oil, and PE\EA = 2\1 to elute ~0.5 g of the trans intermediate as a yellowish solid, with a total yield of 73.3% (2 steps).

[1115] The above trans intermediate was used as the starting material to synthesize the target product by a method similar to that in Example 140.

[1116] LC / MS: m / z = 685.3 [M+H] + .

[1117] 1 H NMR (400 MHz, CDC13) δ 8.93 (s, 1H), 7.48-7.44 (m, 2H), 7.37-7.33 (m, 1H), 7.25-7.17 (m, 3H), 7.04-6.99 (m, 2H), 4.68-4.41 (m, 5H), 3.74-3.52 (m, 4H), 2.88-2.82 (m, 1H), 2.37-2.23 (m, 4H), 2.11-1.93 (m, 4H), 1.87-1.59 (m, 7H).

[1118] Example 160

[1119] 4-((3R,7aR)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- pyrazin-3-yl)phenyl dimethylcarbamate (Trans racemate)

[1120]

[1121] Step 1: Synthesis of 4-((3R,7aR)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrazin-3-yl) phenol

[1122] To a reaction flask was added tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((3R,7aR)-3-(4- methoxyphenyl)tetrahydro-1H-pyrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.47 mmol) and 5 mL of dichloromethane, BBr3(1 M, 1.5 mL, 1.5 mmol) was added at 0 °C, the mixture was stirred at room temperature for 1 hour. The reaction was poured into 20 mL of water, extracted with dichloromethane, the organic phase was dried and evaporated to dryness to give the crude product which was used directly in the next step.

[1123] Step 2: Synthesis of tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(((3R, 7aR)-3-(4- hydroxyphenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1124] The above crude product was dissolved in 5 mL of dichloromethane, TEA (152 mg, 1.5 mmol), Boc20 (110 mg, 0.5 mmol) was added at room temperature, the reaction mixture was stirred at room temperature for 1 hour. The reaction system was directly concentrated to dryness and purified by Prep-TLC (DCM / MeOH = 30 / 1) to give 120 mg of gray solid, yield: 40.8% (2 steps).

[1125] Step 3: Synthesis of tert-butyl (1R, 5S)-3-(7-chloro-2-(((3R, 7aR)-3-(4-((dimethyl- aminocarbonyl)oxy)phenyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1126] Tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(((3R, 7aR)-3-(4-hydroxyphenyl)tetra- hydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (120 mg, 0.19 mmol) was dissolved in 3 mL of dichloromethane, DIEA (74 mg, 0.57 mmol), dimethylaminocarbonyl chloride (41 mg, 0.38 mmol) was added at room temperature, and stirred overnight. The reaction system was directly concentrated to dryness and purified by Prep-TLC (DCM / MeOH = 40 / 1) to give 60 mg of gray solid, yield: 45.1%.

[1127] The above intermediate was used as raw material to synthesize the target product by a method similar to Example 34.

[1128] LC / MS: m / z = 740.3 [M+H] + .

[1129] Example 161

[1130] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline (Trans racemate)

[1131]

[1132] Step 1: Synthesis of 1-bromo-3-chloro-2-iodo-5-nitrobenzene

[1133] Into a reaction flask was placed 2-bromo-6-chloro-4-nitroaniline (10 g, 40.0 mmol), potassium iodide (13.3 g, 80.1 mmol), copper(I) iodide (15.2 g, 80.0 mmol) and 100 mL of acetonitrile, tert-butyl nitrite (5.5 g, 53.4 mmol) was added at room temperature, the mixture was stirred at 80 °C overnight. The reaction was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated to give the crude product which was used directly in the next step.

[1134] Step 2: Synthesis of 3-bromo-5-chloro-4-iodoaniline

[1135] Into a reaction flask was placed 1-bromo-3-chloro-2-iodo-5-nitrobenzene (crude product from previous step), 10 mL of concentrated hydrochloric acid and 100 mL of ethanol, iron powder (6.7 g, 119.6 mmol) was added at room temperature, the mixture was stirred at 80 °C for 2 hours. The reaction was poured into 500 mL of water, adjusted to basic pH with sodium hydroxide, extracted with ethyl acetate, the organic phase was dried and concentrated to give the crude product which was used directly in the next step.

