KRAS mutant protein inhibitor as well as preparation method and application thereof

Abstract

The invention provides a compound which has KRas inhibiting activity and is shown in a formula I, a pharmaceutical composition containing the compound, and a preparation method and application of the compound. The compound has remarkable selectivity and inhibitory activity, and has a better medicinal prospect.

Description

A KRAS mutant protein inhibitor, and its preparation method and application Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a compound capable of inhibiting KRas. Specifically, the present invention relates to a compound that inhibits the activity of KRas mutant protein, a pharmaceutical composition comprising the compound, and a preparation method and use thereof. Background Art

[0002] RAS is the first human tumor gene discovered. Currently known members of the RAS gene family include KRas, NRAS, and HRAS. KRas is one of the commonly mutated genes in the RAS gene family, accounting for approximately 86% of the total RAS gene mutations (for example, see Salgia et al., (2021) Cell Reports Medicine 2, 100186, January 19.). KRas protein is encoded by Kirsten rat sarcoma viral oncogene homolog (KRas), a small GTPase containing 188 amino acids, and belongs to the RAS superprotein family. KRas protein maintains normal biological function by cyclically switching between "inactive" and "activated" states in response to extracellular signals (for example, see Alamgeer et al., (2013) Current Opin Pharmcol. 13: 394-401).

[0003] As one of the most common drivers of tumor development in the human cancer spectrum, KRas mutations are found in approximately 40%-50% of colorectal cancer patients, 30% of non-small cell lung cancer patients, and 80%-90% of pancreatic cancer patients worldwide (e.g., see Hofmann et al., (2022) Cancer Discovery; 12:924-937). According to Frost & Sullivan, the global incidence of major KRas mutation-positive cancers increased from 1.8 million in 2016 to 2.009 million in 2020, and is expected to increase to 2.276 million in 2025. Faced with this huge treatment demand, there is no effective clinical solution. Therefore, there is a huge unmet medical need for therapeutic intervention for cancer patients with RAS mutations.

[0004] Currently, Mirati Therapeutics and Innovent Biologics have successively disclosed KRas G12DThe inhibitor patents are WO2021041671 and WO2022042630. The molecular structures of the representative compound MRTX1133 of patent WO2021041671 and the representative compound PC-1 of WO2022042630 are shown in the following structural formulas:

[0005] Although both companies have publicly disclosed their research patents, both MRTX1133 and PC-1 are currently in clinical trials, and uncertainty remains regarding their drug activity and clinical efficacy. KRas mutations are a key factor in colorectal, lung, and pancreatic cancers, particularly in pancreatic cancer, where they occur in up to 36% of cases. There are currently no therapeutic drugs targeting this target, creating a significant market demand. The development of new KRas mutant protein inhibitors is crucial to provide patients with more treatment options.

[0006] Summary of the Invention

[0007] One object of the present invention is to provide a novel compound that inhibits the activity of KRas mutant proteins. The compounds provided by the present invention can selectively inhibit the activity of KRas mutant proteins and, to a certain extent, can be used to treat cell proliferation disorders. To achieve this effect, the present invention employs the following technical solutions:

[0008] In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein:

[0009] Among them, R1 is CR 1a or N; R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -COOalkyl, carboxyl, amino, -CONH2, -NHCOalkyl, alkyl, alkylene cyano, alkenyl and alkynyl; preferably, R 1a Selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COOC 1-6 Alkyl, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0010] R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring containing at least one nitrogen atom, wherein the saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring is optionally replaced by one, two or more R2a Preferably, R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring containing 1, 2 or 3 ring N, wherein the saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring is optionally replaced by one or more R 2a Preferably, R2 is a saturated or partially saturated 3-10 membered monocyclic ring, 6-12 membered bridged ring, 4-10 membered fused ring or 5-12 membered spirocyclic ring containing 1 or 2 ring N, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring is optionally replaced by one or more R 2a substituted; preferably, R2 is a saturated or partially saturated 3, 5, 6, 7, or 8-membered monocyclic ring, a 6, 7, 8, 9, or 10-membered bridged ring, a 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or a 5, 6, 7, 8, 9, 10, 11 or 12-membered spirocyclic ring containing 1 or 2 ring N and 0, 1, 2 or 3 ring heteroatoms independently selected from O and S, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring is optionally replaced by one or more R 2a Replace; each time R 2a Each of the groups independently selected from halogen, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, amino, -CONH2, -NHCOalkyl, alkyl, alkylene cyano, alkylene alkynyl, alkylene COOalkyl, -NHCOC 1-6 alkyl, alkenyl, oxo (=O), cycloalkyl, heterocyclyl and alkynyl, optionally, the alkylene, alkyl, alkynyl, alkenyl, cycloalkyl, and heterocyclyl are substituted by one, two or more groups selected from halogen, cyano, amino, hydroxy, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, alkyl, alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted with a substituent of the alkynyl group; preferably, each R 2a Each of the following is independently selected from F, Cl, Br, I, cyano, hydroxyl, mercapto, hydroxyl C 1-6Alkylene, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylene cyano, C 1-6 Alkylene alkynyl, C 1-6 AlkyleneCOO C 1-6 Alkyl, -NHCOC 1-6 Alkyl, C 2-6 Alkenyl, oxo (=O) and C 2-6 Alkynyl, optionally, the C 1-6 Alkylene, C 1-6 Alkyl, C 2-6 Alkynyl, and C 2-6 The alkenyl group is replaced by one, two or more groups selected from halogen, cyano, amino, hydroxy, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted by a substituent of the alkynyl group;

[0011] Y is CR x R y ,O,S,S=O,S(=O)2 or NR x , R x and R y Each occurrence is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, alkyleneaminoalkyl, aryl and alkylenearyl; preferably, R x and R y Each occurrence is independently selected from hydrogen, and C 1-6 alkyl;

[0012] R3 is selected from alkyl, alkylene hydroxyl, -L-heterocyclyl, -L-aryl, -L-arylene-L-heterocyclyl, -L-heteroarylene-L-heterocyclyl, -L-heteroaryl, -L-heterocyclylene-L-OCO-N(R5)2, -L-heterocyclylene-L-NR5-CO-N(R5)2, -L-heterocyclylene-L-NR5-CO-R5, -L-cycloalkyl, -L-cycloalkylene-LN(R5)2, -L-cycloalkylene-L-heterocyclyl and -L-cycloalkylene-LN(R5)2, wherein wherein the heterocyclyl, heteroarylene, heteroaryl, and heterocyclylene groups each independently contain 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, and the alkyl, alkylhydroxy, heterocyclyl, aryl, arylene, heteroarylene, heteroaryl, heterocyclylene, cycloalkyl, and cycloalkylene groups may be optionally substituted by one, two, or more groups selected from halogen, cyano, amino, hydroxyl, hydroxyalkyl, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, alkyl, alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl substituted pyrazolyl, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 Preferably, R3 is selected from C 1-6 Alkyl, C 1-6Alkylhydroxy, -L-(3-12 membered heterocyclyl), -L-(6-10 membered arylene), -L-(6-10 membered arylene)-L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene)-L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene), -L-(3-12 membered heterocyclyl)-L-OCO-N(R5)2, -L-(3-12 membered heterocyclyl)-L-NR5-CO-N(R5)2, -L-(3-12 membered heterocyclyl)- L-NR5-CO-R5, -L-(3-10-membered cycloalkyl), -L-(3-10-membered cycloalkylene)-LN(R5)2, -L-(3-10-membered cycloalkylene)-L-(3-12-membered heterocyclyl) and -L-(3-10-membered cycloalkylene)-LN(R5)2, wherein the 3-12-membered heterocyclyl, 3-12-membered heterocyclylene, 5-12-membered heteroarylene and 5-12-membered heteroaryl each independently contain 1, 2, or 3 heteroatoms each independently selected from N, O and S, and the C 1-6 Alkyl, C 1-6 Alkylene hydroxyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 6-10 membered arylene, 5-12 membered heteroarylene, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, 3-10 membered cycloalkyl and 3-10 membered cycloalkyl may be optionally substituted by one, two or more groups selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 Hydroxyalkyl, mercapto, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl substituted pyrazolyl, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted by a substituent of the alkynyl group;

[0013] Each occurrence of L is independently selected from a covalent bond, C 1-6 Alkylene, C 1-6 Hydroxyalkylene, -C(O)C 1-6 Alkylene, -C(O)O-, -OC(O)-, C 1-6 Deuterated alkylene, C 1-6 Halogenated alkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, optionally, the C 1-6 Alkylene, C 1-6 Hydroxyalkylene, C 1-6 Deuterated alkylene, C 1-6 The haloalkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene groups are substituted by one, two or more groups selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 Hydroxyalkyl, mercapto, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted by a substituent of the alkynyl group;

[0014] R5 is independently selected at each occurrence from hydrogen, halogen, cyano, amino, hydroxy, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkyl, alkyl, alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl substituted pyrazolyl, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCO C 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0015] Cy2 is an aryl group fused to Cy1, a saturated or partially unsaturated cycloalkyl group, a heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a saturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the aryl group, saturated or partially unsaturated cycloalkyl group, heteroaryl group or heterocycloalkyl group may be optionally substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents, optionally, the alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents are substituted by 1, 2, 3 or more halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Cy2 is a 6-10 membered aryl group fused to Cy1, a saturated or partially unsaturated 3-10 membered cycloalkyl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 5-10 membered saturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5-10 membered partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the aryl group, saturated or partially unsaturated cycloalkyl group, heteroaryl group, heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more groups selected from F, Cl, Br, I, C 1-6 Alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C3-10 Heterocyclic group, and C 5-10 Substituted by a heteroaryl substituent, optionally, the C 1-6 Alkyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 Heteroaryl is substituted by 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 Alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 Preferably, Cy2 is selected from in represents the connection site with R4, Indicates the fusion position of Cy2 and Cy1;

[0016] q is 0, 1, or 2;

[0017] R a Each occurrence is independently selected from hydrogen, halogen, alkyl, alkynyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, aryl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the alkyl, alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, aryl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, and heteroaryl are substituted by 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 Alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 When R2 contains two ring N atoms, Cy2 is And R a When H, R4 is R3 is When Cy2 is And R a When H, R4 is R3 is

[0018] When with R b Connected When it is a double bond, R b Each occurrence is independently O, S or C(R5)2; when b Connected When it is a single bond, R b Each occurrence is independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkyleneamino, cycloalkyl, heterocyclyl, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, alkylenehydroxy, aryl, alkynyl, alkenyl, and heteroaryl, preferably, R b Each occurrence is independently selected from hydrogen, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, cyano, amino, amino C 1-6 Alkyl, C 1-6 Alkyleneamino, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, and C 5-10 heteroaryl;

[0019] R c Selected from H, C 1-6 Alkyl, -CN, -≡-R ca , -CONH2 and -OCONH2; when R2 contains 2 ring N atoms, and when R c C 1-6When alkyl or H, R1 is N, R4 is When R2 contains 2 ring N atoms, when R c When H, R1 is CR 1a , R 1a When it is CN, R4 is R3 is

[0020] R ca Each time it appears, each R ca are each independently selected from hydrogen, amino, hydroxy, halogen, cyano, -CONH2, -NHC(O)C 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyleneamino, C 1-6 Alkylene NHC 1-6 Alkyl, C 1-6 Alkylene hydroxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkynyl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R ca Each time it appears, each R ca Each independently selected from hydrogen, amino, hydroxy, F, Cl, Br, I, cyano, -CONH2, -NHC(O)C 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyleneamino, C 1-6 Alkylene NHC 1-6 Alkyl, C 1-6 Alkylene hydroxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl and C5-10 Heteroaryl, optionally, the C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl is substituted by 1, 2, 3 or more groups selected from F, Cl, Br, I, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R ca Each time it appears, each R ca each independently selected from hydrogen, -CH3, -C(CH3)3, -C(CH3)2OH, -CH(CH3)OH, -C2H5, -C3H7, -C4H9, -CH2OH, -C2H4OH, -C3H6OH, -CH2NH2, -CH2NHCH3, and cyclopropyl;

[0021] When R2 is R4 is And when R ca When it is hydrogen, R d When Y is O, R3 is not

[0022] R d Each occurrence is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, mercapto, hydroxyalkylene, carboxyl, oxo, alkoxy, amino, -CONH2, -NHC(O)alkyl, alkyl, C 1-6 Alkylene cyano, -CO-alkyl, alkylamino, alkyleneamino, alkyleneNHalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, alkenyl and alkynyl, optionally, the alkyl, alkylene, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R d Each occurrence is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, mercapto, hydroxyl C 1-6 Alkylene, carboxyl, oxo, C 1-6Alkoxy, amino, -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylene cyano, -CO-C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyleneamino, C 1-6 Alkylene NH alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 5-10 Heteroaryl, C 2-6 Alkenyl and C 2-6 Alkynyl, optionally, the C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl is substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 substituted by a heteroaryl substituent;

[0023] R4 is selected from 0, 1, 2, 3, 4, 5, or more R 4a Substituted aryl and heteroaryl, the heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, R4 is selected from 0, 1, 2, 3, 4, 5 or more R 4a substituted 6-12 membered aryl and 5-12 membered heteroaryl, wherein the 5-12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, R4 is selected from 0, 1, 2, 3, 4, 5 or more R 4a substituted phenyl, naphthyl, 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; R4a Each occurrence is independently selected from halogen, alkynyl, alkenyl, alkynylenealkyl, alkenylenealkyl, alkylenecyano, alkoxy, -OH, -SH, -NH2, -NH-R 4c 、-CN、-CO-alkyl、-CON(R 4c )2, alkyl-CO-NR 4c -, alkyl, haloalkyl, haloalkoxy, alkylamino, alkyleneamino, cycloalkyl, cycloalkylenealkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylenealkyl, optionally, the alkynyl, alkenyl, alkynylene, alkenylene, alkylene, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylene are replaced by one or more selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R 4a Each occurrence is independently selected from C 1-6 Alkyl, F, Cl, Br, I, C 2-6 Alkynyl, C 2-6 Alkenyl, C 2-6 Alkynylidene C 1-6 Alkyl, C 2-6 Alkenylene C 1-6 Alkyl, C 1-6 Alkylene cyano, C 1-6 Alkoxy, -OH, -SH, -NH2, -NH-R 4c 、-CN、-CO 1-6 Alkyl, -CON(R 4c )2、C 1-6 Alkyl-CO-NR 4c -、Halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyleneamino, 3-10 membered cycloalkyl, 3-10 membered cycloalkylene C 1-6 Alkyl, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkylene C 1-6 Alkyl, optionally, the C 2-6 Alkynyl, C 2-6 Alkenyl, C 2-6 Alkynylidene, C 2-6 Alkenylene, C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, C3-10 Heterocycloalkyl and C 3-10 Heterocycloalkylene is replaced by one or more selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 substituted by a heteroaryl substituent;

[0024] R 4c Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, hydroxyalkylene, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, alkyl, C 1-6 alkylene cyano, alkenyl, and alkynyl groups;

[0025] The compound of formula I is not:

[0026] Another aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein:

[0027] Among them, R1 is CR 1a or N; R 1a independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, -CONH2, amino, -NHCOC 1-6 Alkyl, alkyl, C 1-4 alkylcyano, alkenyl, and alkynyl groups;

[0028] R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing at least one N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally replaced by one or more R 2a Replace; each time R 2a When it appears, each R 2a are independently selected from halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, carbonyl, amino, -CONH2-NHCOC 1-6 Alkyl, alkyl, C 1-4Alkyl cyano, alkenyl and alkynyl; preferably, R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing 1 ring N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally replaced by one or more R 2a substituted; preferably, R2 is a saturated or partially saturated 3, 5, 6, 7, or 8-membered monocyclic ring, a 6, 7, 8, 9, or 10-membered bridged ring, a 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or a 5, 6, 7, 8, 9, 10, 11 or 12-membered spirocyclic ring containing 1 ring N and 0, 1, 2 or 3 ring heteroatoms independently selected from O and S, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring is optionally substituted with one or more R2a; each R 2a When it appears, each R 2a are independently selected from halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COOalkyl, carboxyl, oxo, -NH2, -CONH2, -NHC(O)C 1-6 Alkyl, alkyl, C 1-4 alkylcyano, alkenyl, and alkynyl groups;

[0029] Y is -CR x R y -, -O-, -S-, -S=O-, -S(=O)2- or -NR x -, R x and R y are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, alkylaminoalkyl, aryl, and alkylaryl;

[0030] R3 is each independently selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, heterocyclic group, -LN(R5)2, -L-NHC(=NH)NH2, -LC(O)N(R5)2, -L-NR5C(O)-aryl, -LC 1-6 haloalkyl, -L-OR5, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, aza-saturated or partially saturated monocyclic or fused rings, and oxa-saturated or partially saturated monocyclic or fused rings, wherein the heteroaryl, aryl, saturated or partially saturated monocyclic or fused ring portion and the heterocyclyl portion of -L-heterocyclyl and the cycloalkyl portion of -L-cycloalkyl may be optionally substituted with one or more R5;

[0031] Each L is independently selected from C 1-6 Alkylene, C 1-6 hydroxyalkyl and heteroaryl groups;

[0032] Each occurrence of R5 is independently selected from hydrogen, halogen, cyano, hydroxyl, thiol, hydroxymethyl, ester, carboxyl, carbonyl, -NH2, -CONH2, -NHC(O)C1-6 Alkyl, alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl substituted pyrazolyl, aryl C 1-4 Alkyl, (C 1-4 Alkoxy) C 1-4 Alkyl-, (C 1-4 alkyl)C(=O)-, (C 1-4 haloalkyl)C(=O)-, -CH2NHCO C 1-6 Alkyl, C 1-4 Alkyl cyano, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0033] Cy2 is fused with Cy1, and Cy2 is an aryl group or a 5-7 membered heteroaryl group containing 1 or 2 heteroatoms, a 5-7 membered saturated heterocycloalkyl group or a 5-7 membered unsaturated heterocycloalkyl group; and when Cy2 is an aryl group or a pyridyl group, it has the structural formula R a Each time it appears, each R a independently selected from hydrogen, halo, alkyl, alkynyl, hydroxyl, cyano, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkyl hydroxyl, aryl, C 2-4 Alkynyl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, heteroaryl; R c Selected from -CN, -≡-R ca 、 R ca Each time it appears, each R ca independently selected from hydrogen, halogen, cyano, -COO-alkyl, -NHC(O)C 1-6 Alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkyl hydroxyl, aryl, C 2-4 Alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0034] Each time R d Each of the groups is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, oxo, oxyalkyl, amino, -CONH2, -NHC(O)C 1-6 Alkyl, alkyl, C 1-4 alkylcyano, alkenyl, and alkynyl groups;

[0035] R4 is selected from 1, 2, or 3 R 4a or 1, 2 or 3 Rs 4b substituted phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered heterocyclic group, benzo 5-6 membered cycloalkenyl group and benzo 5-6 membered heteroaryl group; each R 4a independently selected from halo, -OH, -SH, -NH2, -CN, -CO-alkyl, -CON(R 4c )2、C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkyl C 1-4 Alkyl; each R 4b Each independently selected from halogen, -OH, -SH, -NH2, -NO2, -CN, -CO-alkyl, -CON(R 4c )2, triazole, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl cyanide, di-C 1-6 Alkylamino, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkylthio, di(halogenated C 1-6 Alkyl)amino; R 4c Each time it appears, each R 4c Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, alkyl, C 1-4 Alkylcyano, alkenyl and alkynyl, or two R attached to the same C atom 4c Formation = O;

[0036] When R4 is When m is an integer from 0 to 6, each time R 4a When it appears, each R 4a Independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4Alkoxy, halogen, -OH, -SH, -CN, -COR5, -CON(R5)2, -OCON(R5)2 and -≡-R ca ;

[0037] Each time R ca When it appears, each R ca independently selected from hydrogen, halogen, -CN, -COO-alkyl, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkyl hydroxyl, aryl, C 2-4 Alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0038] Each occurrence of R6 is independently selected from H and C 1-4 alkyl;

[0039] Preferably, the compound of formula I is not:

[0040] In one of the technical solutions, R4 is selected from

[0041] In one of the technical solutions, R2 is selected from

[0042] In one of the technical solutions, wherein R3 is selected from C 1-6 alkyl,

[0043] Where n = 0, 1, 2 or 3; each time R 3b When present, independently selected from a covalent bond, -COC 1-6 Alkylene, C 1-6 Alkylene, C 1-6 Deuterated alkylene, cycloalkylene, C 1-6 Haloalkylene, heterocyclylene, arylene, and heteroarylene; and

[0044] Each time R 3c When it appears, each R 3c independently selected from hydrogen, deuterium atoms, halogen groups, C 1-6 Alkyl, -CONH2, -NHCOC 1-6Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkyl, hydroxy, amino, hydroxyalkylene, cyano, alkylamino, haloalkyl, C 1-6 Alkoxy.

[0045] In one of the technical solutions, R3 is selected from

[0046] In one of the technical solutions, the compound is selected from Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is a formate salt of the compound, preferably the formate salt contains 0.1-3 moles of formate ions per mole of the compound, preferably the formate salt contains 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2 or 3 moles of formate ions per mole of the compound.

[0047] Another aspect of the present invention provides a pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of any compound as described above, its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound, and a pharmaceutically acceptable excipient.

[0048] The present invention also provides the use of the compound as described above or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound, or the pharmaceutical composition as described above in the preparation of a medicament for inhibiting the activity of KRas mutant protein, preferably, in the preparation of a medicament for inhibiting the activity of KRas G12D.

[0049] In one embodiment, the KRas mutant protein-related cancer is selected from:

[0050] Non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer and pancreatic cancer; bronchogenic carcinoma, alveolar carcinoma, sarcoma, lymphoma, bronchial adenoma, chondroma, hamartoma, mesothelioma; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vipoma, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal Kaposi's sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal hamartoma, large intestinal villous adenoma, large intestinal leiomyosarcoma; cardiac sarcoma, cardiac angiosarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac Myxoma, cardiac fibroma, cardiac rhabdomyoma, cardiac lipoma, and cardiac teratoma; hepatocellular carcinoma or hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, and hemangioma of the liver; gallbladder cancer, bile duct cancer, and ampullary carcinoma; Wilms' tumor, Wilms' tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratocarcinoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular fibroma, testicular adenomatoid tumor, and testicular lipoma; osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, and reticulocyte Sarcoma, benign enchondroma, malignant giant cell tumor, chordoma, chondroblastoma, osteochondroma, osteochondral exostosis, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; osteoma, xanthomas, hemangiomas, granulomas, osteitis deformans, meningioma, glioma, meningiosarcoma, astrocytoma, medulloblastoma, ependymoma, glioma, germ cell tumor, pinealoma, neurilemoma, oligodendroglioma, glioblastoma multiforme, retinoblastoma, glioma, congenital tumor, meningioma, spinal neurofibroma, sarcoma; endometrial carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa cell-theca cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma vulvar cell carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; one or more of the following: malignant melanoma of the skin, Kaposi's sarcoma of the skin, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, dysplastic nevus of the skin, lipoma of the skin, hemangioma of the skin, dermatofibroma, keloid of the skin, psoriasis; adrenal neuroblastoma.

[0051] The novel KRas inhibitor provided by the present invention has better activity and stability than the drugs used in clinical practice in the prior art and has good pharmaceutical prospects. Specific embodiments

[0052] Definition and detailed description

[0053] Unless otherwise specified, all technical and scientific terms used in the present invention should be understood according to their common meanings in the art. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0054] Also included within the scope of the present invention are metabolites of compounds of Formula I, that is, compounds produced in vivo following administration of the drug. Certain examples of metabolites according to the present invention include: (i) when the compound of Formula I contains a methyl group, its hydroxymethyl derivatives (-CH3->-CH2OH); (ii) when the compound of Formula I contains an alkoxy group, its hydroxy derivatives (-OR->-OH); (iii) when the compound of Formula I contains a tertiary amino group, its secondary amino derivatives (-NR1R2->-NHR1 or -NHR2); (iv) when the compound of Formula I contains a secondary amino group, its primary amino derivatives (-NHR1->-NH2); (v) when the compound of Formula I contains a phenyl moiety, its phenol derivatives (-Ph->-PhOH); and (vi) when the compound of Formula I contains an amide group, its carboxylic acid derivatives (-CONH2->COOH).

[0055] The term "solvate" refers to a form of the compound of the present invention that forms a solid or liquid complex by coordination with solvent molecules. Examples of such forms are hydrates, alcoholates, and the like.

[0056] The term "prodrug" refers to any pharmaceutical agent that is converted into a parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they are easier to administer than the parent drug. For example, they are bioavailable by oral administration, whereas the parent drug is not. Prodrugs can also improve solubility in pharmaceutical compositions relative to the parent drug. Prodrugs can be converted to the parent drug via enzymatic methods as well as metabolic hydrolysis.

[0057] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and base of the specified compound without any adverse biological effects. Examples of pharmaceutically acceptable salts include, but are not limited to, salts formed by compound (I) with any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid; preferably, fumarate.

[0058] The "KRas mutant proteins" herein include but are not limited to KRAS G12D, KRAS G12C, KRAS G12S, KRAS G12V, KRAS G12A and KRAS G13D.

[0059] In this article, "KRas G12C " refers to a mutant form of the mammalian KRas protein in which the glycine at position 12 is mutated to cysteine. Similarly, "KRas G12D " is the mutation of glycine at position 12 of the KRas protein to aspartic acid. The mutations of KRAS G12D, KRAS G12C, KRAS G12S, KRAS G12V, KRAS G12A and KRAS G13D are similar to the above, except for the specific amino acid residue or the specific mutation position.

[0060] In this article, "KRas G12D KRas-related diseases or conditions G12D A disease or condition associated with or induced by a mutation or having said mutation, a non-limiting example of which is KRas G12D Mutations causing cancers.

[0061] As used herein, an "effective dose" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a KRas mutant protein, and such a dose may be administered alone or according to an effective regimen.

[0062] As used herein, a "therapeutically effective dose" of a compound is an amount that negatively regulates or inhibits the activity of a KRas mutant protein, such an amount being sufficient to improve or alleviate symptoms or eliminate or reverse the progression of the condition, and can be administered in a single dose or according to an effective regimen. The amount of the compound of the present application that constitutes a "therapeutically effective dose" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, and can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0063] The concentration and route of administration to the patient may vary depending on the cancer to be treated. The compound or its pharmaceutical composition, or its pharmaceutically acceptable salt may be co-administered with other anti-tumor compounds, or used in combination with other treatments (such as radiotherapy or surgical intervention) as a pre- or post-operative adjuvant.

[0064] As used herein, "treatment" refers to the administration of the compounds or compositions described herein to prevent, ameliorate, or eliminate a disease or a condition associated with the disease, and includes: 1) preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state; 2) alleviating the disease or causing the disease state to regress; 3) inhibiting the disease or curbing its progression.

[0065] Herein, "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.

[0066] As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, allergic reactions, irritation or other problems or complications.

[0067] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound and exhibits minimal or no undesirable toxicological effects, such as salts formed with organic bases or acids, inorganic bases or acids, and basic or acidic amino acids, and can be metal salts, quaternary ammonium salts, sulfates, hydrochlorides, formates, trifluoroacetates, phosphates, fumarates, maleates, tartrates, citrates, benzoates, and the like.

[0068] The term "optical isomer" refers to a rotation of polarized light beams caused by the presence of one or more axes and / or centers of symmetry in a molecule. The term "optical isomer" more specifically includes enantiomers and diastereomers, in pure form or as a mixture; two compounds that are isomers of each other may have significantly different pharmaceutical activities.

[0069] As used herein, "include" or "comprising" should be understood as having an inclusive and non-exclusive meaning, ie, "including but not limited to".

[0070] The present application also includes compounds in which one or more atoms of the compound are replaced by isotopes, and the isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, iodine, etc., preferably deuterium ( 2 H) substitution, wherein the deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

[0071] The term "substituted" means that any one or more H atoms on a particular atom are replaced by a substituent, as long as the atomic valence rules are met and the substituted compound is stable.

[0072] The term "optionally" or "optionally" means that the described situation may or may not occur, for example, a methyl group is "optionally" substituted with a halogen, which means that the methyl group may be unsubstituted (CH3), monosubstituted (such as CH2F), polysubstituted (such as CHF2) or fully substituted (CF3). For any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible or cannot be synthesized will be introduced.

[0073] “C 1-6 " means that the group may have an integer number of carbon atoms from 1 to 6. Similarly, "C 2-6 ” means that the group may have an integer number of 2 to 6 carbon atoms.

[0074] When any variable (e.g., R1) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with two R1s, each R1 has an independent option.

[0075] The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

[0076] The term "cyano" refers to a -CN group; "hydroxy" refers to an -OH group; "hydroxymethyl" refers to a -CH2OH group; "mercapto" refers to a -SH group; and "amino" refers to a -NH2 group.

[0077] "Amide" refers to a group containing -CONH-, "acyl" refers to a group containing RC(=O)-, and "ester" refers to a group containing -COOR, wherein R is an alkyl group.

[0078] When "---" or When it points to the inside of the ring group rather than a specific position, it means that the substitution position of the substituent on the ring group is not fixed; when "---" or When pointing to a specific position of a group, it means that the substituent is substituted and attached to the fixed substitution position.

[0079] "Carboxyl" refers to a group containing -CO-, and "carboxyl" refers to a group containing -COOH.

[0080] "Alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon and hydrogen atoms, with at least one carbon-carbon triple bond, such as ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (HC≡C-CH2-), and propargyl alcohol (-C≡C-CH2OH).

[0081] "Alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one carbon-carbon double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (CH3-CH=CH-), isobutenyl, 1,3-butadienyl, and the like.

[0082] The term "alkyl" refers to a group of the formula C n CH 2n The alkyl group may be a straight-chain or branched-chain hydrocarbon group (e.g., methyl, ethyl, isopropyl, n-butyl, isobutyl, 2-methylbutyl, etc.). Similarly, the alkyl portion of alkoxy, alkylamino, and alkylthio has the same definition.

[0083] The term "alkoxy" refers to an -O-alkyl group.

[0084] The term "alkylthio" refers to an -S-alkyl group.

[0085] The term "alkylamino," "aminoalkyl," or "aminoalkyl" refers to an -NH-alkyl group.

[0086] The term "dialkylamino" or "dialkylamino" refers to -N(alkyl)2.

[0087] The term "alkylene" refers to an alkyl group containing two hydrogen atoms on a carbon atom, such as methylene (-CH2-).

[0088] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, fused, or spirocyclic ring. It is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like.

[0089] The term "partially saturated" refers to a group containing some double bonds, such as cyclopentenyl, cyclohexenyl, cycloimino, etc.

[0090] The term "heterocycloalkyl" or "heterocyclyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered ring containing 1 to 4 heteroatoms independently selected from N, O, or S, wherein the ring N atoms can be oxidized to NO and the ring S atoms can be oxidized to SO or SO2, and the remaining ring atoms are carbon. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, propylene oxide, thioethane, and aziridine groups; examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thiazole, and the like; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolidinyl, pyrrolidonyl, imidazolidinyl, oxazolidinyl, oxazolidinone, and isothiazolidinyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1,4-dioxane, 1,4-thioxanyl, thiomorpholinyl, 1,3-dithianyl, piperidinone, and the like; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxazepanyl, oxa- or thiazole, and the like. Examples of cyclic rings include, but are not limited to, azabicyclopentanyl, azabicyclohexyl, azabicyclooctanyl, decahydroquinolinyl, etc. Examples of bridged rings include, but are not limited to, quinuclidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, etc. Examples of spiro rings include, but are not limited to, azaspiroheptane, oxazaspironanyl, oxazaspirooctane, etc. The heterocyclic group is optionally substituted with one or more R8 at one or more ring carbon or ring nitrogen positions, wherein R8 is as defined for Formula I or Formula II.

[0091] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and 1,2,3,4-tetrahydronaphthalene. Aryl also refers to a bicyclic or tricyclic ring system, wherein one or both rings of the aryl ring system may be saturated or partially saturated, and wherein if the ring system includes two saturated rings, the saturated rings may be fused or spirocyclic.

[0092] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C and having at least one aromatic ring. Preferably, the heteroaryl group has 4 to 8 ring members, especially 5 to 8 ring members, or comprises 6 to 14, especially 6 to 10 ring members, multiple fused rings. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, triazinyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzimidazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, etc. "Heteroaryl" also refers to a bicyclic ring system having, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of O, S and N in each ring, wherein one ring may be saturated or partially saturated.

[0093] The compounds of the present application may be asymmetric (having one or more stereoisomers), and unless otherwise specified, all stereoisomers include enantiomers and diastereomers. The isomers thereof can be separated by means of chiral resolution.

[0094] The compounds of the present application may have one or more atropisomers. Unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds. The isomers can be separated by chiral resolution.

[0095] When compound shown in Formula I and pharmaceutically acceptable salt thereof exist in the form of solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent forming the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, similar solvents such as water, ethanol, propyl alcohol, acetone can be adopted.

[0096] When the compound represented by Formula I exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0097] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known or generally accepted cell and / or animal models can be predictive of the ability of a test compound to treat or prevent a given condition. Human clinical trials in patients, including first-in-human studies, dose-ranging studies, and efficacy studies, can be performed according to methods well known in the clinical and medical arts.

[0098] The present invention is further described below by way of examples. It should be noted that these examples do not limit the scope of protection of the present invention.

[0099] 1. Experimental Reagents List

[0100] 2. Experimental instruments and consumables

[0101] The compounds of the present invention can be prepared using the synthetic methods and preparation schemes described herein by commercially available reagents (commercially available reagents can be used without further purification). Other reagents and conventional methods well known to those skilled in the art can also be used to prepare the compounds of the present invention.

[0102] 3. Preparation plan

[0103] Each product or intermediate obtained by the reaction in the synthetic route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, recrystallization, preparative TLC, column chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (for example, but not limited to Bidex, Anergy, Inochem, and Exploration Platform). These raw materials can be characterized using conventional means, such as physical constants and spectral data.

[0104] This application uses the following abbreviations:

[0105] DCM stands for dichloromethane; DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; THF stands for tetrahydrofuran; DCE stands for 1,2-dichloroethane; ACN stands for acetonitrile; PE stands for petroleum ether; EtOAc stands for ethyl acetate; Tol stands for toluene; NMP stands for N-methylpyrrolidone; i-PrOH stands for isopropyl alcohol; MeOH stands for methanol; MeONa stands for sodium methoxide; EtOH stands for ethanol; Boc stands for tert-butyloxycarbonyl; Boc2O stands for di-tert-butyl dicarbonate; TEA stands for triethylamine; DIEA stands for N,N-diisopropylethylamine; Bn stands for benzyl; TFA stands for trifluoroacetic acid; TFAA stands for trifluoroacetic anhydride; NCS stands for chlorosuccinimide; NBS stands for bromosuccinimide; NaH stands for sodium hydride; AcOH stands for acetic acid; MsCl stands for methanesulfonyl chloride; Ph3P stands for triphenylphosphine; DPPF stands for 1,1'-bis(diphenylphosphino)diocene Iron; HATU is 2-(7-benzotriazole oxide)-N,N,N,N'-tetramethyluronium hexafluorophosphate; n-BuLi is n-butyllithium; t-BuOK is potassium tert-butoxide; t-BuONa is potassium tert-butoxide; LiHMDS is lithium bis(trimethylsilylamide); DEAD is diethyl azodicarboxylate; DIAD is diisopropyl azodicarboxylate; Pd(OAc)2 is palladium acetate; Pd(PPh3P)2Cl2 is bis(trimethylsilylamide) phenylphosphine) palladium chloride; SEMCl represents (2-(chloromethoxy)ethyl)trimethylsilane; MOMBr is bromomethyl methyl ether; RuPhos-Pd-G3 is methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II); Pd2(dba)3 is tris(benzylideneacetone)dipalladium; BINAP is 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; X-Phos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; PyBOP is 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate; m-CPBA is meta-chloroperbenzoic acid, etc.

[0106] Some embodiments of Formula I can be prepared according to General Scheme I.

[0107] 1. Plan I

[0108] Wherein, X is selected from halogen groups such as F, Cl, Br, and except that -Y-R3 is not hydrogen, all substituents are prepared according to Scheme 1 as defined for the compound of Formula I. Step A refers to the preparation method in patent WO2021041671, and compound I-1 is reacted with trichloroacetyl isocyanate, and then the intermediate is cyclized in a methanol solution of ammonia to obtain compound I-2. In step B, compound I-2 and phosphorus oxychloride are reacted with an organic base (such as DIEA) to prepare dichloropyrimidine compound I-3. In step C, nitrogen-containing heterocycle R2 is selectively substituted with dichloropyrimidine compound I-3 under the action of alkali and DMF to obtain compound I-4, and compound I-4 can also be obtained by Suzuki coupling reaction of boron-containing R2 with dichloropyrimidine. In Step D, a nucleophile of the formula HY-R3 is used in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent to replace the chlorine in compound I-4, thereby introducing the substituent -Y-R3 to yield compound I-5. In Step E, the thiomethyl group is replaced with a chlorine group using trimethylsilyl chloride to yield compound I-6. In Step F, a Suzuki coupling reaction is performed with a boronic acid ester or boronic acid and a pyrimidine chloride to yield a compound containing R4. The target compound is then deprotected as in Step G to yield the target compound, which is typically purified by reverse-phase preparative HPLC and concentrated and lyophilized.

[0109] 2. Plan II

[0110] Some of the examples in Formula I can be prepared by General Scheme II.

[0111] Wherein, X and X' are each selected from a halogen group, and the electronegativity of X is greater than that of X', for example, when X is Cl, X' is Br; or when X is F, X' is Cl or Br. In step A, the starting material II-1 is reacted with a 5 The acyl chloride reaction of a group (preferably an electron-withdrawing group such as a cyano group or an ester group) yields amide II-2. In step B, ring closure is carried out in the presence of a strong base such as sodium hydride to yield compound II-3. In step C, phosphorus oxychloride is used to selectively chlorinate the hydroxyl group to yield compound II-4. In step D, a nitrogen-containing heterocycle R2 undergoes selective nucleophilic substitution of chloropyridine compound II-4 in the presence of a base and DMF to yield compound II-5. In step E, compound II-5 is subjected to a Mitsnobu reaction in the presence of DEAD or DIAD, triphenylphosphine, and a fatty alcohol HO-R3 to yield ether II-6. In step F, a Suzuki coupling reaction is carried out with a boric acid ester or boronic acid and a pyrimidine chloride to yield a compound containing R4, which is then deprotected in step G to yield the target compound II-7, which is typically purified by reverse-phase preparative HPLC and concentrated and lyophilized.

[0112] 3. Plan III

[0113] Some of the examples in Formula I can also be prepared by General Scheme III.

[0114] Wherein, X and X' are each independently selected from a halogen group, and X has a greater electronegativity than X'. For example, when X is Cl, X' is Br; or, when X is F, X' is Cl or Br. All substituents are prepared according to Scheme III as defined for the compound of Formula I, except that -Y-R3 is not hydrogen. In Step A, methyl orotate is brominated with bromine to produce compound III-2. In Step B, the hydroxyl group is chlorinated using phosphorus oxychloride and DIEA to produce dichloropyrimidine compound III-3. In Step C, the nitrogen-containing heterocycle R2 undergoes selective nucleophilic substitution of dichloropyrimidine compound III-3 in the presence of a base and DMF to produce compound III-4. In Step D, an allylamine containing an R4 group undergoes amine transesterification with the methyl ester compound III-4 in the presence of LiHMDS to produce amide compound III-5. In step E, a nucleophile having the formula HY-R3 is used to replace the chlorine of the chloropyrimidine compound III-5 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent to introduce a substituent -Y-R3 to obtain compound III-6. In step F, compound III-6 undergoes a Heck reaction in the presence of a palladium catalyst and an organic base (such as triethylamine) to close the ring and obtain an intermediate with an exocyclic double bond. This intermediate is then deprotected in step G to obtain the target compound III-7, which is generally purified by reverse-phase preparative HPLC and obtained by concentration and lyophilization.

[0115] 4. Plan IV

[0116] Some of the examples of Formula I can be prepared by General Scheme IV.

[0117] Wherein, X and X' are each independently selected from a halogen group, and X has a greater electronegativity than X'. For example, when X is Cl, X' is Br; or, when X is F, X' is Cl or Br. All substituents are prepared as defined for compounds of Formula I according to Scheme IV, except that -Y-R3 is not hydrogen. In Step A, ethyl chloroacetoacetate is cyclized with S-methylisothiourea sulfate to provide pyrimidine compound IV-2. In Step B, bromine substitution on the pyrimidine ring is performed using NBS as a brominating agent to provide intermediate IV-3. In Step C, intermediate IV-3 is reacted with PyBOP, a base (DIEA), and a nitrogen-containing heterocycle R2 to synthesize compound IV-4 in a one-pot reaction. In Step D, a propenylamine containing an R4 group is substituted with chlorinated compound IV-4 in the presence of a base such as K2CO3 and acetonitrile under heating to provide compound IV-5. In Step E, a Heck reaction is performed using a palladium catalyst to provide an exocyclic double bond compound IV-6. In step F, the sulfide compound IV-6 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of the formula HY-R3 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce the substituent -Y-R3 to obtain an intermediate compound. The intermediate is then deprotected in step G to obtain the target compound IV-7, which is generally purified by reverse-phase preparative HPLC and obtained by concentration and lyophilization.

[0118] 5. Plan V

[0119] Some embodiments of Formula I can be prepared by General Scheme V.

[0120] Wherein, X is selected from a halide such as F, Cl, or Br. Except for -Y-R3 not being hydrogen, all substituents are prepared as defined for the compound of Formula I according to Scheme V. In Step A, sodium salt of diethyl oxaloacetate is reacted with S-methylisothiourea sulfate under strong alkaline conditions such as sodium hydroxide to produce pyrimidinecarboxylic acid compound V-2. In Step B, bromine substitution on the pyrimidine ring is carried out using NBS as a brominating agent to produce bromo intermediate V-3. In Step C, carboxylic acid V-3 is subjected to amide condensation with allylamine to produce compound V-4. In Step D, intermediate V-4 is reacted with PyBOP, a base (DIEA), and a nitrogen-containing heterocycle R2 to synthesize compound V-5 in a one-pot process. In Step E, a Heck reaction is performed using a palladium catalyst to produce compound V-6 with an intracyclic double bond. In step F, a boronic acid containing an R4 group is subjected to Chan-Lam coupling with lactam V-6 under the catalysis of a copper salt to obtain compound V-7 containing R4. In step G, sulfide compound V-7 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of the formula HY-R3 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce a substituent -Y-R3 to obtain an intermediate compound. The intermediate is then deprotected in step H to obtain the target compound V-8, which is generally purified by reverse-phase preparative HPLC and obtained by concentration and lyophilization.

[0121] 6. Plan VI

[0122] Some of the examples of Formula I can be prepared by General Scheme VI.

[0123] Except for -Y-R3 not being hydrogen, all substituents are as defined for the compound of Formula I, as prepared according to Scheme VI. Intermediate VI-1 can be prepared from 4-amino-2,6-dichloropyridine according to the method described in patent WO2022042630. In Step A, the hydroxyl group is chlorinated with phosphorus oxychloride and then reacted with a nitrogen-containing heterocycle R2 to produce compound VI-2. In Step B, chloropyridine compound VI-2 undergoes a Suzuki coupling with methylboronic acid under the catalysis of a palladium reagent to introduce a methyl group to produce compound VI-3. In Step C, chloropyridine VI-3 undergoes a Suzuki coupling with a boric acid ester or boronic acid under the catalysis of a palladium reagent to produce compound VI-4 containing R4. In Step D, the methyl group is oxidized with selenium dioxide to produce aldehyde VI-5. In step E, dimethyl (1-diazo-2-oxopropyl)phosphonate (Ohira-Bestman reagent) is used to react with aldehyde VI-5 in the presence of potassium carbonate and methanol to generate alkyne VI-6. In step F, sulfide compound VI-6 is oxidized with m-CPBA to obtain sulfoxide, which is then reacted with a nucleophile of formula HY-R3 in the presence of a base such as LiHMDS and THF as a solvent to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce the substituent -Y-R3 to obtain an intermediate compound. The intermediate is then deprotected in step G to obtain the target compound VI-7, which is generally purified by reverse phase preparative HPLC and obtained by concentration and lyophilization.

[0124] 7. Plan VII

[0125] As described above for intermediates VI-5 and VI-6 for Scheme VI, some examples of compounds of Formula I can be prepared according to General Scheme VII.

[0126] Compounds wherein -Y-R3 is not hydrogen and all substituents are as defined for Formula I are prepared from intermediates VI-5 and VI-6 according to Scheme VII. In Step A, intermediate aldehyde VI-5 is treated with hydroxylamine hydrochloride and a base such as potassium carbonate to yield intermediate oxime VII-1. In Step B, the oxime is dehydrated with acetic anhydride to form a cyano group. In Step C, sulfoxide is oxidized by m-CPBA using sulfide compound VII-2. This sulfoxide is then introduced into the intermediate compound by replacing the sulfoxide group of the sulfoxide pyrimidine compound with a nucleophile of the formula HY-R3 in the presence of a base such as LiHMDS and THF as a solvent. Deprotection of this intermediate in Step D yields the target compound VII-3, which is typically purified by reverse-phase preparative HPLC and concentrated and lyophilized. In step E, a base such as LiHMDS is used in anhydrous THF at low temperature to abstract the hydrogen of the terminal alkyne. This is then reacted with an electrophilic reagent containing an R group (excluding the hydrogen) (e.g., deuterated water, halogenated hydrocarbons, aldehydes, ketones, etc.) to produce the substituted alkynyl compound VII-4. Similar operations to steps C and D are then performed to obtain the target compound VII-5.

[0127] 8. Scheme VIII:

[0128] Some embodiments of Formula I can be prepared by General Scheme VIII.

[0129] Compounds prepared according to Scheme VIII are prepared, except that -Y-R3 is not hydrogen, by reacting all substituents as defined for Formula I. In Step A, trifluoroethyl triflate reacts with starting material VI-1 in the presence of DMF and a base to produce phenol ether VIII-1. In Step B, an acetylene reagent substituted with Rca undergoes a coupling reaction with chloropyridine VIII-1 under the catalysis of a palladium reagent to produce pyridopyrimidine derivative VIII-2 containing an alkynyl group. In Step C, a nitrogen-containing heterocycle R2 undergoes a nucleophilic substitution reaction with VIII-2 under the catalysis of a base to introduce compound VIII-3 containing an R2 group. In Step D, a borate ester or acid containing an R4 group, or an organotin reagent, undergoes a Suzuki or Stille coupling reaction with chloropyridine VI-3 under the catalysis of a palladium reagent to produce compound VIII-4 containing R4. In step E, the sulfide compound VIII-4 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of formula HY-R3 in the presence of a base such as LiHMDS and THF as a solvent to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce a substituent -Y-R3 to obtain an intermediate compound. The intermediate is then deprotected in step F to obtain the target compound VIII-5, which is generally purified by reverse-phase preparative HPLC and obtained by concentration and lyophilization.

[0130] Example 1 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-chloronaphthalen-1-yl)-5-enyl-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,7-dihydropyridone[3,4-d]pyrimidin-8(5H)-one

[0131] Step A N-allyl-8-chloronaphthalene-1-amine: 1-bromo-8-chloronaphthalene (500 mg, 2.07 mmol), allylamine hydrochloride (293 mg, 3.11 mmol), cesium carbonate (1.35 g, 4.15 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (240 mg, 0.42 mmol) and tris(dibenzylideneacetone)dipalladium (190 mg, 0.21 mmol) in 1,4-dioxane (8 mL) were stirred at 110 ° C. overnight under nitrogen protection. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=10:1 to 5:1) to give the product (180.0 mg, 0.83 mmol, 40% yield) as an oil, LCMS: m / z 218.2 (M+H).

[0132] Step B. Methyl 5-bromo-2,6-dihydroxypyrimidine-4-carboxylate: To a solution of methyl orotate (10 g, 58.82 mmol) in methanol (120.0 mL) was added bromine (3 mL, 58.82 mmol) dropwise. The mixture was stirred at 65°C overnight. Filtered under reduced pressure and the filter cake washed with methanol to afford a white solid (10.67 g, 43.02 mmol, 73% yield). LCMS: m / z 249.2 (M+H).

[0133] Step C.5-bromo-2,6-dichloropyrimidine-4-methyl carboxylate: A mixture of 5-bromo-2,6-dihydroxypyrimidine-4-methyl carboxylate (5.00 g, 20.08 mmol), phosphorus oxychloride (50 mL) and N,N-dimethylformamide (0.9 ml) was heated at 100 ° C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The combined organic layer was washed with brine, dried, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 1 to 100: 5) to give a white solid (4.0 g, 14.08 mmol, 70% yield), LCMS: m / z 285.2 (M+H).

[0134] Step D. tert-Butyl (1R,5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of methyl 5-bromo-2,6-dichloropyrimidine-4-carboxylate (500 mg, 1.76 mmol) in dichloromethane (5.0 mL) was added triethylamine (213 mg, 2.11 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (336 mg, 1.59 mmol). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=10:0 to 5:1) to give a white solid (664.0 mg, 1.43 mmol, 82% yield), LCMS: m / z 463.2 (M+H).

[0135] Step E. tert-Butyl (1R,5S)-3-(6-(allyl(8-chloronaphthalen-1-yl)carbamoyl)-5-bromo-2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of tert-butyl (1R,5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (211 mg, 0.45 mmol) and N-allyl-8-chloronaphthalen-1-amine (100 mg, 0.45 mmol) in toluene (8.0 mL) was added LiHMDS (917 μL, 0.92 mmol) under nitrogen at -20°C and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=4:1) to give a yellow oil (110.0 mg, 38% yield), LCMS: m / z 646.2 (M+H).

[0136] Step F. (1R,5S)-3-(6-(allyl(8-chloronaphthalen-1-yl)carbamoyl)-5-bromo-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To (1R,5S)-3-(6-(allyl(8-chloronaphthalen-1-yl)carbamoyl)-5-bromo-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl (110 mg, 0.17 mmol) in 2-methyltetrahydrofuran (2.0 mL) was added N, N-diisopropylethylamine (219 mg, 1.70 mmol) and (hexahydro-1H-pyrrolidine-7a-yl)methanol (240 mg, 1.70 mmol). The mixture was stirred at 90 ° C for 48 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. Purification by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0: 1) gave a yellow solid (90 mg, 0.12 mmol, 71% yield), LCMS: m / z 751.2 (M + H).

[0137] Step G. (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-5-enyl)-8-oxo-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyridone[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(6-(allyl(8-chloronaphthalen-1-yl)carbamoyl)-5-bromo-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyridone[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 1% ethyl acetate. A solution of tert-butyl 7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.08 mmol), triethylamine (20 mg, 0.2 mmol), palladium acetate (4 mg, 0.016 mmol), triphenylphosphine (4 mg, 0.016 mmol) and tetrabutylammonium bromide (64 mg, 0.2 mmol) in dimethylformamide (2.00 mL) was stirred at 90 ° C for 12 hours under nitrogen protection. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give a crude product. Purification by preparative TLC (SiO2, dichloromethane: methanol = 10: 1) gave a yellow oil (30.0 mg, 0.045 mmol, 56% yield), LCMS: m / z 671.2 (M + H).

[0138] Step H. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-5-enyl-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydropyridone[3,4-d]pyrimidin-8(5H)-one: To (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-5-enyl)- To a solution of tert-butyl 8-oxo-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyridone[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.059 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was collected and concentrated to yield the crude product. The crude product was purified by preparative HPLC to afford Example 1 (2 mg, 0.0035 mmol, 5.9% yield). LCMS: m / z 571.3 (M+H). 1 HNMR (600MHz, DMSO-d6) δ8.12(d,J=8.4Hz,1H),8.08(d,J=8.1Hz,1H),7.71(t,J=7.8Hz,1H),7.66(dd,J= 7.5,1.2Hz,1H),7.63(dd,J=7.3,1.3Hz,1H),7.55(t,J=7.9Hz,1H),5.53(s,1H),5.07(s,1H),4.72(d,J=1 3.7Hz,1H),4.48(d,J=13.7Hz,1H),4.13–3.97(m,3H),3.52(d,J=13.0Hz,2H),3.18–3.09(m,3H),3.08–2. 95(m,3H),2.69–2.62(m,1H),1.95–1.89(m,2H),1.89–1.81(m,2H),1.80–1.70(m,3H),1.69–1.57(m,5H).

[0139] Example 2 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine-3-carbonitrile

[0140] Step A. Ethyl 6-chloro-4-(2-cyanoacetamide)-5-fluoronicotinate: To a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (2.0 g, 9.1 mmol) in DMF (25 mL) was added sodium hydride (734 mg, 18.2 mmol) at 0°C and stirred at room temperature for 1 h. 2-Cyanoacetyl chloride (3.0 g, 29.4 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 h. The residue was partitioned between EtOAc and water and extracted with EtOAc (2x). The aqueous layer was extracted and the organic phase was washed with saturated NaCl and dried over NaSO. The combined organic phases were filtered, dry-loaded onto silica gel, and purified by flash column chromatography eluting with 0-50% EtOAc / petroleum ether to afford the product (1.8 g, 6.2 mmol, 69% yield). LCMS: m / z 286.0 (M+H).

[0141] Step B. 7-Chloro-8-fluoro-2,4-dioxacyclopent ...

[0142] Step C. 4,7-Dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile: 7-Chloro-8-fluoro-2,4-dioxacyclo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (500 mg, 2.0 mmol) was stirred in phosphorus oxychloride (5 mL) at 90°C for 1.5 h. The residue was added dropwise to ice-cold water and the pH was adjusted to 7-8 with saturated NaHCO₃. The aqueous layer was extracted with EtOAc, and the organic layer was filtered and concentrated in vacuo to afford the product (460 mg, 1.8 mmol, 89% yield). LCMS: m / z 258.0 (M+H).

[0143] Step D. (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To a solution of 4,7-dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile (460 mg, 1.8 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530.0 mg, 2.5 mmol) in DMF (10 mL) was added DIEA (804.0 mg, 6.2 mmol) and stirred at 80°C for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-5% MeOH / DCM to give the product (400 mg, 0.9 mmol, 52% yield) LCMS: m / z 434.1 (M+H).