[1136] Step 3: Synthesis of tert-butyl (3-bromo-5-chloro-4-iodophenyl)carbamate

[1137] Into a reaction flask was placed 3-bromo-5-chloro-4-iodoaniline (crude product from previous step), triethylamine (8.1 g, 80.2 mmol), DMAP (1.2 g, 9.8 mmol) and 100 mL of dichloromethane, Boc20 (17.4 g, 80.0 mmol) was added at room temperature, the mixture was stirred at 50 °C overnight. The reaction was poured into 500 mL of water, extracted with ethyl acetate, the organic phase was dried and concentrated, purified by column chromatography (DCM / MeOH = 50 / 1) to give 3.5 g of light yellow solid, three steps yield: 20%.

[1138] Step 4: Synthesis of tert-butyl (3-bromo-5-chloro-4-(trifluoromethyl)phenyl)carbamate

[1139] To a reaction flask was added tert-butyl (3-bromo-5-chloro-4-iodophenyl)carbamate (3.5 g, 8.1 mmol), 2,2-difluoro-2-(fluorosulfonyl)acetate (3.1 g, 16.2 mmol), cuprous iodide (1 g, 5.3 mmol) and 50 mL of DMF. The mixture was stirred at 90 °C under nitrogen for 4 hours. The reaction was poured into 200 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give 1.6 g of a light yellow solid in 53% yield.

[1140] Step 5: Synthesis of 3-bromo-5-chloro-4-(trifluoromethyl)aniline

[1141] To a reaction flask was added tert-butyl (3-bromo-5-chloro-4-iodophenyl)carbamate (3.5 g, 8.1 mmol), 2,2-difluoro-2-(fluorosulfonyl)acetate (3.1 g, 16.2 mmol), cuprous iodide (1 g, 5.3 mmol) and 50 mL of DMF. The mixture was stirred at 90 °C under nitrogen for 4 hours. The reaction was poured into 200 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give 1.6 g of a light yellow solid in 53% yield.

[1142] Step 6: Synthesis of 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)aniline

[1143] To a reaction flask was added tert-butyl (3-bromo-5-chloro-4-iodophenyl)carbamate (3.5 g, 8.1 mmol), 2,2-difluoro-2-(fluorosulfonyl)acetate (3.1 g, 16.2 mmol), cuprous iodide (1 g, 5.3 mmol) and 50 mL of DMF. The mixture was stirred at 90 °C under nitrogen for 4 hours. The reaction was poured into 200 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give 1.6 g of a light yellow solid in 53% yield.

[1144] Step 7: Synthesis of 3-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)tetrahydro-lH-pyrrozin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline (Trans racemate)

[1145] The target product was synthesized by a similar method to Example 34, using the boronate ester drawn in the synthetic route as a starting material.

[1146] LC / MS: m / z = 748.2 [M+H] + .

[1147] Example 162

[1148] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)aniline (Trans racemate)

[1149]

[1150] Step 1: Synthesis of 2-bromo-1-((1,1,1,3,3-hexafluoropropan-2-yl)oxy)-4-nitrobenzene

[1151] Into a reaction flask was added 3-bromo-4-fluoronitrobenzene (2.2 g, 10.0 mmol), hexafluoroisopropanol (2.52 g, 15.0 mmol) and 15 mL of tetrahydrofuran, potassium tert-butoxide (2.24 g, 20.0 mmol) was added at 0 °C, the mixture was heated to 50 °C and stirred for 6 hours. The reaction was poured into 50 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated to get the crude product which was used directly for the next step.

[1152] Step 2: Synthesis of 3-bromo-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)aniline

[1153] The above crude product was dissolved in 20 mL of ethanol, 4 mL of water was added at room temperature, iron powder (2.79 g, 50.0 mmol), ammonium chloride (2.68 g, 50.0 mmol), the reaction mixture was stirred at 80 °C for 4 hours. The reaction system was diluted with ethyl acetate, suction filtered, the filtrate was concentrated to dryness to get the crude product, which was purified by column chromatography (PE\EA = 5 / 1) to get 300 mg of gray solid, yield: 8.9% (2 steps).

[1154] The above intermediate was used as raw material, and the target product was synthesized by a method similar to that of Example 161.

[1155] LC / MS: m / z = 812.3 [M+H] + .

[1156] Example 163

[1157] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethoxy)(Trans racemate)

[1158]

[1159] The title compound was synthesized by a similar method to that described in Example 161, using the starting material drawn in the synthetic route as the raw material.

[1160] LC / MS: m / z = 730.3 [M+H] + .

[1161] 1 H NMR (400 MHz, CDC13) δ 9.02 (s, 1H), 7.24-7.15 (m, 3H), 7.03-7.00 (m, 1H), 6.88-6.86 (m, 1H), 6.78-6.75 (m, 1H), 4.62-4.31 (m, 5H), 3.81 (br s, 2H), 3.73-3.57 (s, 4H), 2.62-2.52 (m, 1H), 2.38-2.24 (m, 2H), 2.17-1.99 (m, 4H), 1.76-1.56 (m, 7H).

[1162] Example 164

[1163] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-fluoro-4-(trifluoromethoxy)(Trans racemate)

[1164]

[1165] Step 1: Synthesis of 2-bromo-6-fluoro-4-nitrophenol

[1166] Into a reaction flask was placed 2-fluoro-4-nitrophenol (2.0 g, 12.74 mmol) and 20 mL of acetonitrile, at 0 °C was added NBS (2.72 g, 15.29 mmol), the mixture was stirred at room temperature for 1 hour. The reaction was poured into 80 mL of water, extracted with ethyl acetate, the organic phase was washed with 2 times of appropriate amount of sodium bisulfite aqueous solution, dried and rotary evaporated, purified by flash column chromatography (PE / EA = 5 / 1) to give 2.2 g of yellow solid, yield: 73.3%.

[1167] Step 2: Synthesis of 1-bromo-3-fluoro-5-nitro-2-(trifluoromethoxy)benzene

[1168] Into a reaction flask was placed 2-bromo-6-fluoro-4-nitrophenol (2.2 g, 7.33 mmol), silver trifluoromethanesulfonate (5.65 g, 21.99 mmol), N-fluorobenzensulfonimide (6.93 g, 21.99 mmol), Selectfluor (7.79 g, 21.99 mmol), cesium fluoride (3.34 g, 21.99 mmol), 2,6-di-tert-butylphenol (6.05 g, 29.32 mmol) and 100 mL of toluene, at room temperature was added 2-fluoropyridine (2.85 g, 29.32 mmol), (trifluoromethyl)trimethylsilane (5.21 g, 36.65 mmol) with stirring. The reaction mixture was heated to 70 °C under nitrogen protection for 6 hours. After the reaction system was cooled to room temperature, it was directly filtered, the filtrate was poured into 200 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, the crude product was purified by column chromatography (PE / EA = 50 / 1) to give 0.4 g of yellow solid, yield: 14.1%.

[1169] The above intermediate was used as raw material to synthesize the target product by a method similar to that in Example 161.

[1170] LC / MS: m / z = 748.2 [M+H] + .

[1171] 1 H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1H), 7.35-7.33 (m, 2H), 7.18-7.16 (m, 1H), 6.66-6.57 (m, 2H), 5.88 (br s, 2H), 4.41-4.38 (m, 2H), 4.29-4.17 (m, 3H), 3.61-3.55 (m, 4H), 2.30-2.10 (m, 4H), 1.96-1.85 (m, 3H), 1.61-1.53 (m, 7H).

[1172] Example 165

[1173] 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-amine (Trans racemate)

[1174]

[1175] Step 1 : Synthesis of tert-butyl (1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Trans racemate)

[1176] To a reaction vial was added tert-butyl (1R,5S)-3-(7-(5-amino-3-chloro-2- (trifluoromethyl)phenyl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate in Example 161, Trans racemate, 85 mg, 0.1 mmol), phenylboronic acid (24 mg, 0.2 mmol), potassium carbonate (41 mg, 0.3 mmol) and dioxane / water (2 mL / 0.2 mL), and 1 mg of Pd(dppf)Cl2was added after purging with nitrogen. The reaction mixture was heated to 100 °C under nitrogen for 6 h with stirring. After cooling to room temperature, the reaction mixture was poured into 5 mL of water, extracted with ethyl acetate, and the organic phase was dried and concentrated. Purification by Prep-TLC (DCM / MeOH = 10 / 1) gave 60 mg of a gray solid in 67% yield.

[1177] Step 2: Synthesis of 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-amine (Trans racemate)

[1178] Tert-butyl (1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.067 mmol) was dissolved in 2 mL of ethyl acetate, HCl / EA (4 M, 0.5 mL) was added, and it was stirred for 10 minutes. The reaction was poured into 10 mL of water, and sodium carbonate was added to make it weakly basic. Ethyl acetate was added to extract the organic phase, which was dried and rotary evaporated. Purification by Prep-TLC gave 45 mg of a gray solid in a yield of 85%.