[0144] Step E. (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To a solution of (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg, 0.9 mmol), N-methyl-L-prolinol (147.0 mg, 1.4 mmol) and triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was added dropwise DIAD (545.0 mg, 2.7 mmol) at 0°C and stirred at room temperature for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (300 mg, 0.6 mmol, 63% yield) LCMS: m / z 531.2 (M+H).

[0145] Step F. (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane in 1% ethyl acetate. A solution of tert-butyl-8-carboxylate (300.0 mg, 0.6 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (369.0 mg, 0.7 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (44.0 mg, 0.06 mmol), and potassium phosphate (381.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (220 mg, 0.25 mmol, 42% yield) LCMS: m / z 881.5 (M+H).

[0146] Step G. (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. A solution of tert-butyl (((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220.0 mg, 0.25 mmol) and cesium fluoride (151.0 mg, 1.0 mmol) in DMF (10 mL) was stirred at room temperature for 1 hour under nitrogen. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over NaSO. The combined organic phases were filtered, dry-loaded onto silica gel, and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (140 mg, 0.19 mmol, 77% yield). LCMS: m / z 725.3 (M+H).

[0147] Step H. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine-3-carbonitrile: Resuspend (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3- To a solution of tert-butyl (((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140.0 mg, 0.19 mmol) in dichloromethane (3 mL) was added dropwise a 1,4-dioxane solution of hydrochloric acid. The mixture was stirred at room temperature for 1 h. Concentrated, the residue was poured into a mixture of saturated NaHCO 3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). The product was extracted with sodium bicarbonate, DCM, and MeOH, and the organic phase was dried and concentrated, added with purified water, and lyophilized to obtain Example 2 (17.0 mg, 0.03 mmol, 15% yield). LCMS: m / z 581.2 (M+H). 1H NMR (600MHz, DMSO-d6) δ10.30(s,1H),9.03(s,1H),7.98(dd,J=9.2,5.8Hz,1H),7.47(t,J=9.0Hz,1H),7.4 0(d,J=2.6Hz,1H),7.22(t,J=2.2Hz,1H),4.48(td,J=10.8,5.0Hz,1H),4.38(ddd,J=10.9,8.8,5.5Hz,1H) ,3.99(d,J=3.4Hz,1H),3.84–3.78(m,2H),3.72–3.66(m,2H),3.05–2.99(m,2H),2.99–2.93(m,3H),2.67– 2.61(m,1H),2.40(s,3H),2.23–2.19(m,1H),2.18(d,J=9.4Hz,1H),1.99–1.93(m,1H),1.71–1.64(m,2H).

[0148] Example 3 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5-enyl-6,7-dihydropyridone[3,4-d]pyrimidin-8(5H)-one

[0149] The reaction formula is:

[0150] Step A.1-bromo-3-(methoxymethoxy)naphthalene: Under nitrogen protection, bromomethyl methyl ether (0.27 mL, 3.36 mmol) was added to a solution of 1-bromo-3-hydroxynaphthalene (500 mg, 2.24 mmol) and DIEA (868 mg, 6.27 mmol) in dichloromethane (8 mL). The mixture was stirred at 0 ° C for 0.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give a crude product. The mixture was directly purified by column chromatography and eluted with (PE / EtOAc=1:10) to give the product (160 mg, 0.60 mmol, 27% yield).

[0151] Step B N-allyl-3-(methoxymethoxy)naphthalene-1-amine: A solution of 1-bromo-3-(methoxymethoxy)naphthalene (30 mg, 0.113 mmol), allylamine (16 mg, 0.169 mmol), Xantphos (13 mg, 0.023 mmol), Pd2(dba)3 (10 mg, 0.011 mmol) and cesium carbonate (73 mg, 0.226 mmol) in 1,4-dioxane (1.00 mL) was stirred at 110 ° C for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 10: 1) to give a yellow oil (20.0 mg, 0.0819 mmol, 73% yield), LCMS: m / z 244.2 (M+H).

[0152] Step C. Using (1R,5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as starting material, replacing N-allyl-8-chloronaphthalene-1-amine with N-allyl-3-(methoxymethoxy)naphthalene-1-amine, and replacing (hexahydro-1H-pyrrolidine-7a-yl)methanol with (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-ylmethanol, Example 3 was synthesized according to Steps EH of Example 1. LCMS: m / z 571.3 (M+H). 1 HNMR(600MHz,DMSO-d6)δ7.83(d,J=8.3Hz,1H),7.57(d,J=8.4Hz,1H),7.49–7.43(m,1H),7.31–7.27(m,2H),7.21(d ,J=2.3Hz,1H),7.13(t,J=2.1Hz,1H),5.53(s,1H),5.35–5.22(m,1H),5.06(s,1H),4.67(d,J=13.3Hz,1H),4.33(d,J =13.3Hz,1H),4.06(d,J=10.2Hz,2H),3.95(d,J=10.3Hz,1H),3.48–3.40(m,4H),3.12–3.07(m,3H),2.86–2.80(m,2H ),2.13–2.10(m,2H),2.07–2.04(m,1H),2.02–1.96(m,1H),1.88–1.83(m,1H),1.81–1.73(m,2H),1.64–1.50(m,3H).

[0153] Example 4 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylene-5,8-dihydropyridone[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol

[0154] The reaction formula is:

[0155] Step A. 6-(Chloromethyl)-2-(methylthio)pyrimidin-4-ol: To a solution of ethyl chloroacetoacetate (10 g, 60.6 mmol) and 2-methyl-2-mercaptosulfuronamide (16.8 g, 60.6 mmol) in water (100 mL) was added sodium carbonate (9.6 g, 90.9 mmol). The reaction mixture was stirred at 25°C for 6 hours. The pH was adjusted to acidic with 5 M HCl, filtered, and the filter cake was dried in a vacuum oven to afford the product (7.8 g, 68% yield), which was used in the next step. LCMS: m / z 191.1 (M+H).

[0156] Step B. 5-Bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol: To a solution of 6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol (3.68 g, 19.26 mmol) in acetonitrile (40 ml) was added N-bromosuccinimide (NBS) (3.4 g, 19.26 mmol), heated to 80° C. and stirred for 3 hours. The reaction mixture was filtered and rinsed with petroleum ether / ethyl acetate = 40 / 1. The filter cake was the product (3.8 g, 74% yield). LCMS: m / z 268.9 (M+H).

[0157] Step C. tert-Butyl (1R,5S)-3-(5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol (2 g, 7.43 mmol) in acetonitrile (15 mL) at 0°C was added 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (3.9 g, 7.43 mmol) and DIEA (2.9 g, 22.3 mmol). The mixture was stirred under nitrogen for 5 min before tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 8.18 mmol) was added. Stirring was continued for 1 hour. The reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated to obtain the crude product. Then it was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1) to give a yellow oil (1.1 g, 32% yield), LCMS: m / z 463.1 (M+H).

[0158] Step D. Tert-butyl (1R,5S)-3-(6-((allyl(3-(methoxymethoxy)naphthalen-1-yl)amino)methyl)-5-bromo-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,5S)-3-(5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (63 mg, 0.26 mmol), N-allyl-3-(methoxymethoxy)naphthalen-1-amine (86 mg, 0.19 mmol), potassium iodide (3 mg, 0.02 mmol), and potassium carbonate (77 mg, 0.56 mmol) in acetonitrile (1 ml) was heated to 80°C under nitrogen and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and extracted with water and ethyl acetate, dried over Na2SO4, filtered and concentrated to give a crude product. It was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give a yellow oil (40 mg, 32% yield), LCMS: m / z 670.2 (M+H).

[0159] Step E. (1R,5S)-3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-enyl-2-(methylthio)-5,6,7,8-tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(6-((allyl(3-(methoxymethoxy)naphthalen-1-yl)amino)methyl)- A solution of tert-butyl 5-bromo-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.30 mmol), triphenylphosphine (16 mg, 0.06 mmol), palladium acetate (7 mg, 0.03 mmol), and cesium carbonate (244 mg, 0.75 mmol) in toluene (5 ml) was heated to 110° C. under a nitrogen atmosphere and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate and extracted with water and ethyl acetate, dried over Na2SO4, filtered, and concentrated to obtain the crude product. The product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to afford a yellow solid (135 mg, 77% yield). LCMS: m / z 590.3 (M+H).

[0160] Step F. (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5-enyl-5,6,7,8-tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: At -40°C, add (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5-enyl-5,6,7,8-tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to a 1% ethanol solution. To a solution of tert-butyl-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-enyl-2-(methylthio)-5,6,7,8-tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.170 mmol) in dichloromethane (2 ml) was added meta-chloroperbenzoic acid (29 mg, 0.170 mmol) and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with dichloromethane (50 ml) and aqueous sodium carbonate. The mixture was dried over NaSO and concentrated by rotary evaporation to afford the crude product, which was used in the next step without further purification. A solution of this crude product (130 mg, 0.21 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol (68 mg, 0.42 mmol), and DIEA (83 mg, 0.63 mmol) in isopropanol (0.7 ml) was heated to 90° C. and stirred for 10 hours. The reaction mixture was diluted with ethyl acetate and extracted with water and ethyl acetate, dried over Na₂SO₄, filtered, and concentrated to afford the crude product. The product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 3 / 1) to afford a yellow solid (60 mg, 40% yield). LCMS: m / z 701.4 (M+H).

[0161] Step G. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl))-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylene-5,8-dihydropyridone[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol: To (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro To a solution of tert-butyl (5-((1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5-enyl-5,6,7,8-tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.08 mmol) in dichloromethane (2 mL) was added dropwise a solution of hydrochloric acid in 1,4-dioxane. The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO₃, DCM, and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min) and lyophilization afforded Example 4 as a salt containing one formic acid (3.55 mg, 7% yield), LCMS: m / z 557.2 (M+H). 1 HNMR (600MHz, DMSO-d6) δ9.68(s,1H),8.27(s,1H),7.91(d,J=8.4Hz,1H),7.64(d,J=8.2Hz,1H),7.37(t,J=7.4Hz,1H),7.27(t ,J=7.6Hz,1H),6.81(d,J=2.2Hz,1H),6.60(d,J=2.2Hz,1H),5.27(d,J=54.3Hz,1H),5.11(s,1H),4.92(s,1H),4.19(s,2H),4. 04(s,2H),4.00(d,J=10.2Hz,1H),3.89(d,J=10.2Hz,1H),3.48(s,3H),3.12–3.04(m,4H),3.01(s,1H),2.82(q,J=8.3Hz,1H), 2.11–2.06(m,1H),2.03(d,J=3.1Hz,1H),2.01–1.94(m,1H),1.84(d,J=10.0Hz,1H),1.76(d,J=11.7Hz,2H),1.59-1.53(m,4H).

[0162] Example 5 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile

[0163] Step A. (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3 To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]octane-8-carboxylic acid tert-butyl ester (400 mg, 0.9 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (222.0 mg, 1.4 mmol), and triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was added DIAD (545.0 mg, 2.7 mmol) dropwise at 0°C and stirred at room temperature for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over NaSO. The combined organic phases were filtered, dry-loaded onto silica gel, and purified by flash column chromatography eluting with 0-10% MeOH / DCM to afford the product (300 mg, 0.5 mmol, 58% yield). LCMS: m / z 575.4 (M+H).

[0164] Step B. (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8 A solution of tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate (300.0 mg, 0.5 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (369.0 mg, 0.7 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (44.0 mg, 0.06 mmol), and potassium phosphate (381.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (220 mg, 0.23 mmol, 47% yield) LCMS: m / z 925.5 (M+H).

[0165] Step C. (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3 A solution of tert-butyl-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220.0 mg, 0.23 mmol) and cesium fluoride (139.0 mg, 0.9 mmol) in DMF (10 mL) was stirred at room temperature under nitrogen for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (140 mg, 0.18 mmol, 79% yield) LCMS: m / z 769.3 (M+H).

[0166] Step D. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile: Resuspend (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3- To a solution of tert-butyl (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140.0 mg, 0.18 mmol) in dichloromethane (3 mL) was added dropwise a 1,4-dioxane solution of hydrochloric acid. The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO 3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography and purified with preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). The product was extracted with sodium bicarbonate, DCM, and MeOH, and the organic phase was dried and concentrated, added with purified water, and lyophilized to obtain Example 5 (6.97 mg, 0.01 mmol, 6% yield). LCMS: m / z 625.2 (M+H). 1 H NMR (600MHz, DMSO-d6) δ9.15(s,1H),8.45(s,1H),7.97(dd,J=9.2,5.9Hz,1H),7.46(t,J=9.0Hz,1H),7.40 (d,J=2.5Hz,1H),7.21(d,J=2.5Hz,1H),5.36–5.24(m,1H),4.22(dd,J=10.4,7.9Hz,1H),4.16(dd,J=10.4 ,5.5Hz,1H),3.95–3.89(m,3H),3.71–3.65(m,2H),3.57–3.51(m,2H),3.21–3.14(m,1H),3.13–3.08(m,1H ),3.07–3.00(m,1H),2.83(q,J=7.9,7.5Hz,1H),2.16–2.08(m,2H),2.07–1.95(m,3H),1.86–1.73(m,5H).

[0167] Example 6 Preparation of 4-(5-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-2-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0168] The reaction formula is as follows:

[0169] Step A. Ethyl 2-(methylthio)-4-(3-(2,2,2-trichloroacetyl)urea)pyrimidine-5-carboxylate: To a solution of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (500 mg, 2.35 mmol) in THF (4 ml) under an ice-water bath was added trichloroacetyl isocyanate (530 mg) and stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 ml x 2) and extracted with water (100 ml x 2), dried over NaSO, and concentrated by rotary evaporation to give a white solid (550 mg, crude) which was used in the next step without purification. LCMS: m / z 401.0 (M+H).

[0170] Step B. 7-(Methylthio)pyrimido[4,5-d]pyrimidine-2,4-diol: To ethyl 2-(methylthio)-4-(3-(2,2,2-trichloroacetyl)urea)pyrimidine-5-carboxylate was added a 7 M methanolic ammonia solution (8 mL) at 0°C and stirred at 25°C for 2 hours. The mixture was filtered and washed with methanol (500 mL x 3) to afford the crude product (480 mg) for use in the next step. LCMS: m / z 210.0 (M+H).

[0171] Step C. 2,4-Dichloro-7-(methylthio)pyrimido[4,5-d]pyrimidine: To a solution of 7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4-diol (480 mg, 2.28 mmol) in POCl3 (4 mL) was slowly added dropwise DIEA (888 mg, 6.85 mmol) at 0°C. The reaction was heated to 100°C and stirred for 2 hours. The reaction was concentrated and used directly in the next step. LCMS: m / z 247.0 (M+H).

[0172] Step D. (1R, 5S) -3- (2-chloro-7- (methylthio) pyrimido [4, 5-d] pyrimidin-4-yl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester: 2, 4- dichloro-7- (methylthio) pyrimido [4, 5-d] pyrimidine was diluted with DCM (5 ml), 3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (480 mg, 2.26 mmol) and DIEA (10 ml) were slowly added thereto at 0 ° C and stirred at 25 ° C for 2 hours. The reaction mixture was diluted with DCM and water was added, extracted with dichloromethane, dried over Na2SO4, and concentrated by rotary evaporation to give the crude product. It was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give the product as a yellow solid (620 mg, 62% yield). LCMS: m / z 423.1 (M+H).

[0173] Step E. (1R,5S)-tert-Butyl 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: (1R,5S)-tert-Butyl 3-(2-chloro-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.24 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (75 mg, 0.47 mmol), DIEA (92 mg, 0.71 mmol) was added to a solution of 1,4-dioxane (1 ml). The reaction mixture was heated to 90°C and stirred overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and water was added. The mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated to yield the crude product. The product was then purified by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to afford a yellow solid (70 mg, 54% yield). LCMS: m / z 546.3 (M+H).

[0174] Step F. (1R,5S)-3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was added at 0°C. To a solution of tert-butyl cyclo-7a(5H)-yl)methoxy)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.55 mmol) in THF / DCM = 1 / 1 (5 ml) was added sulfonyl chloride (742 mg, 5.50 mmol) dropwise under nitrogen protection, and the reaction solution was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (8 ml), extracted with DCM (50 ml), dried over Na2SO4, and concentrated to give the crude product. It was then purified by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to give a yellow solid (216 mg, 74% yield). LCMS: m / z 534.2 (M+H).

[0175] Step G. (1R,5S)-3-(7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3 .2.1] tert-butyl octane-8-carboxylate (130 mg, 0.24 mmol, 1 equivalent), ((2-fluoro-6-(methoxymethyl ether)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (236 mg, 0.27 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (18 mg, 0.02 mmol), potassium phosphate (155 mg, 0.73 mmol), in a THF / H2O=4 / 1 solution, heated to 60°C under nitrogen protection and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, and the organic phase was washed with saturated NaCl, dried over Na2SO4, and concentrated to obtain a crude product. The product was then purified by column chromatography (SiO2, dichloromethane / methanol = 8 / 1) to give a yellow solid (70 mg, 33% yield). LCMS: m / z 884.5 (M+H).

[0176] Step H. (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 1% ethyl acetate. )-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg, 0.08 mmol) and cesium fluoride (24 mg, 0.16 mmol) were added to a solution of DMF (2 mL). Stirred at 25 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, and the organic phase was washed with saturated NaCl, dried over Na2SO4, and concentrated to give a crude product. The product was then purified by column chromatography (SiO2, dichloromethane / methanol = 8 / 1) to give the product (50 mg, 89% yield) LCMS: m / z 728.3 (M+H).

[0177] Step I. 4-(5-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Resuspend (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.07 mmol) in dichloromethane (2 mL) was added dropwise to a 1,4-dioxane solution of hydrochloric acid. Stirred at room temperature for 1 h. Concentrated, the residue was poured into a mixture of saturated NaHCO3, DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). The product was extracted with sodium bicarbonate and DCM:MeOH (10:1), and the organic phase was dried and concentrated, added with purified water, and lyophilized to obtain Example 6 (2.21 mg, 6% yield). LCMS: m / z 584.3 (M+H). 1H NMR (600MHz, DMSO-d6) δ9.34(s,1H),8.21(s,2H),7.97(dd,J=9.2,5.8Hz,1H),7.46(t,J=9.0Hz,1H),7.37(d,J=2.5 Hz,1H),7.28(d,J=2.5Hz,1H),5.33(s,1H),5.25–5.23(m,1H),4.11(d,J=10.4Hz,1H),4.03(d,J=10.4Hz,1H),4.01( s,1H),3.64(s,3H),3.12–3.07(m,3H),3.03(s,1H),2.87–2.81(m,2H),2.63–2.60(m,1H),2.41–2.38(m,1H),2.13– 2.10(m,1H),2.06(d,J=3.2Hz,1H),2.00(dd,J=11.8,6.5Hz,2H),1.87–1.84(m,1H),1.81–1.76(m,2H),1.70(s,3H).

[0178] Example 7 Preparation of (S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-1,6-naphthalene-3-carbonitrile

[0179] Step A. tert-Butyl 4-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyl-4-yl)piperazine-1-carboxylate: Add DIEA (804.0 mg, 6.2 mmol) to a solution of 4,7-dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile (460 mg, 1.8 mmol) and tert-butyl piperazine-1-carboxylate (530.0 mg, 2.5 mmol) in DMF (10 mL) and stir at 80°C for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-5% MeOH / DCM to give the product (380 mg, 0.7 mmol, 50% yield) LCMS: m / z 408.1 (M+H).

[0180] Step B. (S)-tert-Butyl 4-(7-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate: To a solution of tert-butyl 4-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthalen-4-yl)piperazine-1-carboxylate (380 mg, 0.7 mmol), N-methyl-L-prolinol (125.0 mg, 1.4 mmol) and triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was added dropwise with DIAD (545.0 mg, 2.7 mmol) at 0°C and stirred at room temperature for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (300 mg, 0.6 mmol, 63% yield) LCMS: m / z 505.2 (M+H).

[0181] Step C. (S)-tert-Butyl 4-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate: (S)-tert-Butyl 4-(7-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate (300.0 mg, 0.6 mmol), A solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (369.0 mg, 0.7 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (44.0 mg, 0.06 mmol), and potassium phosphate (381.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (200 mg, 0.22 mmol, 42% yield) LCMS: m / z 855.4 (M+H).

[0182] Step D. (S)-tert-Butyl 4-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate: A solution of (S)-tert-butyl 4-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate (200.0 mg, 0.25 mmol) and cesium fluoride (131.0 mg, 0.9 mmol) in DMF (10 mL) was stirred at room temperature under nitrogen for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (100 mg, 0.14 mmol, 68% yield) LCMS: m / z 699.3 (M+H).

[0183] Step E. (S)-7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-1,6-naphthalen-3-carbonitrile: A solution of (S)-tert-butyl 4-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate (100.0 mg, 0.14 mmol) in dichloromethane (3 mL) was added dropwise to a solution of hydrochloric acid in 1,4-dioxane. The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO, DCM, and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification was performed by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). The product was extracted with sodium bicarbonate, DCM, and MeOH. The organic phase was dried, concentrated, added to purified water, and lyophilized to afford Example 7 (36.4 mg, 0.06 mmol, 46% yield). LCMS: m / z 555.2 (M+H). 1H NMR (600MHz, DMSO-d6) δ10.30(s,1H),9.03(s,1H),7.98(dd,J=9.2,5.8Hz,1H),7.47(t,J=9.0Hz,1H),7.4 0(d,J=2.6Hz,1H),7.22(t,J=2.2Hz,1H),4.48(td,J=10.8,5.0Hz,1H),4.38(ddd,J=10.9,8.8,5.5Hz,1H) ,3.99(d,J=3.4Hz,1H),3.84–3.78(m,2H),3.72–3.66(m,2H),3.05–2.99(m,2H),2.99–2.93(m,3H),2.67– 2.61(m,1H),2.40(s,3H),2.23–2.19(m,1H),2.18(d,J=9.4Hz,1H),1.99–1.93(m,1H),1.71–1.64(m,2H).

[0184] Example 8 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5-methylpyridin[3,4-d]pyrimidin-8(7H)-one

[0185] The reaction formula is as follows:

[0186] Step A. 6-Hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid: To a solution of diethyl oxaloacetate sodium salt (2 g, 9.4 mmol) and 2-methyl-2-mercaptosulfuric acid urea (1.3 g, 9.4 mmol) in H₂O (20.0 mL) was added NaOH (750 mg, 18.8 mmol). The mixture was stirred at room temperature for 12 hours. The pH of the reaction solution was adjusted to approximately 1.0 with 4 M HCl to precipitate a white solid, which was filtered and washed with H₂O to give a white solid (500 mg, 2.69 mmol, 29% yield). LCMS: m / z 187.2 (M+H).

[0187] Step B.5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid: To a solution of 6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid (800 mg, 4.30 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (1.14 g, 6.45 mmol). The mixture was stirred at 40 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The product was slurried in ethyl acetate and filtered to give a yellow solid (1.00 g, 3.79 mmol, 88% yield). LCMS: m / z 264.9 (M + H).

[0188] Step C N-allyl-5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxamide: To a solution of 5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid (1.1 g, 4.17 mmol) in dimethylformamide (10.0 mL) was added HATU (2.37 g, 6.25 mmol). The mixture was stirred at room temperature for 0.5 hours. Allylamine (587 mg, 6.25 mmol) and N,N-diisopropylethylamine (1.61 g, 12.50 mmol) were then added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to approximately 6 with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:1 to 0:1) to give the product as a white solid (650.0 mg, 2.13 mmol, 51% yield), LCMS: m / z 463.2 (M+H).

[0189] Step D. tert-Butyl (1R,5S)-3-(6-(allylcarbamoyl)-5-bromo-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of N-allyl-5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxamide (200 mg, 0.65 mmol) in acetonitrile (10.0 mL) was added 1H-benzotriazole-1-oxytris(1-pyrrolidinyl)phosphine hexafluorophosphate (PyBop) (512 mg, 0.98 mmol). The mixture was stirred at room temperature for 5 minutes. tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (208 mg, 0.98 mmol) and DIEA (256 mg, 1.97 mmol) were then added to the reaction. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, dichloromethane: methanol = 20: 1) to give a white solid (250.0 mg, 0.50 mmol, 77% yield), LCMS: m / z 498.2 (M+H).

[0190] Step E. tert-Butyl 3-(5-methyl-2-(methylthio)-8-oxo-7,8-dihydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,5S)-3-(6-(allylcarbamoyl)-5-bromo-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.00 mmol), N,N-diisopropylethylamine (648 mg, 5.02 mmol) and trans-bis[o-(di-o-tolylphosphino)benzyl]diacetatedipalladium(II) (188 mg, 0.20 mmol) in N,N-dimethylaniline (4.00 mL) was stirred at 150° C. under nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure to give the crude product. Purification by preparative TLC (SiO2, dichloromethane:methanol=10:1) gave a yellow solid (200.0 mg, 0.478 mmol, 24% yield). LCMS: m / z 418.2 (M+H).

[0191] Step F. tert-Butyl 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-methyl-2-(methylthio)-8-oxo-7,8-dihydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Resuspend 3-(5-methyl-2-(methylthio)-8-oxo-7,8-dihydropyridono[3,4-d]pyrimidin-4-yl)-3,8 A solution of tert-butyl-diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.622 mmol), (3-(methoxymethoxy)naphthalen-1-yl)boronic acid (226 mg, 1.244 mmol), pyridine (492 mg, 6.22 mmol) and copper acetate (169 mg, 0.93 mmol) in dichloromethane (4.00 mL) was stirred at room temperature for 12 hours under an oxygen atmosphere. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give a crude product. Purification by preparative TLC (SiO2, dichloromethane: methanol = 10: 1) gave a yellow solid (170.0 mg, 281 mmol, 45% yield), LCMS: m / z 604.2 (M+H).

[0192] Step G. tert-Butyl 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-3-(methoxymethoxy)naphthalen-1-yl)5-methyl-8-oxo-7,8-dihydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Add 3-(7- To a solution of tert-butyl (3-(methoxymethoxy)naphthalen-1-yl)-5-methyl-2-(methylthio)-8-oxo-7,8-dihydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.232 mmol) in dichloromethane (2.0 ml) was added 3-chloroperoxybenzoic acid (44 mg, 0.255 mmol). The solution was stirred for 1 hour. The reaction was concentrated in vacuo and extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was collected and concentrated to yield the crude intermediate. To a solution of the intermediate in 1,4-dioxane (2.0 mL) was added ((2R, 8S) -2-fluoro-1,2,3,4,5,6,7-hexahydropyrrolazin-7-yl) methanol (74 mg, 0.467 mmol) and N, N-diisopropylethylamine (90 mg, 0.695 mmol). The mixture was stirred at 90 ° C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Purification by column chromatography (SiO2, dichloromethane: methanol = 10: 1) gave a white solid (130.0 mg, 0.18 mmol, 78% yield), LCMS: m / z 358.2 (M / 2 + H).