[1179] LC / MS: m / z = 790.3 [M+H] + .

[1180] Example 166

[1181] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-ethynylaniline (Trans racemate)

[1182]

[1183] Step 1: Synthesis of 3-bromo-4-((triisopropylsilyl)ethynyl)aniline

[1184] Into a reaction flask was added 3-bromo-4-iodoaniline (1.0 g, 3.36 mmol) and 10 mL of DMF, and triisopropylsilylacetylene (1.23 g, 6.72 mmol), TEA (1.36 g, 13.44 mmol), cuprous iodide (65 mg, 0.34 mmol), and Pd(PPh3)2Cl2 (239 mg, 0.34 mmol) were added at room temperature. The mixture was stirred at 70°C for 4 hours. The reaction was poured into 20 mL of water, and ethyl acetate was added to extract the organic phase, which was dried and rotary evaporated. The crude product was purified by column chromatography (PE / EA = 10 / 1) to obtain 0.6 g of a yellowish solid in a yield of 50.9%.

[1185] Step 2: Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((triisopropylsilyl)ethynyl)aniline

[1186] To a reaction flask was added 3-bromo-4-((triisopropylsilyl)ethynyl)aniline (0.6 g, 1.70 mmol), bis(pinacolato)diboron (0.5 g, 1.97 mmol), potassium acetate (0.4 g, 4.08 mmol) and 50 mL of dioxane, after purging with nitrogen, Pd(dppf)Cl2(73 mg, 0.1 mmol) was added. The reaction mixture was heated to 80 °C with stirring overnight under nitrogen protection. After the reaction system was cooled to room temperature, it was poured into 20 mL of water, extracted with ethyl acetate, the organic phase was dried and rotary evaporated, then purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain 445 mg of white solid, yield: 65.4%.

[1187] The above intermediate was used as raw material, and the target product was synthesized by a method similar to Example 52.

[1188] LC / MS: m / z = 670.3 [M+H] + .

[1189] Example 167

[1190] (Iso-butyryloxy)methyl (1R, 5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-(4- fluorophenyl)tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[1191]

[1192] Step 1: Synthesis of (Iso-butyryloxy)methyl (1R, 5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1193] To a reaction vial was added 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8- fluoro-2-((3-(4-fluorophenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (150 mg, 0.22 mmol), TEA (89 mg, 0.88 mmol) and 5 mL of dichloromethane, and ((chlorocarbonyl)oxy)isobutyric acid methyl ester (43 mg, 0.24 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was directly concentrated and purified by Prep-TLC (DCM / MeOH = 35 / 1) to give 105 mg of white solid, yield: 58.7%.

[1194] LC / MS: m / z = 815.3 [M+H] + .

[1195] Example 168

[1196] Isobutyryloxy)methyl (lR,5S)-3-(7-(3-acetyloxy-7,8-difluoronaphthalen-l-yl)-8- fluoro-2-((3-(4-fluorophenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1197]

[1198] Step 1: Synthesis of ((isobutyryloxy)methyl (lR,5S)-3-(7-(3-acetyloxy-7,8- difluoronaphthalen-l-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1199] To a reaction vial was added isobutyryloxy)methyl (lR,5S)-3-(7-(7,8-difluoro-3- hydroxynaphthalen-l-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.06 mmol), TEA (31 mg, 0.36 mmol) and 5 mL of dichloromethane, and acetyl chloride (14 mg, 0.18 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was directly concentrated and purified by Prep-TLC (DCM / MeOH = 50 / 1) to give 35 mg of white solid, yield: 66.1%.

[1200] LC / MS: m / z = 857.3 [M+H] + .

[1201] Example 169

[1202] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4- fluorophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 5,6-difluoronaphthalen-2-yl dimethylcarbamate

[1203]

[1204] Step 1: Synthesis of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1205] To the reaction flask was added 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro- 2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-5,6-difluoronaphthalen-2-ol (670 mg, 1.0 mmol), triethylamine (303 mg, 3.0 mmol) and 5 mL of dichloromethane, Boc20 (218 mg, 1.0 mmol) was added at 0 °C, the mixture was stirred at room temperature for 1 hour. The reaction solution was used directly for the next step.

[1206] Step 2: Synthesis of tert-butyl (1R,5S)-3-(7-(3-((dimethylcarbamoyl)oxy)-7,8-difluoronaphthalen-1-yl)-8-fluoro-2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1207] To the reaction flask was added 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro- 2-((3-(4-fluorophenyl)tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-5,6-difluoronaphthalen-2-ol (670 mg, 1.0 mmol), triethylamine (303 mg, 3.0 mmol) and 5 mL of dichloromethane, Boc20 (218 mg, 1.0 mmol) was added at 0 °C, the mixture was stirred at room temperature for 1 hour. The reaction solution was used directly for the next step.

[1208] Step 3: Synthesis of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((3-(4- fluorophenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2-yl dimethylcarbamate

[1209] Tert-butyl (lR,5S)-3-(7-(3-((dimethylcarbamoyl)oxy)-7,8-difluoronaphthalen-l-yl)-8-fluoro- 2-((3-(4-fluorophenyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added at room temperature, and stirring was performed at room temperature for 0.5 hours. The reaction system was poured into 10 mL of water, sodium carbonate was added to make it weakly basic, and extraction was performed with ethyl acetate. The organic phase was dried and concentrated under reduced pressure, and purification was performed by Prep-TLC to obtain 150 mg of a gray solid at a yield of 74%.

[1210] LC / MS: m / z = 742.3 [M+H] + .

[1211] The compounds of Examples 170 to 246 were prepared according to procedures analogous to those described above in the Examples, using commercially available corresponding reagents as starting materials.

[1212] Table 2

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225] Pharmacodynamic test

[1226] Test Example 1: KRAS G12D GTP::SOS1 Homogeneous Time-Resolved Fluorescence Binding Assay

[1227] 1. Test method:

[1228] The interaction between proteins was determined by homogeneous time-resolved fluorescence technology.

[1229] In a 384 reaction plate (Corning, CLS4514), 0.1 microliter of compound was added, and after centrifugation, 5 microliters of Tag2-KRAS G12D (Cisbio, 63ADK000CB17PEG) protein and GTP (SIGMA, V900868) mixture solution with a final concentration of 10 micromolar were added. Then 5 microliters of Tag1-SOS1 (Cisbio, 63ADK000CB17PEG) protein solution was added, and the reaction was carried out at room temperature for 15 minutes. All protein interactions occurred in a Dilluent (Cisbio, 62DLBDDF) buffer solution. 10 microliters of pre-mixed 100X Anti-Tag1-Tb and 25X Anti-Tag2-XL665 detection solution were added, and the reaction was carried out at 4 degrees Celsius for 180 minutes. The detection reagent was in a Detection Buffer (Cisbio, 62DB2FDG). The reaction signal was detected by a multifunctional microplate reader, and the data was analyzed by GraphPad Prism data analysis software.

[1230] 2. The KRAS G12D GTP::SOS1 binding inhibition activity of the compound of the present application is shown in Table 3.

[1231] Table 3: KRAS G12D GTP::SOS1 binding inhibition activity (IC50: A <= 100, 100 < B <= 500, 500 < C <= 1000, D > 1000) of the compound of the present application

[1232]

[1233]

[1234] Conclusion: From the above data, it can be seen that some of the compounds of the present application can effectively block the binding of KRAS G12D protein to SOS1, and can be used in the fields of treatment of pancreatic ductal adenocarcinoma, colon cancer, rectal cancer and non-small cell lung cancer, etc., and has a broad application prospect.

[1235] Test Example 2: Test of inhibitory activity of compounds on KRas Gl2D-mediated ERK phosphorylation

[1236] 1. Test method:

[1237] Day 1: AGS cells were seeded in 384-well cell culture plates and incubated overnight at 37°C in a 5% CO2 incubator.

[1238] Day 2: Compounds were added to the plates using Echo550 and incubated at 37°C in a 5% CO2 incubator for 3 hours. Then cells were fixed with paraformaldehyde, permeabilized with methanol, blocked with blocking solution, and finally incubated with primary antibody cocktail (rabbit anti pERK, mouse anti GAPDH) at 4°C overnight.

[1239] Day 3: The primary antibody was discarded and secondary antibody cocktail (goat anti rabbit 800CW, goat anti mouse 680RD) was added and incubated at room temperature in the dark. After washing with PBST, the cell plates were inverted and centrifuged for 1 minute. The fluorescence signal values were read using Odyssey CLx.