[0193] Step H. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5-methylpyridin[3,4-d]pyrimidin-8(7H)-one: To 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5-methylpyridin[3,4-d]pyrimidin-8(7H)-one To a solution of tert-butyl (5-( ... 1 H NMR(600MHz, DMSO-d6)δ8.26(s,2H),7.83(d,J=8.3Hz,1H),7.47(ddd,J=8.1,6.2,1.6Hz,1H),7.29(q,J=6.7, 5.1Hz,3H),7.13(t,J=2.1Hz,1H),7.04(s,1H),5.34–5.20(m,1H),4.20–4.02(m,2H),4.10(dd,J=10.3,3.7Hz ,2H),4.00(dd,J=10.3,2.3Hz,2H),3.63–3.53(m,2H),3.14–3.07(m,2H),3.04(s,1H),2.87–2.81(m,1H),2.1 8–2.10(m,4H),2.08–2.05(m,1H),2.03–1.97(m,1H),1.88–1.83(m,1H),1.81–1.73(m,2H),1.70–1.43(m,4H).

[0194] Example 9 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0195] The reaction formula is as follows:

[0196] Step A. 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: This intermediate can be prepared using 4-amino-2,6-dichloropyridine according to the method in patent WO2022042630.

[0197] Step B. tert-Butyl (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (5.0 g, 17.8 mmol) in acetonitrile (50 mL) was added with phosphorus oxychloride (4.0 g, 26.7 mmol) and DIEA (4.6 g, 35.6 mmol) and stirred at 80°C for 2 h. DIEA (4.6 g, 35.6 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.6 g, 26.7 mmol) were added to the reaction at 0°C. The mixture was stirred at room temperature for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-20% ethyl acetate in petroleum ether to give the product (5.0 g, 10.5 mmol, 59% yield) LCMS: m / z 474.1 (M+H).

[0198] Step C. tert-Butyl (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 17.8 mmol), methylboronic acid (2.6 g, 44.5 mmol), Pd(dppf)Cl2 (1.3 g, 1.8 mmol), and potassium phosphate (11.3 g, 53.4 mmol) in toluene (80 mL) and water (8 mL) was stirred at 105°C under nitrogen for 12 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give the product (2.0 g, 4.4 mmol, 25% yield) LCMS: m / z 454.1 (M+H).

[0199] Step D. (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2- A solution of tert-butyl (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 4.4 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.9 g, 5.7 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (320.0 mg, 0.44 mmol), and potassium phosphate (2.8 g, 13.2 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (2.2 g, 2.7 mmol, 63% yield).

[0200] Step E. (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 1% ethyl acetate. To a solution of tert-butyl (((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 2.7 mmol) in 1,4-dioxane (15 mL) was added selenium dioxide (594.0 mg, 5.4 mmol). Stirred at 105° C. for 1 h under nitrogen. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na₂SO₄, and the combined organic phases were filtered, dry-loaded onto silica gel, and purified by flash column chromatography eluting with 0-30% ethyl acetate / petroleum ether to afford the product (2.2 g, 2.4 mmol, 91% yield).

[0201] Step F. (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 1% ethyl acetate. To a solution of tert-butyl (1,2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 2.7 mmol) in MeOH (15 mL) was added cesium carbonate (1.7 g, 5.4 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 g, 5.4 mmol), and the mixture was stirred at room temperature for 1 hour. The residue was partitioned between dichloromethane and water, and the aqueous layer was extracted with dichloromethane. The organic phase was washed with saturated NaCl, dried over NaSO, dry-loaded onto silica gel, and purified by flash column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford the product (1.3 g, 1.5 mmol, 59% yield).

[0202] Step G. (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of tert-butyl fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 1.5 mmol) in DCM (10 mL) was added meta-chloroperbenzoic acid (387.0 mg, 2.2 mmol) and stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to quench the mixture, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic phase was washed with saturated NaCl, dried over NaSO, and concentrated to yield the crude product, which was used directly in the next step. LCMS: m / z 830.4 (M+H).

[0203] Step H. (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine-7a

[00145] Tert-butyl (5H)-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl-methanol (131.0 mg, 0.9 mmol) was dissolved in THF (10 mL). Under nitrogen, LiHMDS (3.0 ml, 3.0 mmol) was added dropwise at 0° C. and stirred for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl and dried over Na 2 SO 4 . The combined organic phases were filtered, dry-loaded onto silica gel, and purified by flash column chromatography, eluting with 0-10% MeOH / DCM to give the product (800.0 mg, 0.86 mmol, 57% yield), LCMS: m / z 925.5 (M+H).

[0204] Step I. (1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3 A solution of tert-butyl-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800.0 mg, 0.86 mmol) and cesium fluoride (498.0 mg, 3.3 mmol) in DMF (10 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (540 mg, 0.70 mmol, 82% yield) LCMS: m / z 769.3 (M+H).

[0205] Step J. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring)-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Resuspend (1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7 To a solution of tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.10 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 ml) dropwise. The product was stirred at room temperature for 20 min. Concentration was performed and the residue was poured into a mixture of saturated NaHCO , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na SO , filtered and concentrated in vacuo. It was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). Lyophilization gave Example 9 as a salt containing one formic acid (6.72 mg, 0.01 mmol, 10% yield). LCMS: m / z 625.2 (M+H). 1 HNMR(600MHz, Methanol-d4)δ8.52(s,1H),7.89(dd,J=9.1,5.6Hz,1H),7.41–7.33(m,2H),7.24(t,J=2.5H z,1H),5.45–5.34(m,1H),4.63–4.58(m,3H),4.44(dd,J=11.0,5.5Hz,1H),4.38(dd,J=10.9,5.5Hz,1H),3 .84–3.74(m,3H),3.46–3.38(m,2H),3.23–3.11(m,2H),2.45(d,J=15.9Hz,1H),2.42–2.29(m,2H),2.26–2 .18(m,1H),2.16–2.08(m,2H),2.03–1.96(m,2H),1.91–1.82(m,2H),1.71–1.60(m,1H),1.37–1.26(m,1H).

[0206] Example 10 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0207] Using N-methyl-D-prolinol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the compound was synthesized according to Steps H-J of Example 9 to obtain Example 10, a salt containing a formic acid (10.4 mg, 0.01 mmol, 10% yield). LCMS: m / z 581.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.99(dd,J=9.2,5.9Hz,1H),7.48(t,J=9.0Hz,1H),7.40(d,J =2.6Hz,1H),7.22(d,J=2.5Hz,1H),4.75(s,1H),4.40(dd,J=10.7,4.9Hz,1H),4.20(dd,J=10.8,6 .3Hz,1H),3.80(s,1H),3.56–3.44(m,5H),2.96(dt,J=8.9,4.3Hz,2H),2.60(dd,J=8.5,5.3Hz,1H ),2.38(d,J=5.5Hz,1H),2.36(s,3H),2.19(q,J=8.6Hz,1H),1.99–1.89(m,1H),1.74–1.51(m,6H).

[0208] Example 11 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0209] Using N-methyl-L-prolinol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the product of Example 11 (4.75 mg, 7% yield) containing a formic acid salt was synthesized according to Steps H-J of Example 9. LCMS: m / z 581.2 (M+H). 1H NMR(400MHz, DMSO-d6)δ8.26(s,1H),7.99(dd,J=9.3,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7.42– 7.39(m,1H),7.23(d,J=2.6Hz,1H),4.75(s,1H),4.40(dd,J=11.2,4.7Hz,1H),4.20(dd,J=10.8 ,6.2Hz,1H),3.38–3.24(m,2H),3.80(s,1H),2.95(dt,J=8.9,4.3Hz,2H),2.59(t,J=7.0Hz,1H ), 2.38 (d, J = 4.0Hz, 1H), 2.36 (s, 3H), 2.28–2.14 (m, 2H), 2.00–1.88 (m, 2H), 1.74–1.51 (m, 7H).

[0210] Example 12 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0211] Substituting (hexahydro-1H-pyrrolizin-7a-yl)methanol for (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the product was synthesized according to Steps HJ of Example 9 (3.3 mg, 0.01 mmol, 10% yield). LCMS: m / z 606.3 (M+H). 1 H NMR(400MHz, DMSO-d6)δ7.72(s,1H),7.07(dd,J=9.2,5.6Hz,1H),6.57–6.50( m,2H),6.42(d,J=2.6Hz,1H),4.08–4.01(m,4H),3.82–3.77(m,2H),2.88–2.7 7(m,4H),2.73–2.63(m,2H),2.42(dd,J=11.8,6.1Hz,2H),1.49(dt,J=11.4,5 .2Hz,2H),1.43–1.21(m,7H),1.11(dd,J=11.5,5.3Hz,1H),1.03–0.95(m,2H).

[0212] Example 13 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-5-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0213] Step A. (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: Substitute tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate for tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate and synthesize according to step B of Example 9. LCMS: m / z 474.1 (M+H).

[0214] Example 13 (4.75 mg, 7% yield) containing a formic acid salt was synthesized using tert-butyl (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as the starting material according to Steps C to J of Example 9. LCMS: m / z 625.2 (M+H). 1 H NMR (400MHz, Methanol-d4) δ8.54 (s, 1H), 7.88 (dd, J = 9.2, 5.7Hz, 1H), 7.39–7.36 (m, 1H ),7.33(d,J=9.0Hz,1H),7.26(d,J=2.6Hz,1H),5.46–5.28(m,1H),4.95(d,J=20.1Hz,2H ),4.44–4.38(m,1H),4.34(d,J=10.9Hz,1H),3.69–3.56(m,2H),3.52–3.44(m,1H),3.20 –3.02(m,3H),2.84(d,J=13.5Hz,2H),2.31(dd,J=24.2,14.7Hz,5H),2.24–1.91(m,7H).

[0215] Example 14 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carbonitrile

[0216] The reaction formula is as follows:

[0217] Step A. (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: Using (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester as starting material, the product was synthesized by CE according to the steps of Example 9. LCMS: m / z 818.4 (M+H).

[0218] Step B. tert-Butyl (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-((E)-(hydroxyimino)methyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: To (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-((E)-(hydroxyimino)methyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. To a solution of tert-butyl ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (20 mg, 0.024 mmol) in dimethyl sulfoxide (0.5 ml) was added triethylamine (5 mg, 0.049 mmol) and hydroxylamine hydrochloride (2 mg, 0.032 mmol), and the mixture was heated to 110°C and stirred for 1 hour. The reaction mixture was used in the next step without post-treatment.

[0219] Step C. tert-Butyl (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: To the reaction mixture from the previous step, acetic anhydride (4 mg, 0.037 mmol) and potassium carbonate (7 mg, 0.048 mmol) were added and heated to 55°C with stirring for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated to yield the crude product. The product was used in the next step without further purification.

[0220] Step D. (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: To (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3 To a solution of tert-butyl (20 mg, 0.024 mmol)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in dichloromethane (2 ml) was added meta-chloroperbenzoic acid (5 mg, 0.032 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with dichloromethane (50 ml) and aqueous sodium carbonate. The mixture was dried over Na2SO4, filtered, and concentrated to obtain a crude product that was used in the next step without purification.

[0221] Step E. (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: To (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate To a THF solution (1 ml) of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-ylmethanol (76 mg, 0.48 mmol) and (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-ylmethanol (76 mg, 0.48 mmol) was slowly added lithium bistrimethylsilylamide (0.072 mL, 0.072 mmol) under a nitrogen atmosphere at 0°C and stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated to obtain a crude product. It was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 2) to obtain a yellow solid (174 mg, 50% yield). LCMS: m / z 926.5 (M+H).

[0222] Step F. (1R,5S)-8-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: To (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate To a solution of tert-butyl ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (174 mg, 0.188 mmol) in DMF (2 ml) was added cesium fluoride (57 mg, 0.376 mmol), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated to obtain the crude product. It was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 2) to obtain a yellow solid (83 mg, 57% yield). LCMS: m / z 770.3 (M+H).

[0223] Step G. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carbonitrile: To (1R,5S)-8-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-carbonitrile To a solution of tert-butyl (3,8-diazabicyclo[3.2.1]octane-3-carboxylate (80 mg, 0.10 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid dropwise. The mixture was stirred at room temperature for 20 min. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO₃, DCM, and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification was performed by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). Lyophilization afforded Example 14 as a salt containing one formic acid (4.75 mg, 7% yield). LCMS: m / z 626.2 (M+H). 1H NMR (600MHz, DMSO-d6) δ10.28(s,1H),8.16(s,1H),8.03(dd,J=9.2,5.8Hz,1H),7.51(t,J=9.0Hz,1H),7.46(d,J=2.6Hz,1H) ,7.29(t,J=2.4Hz,1H),5.34(s,1H),5.25(s,1H),4.68(d,J=4.7Hz,2H),4.18(t,J=10.3Hz,1H),4.08(dd,J=10.4,7.8Hz,1H ),4.00(d,J=2.4Hz,1H),3.19(d,J=11.5Hz,2H),3.09(d,J=6.9Hz,2H),3.04(d,J=2.6Hz,1H),2.84(q,J=8.5,7.6Hz,1H),2. 76–2.69(m,2H),2.17(s,1H),2.13(d,J=3.2Hz,1H),2.09–1.98(m,4H),1.89–1.84(m,1H),1.79(dq,J=14.9,8.8,7.9Hz,3H).

[0224] Example 15 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carbonitrile

[0225] Starting from tert-butyl (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, the compound was synthesized according to Steps A to G of Example 14 to obtain Example 15, a salt containing two formic acids. LCMS: m / z 626.2 (M+H). 1H NMR (600MHz, DMSO-d6) δ8.36(s,2H),8.01(dd,J=9.2,5.8Hz,1H),7.50(t,J=9.0Hz,1H),7.45(d,J=2.6Hz ,1H),7.26(t,J=2.5Hz,1H),5.35–5.23(m,1H),4.18(t,J=10.8Hz,1H),4.07(dd,J=10.3,5.6Hz,1H),3.9 9(s,1H),3.56–3.46(m,2H),3.12–3.06(m,4H),3.03(s,1H),2.84(dd,J=9.7,6.3Hz,2H),2.13(d,J=3.9H z,1H),2.07(d,J=3.7Hz,1H),2.03–1.97(m,2H),1.88–1.83(m,1H),1.82–1.74(m,3H),1.62–1.55(m,3H).

[0226] Example 16 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-((1-(piperidin-1-yl)propan-2-yl)alcohol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0227] Using 1-(piperidin-1-yl)propan-2-ol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the compound was synthesized according to Steps H-J of Example 9 to obtain Example 16 as a salt containing two formic acids. LCMS: m / z 609.3 (M+H). 1 H NMR (600MHz, DMSO-d6) δ8.30(s,2H),7.99(dd,J=9.2,5.8Hz,1H),7.48(t,J=9.0Hz,1H),7.41( d,J=2.6Hz,1H),7.23(d,J=12.5Hz,1H),5.45–5.37(m,1H),4.76(s,1H),3.79(d,J=16.8Hz,2H ),3.50(s,1H),3.37(dd,J=10.9,5.2Hz,1H),3.29(dd,J=10.8,5.7Hz,1H),2.63–2.57(m,1H), 2.47–2.34(m,6H),1.60–1.53(m,2H),1.44–1.36(m,4H),1.36–1.28(m,6H),1.26–1.21(m,2H).

[0228] Example 17 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0229] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol, the synthesis was carried out according to Steps H-J of Example 9 to give Example 17 as a salt containing three formic acids. LCMS: m / z 599.2 (M+H). 1 H NMR(400MHz, DMSO-d6)δ8.40(s,3H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1 H),7.40(d,J=2.6Hz,1H),7.23(d,J=2.6Hz,1H),5.24–5.06(m,1H),4.76(s,1H),4.47 (dd,J=10.9,5.1Hz,1H),4.29–4.24(m,1H),3.80(s,1H),3.42–3.26(m,3H),3.22–3.1 0(m,3H),2.70–2.62(m,2H),2.47–2.30(m,6H),1.90–1.74(m,2H),1.59–1.49(m,2H).

[0230] Example 18 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0231] Using (1-(morpholinomethyl)cyclopropyl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 18 as a salt containing a formic acid. LCMS: m / z 637.3 (M+H). 1H NMR(400MHz, Methanol-d4)δ8.53(s,1H),7.89(dd,J=9.1,5.7Hz,1H),7.39–7.31(m,2H),7.24(d, J=2.6Hz,1H),4.65–4.55(m,1H),4.46(s,1H),4.40–4.27(m,1H),4.07–3.95(m,1H),3.92–3.76(d ,J=19.8Hz,3H),3.73–3.63(m,4H),3.55–3.48(m,1H),3.35(s,2H),2.59–2.50(m,3H),2.50–2.34 (m,3H),1.98(s,1H),1.92–1.82(s,2H),1.69(s,1H),0.74(t,J=5.5Hz,2H),0.55(t,J=5.6Hz,2H).

[0232] Example 19 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0233] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol, the compound was synthesized according to Steps H-J of Example 9 to afford Example 19 as a salt containing a formic acid. LCMS: m / z 599.2 (M+H). 1 H NMR (600MHz, DMSO-d6) δ8.22(s,1H),8.00(dd,J=9.2,5.9Hz,1H),7.49(t,J=9.0Hz,1H),7.41( d,J=2.5Hz,1H),7.23(s,1H),5.26–5.13(m,1H),4.78(s,1H),4.44(dt,J=9.8,4.5Hz,1H),4.3 2(dt,J=10.0,4.3Hz,1H),3.82(s,2H),3.60–3.48(m,5H),2.94(dq,J=10.7,5.4Hz,2H),2.45( dd,J=11.5,3.0Hz,1H),2.41(s,3H),2.19–2.09(m,2H),1.99–1.86(m,2H),1.64–1.52(m,2H).

[0234] Example 20 Preparation of 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0235] The reaction formula is as follows:

[0236] Step A: 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine: Dissolve 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (2.0 g, 7.5 mmol) in phosphorus oxychloride. Add DIEA (2.9 g, 22.6 mmol) under ice-cooling and stir at 100°C overnight. Concentrate in vacuo to afford the crude product (9.0 g). LCMS: m / z 265.9 (M+H).

[0237] Step B: 2,5,7-Trichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A solution of 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (5.0 g, 17.8 mmol) in toluene (50 mL) was added trifluoroethanol (4.0 g, 26.7 mmol) and sodium tert-butoxide (4.6 g, 35.6 mmol) and stirred at 0°C for 2 h. The reaction was monitored for completion by TLC and extracted with EtOAc and saturated aqueous ammonium chloride. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate in petroleum ether to afford the product (800 mg, 2.29 mmol, 30% yield). LCMS: m / z 350.1 (M+H).

[0238]

[0266] Step C: 5,7-Dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,5,7-trichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.3 g, 3.72 mmol) in 2-methyltetrahydrofuran (10.0 mL) was added N,N-diisopropylethylamine (961 mg, 7.45 mmol) and (hexahydro-1H-pyrrolizin-7a-yl)methanol (1.18 g, 7.45 mmol). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Purify by column chromatography eluting with 30-60% ethyl acetate / petroleum ether to give the product (760 mg, 1.61 mmol, 43% yield) LCMS: m / z 473.1 (M+H).

[0239] Step D: 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: Resuspend 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine in 1% ethanol. A mixture of (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (260 mg, 0.55 mmol), propyne (123 mg, 2.2 mmol), triethylamine (167 mg, 1.65 mmol) and bis(triphenylphosphine)bis(acetic acid)palladium(II) (41 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100 ° C. under a nitrogen atmosphere for 2 hours. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 40-70% ethyl acetate / petroleum ether to give the product (180 mg, 0.38 mmol, 69% yield). LCMS: m / z 477.1 (M+H).

[0240] Step E: tert-Butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, To a solution of (5H)-yl)methoxy)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (180 mg, 0.38 mmol) in N,N-dimethylformamide (4.0 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.57 mmol) and potassium carbonate (104 mg, 0.76 mmol). The mixture was stirred at 0°C for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel, and purified by column chromatography eluting with 0-30% MeOH / DCM to give the product (130 mg, 0.22 mmol, 60% yield), LCMS: m / z 589.1 (M+H).

[0241] Step F: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Resuspend (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl) A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.20 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (126 mg, 0.24 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (15 mg, 0.02 mmol), and potassium phosphate (130 mg, 0.61 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-10% MeOH / DCM to give the product (100 mg, 0.11 mmol, 52% yield), LCMS: m / z 470.8 (M / 2+H).

[0242] Step G: tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl)-1-yl)-1-(1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0368] Tert-butyl 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.11 mmol) and cesium fluoride (65 mg, 0.43 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 1 h under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-10% MeOH / DCM to give the product (70 mg, 0.09 mmol, 84% yield), LCMS: m / z 783.3 (M+H).

[0243] Step H: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol: 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene To a solution of tert-butyl)-1-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) dropwise. The mixture was stirred at room temperature for 40 min. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO₃ (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2×15 mL), and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). Lyophilization afforded Example 20 as a salt containing 0.5 formic acid (18.0 mg, 0.028 mmol, 31% yield). LCMS: m / z 639.3 (M+H). 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 0.5H), 7.89 (dd, J = 9.2, 5.7 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.24–7.21 (m, 1H), 5.54–5.35 (m, 1H), 4.47– (m, 3H), 3.86 (d, J=11.8Hz,2H),3.59–3.45(m,3H),3.28–3.17(m,1H),2.55–2.32(m,2H),2.31–2.24(m,1H) ),2.22(s,3H),2.19–2.11(m,2H),2.09–1.98(m,2H),1.91(br.s,3H),1.38–1.30(m,4H).

[0244] Example 21 Preparation of 4-(5-(3-aminopropynyl)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0245] The reaction formula is as follows:

[0246] Step A. tert-Butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-5-yl)propynyl)carbamate: Resuspend 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-5-yl)propynyl)carbamate in 1% ethyl acetate. A mixture of (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 0.42 mmol), N-(tert-butoxycarbonyl)propargylamine (263 mg, 1.7 mmol), triethylamine (128 mg, 1.27 mmol) and bis(triphenylphosphine)bis(acetic acid)palladium(II) (31 mg, 0.042 mmol) in 1,4-dioxane (4 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 40-70% ethyl acetate in petroleum ether to give the product (150 mg, 0.25 mmol, 60% yield), LCMS: m / z 592.1 (M+H).

[0247] Step B. tert-Butyl (1R,5S)-3-(5-(3-(tert-butylcarbamate)propynyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate: To tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate was added. To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (64 mg, 0.30 mmol) and potassium carbonate (56 mg, 0.41 mmol) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (64 mg, 0.30 mmol) and potassium carbonate (56 mg, 0.41 mmol). The mixture was stirred at 0°C for 2 hours. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-30% MeOH / DCM to give the product (80 mg, 0.11 mmol, 57% yield), LCMS: m / z 704.1 (M+H).

[0248] Step C. tert-Butyl 3-(5-(tert-butylcarbamate)propynyl)-8-fluoro-7-chloro-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Resuspend (1R,5S)-3-(5-(tert-butylcarbamate)propynyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) A solution of tert-butyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (76 mg, 0.15 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (7 mg, 0.009 mmol) and potassium phosphate (63 mg, 0.29 mmol) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was stirred at 65 ° C for 2 h under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-10% MeOH / DCM to give the product (60 mg, 0.057 mmol, 58% yield), LCMS: m / z 527.8 (M / 2+H).

[0249] Step D. tert-Butyl 3-(5-(3-(tert-butylcarbamate)propynyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Resuspend 3-(5-(3-(tert-butylcarbamate)propynyl)-8-fluoro-7-chloro-(7 Tert-butyl 2-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.057 mmol) and cesium fluoride (43 mg, 0.28 mmol) were dissolved in DMF (4 mL) and stirred at room temperature under nitrogen for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-10% MeOH / DCM to give the product (30 mg, 0.033 mmol, 59% yield) LCMS: m / z 449.8 (M / 2+H).

[0250] Step E. 4-(5-(3-aminopropynyl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Resuspend 3-(5-(3-(tert-butylcarbamate)propynyl)-7-(8-ethynyl- To a solution of tert-butyl (7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.022 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) dropwise. The mixture was stirred at room temperature for 40 min. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO₃ (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL), and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min) and lyophilized to afford Example 21 as a formic acid salt (2.0 mg, 0.003 mmol, 14% yield). LCMS: m / z 654.3 (M+H).

[0251] Example 22 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2-ol

[0252] Replacing ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane with ((6-(methoxymethyl ether)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane, the synthesis of Example 22 was performed according to Steps FH of Example 20, which is a salt containing a formic acid (1.6 mg, 0.0026 mmol, 10% yield).

[0253] LCMS: m / z 621.2 (M+H).

[0254] 1H NMR (400MHz, Methanol-d4) δ8.51(s,1H),7.84(dd,J=8.4,1.3Hz,1H),7.54(dd,J=7.2,1.3Hz,1H),7.4 2(dd,J=8.3,7.1Hz,1H),7.35(d,J=2.6Hz,1H),7.18(t,J=2.0Hz,1H),5.52–5.34(m,1H),4.45(q,J=11. 7,11.1Hz,3H),4.04–3.78(m,4H),3.56–3.44(m,3H),3.23(q,J=7.3Hz,2H),3.01(d,J=4.5Hz,1H),2.45 –2.34(m,2H),2.30–2.22(m,1H),2.21(s,3H),2.19–2.10(m,2H),2.08–1.95(m,2H),1.95–1.82(m,3H).

[0255] Example 23 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0256] Example 23 was synthesized according to Steps FH of Example 20, using ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane instead of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. The resulting product was a formic acid salt (18 mg, 0.029 mmol). LCMS: m / z 621.2 (M+H). 1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),8.17–8.12(m,2H),7.71–7.64(m,2H),7.4 7(t,J=9.0Hz,1H),5.50–5.33(m,1H),4.49–4.38(m,3H),4.04–3.78(m,4H),3.60–3 .43(m,3H),3.42(dd,J=4.2,1.0Hz,1H),3.23–3.14(m,1H),2.56–2.33(m,2H),2.32 –2.23(m,2H),2.22(s,3H),2.19–2.08(m,2H),2.06–1.96(m,1H),1.92–1.64(m,4H).

[0257] Example 24 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0258] Example 24 was synthesized according to Steps F and H of Example 20, using 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane instead of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. The salt containing two formic acids (14 mg, 0.023 mmol) was synthesized. LCMS: m / z 617.2 (M+H).

[0259] 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 2H), 8.23–8.19 (m, 1H), 8.02 (ddd, J=9.2, 5.1, 1.6Hz, 1H),7.78–7.69(m,3H),5.36–5.19(m,1H),4.14(d,J=10.3Hz,2H),4.04(d,J=10.3Hz, 2H),3.55(br.s,2H),3.13–3.04(m,3H),3.02–2.98(m,1H),2.87–2.77(m,1H),2.17(s ,3H),2.13(d,J=5.1Hz,1H),2.09–1.95(m,3H),1.88–1.71(m,4H),1.64–1.55(m,3H).

[0260] Example 25 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzothiazol-2-amine

[0261] The reaction formula is as follows:

[0262] Step A. (1R,5S)-3-(7-(2-((tert-Butyl formate)amino)-7-fluorobenzothiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Compound (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was prepared by mixing the following mixture: A solution of tert-butyl (5H)-(((tert-butyloxycarbonyl)amino)-7-fluorobenzo[D]thiazol-4-yl)boronic acid (424 mg, 1.36 mmol), tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol), and sodium carbonate (54 mg, 0.51 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-10% MeOH / DCM to give the product (140 mg, 0.17 mmol, 99% yield), LCMS: m / z 411.2 (M / 2+H).