[1240] The ERK phosphorylation was calculated according to the following formula:

[1241] Relative expression: (fluorescence signal ratio of compound - average value of positive control) / (average value of negative control - average value of positive control)

[1242] Negative control: DMSO

[1243] Positive control: 10 μM Reference

[1244] IC50 values were calculated by XLFit 5.0 according to the parameter formula:

[1245] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) x HillSlope))

[1246] X: Compound concentration log value

[1247] Y: Average value of p-ERK relative expression between wells

[1248] 2. The inhibitory activity of the compounds of the present application on ERK phosphorylation is shown in Table 4.

[1249] Table 4: Inhibitory activity of the compounds of the present application on ERK phosphorylation (IC50: A <= 200, 200 < B <= 1000, 1000 < C <= 10000, D > 10000)

[1250]

[1251]

[1252]

[1253] Table 5: AGS-pERK IC50 values of some compounds

[1254]

[1255] Conclusion: From the above data, it can be seen that the compound of the present application can effectively inhibit the phosphorylation of the downstream target ERK of KRAS pathway, the activity of some compounds is equivalent to MRTX1133, the activity of some compounds is better than MRTX1133, and has broad application prospect.

[1256] Test example 3: 3D cell proliferation inhibition test of the compound

[1257] Diluted test compound is added to a 384-well low-adsorption cell culture plate using a nanoliter pipetting system (LABCYTE, P-0200), then the cells are plated and placed in a 37°C, 5% CO2 incubator for incubation for 7 days, then reagents, and the luminescence value (the light signal is proportional to the amount of ATP in the system, and the content of ATP directly represents the number of living cells in the system) is read by Envision multifunctional enzyme label instrument. Finally, the IC50 (half inhibitory concentration) of the compound is obtained by using XLFIT software with a nonlinear fitting formula.

[1258] 1. Experimental method

[1259] a) Diluted test compound is added to a 384-well low-adsorption cell culture plate using a nanoliter pipetting system.

[1260] b) The cells are inoculated into the 384 culture plate of a), centrifuged at 1000 rpm at room temperature for 1 min, the final DMSO concentration of the compound is 0.5%, and placed in a 37°C, 5% CO2 constant temperature incubator for incubation for 7 days.

[1261] c) Add to the 384-well cell culture plate of b), avoid light shock, and incubate at room temperature.

[1262] d) Read the luminescence value by Envision multifunctional enzyme label instrument.

[1263] 2. Data analysis

[1264] The IC50 (half inhibitory concentration) of the compound is obtained by using XLFIT software with the following nonlinear fitting formula:

[1265] Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X) x HillSlope))

[1266] X: Compound concentration log value

[1267] Y: Inhibition rate (%)

[1268] Inhibition rate (%) = 100 x (Negative control mean - Compound reading) / (Negative control mean - Positive control mean)

[1269] Negative control: DMSO

[1270] Positive control: Medium only

[1271] 3、The 3D cell proliferation inhibition activity data of part of the compounds of the present application are shown in Table 6.

[1272] Table 6: Anti-cell proliferation activity data of part of the compounds

[1273]

[1274] Conclusion: From the above data, it can be seen that part of the compounds of the present application can effectively inhibit the proliferation of KRAS G12D mutant cells, and the activity is comparable to MRTX1133.

[1275] Test Example 4: In vivo pharmacokinetic test of compounds in rats

[1276] SD rats, male (purchased from Shanghai Xipu-Bikai Experimental Animal Co., Ltd.). Each test compound was administered to SD rats in an oral (3 rats per group) manner for pharmacokinetic study. The test compound was prepared on the day of administration, suspended with 5% DMSO + 95% saline, and prepared into the administration system after vortexing for 2 min and ultrasonicating for 5 min. The animals were fasted for 10-14 hours before oral administration, and the feeding was resumed 4 hours after administration. After oral administration by gavage, the SD rats were collected for pharmacokinetic samples from the jugular vein, and the collection time points were: before administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration. Three whole blood samples were collected at each time point, with a collection volume of about 0.2 mL, and were anticoagulated with heparin sodium. The blood samples were immediately placed on ice after collection, and the plasma was separated by centrifugation (centrifugation conditions: 6800 rpm, 6 min, 2-8°C) within 1 hour. The collected plasma was stored in a -80°C refrigerator before analysis.