[0263] Step B. 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)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzothiazol-2-amine: 1R,5S)-3-(7-(2-((tert-butyl formate)amino)-7- To a solution of tert-butyl (2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.061 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) dropwise. The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was poured into a mixture of saturated NaHCO₃ (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2×15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min) and lyophilized to afford Example 25 as a salt containing two formic acids (15 mg, 0.024 mmol). LCMS: m / z 621.2 (M+H).

[0264] 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 2H), 7.96 (s, 2H), 7.46 (dd, J = 8.5, 5.8Hz, 1H), 7.07 (t,J=8.8Hz,1H),5.37–5.18(m,1H),4.13(d,J=10.4Hz,2H),4.04(d,J=10.4Hz,2H) ,3.50(br,s,2H),3.12–3.04(m,3H),3.03–2.98(m,1H),2.86–2.78(m,1H),2.18(s, 3H), 2.12 (d, J = 3.7Hz, 1H), 2.06–1.94 (m, 3H), 1.87–1.71 (m, 4H), 1.59–1.53 (s, 3H).

[0265] Example 26 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0266] The reaction formula is as follows:

[0267] Step A. 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (5.0 g, 17.9 mmol) in DMF was added N,N-diisopropylethylamine (6.9 g, 53.6 mmol) and trifluoroethyl trifluoromethanesulfonate (6.2 g, 26.9 mmol). The mixture was stirred at room temperature for 5 hours. The residue was partitioned between EtOAc and saturated aqueous ammonium chloride, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-20% ethyl acetate in petroleum ether to give the product (2 g, 5.54 mmol, 31% yield) LCMS: m / z 362.1 (M+H).

[0268] Step B.5-(3-((tert-Butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A mixture of 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.2 g, 3.32 mmol), tert-butyldimethyl(2-propynyloxy)silane (1.7 g, 9.97 mmol), triethylamine (1.0 g, 9.97 mmol) and bis(triphenylphosphine)bis(acetic acid)palladium(II) (249 mg, 0.33 mmol) in 1,4-dioxane (7 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 90 °C under nitrogen atmosphere for 2 hours. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-15% ethyl acetate in petroleum ether to give the product (700 mg, 1.41 mmol, 43% yield), LCMS: m / z 496.2 (M+H).

[0269] Step C. tert-Butyl (1R,5S)-3-(5-(3-((tert-Butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 5-(3-((tert-Butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (700 mg, 1.41 mmol) in N,N-dimethylformamide (9.0 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 2.21 mmol) and potassium carbonate (390 mg, 2.83 mmol). The mixture was stirred for 1 hour at 0° C. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 , and the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-20% ethyl acetate in petroleum ether to give the product (560 mg, 0.92 mmol, 65% yield).

[0270] Step D. Tert-butyl (1R,5S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate: Resuspend (1R,5S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate in 1% ethyl acetate. A solution of tert-butyl bicyclo[3.2.1]octan-8-carboxylate (320 mg, 0.53 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (540 mg, 1.05 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (38 mg, 0.053 mmol), and potassium phosphate (335 mg, 1.58 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 20-60% ethyl acetate in petroleum ether to give the product (200 mg, 0.21 mmol, 40% yield).

[0271] Step E. tert-Butyl 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate: To (1R,5S)-3-(5-(3-( To a solution of tert-butyl ((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (200.0 mg, 0.21 mmol) in DCM (10 mL) was added meta-chloroperbenzoic acid (43.0 mg, 0.25 mmol) and stirred at 0°C for 1 h. The mixture was quenched by the addition of aqueous sodium thiosulfate, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic phase was washed with saturated NaCl, dried over Na2SO4, and concentrated to give the crude product, which was used directly in the next step. The crude product (200.0 mg, 0.21 mmol) and (hexahydro-1H-pyrrolidine-7a-yl)methanol (50.0 mg, 0.32 mmol) were dissolved in THF (5 mL). LiHMDS (0.63 ml, 0.63 mmol) was added dropwise at 0°C under a nitrogen atmosphere and stirred for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc (2x). The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel, and purified by column chromatography using 0-10% MeOH / DCM as the eluent to give the product (100.0 mg, 0.09 mmol, 45% yield). LCMS: m / z 535.5 (M / 2+H)

[0272] Step F. tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Resuspend 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Tert-butyl pyrrolizin-7a(5H)-yl)methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (100 mg, 0.09 mmol) and cesium fluoride (70 mg, 0.46 mmol) were dissolved in DMF (5 mL) and stirred at room temperature under nitrogen for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over NaSO. The combined organic phases were filtered, dried, loaded onto silica gel, and purified by column chromatography eluting with 0-10% MeOH / DCM to give the product (55 mg, 0.069 mmol, 76% yield). LCMS: m / z 799.3 (M+H).

[0273] Step G. 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)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: To 3-(7-(8-ethynyl-7-fluoro-3-(methoxy)-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol To a solution of tert-butyl (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (25 mg, 0.03 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) dropwise. The mixture was stirred at room temperature for 40 min. After concentration, the residue was poured into a mixture of saturated NaHCO₃ (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL), and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min) and lyophilized to afford Example 26 as a formic acid salt (6.0 mg, 0.009 mmol). LCMS: m / z 655.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ10.20(br.s,1H),8.18(s,1H),8.00(dd,J=9.2,5.9Hz,1H),7.48(t,J=9.0Hz,1H),7.41(d,J= 2.6Hz,1H),7.21(t,J=2.2Hz,1H),5.53(br.s,1H),5.37–5.20(m,1H),4.40(s,2H),4.15(dd,J=10.4,4.6Hz,1H),4.0 4(dd,J=10.3,2.6Hz,1H),3.83(s,1H),3.72(br.s,3H),3.17–3.05(m,3H),3.05–2.97(m,2H),2.87–2.80(m,1H),2.1 3(d,J=3.6Hz,1H),2.05(d,J=3.9Hz,1H),2.03–1.96(m,1H),1.89–1.72(m,4H),1.71–1.58(m,3H),1.56–1.41(m,1H).

[0274] Example 27 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-5-ethynyl-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0275] Starting from tert-butyl (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and substituting (hexahydro-1H-pyrrolin-7a-yl)methanol for (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-7-ylmethanol, the product was synthesized according to Steps H-J of Example 9 to give the salt containing two formic acids (4.72 mg, 0.007 mmol). LCMS: m / z 607.6 (M+H). 1 H NMR (600MHz, DMSO-d6) δ8.28(s,2H),7.99(dd,J=9.2,5.9Hz,1H),7.48(t,J=8.9Hz,1H),7.41(d,J=2.5Hz,1H),7.25(d,J=2.5Hz,1H),4.88(s, 1H),4.76–4.69(m,2H),4.10–4.04(m,2H),3.87(d,J=6.4Hz,1H),2.98 –2.93(m,2H),2.67–2.60(m,2H),2.60–2.54(m,2H),2.06–1.98(m,3H), 1.93–1.87(m,3H),1.86–1.73(m,5H),1.62–1.56(m,3H).

[0276] Example 28 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1-(piperidin-1-methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0277] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with (1-(piperidin-1-methyl)cyclopropyl)methanol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 28 as a salt containing 0.5 formic acid (1.51 mg, 0.002 mmol). LCMS: m / z 635.6 (M+H). 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.14(s,0.5H),8.01(dd,J=9.2,5.9H z,1H),7.50(t,J=9.0Hz,1H),7.43(d,J=2.5Hz,1H),7.22(d,J=2.5Hz,1H),4 .99–4.75(m,2H),4.63–4.43(m,2H),4.42–4.25(m,3H),4.23–3.75(m,7H),2 .82–2.62(m,2H),1.90–1.32(m,10H),0.82–0.69(m,2H),0.66–0.49(m,2H).

[0278] Example 29 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-(4,4-difluoropiperidin-1-yl)propan-2-yl)ol)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0279] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with (S)-1-(4,4-difluoropiperidin-1-yl)propan-2-ol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 29 as a formic acid salt (16.72 mg, 0.024 mmol). LCMS: m / z 645.6 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 8.00 (dd, J=9.2, 5.9Hz, 1H), 7.49 (t, J= 9.0Hz,1H),7.41(d,J=2.5Hz,1H),7.23(dd,J=8.9,2.5Hz,1H),5.47–5.38(m ,1H),4.78(s,1H),3.83(br.s,1H),3.76(s,1H),3.62–3.45(m,3H),2.75–2. 53(m,8H),1.92–1.77(m,5H),1.63–1.53(m,3H),1.32(dd,J=6.3,4.4Hz,3H).

[0280] Example 30 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-(((S)-1-(pyrrolidin-1-yl)propan-2-yl)alcohol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0281] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with ((S)-1-(pyrrolidin-1-yl)propan-2-ol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 30 as a formic acid salt (9.09 mg, 0.014 mmol). LCMS: m / z 595.6 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),8.00(dd,J=9.2,5.9Hz,1H),7.49(t,J=9.0Hz,1H),7.41(d,J=2.6Hz,1H),7.23(d,J=2.4Hz,1H),5.41–5.33(m, 1H),4.78(s,1H),3.82(d,J=7.9Hz,1H),3.57(br.s,4H),2.76(dd,J=12.5 ,6.9Hz,1H),2.69–2.52(m,7H),1.69–1.43(m,8H),1.33(t,J=6.0Hz,3H).

[0282] Example 31 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-(((S)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-yl)alcohol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0283] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with (S)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-ol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 31 as a formic acid salt (3.1 mg, 0.005 mmol). LCMS: m / z 613.6 (M+H). 1H NMR(400MHz, Methanol-d4)δ8.53(s,1H),7.89(dd,J=9.2,5.7Hz,1H),7.41–7.31( m,2H),7.24(t,J=3.2Hz,1H),5.60(s,1H),5.26–5.08(m,2H),4.62(s,1H),4.31(s, 1H),4.10–3.80(m,4H),3.17–3.12(m,1H),3.06–2.94(m,2H),2.92–2.75(m,2H),2. 73–2.61(m,2H),2.26–2.08(m,2H),1.96–1.68(m,4H),1.45(dd,J=6.2,4.1Hz,3H).

[0284] Example 32 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0285] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with 1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methanol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 32 as a formic acid salt (5.15 mg, 0.007 mmol). LCMS: m / z 650.6 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.99(t,J=7.5Hz,1H),7.48(t,J=9.0Hz ,1H),7.41(br.s,1H),7.22(s,1H),4.76(s,1H),4.34–4.24(m,2H),3.80(s, 2H),3.52–3.49(m,6H),2.45–2.22(m,8H),2.13(s,3H),2.08–2.05(m,1H),1 .61(br.s,3H),1.23(br.s,1H),0.63(t,J=5.1Hz,2H),0.41(t,J=5.1Hz,2H).

[0286] Example 33 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0287] Substituting (S)-(1-isopropylpyrrolidin-2-yl)methanol for (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the product was synthesized according to Steps H-J of Example 9 to obtain Example 33 as a formic acid salt (5.97 mg, 0.009 mmol). LCMS: m / z 609.6 (M+H). 1 H NMR(400MHz, Methanol-d4)δ8.55(s,1H),7.90(dd,J=9.2,5.7Hz,1H),7.40–7.32(m ,2H),7.25(t,J=2.8Hz,1H),4.69–4.59(m,2H),4.33(s,1H),4.00–3.79(m,3H),3.72 –3.58(m,3H),3.45–3.35(m,2H),3.23–3.13(m,2H),2.28–2.17(m,2H),2.05(br.s,3 H),1.82(br.s,3H),1.65–1.50(m,1H),1.38(d,J=6.6Hz,3H),1.33(d,J=6.5Hz,3H).

[0288] Example 34 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-5-ethynyl-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0289] Using (S)-(1-ethylpyrrolidin-2-yl)methanol in place of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 34 as a salt containing a formic acid (3.72 mg, 23% yield). LCMS: m / z 595.6 (M+H). 1H NMR(400MHz, Methanol-d4)δ8.52(s,1H),7.90(dd,J=9.2,5.7Hz,1H),7.40–7.33(m ,2H),7.25(t,J=2.8Hz,1H),4.80–4.72(m,1H),4.70–4.58(m,2H),4.35(s,1H),4.09 –3.84(m,2H),3.77(br.s,3H),3.66–3.47(m,3H),3.14–3.02(m,2H),2.39–2.27(m, 1H), 2.17–1.95 (m, 4H), 1.92–1.72 (m, 3H), 1.69–1.57 (m, 1H), 1.36 (t, J = 7.2Hz, 3H).

[0290] Example 35 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-((1-(((S)-2-methylmorpholinyl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0291] Replacing (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol with (S)-(1-((2-methylmorpholinyl)methyl)cyclopropyl)methanol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 35 as a formic acid salt (3.09 mg, 0.004 mmol). LCMS: m / z 651.6 (M+H). 1 H NMR(600MHz, Methanol-d4)δ8.48(s,1H),7.89(dd,J=9.1,5.6Hz,1H),7.39–7.33(m,2H),7.24(s,1H),4.6 7–4.57(m,1H),4.47(s,2H),4.32(s,1H),4.10–3.89(m,4H),3.82(d,J=11.2Hz,1H),3.64–3.54(m,2H),3. 38(d,J=2.7Hz,1H),3.01–2.93(m,2H),2.55(d,J=12.6Hz,1H),2.47–2.41(m,1H),2.14(t,J=11.5Hz,1H), 2.00–1.88(m,3H),1.88–1.73(m,3H),1.12(dd,J=6.3,3.5Hz,3H),0.76(br.s,2H),0.56(d,J=4.7Hz,2H).

[0292] Example 36 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-(((R)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-yl)alcohol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0293] Using (R)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-ol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol, the synthesis was carried out according to Steps H-J of Example 9 to obtain Example 36 as a salt containing two formic acids (2.46 mg, 5% yield). LCMS: m / z 613.6 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.44 (s, 2H), 7.89 (dd, J = 9.1, 5.6Hz, 1H), 7.39–7 .34(m,2H),7.24(t,J=2.5Hz,1H),5.62(s,1H),5.26–5.13(m,1H),4.49(br.s ,1H),4.33(s,1H),4.14–3.95(m,4H),3.19–3.10(m,2H),3.07–2.87(m,3H),2 .74–2.66(m,1H),2.26–2.12(m,2H),2.08–1.82(m,6H),1.46(d,J=5.8Hz,3H).

[0294] Example 37 Preparation of 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-1-naphthamide

[0295] The reaction formula is as follows:

[0296] Step A. (1R,5S)-3-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (500 mg, The following mixture was prepared: 1,4-dimethyl-1,3,2-dioxaborolan-2-yl (380 mg, 1.361 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthocarbonitrile (380 mg, 1.361 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (66 mg, 0.091 mmol), and potassium phosphate (385 mg, 1.815 mmol) in a THF / H2O = 4 / 1 solution, heated to 65°C under nitrogen and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and extracted with water (200 ml x 3). The organic phase was washed with saturated NaCl, dried over Na2SO4, and concentrated by rotary evaporation to obtain a residue. The residue was then purified by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to obtain the product (370 mg, 59% yield) as a yellow solid. LCMS: m / z 571.6 (M+H).

[0297] Step B. Tert-butyl (1R,5S)-3-(7-(8-aminoformylnaphthalen-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,5S)-3-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.035 mmol) in concentrated sulfuric acid was heated to 95°C and stirred for 2 hours. The reaction mixture was quenched with 10 M sodium hydroxide solution in an ice bath and extracted with a mixture of dichloromethane / methanol = 10 / 1 (100 ml x 3), dried over Na2SO4, and concentrated by rotary evaporation to obtain a crude product which was used in the next step without further treatment.

[0298] Step C. (1R,5S)-3-(7-(8-carbamoylnaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylic acid tert-butyl ester: To (1R,5S)-3-(7-( To a solution of tert-butyl (8-aminoformylnaphthyl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (20 mg, 0.034 mmol) in dichloromethane (2 ml) was added meta-chloroperbenzoic acid (11 mg, 0.051 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with dichloromethane (50 ml) and aqueous sodium carbonate solution, dried over Na2SO4, and concentrated by rotary evaporation to obtain the crude product, which was used in the next step without purification. To a THF solution (1 ml) of the crude product (0.034 mmol), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (0.068 mmol), lithium bistrimethylsilylamide (0.102 mmol, 3 equivalents) was slowly added at 0°C under a nitrogen atmosphere and stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate (100 ml) and extracted with water (200 ml x 3), dried over Na2SO4, and concentrated by rotary evaporation to obtain a residue. The residue was then purified by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to obtain the product (15 mg, 65% yield) as a yellow solid. LCMS: m / z 699.8 (M+H).

[0299] Step D. 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-1-naphthamide: (1R,5S)-3-(7-(8-carbamoylnaphthalene-1- To a solution of tert-butyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate (10 mg, 0.014 mmol) in dichloromethane (2 mL) was added dropwise a 4 M solution of hydrochloric acid in dioxane. The mixture was stirred at room temperature for 40 min. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO₃ (20 mL) and DCM / MeOH = 10 / 1 (15 mL). The aqueous layer was extracted with DCM / MeOH = 10 / 1 (2×15 mL), and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-20% MeOH / CH2Cl, 2% NH4OH, followed by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min). Concentration and lyophilization afforded Example 37 as a formic acid salt (1 mg, 0.002 mmol). LCMS: m / z 600.6 (M+H).

[0300] 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.13–8.07(m,2H),7.69(br.s,1H),7.67–7.61(m,2H),7.6 1–7.58(m,1H),7.56(d,J=7.2Hz,1H),6.68(br.s,1H),5.38–5.22(m,1H),4.18–4.08(m,2H),4.0 8–3.99(m,2H),3.15–3.08(m,4H),3.06–3.01(m,2H),2.88–2.80(m,2H),2.47(br.s,3H),2.14( d,J=4.2Hz,1H),2.06(d,J=4.2Hz,1H),2.04–1.97(m,2H),1.89–1.74(m,4H),1.58–1.49(m,2H).

[0301] Example 38 Preparation of 4-(4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrinazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0302] The reaction formula is as follows:

[0303] Step A. 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in 1,4-dioxane (20 mL) were added bis(triphenylphosphine)palladium acetate (374.5 mg, 0.5 mmol), triethylamine (1.6 g, 16.5 mmol) and propyne (1 M) (8.2 mL, 8.2 mmol) and stirred at 105 ° C for 1 h under nitrogen environment. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give the product (2 g, 4.3 mmol, 99% yield), LCMS: m / z 366.0 (M+H).

[0304] Step B. tert-Butyl 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in DMF (8 mL) were added potassium carbonate (2.2 g, 16.5 mmol) and 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (1.6 g, 8.2 mmol) and stirred at room temperature for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give the product (2.0 g, 4.4 mmol, 25% yield), LCMS: m / z 464.1 (M+H).

[0305] Step C. tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: tert-Butyl 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (2.0 g) was added. A solution of (4.4 mmol, 4.4 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.9 g, 5.7 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (320.0 mg, 0.44 mmol), and potassium phosphate (2.8 g, 13.2 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give compound 11 (1.5 g, 1.8 mmol, 42% yield).

[0306] Step D. tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrinazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: To tert-butyl 3-(8-fluoro-7-(7 To a solution of tert-butyl (2-(((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 0.2 mmol) in DCM (10 mL) was added meta-chloroperbenzoic acid (51.6 mg, 0.3 mmol), and the mixture was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to quench the mixture, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic phase was washed with saturated NaCl, dried over NaSO, and concentrated to yield the crude product (200 mg), which was used directly in the next step. LCMS: m / z 830.4 (M+H).

[0307] To a solution of the crude product (200 mg, 0.2 mmol) and (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl)methanol (47.0 mg, 0.3 mmol) in THF (3 mL) was added dropwise LiHMDS (0.4 ml, 0.4 mmol) under nitrogen at 0° C., and the mixture was stirred for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na 2 SO 4 . The combined organic phases were filtered, dry-loaded onto silica gel, and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (100.0 mg, 0.1 mmol, 45% yield). LCMS: m / z 925.5 (M+H).

[0308] Step E. tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrinazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(( A solution of tert-butyl (1,2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrinazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (100.0 mg, 0.1 mmol) and cesium fluoride (60.0 mg, 0.4 mmol) in DMF (3 mL) was stirred at room temperature under nitrogen for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (80 mg, 0.1 mmol, 96% yield), LCMS: m / z 769.3 (M+H).

[0309] Step F. 4-(4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrinazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol: To 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene To a solution of tert-butyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrinazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (80.0 mg, 0.1 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) dropwise. The mixture was stirred at room temperature for 20 min. The mixture was concentrated and the residue was poured into a mixture of saturated NaHCO (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2×15 mL), and the combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated in vacuo. The product was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min) and lyophilized to afford Example 38 as a formic acid salt (7.32 mg, 0.01 mmol). LCMS: m / z 625.2 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.53 (s, 1H), 7.89 (dd, J = 9.1, 5.6Hz, 1H), 7.38 (d,J=2.5Hz,1H),7.35(t,J=8.9Hz,1H),7.25(t,J=2.6Hz,1H),5.46–5.3 3(m,1H),5.05–4.96(m,1H),4.58–4.36(m,4H),4.16(br.s,3H),3.50(s, 1H),3.46–3.36(m,2H),3.16(br.s,1H),2.94(br.s,1H),2.48–2.28(m,3 H), 2.22 (br.s, 1H), 2.20 (s, 3H), 2.11 (br.s, 2H), 1.96 (t, J = 13.4Hz, 2H).

[0310] Example 39 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(cyclopropaneethynyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0311] The reaction formula is as follows:

[0312] Step H.7-Chloro-5-(cyclopropaneethynyl)-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A solution of 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in 1,4-dioxane (20 mL) was added with bis(triphenylphosphine)palladium acetate (374.5 mg, 0.5 mmol), triethylamine (1.6 g, 16.5 mmol) and cyclopropaneethynyl (561.0 mg, 8.2 mmol) and stirred at 105 °C under nitrogen for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give the product (2 g, 5.1 mmol, 90% yield), LCMS: m / z 392.0 (M+H).

[0313] Example 39 (20.2 mg, 0.03 mmol) containing a formic acid salt was synthesized using 7-chloro-5-(cyclopropaneethynyl)-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine according to Steps C to G of Example 26. LCMS: m / z 665.4 (M+H). 1H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.99(dd,J=9.2,5.9Hz,1H),7.48(t,J=9.0Hz,1H),7.40(d,J=2.5Hz,1H),7.20(s ,1H),5.35–5.22(m,1H),4.13(dd,J=10.3,5.6Hz,1H),4.02(dd,J=10.3,3.9Hz,1H),3.78(s,1H),3.60–3.50(m,5H),3. 12–3.04(m,3H),3.03(d,J=2.4Hz,1H),2.86–2.80(m,2H),2.11(d,J=3.8Hz,1H),2.06(d,J=3.9Hz,1H),2.02–1.97(m, 1H),1.88–1.83(m,1H),1.82–1.72(m,3H),1.71–1.64(m,1H),1.61–1.54(m,2H),1.01–0.97(m,2H),0.85–0.81(m,2H).

[0314] Example 40 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0315] The reaction formula is as follows:

[0316] Step A. (1R,5S)-tert-Butyl 8-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120 mg, 0.355 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (113 mg, 0.533 mmol), and potassium carbonate (98 mg, 0.71 mmol) in N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted with water, and the organic phase was washed with saturated NaCl, dried over Na SO and concentrated by rotary evaporation to give residue. The residue was then purified by column chromatography (SiO , petroleum ether / ethyl acetate=6 / 1) to give the product (80 mg, 51% yield) as a yellow solid.

[0317] LCMS: m / z 478.4 (M+H).

[0318] Example 40 was synthesized using tert-butyl (1R,5S)-8-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylate as starting material according to the synthetic method of Steps C to F of Example 38 as a salt containing a formic acid (12.18 mg, 0.018 mmol). LCMS: m / z 639.7 (M+H). 1 H NMR(400MHz, Methanol-d4)δ8.52(s,1H),7.89(dd,J=9.1,5.6Hz,1H),7.38(d,J =2.3Hz,1H),7.34(d,J=9.0Hz,1H),7.24(t,J=2.3Hz,1H),5.53–5.36(m,1H),5. 10–4.95(m,3H),4.56–4.40(m,2H),3.70–3.48(m,4H),3.28–3.11(m,2H),2.95( br.s,2H),2.60–2.25(m,5H),2.22(s,3H),2.20–2.11(m,3H),2.10–1.95(m,2H).

[0319] Example 41 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0320] The reaction formula is as follows:

[0321] Step A. Tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120 mg, 0.355 mmol), tert-butyl (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (113 mg, 0.533 mmol), and potassium carbonate (98 mg, 0.71 mmol) in N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic phase was washed with saturated NaCl, dried over NaSO, and concentrated by rotary evaporation to obtain a residue. The residue was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 6 / 1) to obtain the product (80 mg, 51% yield) as a yellow solid. LCMS: m / z 478.4 (M+H).

[0322] Step B. 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol: (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylic acid tert-butyl ester (2.0 g, A solution of (4.2 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.9 g, 5.7 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (320.0 mg, 0.44 mmol), and potassium phosphate (2.8 g, 13.2 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was stirred at 65°C for 2 h under a nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4, the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH / DCM to give the product (1.7 g, 2.49 mmol, 60% yield).

[0323] Example 41 (a formic acid salt) (16.2 mg, 0.023 mmol) was prepared using 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol as the starting material and (1-(morpholinomethyl)cyclopropyl)methanol in place of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-ylmethanol according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 651.3 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.99(dd,J=9.2,5.9Hz,1H),7.48(t,J=9.0Hz,1H),7.40(d,J=2.6Hz,1H),7.21(d,J=2.5Hz,1H),4.30(dd,J=16. 0,10.9Hz,2H),3.81–3.77(br.s,3H),3.56–3.50(m,7H),2.40–2.35(m,4H) ,2.33–2.23(m,3H),2.16(s,3H),1.70–1.36(m,4H),0.63(t,J=5.1Hz,2H), 0.42(t,J=5.2Hz,2H).

[0324] Example 42 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0325] Starting from 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and substituting tert-butyl (1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-carboxylate for 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, the salt of Example 42 containing one formic acid (6.7 mg, 0.01 mmol) was prepared according to the synthetic method of Steps B to F of Example 38.

[0326] LCMS: m / z 653.3 (M+H). 1H NMR(400MHz, Methanol-d4)δ8.49(s,1H),7.88(dd,J=9.1,5.7Hz,1H),7.38–7.31( m,2H),7.22(d,J=10.9Hz,1H),5.51–5.34(m,1H),4.54–4.38(m,3H),3.88–3.76(m ,2H),3.70–3.43(m,5H),3.29–3.17(m,2H),2.46–2.35(m,2H),2.32–2.24(m,2H), 2.20(s,3H),2.18–2.11(m,2H),2.07–1.94(m,2H),1.64–1.53(m,2H),1.42(s,3H).

[0327] Example 43 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0328] Starting from 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and replacing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane with 1-tert-butoxycarbonylpiperazine, Example 43 was prepared according to the synthetic method of Steps B to F of Example 38 as a formic acid salt (4.76 mg, 0.007 mmol). LCMS: m / z 613.3 (M+H). 1 H NMR(400MHz, Methanol-d4)δ8.49(s,1H),7.88(dd,J=9.2,5.7Hz,1H),7.40–7.29(m,2H),7.24(s,1H),5.50–5.33(m,1H),4. 50–4.36(m,3H),4.08–3.93(m,4H),3.58–3.35(m,4H),3.12–3.00(m,4H),2.40–2.33(m,2H),2.23(s,3H),2.17–1.97(m,4H).

[0329] Example 44 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0330] The reaction formula is as follows:

[0331] Step A. Ethyl 6-chloro-4-((4-methoxybenzyl)amino)-2-methylnicotinate: To a solution of ethyl 4,6-dichloro-2-methylnicotinate (10.0 g, 42.7 mmol) in DMSO (50 mL) was added PMBNH (10.5 g, 76.9 mmol) and DIEA (16.5 g, 128.2 mmol) and stirred at 50° C. for 12 h. The residue was partitioned between DCM and water, and the aqueous layer was extracted with DCM. The organic phase was washed with saturated NaCl and dried over NaSO. The combined organic phases were filtered, dried, loaded onto silica gel, and purified by column chromatography eluting with 0-10% EtOAc / petroleum ether to afford the product (9.6 g, 28.7 mmol, 67% yield). LCMS: m / z 335.1 (M+H).

[0332] Step B. 4-Amino-6-chloro-2-methylnicotinic acid ethyl ester: To 6-chloro-4-((4-methoxybenzyl)amino)-2-methylnicotinic acid ethyl ester (9.6 g, 28.7 mmol) was added TFA (100 mL), and the mixture was stirred at 65°C for 12 h. The mixture was concentrated, adjusted to pH 8-9 with saturated NaHCO3 solution, and filtered to collect the filter cake to give the product (5.6 g, 26.4 mmol, 92% yield). LCMS: m / z 215.2 (M+H).

[0333] Step C. 4-amino-6-chloro-2-methylnicotinic acid: To a solution of ethyl 4-amino-6-chloro-2-methylnicotinate (5.6 g, 26.4 mmol) in MeOH / THF / H2O (20 / 20 / 20 mL) was added LiOH·H2O (5.5 g, 132.0 mmol) and stirred at 50°C for 6 h. The mixture was concentrated, adjusted to pH 5-6 with 4 M hydrochloric acid, concentrated in vacuo, loaded onto silica gel and purified by column chromatography to afford the product (4.0 g, 21.6 mmol, 82% yield), LCMS: m / z 187.0 (M+H).

[0334] Step D. 7-Chloro-2-mercapto-5-methylpyridone[4,3-d]pyrimidin-4-ol: A solution of 4-amino-6-chloro-2-methylnicotinic acid (4.0 g, 21.6 mmol) in thionyl chloride (120 mL) was stirred at 50°C for 6 h. Concentrated. The residue was added to a solution of ammonium thiocyanate (4.9 g, 64.8 mmol) in acetone (120 mL) at 0°C. Stirred at room temperature for 1 h. The mixture was filtered through filter paper and the filtrate was concentrated to give the crude product (3.7 g). LCMS: m / z 228.0 (M+H).

[0335] Step E. 7-Chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: A solution of 7-chloro-2-mercapto-5-methylpyrido[4,3-d]pyrimidin-4-ol (3.7 g, 16.3 mmol) and sodium hydroxide (1.3 g, 32.6 mmol) in MeOH (100 mL) and water (25 mL) was added. Methyl iodide (4.6 g, 32.6 mmol) was added at 0°C and stirred at room temperature for 1 h. The residue was added to water (100 mL) and the pH was adjusted to 5-6 with 4 M hydrochloric acid. The mixture was filtered, and acetonitrile (50 mL) was added to the filter cake and stirred for 0.5 h. The filter cake was collected by filtration to afford the product (3.2 g, 13.3 mmol, 62% yield). LCMS: m / z 242.0 (M+H).

[0336] Step F. tert-Butyl (1R,5S)-3-(7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of 7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.2 g, 13.3 mmol) in acetonitrile (50 mL) was added with phosphorus oxychloride (3.1 g, 20.0 mmol) and DIEA (3.4 g, 26.6 mmol). The mixture was stirred at 80°C for 2 h and concentrated to give the crude product. To this crude product in acetonitrile was added DIEA (3.4 g, 26.6 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.2 g, 20.0 mmol) at 0°C. The mixture was stirred at room temperature for 1 h. The residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography eluting with 0-20% ethyl acetate in petroleum ether to give compound 7 (3.5 g, 8.1 mmol, 61% yield) LCMS: m / z 436.1 (M+H).

[0337] Example 44 (8.9 mg, 0.014 mmol) was prepared using tert-butyl (1R,5S)-3-(7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate according to the synthetic method of Steps D to J of Example 9. LCMS: m / z 607.3 (M+H).

[0338] 1HNMR(600MHz, Methanol-d4)δ8.49(s,1H),7.87(dd,J=9.2,5.6Hz,1H),7.48(s,1H),7.37–7.32( m,2H),7.22(s,1H),5.48–5.36(m,1H),4.44(d,J=11.0Hz,1H),4.39(d,J=10.9Hz,1H),4.36(s,1H ),4.11(br.s,1H),3.97–3.80(m,4H),3.52–3.43(m,3H),3.26–3.14(m,2H),2.47(d,J=15.6Hz,1H ),2.42–2.32(m,2H),2.28–2.22(m,1H),2.19–2.10(m,2H),2.06–1.88(m,4H),1.71–1.60(m,1H).

[0339] Example 45 Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol

[0340] Example 45 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(3-chloro-5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The resulting product was a salt containing one formic acid. LCMS: m / z 649.2 (M+H).

[0341] 1H NMR(400MHz, Methanol-d4)δ8.53(s,1H),7.15(d,J=2.3Hz,1H),6.77(s,1H),5.50–5.31(m,1H),4.52–4.31(m,3H),4.00–3.69(m,4H),3.59– 3.38(m,4H),3.24–3.12(m,1H),2.50–2.30(m,2H),2.23(s,3H),2.27– 2.17(m,1H),2.16–2.07(m,2H),2.05–1.95(m,1H),1.91–1.62(m,4H).

[0342] Example 46 Preparation of 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)7-(naphthyl)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0343] Example 46 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-naphthaleneboronic acid according to Steps F and H of Example 20. LCMS: m / z 581.2 (M+H). 1 H NMR(400MHz, Methanol-d4)δ8.51(s,1H),8.07(dd,J=6.6,2.9Hz,1H),8.03–7.99(m,1H) ,7.74(d,J=8.4Hz,1H),7.68–7.63(m,2H),7.59–7.55(m,1H),7.54–7.48(m,1H),5.52–5 .35(m,1H),4.58–4.41(m,3H),4.06–3.80(m,4H),3.65–3.42(m,4H),3.26–3.15(m,1H), 2.55–2.34(m,2H),2.30–2.20(m,1H),2.23(s,3H),2.19–2.11(m,2H),2.09–1.75(m,5H).

[0344] Example 47 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4R)-1-ethyl-4-fluoropyrrolidin-2-yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0345] Example 47, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((2S,4R)-1-ethyl-4-fluoropyrrol-2-yl)methanol as starting materials according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 627.3 (M+H).

[0346] 1 H NMR(400MHz, Methanol-d4)δ8.51(s,1H),7.89(dd,J=9.1,5.7Hz,1H),7.40–7.32(m,2 H),7.23(t,J=2.8Hz,1H),5.35–5.16(m,1H),4.68–4.53(m,3H),4.06–3.81(m,4H),3. 64–3.39(m,3H),3.24–3.14(m,1H),2.96–2.82(m,1H),2.75–2.65(m,1H),2.45–2.31( m,1H),2.22(s,3H),1.98–1.70(m,5H),1.39–1.29(m,1H),1.18(td,J=7.2,2.4Hz,3H).

[0347] Example 48 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0348] Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol of Example 41 and ((S)-1-methylpyrrol-2-yl)methanol as raw materials, the salt containing one formic acid in Example 47 was prepared by referring to the synthetic method of steps D to F of Example 38.

[0349] LCMS: m / z 595.3 (M+H).

[0350] 1 H NMR (400MHz, Methanol-d4) δ8.50 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.39–7.3 2(m,2H),7.23(t,J=2.4Hz,1H),4.77(dt,J=12.2,3.6Hz,1H),4.67–4.60(m,1H) ,4.03–3.76(m,5H),3.62–3.48(m,2H),3.04–2.96(m,2H),2.93(s,3H),2.40–2. 28(m,2H),2.22(s,3H),2.15–1.95(m,4H),1.93–1.84(m,2H),1.67–1.57(m,1H).

[0351] Example 49 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0352] Example 49, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 621.3 (M+H).

[0353] 1H NMR(400MHz, Methanol-d4)δ8.51(s,1H),7.90(dd,J=9.2,5.7Hz,1H),7.39–7.33(m,2H),7.23(d,J=2.5Hz,1H),4.70–4.61(m,2H),4.00–3.83(m,2H) ),3.80–3.64(m,4H),3.34–3.25(m,4H),2.39–2.30(m,2H),2.29–2.24(m, 1H),2.22(s,3H),2.22–2.01(m,6H),1.90–1.82(m,3H),1.66–1.58(m,1H).

[0354] Example 50 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0355] Example 50 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane as starting materials according to Steps F-H of Example 20. The salt contained one formic acid. LCMS: m / z 605.2 (M+H).

[0356] 1H NMR (400MHz, Methanol-d4) δ8.47(s,1H),8.14(dd,J=8.3,1.4Hz,1H),8.09(dd,J=8.3,1.3Hz,1H),7.79(dd,J =7.2,1.4Hz,1H),7.70(dd,J=8.3,7.0Hz,1H),7.61(d,J=7.2Hz,1H),7.56(dd,J=8.3,7.2Hz,1H),5.56–5.39(m ,1H),4.61–4.44(m,3H),4.10–3.88(m,4H),3.72–3.55(m,3H),3.31–3.24(m,1H),3.11(d,J=5.1Hz,1H),2.62– 2.54(m,1H),2.46(t,J=10.8Hz,2H),2.31(d,J=9.7Hz,1H),2.22(s,3H),2.21–2.16(m,2H),2.12–1.72(m,5H).

[0357] Example 51 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(3-hydroxy-3-methylbutynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0358] Example 51, a salt containing a formic acid, was prepared by using 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as the starting material and 2-methyl-3-butyn-2-ol in place of cyclopropylacetylene according to the method of Example 39. LCMS: m / z 683.3 (M+H).

[0359] 1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.48(t,J=9.0Hz,1H),7 .40(d,J=2.6Hz,1H),7.22(s,1H),5.77(s,1H),5.34–5.22(m,1H),4.15–4.11(m,1H),4.04 –3.99(m,1H),3.80–3.72(m,2H),3.12–2.99(m,5H),2.86–2.79(m,2H),2.14–2.04(m,3H) ,2.00–1.96(m,1H),1.88–1.82(m,1H),1.81–1.72(m,3H),1.62–1.54(m,3H),1.49(s,6H).

[0360] Example 52 Preparation of (S)-5-ethynyl-6-fluoro-4-(8-fluoro-2((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

[0361] Example 52, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as starting material, following the method of Example 43. LCMS: m / z 569.2 (M+H).

[0362] 1 H NMR (400MHz, Methanol-d4) δ8.50 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.40–7 .33(m,2H),7.25(t,J=2.3Hz,1H),4.83(dd,J=12.4,3.3Hz,1H),4.68(dd,J=12 .4,6.4Hz,1H),4.14–3.98(m,4H),3.72–3.56(m,2H),3.30–3.19(m,4H),3.13 –3.04(m,1H),2.98(s,3H),2.42–2.32(m,1H),2.25(s,3H),2.17–1.98(m,3H).

[0363] Example 53 Preparation of 4-(4-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-8-fluoro-2-(((2R,7aS))-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0364] Example 53, a salt containing two formic acids, was prepared by using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as the starting material and substituting tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate for 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane according to the method of Example 38. LCMS: m / z 625.2 (M+H).

[0365] 1 H NMR(400MHz, Methanol-d4)δ8.54(s,2H),7.89(dd,J=9.2,5.7Hz,1H),7.39–7.32(m ,2H),7.23(d,J=2.5Hz,1H),5.50–5.32(m,1H),5.22–5.13(m,2H),4.47–4.37(m,2H ),3.58–3.39(m,5H),3.29–3.14(m,3H),3.07–2.99(m,1H),2.54–2.45(m,1H),2.44 –2.29(m,2H),2.29–2.24(m,1H),2.23(s,3H),2.18–2.08(m,2H),2.05–1.96(m,2H).

[0366] Example 54 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)7-(3-chloro-2-cyclopropanylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0367] Example 54 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(3-chloro-2-cyclopropanephenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials according to Steps F and H of Example 20. The resulting product is a salt containing a formic acid. LCMS: m / z 605.2 (M+H).

[0368] 1 H NMR(600MHz, Methanol-d4)δ8.48(s,1H),7.58–7.55(t,J=4.7Hz,1H),7.40(d,J=5.2Hz,2 H),5.54–5.42(m,1H),4.51(q,J=11.2Hz,2H),4.06–3.89(m,4H),3.70–3.54(m,3H),3.32 –3.25(m,1H),2.59–2.39(m,3H),2.35–2.28(m,1H),2.24(s,3H),2.23–2.17(m,2H),2.11 –2.03(m,1H),2.03–1.89(m,4H),1.88–1.71(m,2H),0.78–0.71(m,2H),0.20–0.13(m,2H).

[0369] Example 55 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(3,3-dimethyl-1-butyn-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0370] Example 55, a salt containing a formic acid, was prepared using 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as the starting material and 3,3-dimethyl-1-butyne in place of cyclopropylacetylene, following the procedure of Example 39. LCMS: m / z 681.3 (M+H).

[0371] 1H NMR (600MHz, Methanol-d4) δ8.54 (s, 1H), 7.89 (dd, J = 9.2, 5.6Hz, 1H), 7.39–7 .33(m,2H),7.24(br.s,1H),5.46–5.34(m,1H),4.45–4.35(m,2H),3.80–3.65 (m,3H),3.53–3.36(m,4H),3.19–3.13(m,1H),2.49–2.30(m,3H),2.27–2.19( m,2H),2.15–2.07(m,3H),2.03–1.94(m,2H),1.88–1.77(m,3H),1.41(s,9H).

[0372] Example 56 Preparation of 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-3-fluorophenol

[0373] Example 56 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-fluoro-6-hydroxyphenylboronic acid pinacol ester as starting materials according to Steps F and H of Example 20. LCMS: m / z 565.2 (M+H).

[0374] 1 H NMR (400MHz, Methanol-d4) δ7.35(td,J=8.3,6.6Hz,1H),6.80(d,J=8.3Hz,1H),6.75(t,J=8.9Hz,1H),5.48–5.30(m,1H),4.38(q,J=10.8Hz, 2H),3.97–3.65(m,4H),3.53–3.33(m,5H),3.19–3.08(m,1H),2.49–2.28(m ,2H),2.23(s,3H),2.28–2.17(m,1H),2.14–2.04(m,2H),2.03–1.58(m,5H).

[0375] Example 57 Preparation of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS))-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0376] Example 57, a salt containing a formic acid, was prepared by following the method of Example 38, using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as the starting material and substituting (S)-tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate for 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane. LCMS: m / z 652.3 (M+H).

[0377] 1 H NMR (600MHz, Methanol-d4) δ8.48(s,1H),7.89(ddd,J=9.1,5.7,2.0Hz,1H),7.38(t,J=2.5Hz,1H),7.35(t,J= 8.9Hz,1H),7.27–7.20(m,1H),5.55–5.43(m,1H),4.61(d,J=11.6Hz,1H),4.50(dd,J=11.5,6.4Hz,1H),4.31–4 .18(m,1H),3.80–3.57(m,5H),3.40(d,J=10.0Hz,1H),3.34–3.26(m,3H),3.14–3.06(m,1H),2.77–2.67(m,2H ),2.65–2.50(m,2H),2.50–2.40(m,1H),2.38–2.31(m,1H),2.23(s,3H),2.26–2.16(m,2H),2.11–2.04(m,1H).

[0378] Example 58 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0379] Example 58 was synthesized according to Steps F to H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The salt containing one formic acid was synthesized. LCMS: m / z 643.2 (M+H).

[0380] 1 H NMR (400MHz, Methanol-d4) δ8.52(s,1H),7.68(dd,J=9.1,5.8Hz,1H),7.30(d,J=2.6Hz, 1H),7.25(t,J=9.4Hz,1H),7.07(s,1H),5.46–5.29(m,1H),4.45–4.32(m,2H),4.02–3.67 (m,4H),3.53–3.44(m,4H),3.20–3.08(m,1H),2.50–2.28(m,3H),2.26–2.21(m,2H),2.2 0(s,3H),2.13–2.04(m,2H),2.02–1.92(m,2H),1.88–1.78(m,4H),0.82(t,J=7.3Hz,3H).

[0381] Example 59 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(8-fluoronaphthalen-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0382] Example 59 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials according to Steps F and H of Example 20. LCMS: m / z 599.3 (M+H).

[0383] 1H NMR (400MHz, Methanol-d4) δ8.18–8.13(m,1H),7.91–7.86(m,1H),7.73(dd,J=8.3,7.1Hz ,1H),7.63(d,J=7.4Hz,1H),7.57(td,J=8.0,5.1Hz,1H),7.22(dd,J=13.2,7.7Hz,1H),5.6 9–5.53(m,1H),4.78–4.67(m,2H),4.26–4.00(m,5H),3.99–3.87(m,2H),3.55–3.46(m,1H) ,2.71–2.57(m,2H),2.53–2.32(m,4H),2.32–2.16(m,2H),2.24(s,3H),2.12–1.92(m,4H).

[0384] Example 60 Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

[0385] Example 60 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline as starting materials. The salt containing one formic acid was synthesized. LCMS: m / z 648.2 (M+H). 1 H NMR(400MHz, Methanol-d4)δ8.49(s,1H),6.93(d,J=2.3Hz,1H),6.51(d,J=2.4Hz,1H),5.54–5.36(m,1H),4.55–4.42(m,3H),4 .02–3.82(m,4H),3.71–3.47(m,3H),3.30–3.20(m,1H),2.59–2.34(m,2H),2.32–2.13(m,4H),2.23(s,3H),2.11–1.67(m,5H).

[0386] Example 61 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4R)-1-methyl-4-hydroxypyrrolidin-2-yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0387] Example 61, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((2S,4R)-1-methyl-4-hydroxypyrrol-2-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 611.3 (M+H).

[0388] 1 H NMR (400MHz, Methanol-d4) δ8.47(s,1H),7.89(dd,J=9.1,5.7Hz,1H),7.38(d,J=2.3Hz,1H),7.34(d,J=8.9Hz,1 H),7.24–7.21(m,1H),4.78(dt,J=12.2,3.8Hz,1H),4.63(ddd,J=12.2,6.3,4.3Hz,1H),4.51(s,1H),4.08–3.85( m,5H),3.76(dd,J=12.4,4.6Hz,1H),3.66(dd,J=11.6,4.8Hz,1H),3.53–3.47(m,1H),3.37–3.35(m,1H),3.28–3. 20(m,1H),2.94(s,3H),2.93–2.88(m,1H),2.44–2.38(m,1H),2.22(s,3H),2.21–2.11(m,1H),2.01–1.66(m,5H).

[0389] Example 62 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(8-chloronaphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0390] Using (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as raw materials, the salt containing one formic acid in Example 62 was synthesized according to Steps F and H of Example 20.

[0391] LCMS: m / z 615.2 (M+H).

[0392] 1 H NMR (400MHz, Methanol-d4) δ8.53(s,1H),8.16(dd,J=8.2,1.4Hz,1H),8.03(dd,J=8.2,1.3Hz,1H),7. 71(t,J=7.6Hz,1H),7.65–7.61(m,2H),7.53(t,J=7.8Hz,1H),5.48–5.31(m,1H),4.47–4.33(m,2H),4. 05–3.69(m,5H),3.55–3.48(m,1H),3.47–3.36(m,2H),3.21–3.10(m,2H),2.47(dd,J=15.1,4.5Hz,1H ),2.42–2.23(m,2H),2.21(s,3H),2.16–2.06(m,2H),2.00(dd,J=15.5,8.1Hz,1H),1.90–1.54(m,4H).

[0393] Example 63 Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropaneaniline

[0394] Example 63 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-cyclopropaneaniline as starting materials. The resulting product is a salt containing a formic acid. LCMS: m / z 620.3 (M+H).

[0395] 1 H NMR (400MHz, Methanol-d4) δ8.43 (s, 1H), 6.89 (d, J = 2.4Hz, 1H), 6.68 (d, J = 2.4Hz, 1H), 5. 57–5.42(m,1H),4.54(q,J=11.6Hz,2H),4.04–3.92(m,4H),3.79–3.59(m,4H),2.64–2.58( m,1H),2.54–2.41(m,2H),2.37–2.30(m,2H),2.23(s,3H),2.28–2.18(m,2H),2.14–2.06( m,2H),1.99–1.90(m,2H),1.84–1.77(m,2H),0.61(d,J=8.3Hz,2H),0.07(d,J=5.4Hz,2H).

[0396] Example 64 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-7-(8-chloronaphthalen-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0397] Example 63 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The product was obtained as a salt containing 0.5 parts of formic acid. LCMS: m / z 633.2 (M+H).

[0398] 1H NMR(400MHz, Methanol-d4)δ8.54(s,0.5H),8.20–8.16(m,1H),8.10(dd,J=9.1,5.6Hz,1H),7.73–7.67(m,2H),7.55(t,J=8.9Hz,1H),5.48–5.31(m,1H) ,4.39(q,J=10.6Hz,2H),4.01–3.68(m,4H),3.52–3.36(m,3H),3.21–3.10(m ,1H),2.49–2.29(m,3H),2.22(s,3H),2.14–1.93(m,4H),1.90–1.58(m,5H).

[0399] Example 65 Preparation of 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-4-fluoroaniline

[0400] Example 65 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-chloro-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The resulting product is a salt containing a formic acid. LCMS: m / z 598.2 (M+H).

[0401] 1 H NMR(400MHz, Methanol-d4)δ8.51(s,1H),7.27(dd,J=8.1,2.9Hz,1H),7.17(dt,J =9.1,2.5Hz,1H),5.51–5.34(m,1H),4.43(q,J=11.1Hz,2H),3.99–3.74(m,4H),3. 56–3.43(m,3H),3.26–3.17(m,1H),2.54–2.46(m,1H),2.46–2.30(m,2H),2.29–2 .25(m,1H),2.23(s,3H),2.19–2.09(m,2H),2.07–1.96(m,2H),1.89–1.66(m,4H).

[0402] Example 66 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethylnaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0403] Example 66 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-ethylnaphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials according to Steps F and H of Example 20. LCMS: m / z 609.3 (M+H).

[0404] 1 H NMR (600MHz, Methanol-d4) δ8.06(d,J=8.2Hz,1H),7.87(d,J=8.1Hz,1H),7.58(t,J=7.6Hz,1H),7.50( t,J=7.7Hz,2H),7.42(d,J=7.1Hz,1H),5.41–5.30(m,1H),4.62(s,2H),4.37(d,J=10.7Hz,1H),4.31(d ,J=10.6Hz,1H),3.69–3.62(m,3H),3.38–3.35(m,2H),3.11–3.05(m,1H),2.49–2.24(m,5H),2.20(s,3 H),2.19–2.15(m,1H),2.09–2.02(m,3H),1.98–1.90(m,2H),1.86–1.76(m,3H),0.95(t,J=7.5Hz,3H).

[0405] Example 67 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0406] Example 67 was synthesized as a salt containing a formic acid using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and (3-(methoxymethoxy)naphthalen-1-yl)boronic acid as starting materials according to Steps F and H of Example 20. LCMS: m / z 597.3 (M+H).

[0407] 1 H NMR (600MHz, Methanol-d4) δ8.49(s,1H),7.78(d,J=8.3Hz,1H),7.58(d,J=8.5Hz,1H),7.45 (ddd,J=8.1,6.8,1.1Hz,1H),7.31(d,J=2.4Hz,1H),7.29–7.25(m,2H),5.49–5.38(m,1H),4. 52–4.42(m,2H),4.02–3.81(m,5H),3.62–3.47(m,3H),3.28–3.18(m,1H),2.53–2.34(m,3H), 2.27(d,J=9.9Hz,1H),2.23(s,3H),2.20–2.11(m,2H),2.07–1.98(m,2H),1.94–1.74(m,4H).

[0408] Example 68 Preparation of nitrogen-2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-4-fluorophenyl)acetamide

[0409] Example 68 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and nitrogen-(2-chloro-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide as starting materials. The resulting product is a salt containing a formic acid. LCMS: m / z 640.2 (M+H).

[0410] 1H NMR (600MHz, Methanol-d4) δ8.50 (s, 1H), 7.55 (dd, J=8.0, 2.9Hz, 1H), 7.42 (dd, J=8 .5,2.9Hz,1H),5.52–5.39(m,1H),4.52–4.42(m,2H),4.03–3.85(s,4H),3.67–3.51 (m,4H),3.28–3.21(m,1H),2.55–2.37(m,3H),2.31–2.26(m,1H),2.23(s,3H),2.21 –2.14(m,2H),2.08–2.01(m,1H),1.96–1.87(m,2H),1.92(s,3H),1.82–1.68(m,2H).

[0411] Example 69 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0412] The reaction formula is as follows:

[0413] Step A. (1R,5S)-tert-Butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphth-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: (1R,5S)-tert-Butyl 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 ml) was added. g, 0.42mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (302mg, 0.84mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (31mg, 0.042mmol), potassium phosphate (267mg, 1.26mmol) in tetrahydrofuran (10mL) and water (2mL) were stirred at 60°C for 5h under nitrogen environment. The reaction of the starting material was completed as monitored by TLC. The mixture was diluted with EtOAc and added with water. The aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over Na2SO4. The combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography using 10-50% ethyl acetate / petroleum ether as eluent to give the product (130 mg, 0.19 mmol, 47% yield). LCMS: m / z 676.3 (M+H).

[0414] Step B. tert-Butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl (3-( ... To a solution of the crude product (40.0 mg, 0.059 mmol) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (16.0 mg, 0.12 mmol) in THF (3 mL) was added LiHMDS (0.177 ml, 0.177 mmol) dropwise at 0°C and stirred for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over NaSO. The combined organic phases were filtered, dried, loaded onto silica gel, and purified by column chromatography eluting with 0-10% MeOH / DCM to afford the product (35.0 mg, 0.046 mmol, 78% yield). LCMS: m / z 761.2 (M+H).

[0415] Step C. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: to 3-(7-(8-ethyl-7-fluoro-3-(methoxy)- To a solution of tert-butyl (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methyl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.046 mmol) in dichloromethane was added trifluoroacetic acid (0.5 ml) dropwise. The mixture was stirred at room temperature for 40 minutes. The mixture was concentrated, and the residue was poured into a mixture of saturated NaHCO₃ (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2×15 mL), and the combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was then purified by preparative HPLC (5-95% ACN / water / 0.1% FA over 20 min) and lyophilized to afford the product (9.0 mg, 0.014 mmol, 32% yield) as a salt containing one formic acid. LCMS: m / z 617.3 (M+H).