[1277] Table 7: Pharmacokinetic test results of part of the compounds

[1278]

[1279]

[1280] MRTX1133 has a large oral pharmacokinetic range, while the Cmax and AUC of the compound in some embodiments of the present patent are significantly better than MRTX1133, which has great development potential.

[1281] The above-mentioned compound provided by the present application can be used for treating cancer caused by KRAS mutation, wherein the cancer caused by KRAS mutation is one or more selected from the group consisting of cancer caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutation, in particular, the compound can be used as a G12D inhibitor, has high inhibitory activity, has good bioavailability, can be used for preparing a drug for preventing and / or treating KRAS G12D mediated disease, and has good application prospect.

[1282] The above is only a preferred embodiment of the present application, and it should be pointed out that the above preferred embodiment should not be regarded as a limitation of the present application, and the protection scope of the present application should be limited by the scope defined by the claims. For ordinary skilled persons in the art, several improvements and refinements can be made without departing from the spirit and scope of the present application, and these improvements and refinements should also be regarded as the protection scope of the present application.

Claims

1. A compound, its meso, racemic, enantiomeric, diastereomeric forms or mixtures thereof, pharmaceutically acceptable salt, characterized in that, The compound has a structure as shown below: (XIII) or (XIV) Among them, R 39 R 40 Independent selection from -H, -F, -Cl, -CN, C 1-3 Straight-chain alkyl; R 41 R 42 R 43 R 44 Independently selected from -H, -OH, -F, -Cl, -CN, -CF3, -C2F5, -OCF3, monomethylphosphoryl, dimethylphosphoryl, C 1-5 Straight-chain / branched alkyl, C 1-5 Alkoxy, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, -S(C 0-10 Alkyl), -OCON(C) 0-10 Alkyl)(C 0-10 Alkyl), C 5-6 aryl, five-membered heteroaryl, six-membered heteroaryl; or R 42 R 43 With R 42 and R 43 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 cycloalkyl, saturated or unsaturated C 3-8 Heterocyclic alkyl groups, bridged cyclic alkyl groups; R 45 and R 46 Independently selected from -H, -F, -Cl, -NH2, -CN, -CF3, -C2F5, -OCF3, C 1-3 straight-chain alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl; R 47 R 48 R 49 Independently selected from -H, -F, -Cl, -CN, -CF3, -C2F5; or R 47 R 48 With R 47 and R 48 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 Heterocyclic alkyl groups; R on the benzene ring in formula XIII 42 R 43 With R 42 and R 43 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 cycloalkyl, saturated or unsaturated C 3-8 Heterocyclic alkyl groups and bridged alkyl groups are selected from: 、 ； wherein K2, K3, K4 are independently selected from C, N, O, S; R 50 independently selected from -H, -OH, -F, -NO2, -CN, -CF3, -C2F5, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, m6 is an integer selected from 0 to 6; R on the benzene ring in formula XIV 47 R 48 With R 47 and R 48 The carbon atoms between them form saturated or unsaturated C atoms. 3-8 Heterocyclic alkyl groups are selected from: K9, K 11 independently selected from O; K 10 independently selected from C, N; R 54 independently selected from -H, -F, -CN, -CF3, -C2F5, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, m 10 an integer selected from 0 to 4.

2. A compound, its meso, racemic, enantiomeric, diastereomeric forms, mixtures thereof, pharmaceutically acceptable salts, characterized in that, The compound structure is selected from the group consisting of: 。 3. A pharmaceutical composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable carrier. The active compound of the pharmaceutical composition includes one or more selected from the group consisting of the compound according to any one of claims 1-2, meso, racemic, enantiomeric, diastereomeric forms or mixtures thereof, pharmaceutically acceptable salts thereof.

4. Use of the compound according to any one of claims 1-2, meso, racemic, enantiomeric, diastereomeric forms or mixtures thereof, pharmaceutically acceptable salts thereof in the manufacture of a medicament for KRAS inhibitors.

5. Use according to claim 4, characterized in that, The use in the manufacture of a medicament for KRAS inhibitors is for use in KRAS G12D mutant medicaments.

6. Use of the compound according to any one of claims 1-2, meso, racemic, enantiomeric, diastereomeric forms or mixtures thereof, pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating, ameliorating or preventing Noonan Syndrome, Leopard Syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumor, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal disease or disorder.

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