[0416] 1 H NMR (600MHz, Methanol-d4) δ8.51(s,1H),7.69(dd,J=9.0,5.8Hz,1H),7.32(d,J=2.6Hz,1H),7.2 7(t,J=9.3Hz,1H),7.09(s,1H),5.29–5.17(m,1H),4.64–4.52(m,2H),4.07–3.82(m,4H),3.63–3 .52(m,1H),3.28–3.23(m,1H),2.81–2.72(m,1H),2.63(s,3H),2.50–2.42(m,1H),2.40–2.32(m, 1H),2.28–2.18(m,1H),2.22(s,3H),2.13–2.01(m,2H),1.97–1.60(m,5H),0.85(t,J=7.4Hz,3H).

[0417] Example 70 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0418] Example 70, a salt containing two formic acids, was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and N-methyl-L-prolinol as starting materials, following the preparation methods of Steps B and C of Example 69. LCMS: m / z 599.3 (M+H).

[0419] 1 H NMR(600MHz,Methanol-d4)δ8.53(s,2H),7.70(dd,J=9.0,5.8Hz,1H),7.33(d,J=2.6Hz,1H) ,7.27(t,J=9.3Hz,1H),7.10(s,1H),4.78–4.74(m,1H),4.70–4.65(m,1H),4.10–3.82(m,5H ),3.58–3.51(m,2H),3.01–2.95(m,1H),2.92(s,3H),2.49–2.41(m,1H),2.36–2.30(m,1H), 2.29–2.24(m,1H),2.23(s,3H),2.13–1.88(m,6H),1.86–1.60(m,2H),0.84(t,J=7.4Hz,3H).

[0420] Example 71 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0421] Example 71 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(3-chloro-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The resulting product is a salt containing two formic acids. LCMS: m / z 633.2 (M+H).

[0422] 1 H NMR (600MHz, Methanol-d4) δ8.50(d,J=1.0Hz,2H),7.83(d,J=8.1Hz,1H),7.75(t,J=7.9Hz,1H),7.46(d,J=7.8Hz,1H),5.50–5.38(m,1H), 4.49(d,J=11.2Hz,1H),4.44(d,J=11.2Hz,1H),4.05–3.84(m,5H),3.64–3.47(m,2H),3.24–3.19(m,1H),2.54–2.34 (m,3H),2.31–2.25(m,1H),2.24(s,3H),2.20–2.12(m,2H),2.08–2.00(m,1H),1.95–1.87(m,2H),1.85–1.67(m,3H).

[0423] Example 72 Preparation of 1-(7-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-amino-1H-indol-1-yl)ethan-1-one

[0424] Example 72 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 1-(5-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethan-1-one as starting materials. The salt contained five carboxylic acids. LCMS: m / z 627.3 (M+H).

[0425] 1 H NMR (400MHz, Methanol-d4) δ8.54(s,5H),8.01(d,J=1.9Hz,1H),7.92(d,J=1.9Hz,1H),7. 40(d,J=3.2Hz,1H),6.56(d,J=3.2Hz,1H),5.50–5.33(m,1H),4.45(d,J=11.0Hz,1H),4.3 9(d,J=11.0Hz,1H),3.97–3.73(m,5H),3.51–3.42(m,3H),3.21–3.14(m,1H),2.52–2.32( m,4H),2.28(s,3H),2.19(s,3H),2.17–2.08(m,2H),2.05–1.94(m,2H),1.88–1.67(m,3H).

[0426] Example 73 Preparation of 7-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-1H-indole-5-amine

[0427] Example 73 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-amine as starting materials. The salt contained one formic acid. LCMS: m / z 585.3 (M+H).

[0428] 1H NMR (600MHz, Methanol-d4) δ8.49(s,1H),7.44(d,J=2.0Hz,1H),7.32(d,J=3.1Hz,1H),7.22(d,J=2.1Hz,1H),6.42(d,J=3.1Hz,1H),5.52–5.41( m,1H),4.51(d,J=11.2Hz,1H),4.46(d,J=11.2Hz,1H),4.01–3.83(m,5H) ,3.69–3.52(m,3H),3.29–3.24(m,1H),2.58–2.39(m,2H),2.32–2.29(m, 1H),2.28(s,3H),2.22–2.16(m,2H),2.10–2.02(m,1H),1.96–1.86(m,3H),1.83–1.70(m,2H).

[0429] Example 74 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0430] Example 74 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine as starting materials. The product is a salt containing two formic acids. LCMS: m / z 629.3 (M+H).

[0431] 1H NMR(600MHz, Methanol-d4)δ8.51(s,2H),6.37(s,1H),5.48–5.36(m,1H),4.48–4.38(m,2H),3.98–3.74(m,5H),3.54–3.44(m,3H),3.22 –3.17(m,1H),2.57(s,3H),2.51–2.32(m,3H),2.23(s,3H),2.18–2.09(m,2H),2.06–1.97(m,2H),1.93–1.82(m,2H),1.78–1.65(m,2H).

[0432] Example 75 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(5-chloroisoquinolin-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0433] Example 75 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline as starting materials according to Steps F and H of Example 20. The resulting product is a salt containing three formic acids. LCMS: m / z 616.2 (M+H).

[0434] 1 H NMR (600MHz, Methanol-d4) δ9.51(s,1H),8.54(s,1H),8.46(s,3H),8.30(d,J=8.2Hz,1H),7.95(d,J=7.5Hz,1H),7.78(t,J=7.8Hz,1H),5.56–5.43(m, 1H),4.66–4.46(m,2H),4.18–3.84(m,4H),3.78–3.54(m,4H),3.31–3.26(m ,1H),2.65–2.39(m,3H),2.37–2.26(m,2H),2.23(s,3H),2.14–1.72(m,6H).

[0435] Example 76 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(5-fluoroisoquinolin-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0436] Example 76 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline as starting materials according to Steps F and H of Example 20. The resulting product is a salt containing a formic acid. LCMS: m / z 600.3 (M+H).

[0437] 1 H NMR (600MHz, Methanol-d4) δ9.49 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.15 (dd, J = 8.3, 1.0Hz,1H),7.80(td,J=8.0,4.6Hz,1H),7.58(dd,J=12.2,7.7Hz,1H),5.49–5.38(m, 1H),4.53–4.43(m,2H),4.08–3.83(m,4H),3.65–3.46(m,3H),3.26–3.17(m,1H),2.5 5–2.33(m,3H),2.31–2.26(m,1H),2.24(s,3H),2.20–2.12(m,2H),2.08–1.72(m,6H).

[0438] Example 77 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0439] Referring to the preparation method of Example 43, Example 77, a salt containing one formic acid, was prepared using corresponding starting materials and reagents. LCMS: m / z 617.3 (M+H).

[0440] 1H NMR (400MHz, Methanol-d4) δ8.55(s,1H),7.69(dd,J=9.0,5.8Hz,1H),7.32(d,J=2.6H z,1H),7.27(t,J=9.4Hz,1H),7.08(t,J=2.2Hz,1H),5.44–5.27(m,1H),4.42–4.27(m,2 H),4.05–3.89(m,4H),3.30–3.26(m,1H),3.13–3.02(m,5H),2.49–2.35(m,2H),2.34– 2.25(m,2H),2.23(s,3H),2.21–2.15(m,1H),2.11–1.88(m,5H),0.84(t,J=7.4Hz,3H).

[0441] Example 78 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

[0442] Example 78 was synthesized using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and ((2-fluoro-6-amino-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane as starting materials according to Steps F-H of Example 20. The resulting product is a salt containing one formic acid. LCMS: m / z 638.3 (M+H).

[0443] 1H NMR (600MHz, Methanol-d4) δ8.41 (s, 1H), 7.74 (dd, J = 9.2, 5.7Hz, 1H), 7.24 (t ,J=8.9Hz,1H),7.19(d,J=2.4Hz,1H),7.12(s,1H),5.50–5.38(m,1H),4.53–4. 43(m,2H),4.08–3.84(m,5H),3.68–3.51(m,3H),3.27–3.22(m,1H),2.56–2.35 (m,2H),2.31–2.23(m,2H),2.19(s,3H),2.18–2.13(m,2H),2.09–1.65(m,5H).

[0444] Example 79 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4R)-1-methyl-4-fluoropyrrolidin-2-yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0445] Example 79, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((2S,4R)-1-methyl-4-fluoropyrrol-2-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 613.2 (M+H).

[0446] 1 H NMR(400MHz, Methanol-d4)δ8.45(s,1H),7.89(dd,J=9.1,5.7Hz,1H),7.39–7.32(m,2H),7.23(d,J=2.2Hz,1H),5.34–5.16(m,1H),4.69 –4.55(m,2H),4.14–3.86(m,5H),3.67–3.55(m,1H),2.90–2.71(m,2H),2.66(s,3H),2.43–2.31(m,2H),2.22(s,3H),2.04–1.75(m,5H).

[0447] Example 80 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4S)-1-methyl-4-fluoropyrrolidin-2-yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0448] Example 80, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((2S,4S)-1-methyl-4-fluoropyrrol-2-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 613.2 (M+H).

[0449] 1 H NMR(400MHz, Methanol-d4)δ8.50(s,1H),7.86(dd,J=9.1,5.7Hz,1H),7.38–7.33(m,2H),7.26(d,J=2.2Hz,1H),5.36–5.18(m,1H),4.69 –4.57(m,2H),4.15–3.86(m,5H),3.68–3.57(m,1H),2.92–2.73(m,2H),2.68(s,3H),2.43–2.31(m,2H),2.23(s,3H),2.06–1.78(m,5H).

[0450] Example 81 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol

[0451] Example 81 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-chloro-3-(methoxymethyl ether)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The resulting product was a salt containing one formic acid. LCMS: m / z 631.2 (M+H).

[0452] 1 H NMR(400MHz, Methanol-d4)δ8.45(s,1H),7.78(dd,J=7.8,1.7Hz,1H),7.42–7.34(m,3H),7.19(t,J=2.0Hz,1H),5.58–5.42(m,1H),4.62–4.50(m,2H) ),4.12–3.94(m,4H),3.82–3.59(m,4H),2.66–2.44(m,2H),2.39–2.30(m, 2H),2.27–2.24(m,2H),2.23(s,3H),2.15–2.05(m,1H),2.01–1.72(m,5H).

[0453] Example 82 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0454] Example 82, a salt containing a formic acid, was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and (1-(morpholinomethyl)cyclopropane)methanol as starting materials, following the preparation method of Steps B and C of Example 69. LCMS: m / z 655.3 (M+H).

[0455] 1H NMR (400MHz, Methanol-d4) δ8.39(s,1H),7.70(dd,J=9.0,5.8Hz,1H),7.32(d,J=2.6Hz,1H),7.27(t,J=9.4Hz,1H),7.08(d,J=2.6Hz,1H),4.66– 4.41(m,4H),4.14–3.98(m,3H),3.70(t,J=4.6Hz,4H),2.74–2.64(m,4H ),2.61(s,2H),2.52–2.41(m,1H),2.31–2.25(m,1H),2.23(s,3H),2.10– 1.79 (m, 5H), 0.85 (t, J = 7.4Hz, 3H), 0.79 (t, J = 5.6Hz, 2H), 0.60 (t, J = 5.7Hz, 2H).

[0456] Example 83 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine

[0457] Using (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as raw materials, the synthesis of Example 83 was carried out according to Steps F and H of Example 20, which is a salt containing 0.5 formic acid.

[0458] LCMS: m / z 599.3 (M+H).

[0459] 1H NMR(600MHz, Methanol-d4)δ8.55(s,0.5H),8.12–8.09(m,1H),8.08–8.05(m,1H),7.73(d,J=7.0Hz, 1H),7.64(dd,J=8.2,7.1Hz,1H),7.45–7.38(m,2H),5.43–5.32(m,1H),4.40(d,J=10.6Hz,1H),4.33( d,J=10.6Hz,1H),3.96–3.81(m,2H),3.77–3.61(m,3H),3.45–3.35(m,2H),3.16–3.06(m,1H),2.45–2 .27(m,3H),2.23(s,3H),2.22–2.15(m,1H),2.14–2.03(m,3H),2.00–1.92(m,1H),1.87–1.68(m,4H).

[0460] Example 84 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-(4,4-difluoropiperidin-1-yl)propan-2-yl)oxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0461] Example 84 was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and (S)-1-(4,4-difluoropiperidin-1-yl)propan-2-ol as starting materials, following the preparation methods of Steps B and C of Example 69. The salt contained 0.5 units of formic acid. LCMS: m / z 663.3 (M+H).

[0462] 1H NMR (600MHz, Methanol-d4) δ8.53 (s, 0.5H), 7.69 (dd, J = 9.0, 5.7Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J = 9. 3Hz,1H),7.09(d,J=13.9Hz,1H),5.64–5.58(m,1H),4.06–3.75(m,5H),2.88–2.71(m,4H),2.69–2.59(m,3H), 2.49–2.43(m,1H),2.29–2.43(m,2H),2.21(s,3H),1.97–1.71(m,7H),1.42(t,J=6.6Hz,3H),0.85(td,J=7.4,3.8Hz,3H).

[0463] Example 85 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol

[0464] Example 85 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The product was obtained as a salt containing 0.5 parts of formic acid. LCMS: m / z 615.2 (M+H).

[0465] 1 H NMR (600MHz, Methanol-d4) δ8.46 (s, 0.5H), 7.83 (dd, J = 9.4, 5.5Hz, 1H), 7.36– 7.32(m,2H),7.31–7.21(m,2H),5.53–5.39(m,1H),4.56–4.46(m,2H),4.06–3. 87(m,4H),3.66–3.52(m,3H),3.29–3.22(m,1H),2.57–2.38(m,3H),2.33–2.27 (m,1H),2.24(s,3H),2.22–2.13(m,2H),2.10–2.01(m,2H),1.98–1.77(m,4H).

[0466] Example 86 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0467] Example 86 (a salt containing 0.5 parts of formic acid) was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and (1-((4-methylpiperazin-1-yl)methyl)cyclopropane)methanol as starting materials according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 664.3 (M+H).

[0468] 1 H NMR(600MHz, Methanol-d4)δ8.54(s,0.5H),7.89(dd,J=9.1,5.6Hz,1H),7.39–7.32(m,2H) ,7.23(d,J=2.4Hz,1H),4.61(s,1H),4.47(d,J=10.9Hz,1H),4.40(d,J=10.9Hz,1H),4.05–3 .90(m,2H),3.86–3.68(m,3H),2.97–2.62(m,7H),2.51(d,J=13.9Hz,4H),2.41–2.33(m,1H) ,2.21(s,3H),1.85(s,3H),1.68–1.58(m,2H),0.75(d,J=4.8Hz,2H),0.55(d,J=5.2Hz,2H).

[0469] Example 87 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((S)-2-((S)-3-fluoropyrrolidin-1-yl)propoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0470] Example 87, a salt containing 0.5 formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol of Example 41 and ((S)-2-((S)-3-fluoropyrrolidin-1-yl)propanol as starting materials according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 627.3 (M+H).

[0471] 1 H NMR(600MHz, Methanol-d4)δ8.50(s,0.5H),7.88(dd,J=9.2,5.6Hz,1H),7.38–7.32(m,2H),7.24–7.21(m,1H),5.66–5.56(m,1H),5.27–5.12(m,1H) ),4.71–4.55(m,2H),4.10–3.81(m,5H),3.19–2.87(m,4H),2.83–2.63(m ,2H),2.22(s,3H),2.20–2.12(m,1H),2.10–1.70(m,5H),1.45(br.s,3H).

[0472] Example 88 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-1-(4,4-difluoropiperidin-1-yl)propan-2-yl)oxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0473] Example 88, a salt containing three formic acids, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and (S)-1-(4,4-difluoropiperidin-1-yl)propan-2-ol according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 659.3 (M+H).

[0474] 1H NMR(600MHz, Methanol-d4)δ8.54(s,3H),7.88(dd,J=9.1,5.7Hz,1H),7.38–7.32(m,2H),7.23(dd,J=10.0,2.5Hz,1H),5.63–5.57(m,1H),4.07–3.88(m, 3H),3.84–3.76(m,3H),2.84(td,J=13.6,8.0Hz,2H),2.80–2.73(m,2H),2.7 2–2.59(m,3H),2.21(s,3H),1.98–1.82(m,7H),1.42(dd,J=6.3,5.2Hz,3H).

[0475] Example 89 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-(piperidin-1-yl)propan-2-yl)oxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0476] Example 89, a salt containing a formic acid, was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and (S)-1-(piperidin-1-yl)propan-2-ol as starting materials, following the preparation method of Steps B and C of Example 69. LCMS: m / z 627.3 (M+H).

[0477] 1 H NMR(400MHz, Methanol-d4)δ8.53(s,1H),7.70(dd,J=9.0,5.8Hz,1H),7.32(d,J=2.7Hz,1H), 7.27(t,J=9.4Hz,1H),7.09(dd,J=5.8,2.6Hz,1H),5.72–5.63(m,1H),4.06–3.71(m,5H),3.29 –3.20(m,1H),3.14–2.95(m,6H),2.52–2.40(m,1H),2.29–2.23(m,1H),2.21(s,3H),1.93–1. 81(m,3H),1.78–1.68(m,5H),1.62–1.55(m,2H),1.48(t,J=6.0Hz,3H),0.85(t,J=7.4Hz,3H).

[0478] Example 90 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(piperidinylmethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0479] Example 90 (a salt containing a formic acid) was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and (1-(piperidinylmethyl)cyclopropane)methanol as starting materials according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 649.3 (M+H).

[0480] 1 H NMR(400MHz, Methanol-d4)δ8.57(s,1H),7.88(dd,J=9.2,5.7Hz,1H),7.38–7.32(m,2H),7.23(d,J=2.5Hz,1H),4.51–4.40(m,2H),3 .88–3.58(m,6H),3.08–2.79(m,7H),2.21(s,3H),1.86–1.69(m,7H),1.66–1.54(m,3H),0.88(d,J=8.5Hz,2H),0.71(d,J=8.4Hz,2H).

[0481] Example 91 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-(piperidin-1-yl)propan-2-yl)oxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0482] Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol of Example 41 and (S)-1-(piperidin-1-yl)propan-2-ol as raw materials, the synthetic method of steps D to F of Example 38 was referred to prepare Example 91 which is a salt containing a formic acid.

[0483] LCMS: m / z 623.3 (M+H).

[0484] 1 H NMR(400MHz, Methanol-d4)δ8.56(s,1H),7.88(dd,J=9.1,5.7Hz,1H),7.39–7.31(m,2H),7.23(dd,J=5.1,2.5Hz,1H),5.68–5.59(m,1H),4.02– 3.61(m,5H),3.13–3.02(m,1H),2.94–2.73(m,5H),2.21(s,3H),1.88–1 .76(m,3H),1.72–1.59(m,5H),1.56–1.49(m,3H),1.45(t,J=6.0Hz,3H).

[0485] Example 92 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0486] Referring to the preparation method of Example 42, Example 92, a salt containing one formic acid, was prepared using corresponding starting materials and reagents. LCMS: m / z 613.3 (M+H).

[0487] 1 H NMR(400MHz, Methanol-d4)δ8.53(s,1H),7.70(dd,J=9.0,5.8Hz,1H),7.32(d,J=2.6Hz, 1H),7.27(t,J=9.4Hz,1H),7.14–7.08(m,1H),4.73–4.58(m,3H),3.73–3.66(m,2H),3.4 7–3.37(m,3H),2.91–2.79(m,4H),2.52–2.36(m,2H),2.36–2.24(m,3H),2.21(s,3H),2. 09–1.89(m,5H),1.56–1.44(m,2H),1.36(d,J=10.7Hz,3H),0.84(td,J=7.3,5.0Hz,3H).

[0488] Example 93 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0489] Referring to the preparation method of Example 42, Example 93, a salt containing one formic acid, was prepared using corresponding starting materials and reagents. LCMS: m / z 657.3 (M+H).

[0490] 1 H NMR (400MHz, Methanol-d4) δ8.53(s,1H),7.69(dd,J=9.0,5.8Hz,1H),7.32(d,J=2.6Hz,1 H),7.27(t,J=9.4Hz,1H),7.11(d,J=7.1Hz,1H),5.47–5.30(m,1H),4.47–4.31(m,2H),3.7 6–3.64(m,2H),3.45–3.36(m,3H),3.20–3.10(m,1H),2.52–2.27(m,4H),2.21(s,4H),2.15 –2.05(m,2H),2.02–1.91(m,2H),1.56–1.46(m,2H),1.42–1.27(m,3H),0.89–0.77(m,3H).

[0491] Example 94 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-yl)oxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0492] Example 94, a salt containing a formic acid, was synthesized using (1R,5S)-tert-butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and ((S)-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-ol as starting materials and referring to the preparation methods of Steps B and C of Example 69. LCMS: m / z 631.3 (M+H).

[0493] 1H NMR (400MHz, Methanol-d4) δ8.46 (s, 1H), 7.69 (dd, J = 9.1, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H),7.27(t,J=9.4Hz,1H),7.09(d,J=2.6Hz,1H),5.60(br.s,1H),5.28–5.09(m,1H),4.7 1–4.38(m,2H),4.16–3.83(m,4H),3.24–2.83(m,5H),2.74–2.61(m,1H),2.52–2.42(m,1H ),2.31–2.24(m,2H),2.22(s,3H),2.08–1.73(m,5H),1.45(s,3H),0.85(t,J=7.3Hz,3H).

[0494] Example 95 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-yl)oxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0495] Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol of Example 41 and ((S)-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-ol as starting materials, Example 95 (a salt containing a formic acid) was prepared by referring to the synthetic method of Steps D to F of Example 38. LCMS: m / z 627.3 (M+H).

[0496] 1H NMR(400MHz, Methanol-d4)δ8.54(s,1H),7.88(dd,J=9.2,5.7Hz,1H),7.40–7.29(m,2 H),7.23(t,J=2.3Hz,1H),5.62–5.53(m,1H),5.27–5.08(m,1H),4.66–4.36(m,2H),4. 04–3.81(m,4H),3.13–3.02(m,2H),2.99–2.90(m,2H),2.89–2.81(m,2H),2.66–2.56( m,1H),2.21(s,3H),2.20–2.10(m,1H),2.08–1.70(m,5H),1.44(dd,J=6.4,4.1Hz,3H).

[0497] Example 96 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-methylpiperidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0498] Example 96, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and (1-methylpiperidin-2-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 609.3 (M+H).

[0499] 1 H NMR(400MHz, Methanol-d4)δ8.55(s,1H),7.89(dd,J=9.2,5.7Hz,1H),7.39–7.32(m,2H),7.23(d,J=2.6Hz,1H),4.77–4.71(m,1H),4.67–4.60(m,1H) ),4.03–3.65(m,6H),3.30–3.24(m,1H),3.09–3.01(m,1H),2.76(s,3H),2 .21(s,3H),2.01(d,J=13.4Hz,2H),1.96–1.71(m,8H),1.63–1.50(m,2H).

[0500] Example 97 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0501] Example 97 (a salt containing a formic acid) was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 625.3 (M+H).

[0502] 1 H NMR (400MHz, Methanol-d4) δ8.51(s,1H),7.89(dd,J=9.2,5.7Hz,1H),7.37(d,J=2.3Hz,1H),7.34(d,J=9.0Hz,1H),7.23(t,J=2.3Hz,1H), 4.70–4.55(m,3H),4.09–4.01(m,1H),4.00–3.78(m,4H),3.58–3.45(m,2H),3.36(s,3 H),2.83–2.79(m,1H),2.78(s,3H),2.57–2.49(m,1H),2.22(s,3H),2.08–1.59(m,6H).

[0503] Example 98 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0504] Example 98 was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and (hexahydro-1H-pyrrolin-7a-yl)methanol as starting materials, following the preparation method of Steps B and C of Example 69 to obtain a salt containing 0.5 units of formic acid. LCMS: m / z 625.3 (M+H).

[0505] 1 H NMR (600MHz, Methanol-d4) δ8.57 (s, 0.5H), 7.69 (dd, J=9.1, 5.8Hz, 1H), 7.32 (d, J=2.6 Hz,1H),7.27(t,J=9.4Hz,1H),7.10(s,1H),4.49(s,2H),3.66–3.57(m,3H),3.46–3.38( m,2H),3.07–3.00(m,2H),2.49–2.40(m,2H),2.27–2.22(m,2H),2.21(s,3H),2.15–2.01 (m,6H),1.99–1.91(m,3H),1.83–1.77(m,2H),1.38–1.30(m,2H),0.84(t,J=7.4Hz,3H).

[0506] Example 99 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-4-methylmorpholin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0507] Example 99, a salt containing two formic acids, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((S)-4-methylmorpholin-2-yl)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 611.3 (M+H).

[0508] 1H NMR(600MHz, Methanol-d4)δ8.50(s,2H),7.88(dd,J=9.1,5.7Hz,1H),7.40–7.32(m,2H),7.22(t,J=2.3Hz ,1H),4.56–4.50(m,2H),4.05–3.88(m,6H),3.75–3.69(m,2H),2.99(d,J=11.5Hz,1H),2.80(d,J=11.7Hz, 1H),2.39(s,3H),2.35–2.26(m,2H),2.22(s,3H),2.21–2.17(m,1H),1.98–1.74(m,5H).

[0509] Example 100 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0510] Example 100 (a salt containing 0.5 parts of formic acid) was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and ((S)-1-isopropylpyrrolidin-2-yl)methanol as starting materials according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 623.3 (M+H).

[0511] 1 H NMR (600MHz, Methanol-d4) δ8.48 (s, 0.5H), 7.90 (dd, J = 9.2, 5.6Hz, 1H), 7.40 –7.33(m,2H),7.23(t,J=3.4Hz,1H),4.78–4.65(m,2H),4.17–4.09(m,2H),4.0 3–3.75(m,6H),3.55–3.48(m,1H),2.37–2.28(m,2H),2.22(s,3H),2.15–2.06 (m,3H),1.94–1.84(m,5H),1.43(dd,J=6.6,3.5Hz,3H),1.39(d,J=6.5Hz,3H).

[0512] Example 101 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalene-2-ol

[0513] Example 101 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The resulting product was a salt containing a formic acid. LCMS: m / z 615.3 (M+H).

[0514] 1 H NMR (600MHz, Methanol-d4) δ8.52(s,1H),7.61(d,J=8.3Hz,1H),7.41(td,J=8.0,5.0Hz,1H),7.35(t,J=2.3Hz,1H),7.18(s,1H),6.95(dd,J=13. 1,7.6Hz,1H),5.48–5.36(m,1H),4.46(d,J=11.1Hz,1H),4.41(d,J=11. 0Hz,1H),4.02–3.77(m,3H),3.60–3.41(m,4H),3.24–3.14(m,2H),2.51– 2.32(m,3H),2.28–2.25(m,1H),2.22(s,3H),2.18–2.09(m,2H),2.04–1.97(m,1H),1.92–1.70(m,4H).

[0515] Example 102 Preparation of 4-(4-(3,6-diazabicyclo[3.2.1]heptane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0516] Example 102, a salt containing three formic acids, was prepared using tert-butyl 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and corresponding reagents as starting materials, following the synthetic method of Steps C, D, and F of Example 38. LCMS: m / z 629.3 (M+H). 1 H NMR(400MHz, Methanol-d4)δ8.55(s,3H),7.70(dd,J=9.1,5.8Hz,1H),7.33(d,J=2.5Hz,1H), 7.27(t,J=9.4Hz,1H),7.09(s,1H),5.45–5.29(m,1H),4.66–4.53(m,3H),4.48–4.33(m,3H),4 .12–4.02(m,2H),3.78–3.71(m,2H),3.14–3.09(m,1H),2.94–2.86(m,2H),2.47–2.38(m,2H) ,2.36–2.25(m,3H),2.19(s,3H),2.12–2.04(m,3H),1.92–1.83(m,2H),0.86(t,J=7.4Hz,3H).

[0517] Example 103 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol

[0518] Example 103 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(7,8-difluoro-3-(methoxymethyl ether)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The product was obtained as a salt containing 0.5 parts of formic acid. LCMS: m / z 633.3 (M+H). 1H NMR (400MHz, Methanol-d4) δ8.54 (s, 0.5H), 7.63 (ddd, J = 9.3, 4.8, 1.6Hz, 1H), 7.4 5–7.40(m,1H),7.35(t,J=2.2Hz,1H),7.26(s,1H),5.48–5.30(m,1H),4.48–4.31(m ,3H),4.01–3.80(m,2H),3.73(s,2H),3.53–3.37(m,3H),3.18–3.10(m,1H),2.51– 2.26(m,3H),2.22(s,3H),2.16–2.03(m,3H),2.03–1.93(m,2H),1.89–1.60(m,5H).

[0519] Example 104 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((R)-2-methylmorpholino)methyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0520] Example 104, a salt containing 0.5 parts of formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and (R)-(1-((2-methylmorpholino)methyl)cyclopropane)methanol as starting materials according to the synthetic method described in Steps D to F of Example 38. LCMS: m / z 665.3 (M+H). 1H NMR (400MHz, Methanol-d4) δ8.52(s,1H),7.88(dd,J=9.2,5.7Hz,1H),7.37(d,J=2.4Hz,1H),7.33(d,J =9.0Hz,1H),7.22(d,J=2.5Hz,1H),4.46(s,2H),4.01–3.74(m,5H),3.65–3.52(m,3H),2.93(d,J=11.4H z,2H),2.52(dd,J=12.6,5.5Hz,1H),2.40(dd,J=12.6,7.0Hz,1H),2.35(d,J=2.8Hz,1H),2.21(s,3H),2 .16–2.06(m,1H),1.96–1.62(m,6H),1.11(dt,J=6.3,1.8Hz,3H),0.77–0.71(m,2H),0.59–0.49(m,2H).

[0521] Example 105 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene-2-ol

[0522] Example 105 was synthesized according to Steps F and H of Example 20 using tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(8-chloro-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials. The resulting product was a salt containing one formic acid. LCMS: m / z 649.2 (M+H). 1 H NMR (400MHz, Methanol-d4) δ7.84(dd,J=9.2,5.5Hz,1H),7.43(d,J=8.9Hz,1H),7.40(d,J=2.3Hz,1H),7.24(s,1H),5.59–5. 41(m,1H),4.65–4.48(m,3H),4.15–3.87(m,4H),3.79–3.59(m,3H),2.60–2.30(m,5H),2.29–2.15(m,5H),2.14–1.72(m,5H).

[0523] Example 106 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0524] Example 106, a salt containing a formic acid, was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol as starting materials, following the preparation methods of Steps B and C of Example 69. LCMS: m / z 629.3 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.53(s,1H),7.69(dd,J=9.1,5.8Hz,1H),7.32(d,J=2.6Hz,1H),7. 27(t,J=9.3Hz,1H),7.10(s,1H),4.65–4.53(m,2H),4.07–3.98(m,2H),3.88–3.70(m,3H),3.52( dd,J=11.3,5.5Hz,1H),3.41(d,J=11.3Hz,1H),3.35(s,3H),3.27–3.19(m,1H),2.74–2.61(m,3 H),2.56–2.40(m,2H),2.21(s,3H),2.07–2.00(m,1H),1.95–1.71(m,4H),0.84(t,J=7.4Hz,3H).

[0525] Example 107 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0526] Example 107, a salt containing a formic acid, was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and ((S)-1-isopropylpyrrolidin-2-yl)methanol as starting materials, following the preparation method of Steps B and C of Example 69. LCMS: m / z 627.3 (M+H). 1 H NMR(600MHz,Methanol-d4)δ8.55(s,1H),7.70(dd,J=9.1,5.7Hz,1H),7.33(d,J=2.6Hz,1H) ,7.27(t,J=9.3Hz,1H),7.10(s,1H),4.64(s,2H),3.97(s,2H),3.72–3.62(m,4H),3.44–3.38 (m,1H),3.23–3.17(s,2H),2.49–2.41(m,2H),2.28–2.23(m,2H),2.21(s,3H),2.10–2.02(m ,4H),1.86–1.78(m,3H),1.39(d,J=6.7Hz,3H),1.33(d,J=6.4Hz,3H),0.84(t,J=7.4Hz,3H).

[0527] Example 108 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((dimethylamino)methyl)cyclopropane)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0528] Example 108 was synthesized using tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 1-((dimethylamino)methyl)cyclopropane)methanol as starting materials, following the preparation method of Steps B and C of Example 69. The salt contained 0.5 units of formic acid. LCMS: m / z 613.3 (M+H). 1H NMR (600MHz, Methanol-d4) δ8.56 (s, 0.5H), 7.69 (dd, J = 9.1, 5.7Hz, 1H), 7.32 (d, J = 2. 6Hz,1H),7.27(t,J=9.3Hz,1H),7.11(s,1H),4.58(s,1H),4.43(t,J=9.1Hz,2H),4.01 –3.73(m,3H),3.64(s,2H),2.93(s,2H),2.76–2.62(m,5H),2.50–2.41(m,2H),2.21(s ,3H),1.81(s,3H),1.70–1.52(m,2H),0.89(s,2H),0.84(t,J=7.4Hz,3H),0.74(s,2H).

[0529] Example 109 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(((R)-2-methylmorpholino)methyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0530] Example 109 was synthesized using (1R,5S)-tert-butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and (R)-(1-((2-methylmorpholino)methyl)cyclopropane)methanol as starting materials and referring to the preparation method of Steps B and C of Example 69. LCMS: m / z 669.3 (M+H). 1H NMR (600MHz, Methanol-d4) δ7.70(dd,J=9.1,5.7Hz,1H),7.33(d,J=2.7Hz,1H),7.28(t,J=9.4Hz,1H),7.07(d,J=2. 6Hz,1H),4.63(s,2H),4.52(t,J=8.4Hz,2H),4.28–4.18(m,3H),4.16–4.05(m,3H),3.95–3.88(m,2H),3.84–3.70(m ,3H),3.12(t,J=11.8Hz,1H),2.83(t,J=11.5Hz,1H),2.46(dd,J=14.8,7.6Hz,1H),2.32–2.25(m,1H),2.22(s,3H), 2.09(s,2H),1.97(s,2H),1.27(d,J=6.3Hz,3H),1.02(d,J=5.1Hz,2H),0.91(d,J=6.1Hz,2H),0.85(t,J=7.4Hz,3H).

[0531] Example 110 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-4-methylmorpholin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0532] Example 110 was synthesized using (1R,5S)-tert-butyl 3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and ((S)-4-methylmorpholin-2-yl)methanol as starting materials and referring to the preparation method of Steps B and C of Example 69. LCMS: m / z 615.3 (M+H). 1H NMR(600MHz, Methanol-d4)δ7.70(dd,J=9.1,5.8Hz,1H),7.33(d,J=2.7Hz,1H),7.28(t,J=9.4Hz,1H),7.07 (d,J=2.6Hz,1H),4.70(dt,J=12.0,3.5Hz,2H),4.62(d,J=12.2Hz,2H),4.28–4.06(m,6H),3.89(d,J=12.9Hz ,1H),3.69(d,J=12.4Hz,1H),3.51(d,J=12.9Hz,1H),3.22(d,J=6.8Hz,2H),3.00(s,3H),2.47(dd,J=14.6,7 .6Hz,1H),2.30–2.25(m,1H),2.22(s,3H),2.07(t,J=11.2Hz,2H),2.12–2.06(m,2H),0.85(t,J=7.4Hz,3H).

[0533] Example 111 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((dimethylamino)methyl)cyclopropane)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0534] Example 111, a salt containing a formic acid, was prepared using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol from Example 41 and 1-((dimethylamino)methyl)cyclopropane)methanol as starting materials according to the synthetic method of Steps D to F of Example 38. LCMS: m / z 609.3 (M+H). 1H NMR(600MHz, Methanol-d4)δ8.56(s,1H),7.89(dd,J=9.1,5.8Hz,1H),7.41–7.31(m, 3H),7.24(s,1H),4.45(d,J=11.4Hz,1H),4.40(d,J=11.5Hz,1H),3.70–3.61(m,3H),3 .55–3.51(m,1H),3.32–3.28(m,1H),3.06–2.93(m,2H),2.82–2.66(m,5H),2.36–2.32 (m,1H),2.21(s,3H),1.81(s,3H),1.73–1.52(m,3H),0.96–0.85(m,2H),0.76(s,2H).

[0535] Example 112 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-ol

[0536] Referring to the preparation method of Example 69, Example 112, a salt containing one formic acid, was prepared using corresponding starting materials and reagents. LCMS: m / z 571.3 (M+H). 1 H NMR(600MHz, Methanol-d4)δ8.55(s,1H),7.82(dd,J=9.8,5.6Hz,1H),7.35–7.31( m,2H),7.29(dd,J=9.9,5.5Hz,2H),4.66(dd,J=11.6,4.3Hz,1H),4.59(dd,J=11.7, 6.3Hz,1H),4.00–3.78(m,3H),3.69(s,2H),3.39–3.35(m,2H),3.30–3.23(m,1H), 2.77(s,3H),2.29–2.24(m,1H),2.23(s,3H),2.04–1.87(m,3H),1.86–1.67(m,5H).

[0537] Example 113 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-ol

[0538] Example 113, a salt containing one formic acid, was prepared by referring to the preparation method of Example 69 using corresponding starting materials and reagents. LCMS: m / z 599.3 (M+H). 1 H NMR(600MHz, Methanol-d4)δ8.50(s,1H),7.83(dd,J=9.4,5.6Hz,1H),7.35(d,J=2.4Hz,1H),7.33 (d,J=2.5Hz,1H),7.32–7.27(m,2H),4.74(d,J=11.9Hz,1H),4.68(dd,J=12.3,6.6Hz,1H),4.10(s, 1H),3.99–3.83(m,2H),3.82–3.72(m,3H),3.54–3.46(m,2H),2.34–2.27(m,1H),2.24(s,3H),2.1 4–2.05(m,3H),1.90–1.81(m,3H),1.79–1.66(m,2H),1.43(d,J=6.6Hz,3H),1.38(d,J=6.5Hz,3H).

[0539] Example 114 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-ol

[0540] Example 114, a salt containing one formic acid, was prepared by referring to the preparation method of Example 69 using corresponding starting materials and reagents. LCMS: m / z 625.3 (M+H). 1 H NMR (400MHz, Methanol-d4) δ7.83 (dd, J=8.9, 5.7Hz, 1H), 7.37–7.31 (m, 2H), 7.28 (dt, J= 10.6,3.7Hz,2H),4.60–4.46(m,3H),4.09–3.85(m,6H),3.30–3.22(m,2H),3.10–2.90(m, 2H), 2.24 (s, 3H), 2.03–1.60 (m, 11H), 1.00 (d, J = 5.2Hz, 2H), 0.88 (s, 2H).

[0541] Example 115 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0542] Using (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((1-(piperidin-1-yl)methyl)cyclopropane)methanol as raw materials, the preparation method of Example 115 containing 0.5 formic acid was referred to Steps B and C of Example 69 to synthesize Example 115.

[0543] LCMS: m / z 653.3 (M+H). 1 H NMR(600MHz, Methanol-d4)δ8.53(s,0.5H),7.70(dd,J=9.1,5.7Hz,1H),7.32(d,J=2.6Hz,1H),7.27(t,J=9.3Hz,1H),7.09(s,1H),4.46(s,2H),4.06– 3.74(m,5H),3.68(s,2H),3.20–3.08(m,4H),2.48–2.41(m,2H),2.21(s,3H ),1.96–1.77(m,6H),1.76–1.53(m,5H),0.96(s,2H),0.84(t,J=7.5Hz,5H).

[0544] Example 116 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2-((1-(pyrrolidin-1-yl)methyl)cyclopropane)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0545] Using (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((1-(pyrrolidin-1-yl)methyl)cyclopropane)methanol as raw materials, the salt containing a formic acid in Example 116 was synthesized by referring to the preparation method of steps B and C of Example 69.

[0546] LCMS: m / z 639.3 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.52(m,1H),7.69(dd,J=9.1,5.7Hz,1H),7.33(d,J=2.6Hz,1H),7.27(t,J=9.3Hz,1H),7.10(s,1H),4.47(s,2H),4.07–3.65 (m,6H),3.51–3.41(m,2H),2.49–2.40(m,3H),2.36–2.24(m,3H),2.21(s,3H ), 2.14–2.06 (m, 3H), 1.96–1.69 (m, 5H), 0.96 (s, 2H), 0.90 (t, J = 7.5Hz, 5H).

[0547] Example 117 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2-((1-(pyrrolidin-1-yl)methyl)cyclopropane)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-ol

[0548] Referring to the preparation method of Example 69, Example 117 as a salt containing 0.5 formic acid was prepared using corresponding starting materials and reagents. LCMS: m / z 611.3 (M+H). 1 H NMR(600MHz, Methanol-d4)δ8.56(s,0.5H),7.83(dd,J=9.1,5.6Hz,1H),7.36–7.32(m,2H),7.32–7.26(m,2H),4.46(s,2H),4.05 –3.71(m,3H),3.70–3.58(m,3H),3.29–3.11(m,4H),2.23(s,3H),2.11–2.00(m,4H),1.86–1.54(m,6H),0.93(s,2H),0.84(s,2H).

[0549] Example 118 Preparation of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0550] Example 118, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 658.3 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.51(s,1H),7.87(dd,J=9.1,5.6Hz,1H),7.37(d,J=2.6Hz,1H ),7.34(t,J=8.8Hz,1H),7.28(t,J=2.2Hz,1H),5.51–538(m,1H),4.54–4.38(m,4H),4.03– 3.90(m,3H),3.90–3.77(m,2H),3.65–3.44(m,4H),3.27–3.21(m,1H),2.57–2.34(m,3H),2 .31–2.23(m,1H),2.20(s,3H),2.19–2.11(m,2H),2.08–1.97(m,1H),1.11(d,J=1.9Hz,3H).

[0551] Example 119 Preparation of 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0552] Example 119, a salt containing 0.5 parts of formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 662.3 (M+H). 1H NMR (600MHz, Methanol-d4) δ8.53 (s, 0.5H), 7.69 (dt, J = 9.0, 5.5Hz, 1H), 7.32 (t, J = 2.4 Hz,1H),7.27(td,J=9.4,4.1Hz,1H),7.11(dt,J=6.8,2.4Hz,1H),5.45–5.34(m,1H),4.61(s,1H),4.49 –4.40(m,2H),4.40–4.34(m,1H),4.18–4.03(m,2H),3.97(d,J=12.0Hz,1H),3.90(d,J=14.8Hz,1H),3. 71(d,J=12.4Hz,1H),3.65(s,1H),3.55–3.37(m,4H),3.19–3.13(m,1H),2.47–2.29(m,3H),2.27–2.22 (m,2H),2.21(s,3H),2.14–2.07(m,2H),2.03–1.95(m,1H),1.14(d,J=22.3Hz,3H),0.89–0.80(m,3H).

[0553] Example 120 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0554] Example 120, a salt containing 0.5 parts formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 646.3 (M+H). 1H NMR (600MHz, Methanol-d4) δ8.53 (s, 0.5H), 7.69 (ddd, J=9.5, 5.8, 4.1Hz, 1H), 7.32 (d, J=2.6H z,1H),7.26(q,J=9.1Hz,1H),7.14–7.05(m,1H),5.46–5.35(m,1H),4.50–4.33(m,3H),3.93–3. 72(m,3H),3.55–3.37(m,2H),3.19–3.14(m,1H),2.52–2.29(m,4H),2.28–2.22(m,1H),2.20(s ,3H),2.16–2.09(m,3H),2.03–1.96(m,1H),1.83–1.65(m,4H),1.17(s,3H),0.90–0.82(m,3H).

[0555] Example 121 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0556] Example 121, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 658.3 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.54 (s, 0.5H), 7.70 (dd, J=9.1, 5.7Hz, 1H), 7.33 (t, J=3.1Hz, 1H ),7.27(td,J=9.4,5.5Hz,1H),7.18–7.08(m,1H),5.46–5.33(m,1H),4.49–4.31(m,4H),4.23 –3.94(m,2H),3.53–3.38(m,3H),3.19–3.12(m,2H),2.52–2.28(m,5H),2.27–2.19(m,4H),2. 15–2.07(m,3H),2.04–1.87(m,3H),1.82–1.69(m,2H),1.39–1.29(m,1H),0.89–0.84(m,3H).

[0557] Example 122 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)-4-(1,6-dioxa-9-azaspiro[3.6]dec-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0558] Example 122, a salt containing 0.3 parts formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 674.3 (M+H).

[0559] 1 H NMR(600MHz,Methanol-d4)δ8.55(s,0.3H),7.70(ddd,J=8.8,5.9,1.8Hz,1H),7.33(dd,J=4.1,2.6Hz,1H), 7.27(q,J=9.0Hz,1H),7.15–7.03(m,1H),5.42–5.31(m,1H),4.61(s,1H),4.44–4.30(m,4H),4.25–4.14(m,3 H),4.05–3.96(m,2H),3.90–3.79(m,2H),3.42–3.35(m,2H),3.14–3.08(m,1H),2.61–2.38(m,4H),2.38–2.2 5(m,2H),2.23(d,J=4.6Hz,3H),2.21–2.17(m,1H),2.17–2.03(m,3H),1.99–1.93(m,1H),0.88–0.81(m,3H).

[0560] Example 123 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylhexahydroazepin-3-ol

[0561] Example 123, a salt containing 0.5 parts of formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 660.3 (M+H).

[0562] 1 H NMR (600MHz, Methanol-d4) δ8.56(s,0.5H),7.68(dt,J=9.0,6.0Hz,1H),7.32(t,J=3.0Hz,1H),7.26(td,J=9.4,3.8H z,1H),7.14–7.09(m,1H),5.39–5.28(m,1H),4.60(s,1H),4.42–4.24(m,4H),3.96–3.70(m,2H),3.30–3.23(m,2H),3. 08–3.03(m,1H),2.44–2.33(m,2H),2.30–2.20(m,2H),2.19(d,J=2.5Hz,3H),2.18–2.09(m,2H),2.05–1.99(m,2H),1 .96–1.87(m,2H),1.83–1.73(m,2H),1.70–1.64(m,1H),1.61–1.53(m,1H),1.17(d,J=11.1Hz,3H),0.89–0.82(m,3H).

[0563] Example 124 Preparation of 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0564] Example 124, a salt containing 0.3 parts formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of steps B to F of Example 38. LCMS: m / z 658.3 (M+H)

[0565] 1H NMR (600MHz, Methanol-d4) δ8.55 (s, 0.3H), 7.70–7.66 (m, 1H), 7.31 (dd, J = 4.2, 2.6Hz, 1H), 7.28–7.22(m,1H),7.16–6.99(m,1H),5.43–5.31(m,1H),4.59(s,1H),4.43–4.24(m,3H),4.1 8–3.92(m,3H),3.42–3.33(m,3H),3.14–3.08(m,1H),2.49–2.25(m,5H),2.19(s,3H),2.15– 2.04(m,5H),2.01–1.92(m,2H),1.86–1.77(m,1H),1.54–1.46(m,1H),0.85(t,J=7.3Hz,3H).

[0566] Example 125 Preparation of 4-(4-((R)-3-aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0567] Example 125, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 631.3 (M+H). 1 H NMR (400MHz, Methanol-d4) δ8.50(d,J=5.1Hz,1H),7.70(dd,J=9.0,5.8Hz,1H),7.33(d,J =2.7Hz,1H),7.27(t,J=9.4Hz,1H),7.07(dd,J=5.4,2.7Hz,1H),5.47–5.30(m,1H),4.59( s,2H),4.49–4.22(m,4H),3.61–3.36(m,6H),3.20–3.09(m,1H),2.50–2.28(m,4H),2.28– 2.19(m,5H),2.15–2.04(m,2H),2.01–1.90(m,2H),1.80–1.68(m,2H),0.88–0.81(m,3H).

[0568] Example 126 Preparation of 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-2-ol

[0569] Example 126 was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials according to the synthetic method of steps B to F of Example 38. LCMS: m / z 658.3 (M+H).

[0570] Example 127 Preparation of (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0571] Example 127, a salt containing 0.3 parts formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 636.3 (M+H). 1 H NMR (600MHz, Methanol-d4) δ8.54(s,0.3H),7.63(dd,J=9.4,4.6Hz,1H),7.42(q,J=8.9Hz,1H),7.35(s,1H) ,7.31–7.19(m,1H),5.46–5.34(m,1H),4.60(s,1H),4.46(d,J=10.9Hz,1H),4.36(d,J=11.4Hz,1H),3.88(d ,J=10.5Hz,1H),3.77(d,J=11.0Hz,1H),3.53–3.37(m,3H),3.19–3.12(m,1H),2.53–2.28(m,3H),2.22(d,J =5.2Hz,4H),2.18–2.05(m,3H),2.01–1.94(m,1H),1.85–1.76(m,2H),1.75–1.68(m,1H),1.23–1.13(m,3H).

[0572] Example 128-P1 Preparation of (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol

[0573] Example 128-P1 (a salt containing 0.5 parts formic acid) was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 632.3 (M+H).

[0574] 1 H NMR(400MHz, Methanol-d4)δ8.54(s,0.5H),7.69(dd,J=9.1,5.8Hz,1H),7.33–7.31(m,1H),7 .27(td,J=9.4,4.4Hz,1H),7.13–7.04(m,1H),5.49–5.32(m,1H),4.61(s,2H),4.47(dd,J=10 .9,4.0Hz,1H),4.36(d,J=10.9Hz,1H),3.93–3.79(m,2H),3.54–3.38(m,3H),3.20–3.12(m,1 H),2.52–2.30(m,4H),2.21(s,3H),2.16–1.92(m,6H),1.77–1.59(m,3H),0.89–0.81(m,3H).

[0575] Example 128-P2 Preparation of (S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol

[0576] Example 128-P2 (a salt containing 0.5 parts formic acid) was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 632.3 (M+H).

[0577] 1H NMR (600MHz, Methanol-d4) δ8.54 (s, 0.5H), 7.69 (dd, J=9.0, 5.8Hz, 1H), 7.32 (d, J=2 .6Hz,1H),7.26(td,J=9.3,6.3Hz,1H),7.13–7.04(m,1H),5.44–5.33(m,1H),4.61(s, 1H),4.44–4.35(m,2H),3.90–3.77(m,2H),3.50–3.36(m,4H),3.17–3.10(m,1H),2.5 1–2.28(m,4H),2.21(s,3H),2.14–1.93(m,6H),1.76–1.59(m,3H),0.89–0.83(m,3H).

[0578] Example 129 Preparation of 4-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0579] Example 129, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 634.3 (M+H).

[0580] 1 H NMR (400MHz, Methanol-d4) δ8.55(s,1H),7.82(dd,J=9.0,5.7Hz,1H),7.34(q,J=2.5Hz,2 H),7.28(tt,J=10.3,4.8Hz,2H),5.45–5.28(m,1H),4.60(s,1H),4.48–4.25(m,4H),4.05 –3.89(m,4H),3.70(d,J=12.6Hz,1H),3.53–3.35(m,3H),3.15–3.08(m,1H),2.44–2.27(m ,2H),2.23(s,3H),2.22–2.16(m,1H),2.13–2.03(m,2H),2.01–1.92(m,1H),1.19(s,3H).

[0581] Example 130 Preparation of 1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0582] Example 130, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 618.3 (M+H).

[0583] 1 H NMR (400MHz, Methanol-d4) δ8.51(s,1H),7.83(dd,J=9.3,5.6Hz,1H),7.34(d,J=2.5Hz,1H),7.32(d,J =2.3Hz,1H),7.29(d,J=2.0Hz,1H),7.27(s,1H),5.53–5.34(m,1H),4.69–4.39(m,4H),3.91(d,J=13.6 Hz,1H),3.79(d,J=13.5Hz,1H),3.70–3.47(m,3H),3.28–3.20(m,1H),2.59–2.25(m,4H),2.23(s,3H), 2.21–2.13(m,2H),2.10–1.96(m,1H),1.79(q,J=3.9,3.3Hz,2H),1.69(d,J=13.4Hz,1H),1.18(s,3H).

[0584] Example 131 Preparation of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0585] Example 131, a salt containing 0.5 parts of formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 630.3 (M+H).

[0586] 1H NMR (600MHz, Methanol-d4) δ8.54 (s, 0.3H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (t ,J=2.2Hz,2H),7.29(td,J=8.7,2.6Hz,1H),7.23(d,J=10.9Hz,1H),5.44–5.33(m ,1H),4.44(d,J=10.7Hz,2H),4.37(d,J=10.8Hz,2H),4.30–3.96(m,4H),3.49–3. 37(m,3H),3.18–3.09(m,1H),2.47–2.28(m,5H),2.23(s,3H),2.20–1.92(m,7H).

[0587] Example 132 Preparation of (R)-1-(8-fluoro-2(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0588] Example 132, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 592.2 (M+H).

[0589] 1 H NMR(400MHz, Methanol-d4)δ8.50(s,0.3H),7.82(dd,J=9.8,5.7Hz,1H),7.35–7.26(m,4H),5.33–5.14(m,1 H),4.64–4.54(m,2H),3.91(d,J=13.6Hz,1H),3.77(d,J=13.5Hz,1H),3.64–3.52(m,1H),3.30–3.25(m,1H), 2.81(d,J=11.7Hz,1H),2.74(d,J=12.0Hz,1H),2.63(s,3H),2.43–2.30(m,2H),2 .23(s,3H),2.15–1.98(m,2H),1.83–1.75(m,2H),1.73–1.65(m,1H),1.18(s,3H).

[0590] Example 133 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0591] Example 133, a salt containing 0.5 parts of formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 574.3 (M+H).

[0592] 1 H NMR (600MHz, Methanol-d4) δ8.55 (s, 0.5H), 7.82 (dd, J = 9.5, 5.6Hz, 1H), 7.34 (d, J = 2. 4Hz,1H),7.32(d,J=2.2Hz,1H),7.29(t,J=8.4Hz,2H),4.62(d,J=20.8Hz,3H),3.92(d, J=13.7Hz,1H),3.78(d,J=13.6Hz,1H),3.40–3.27(m,2H),2.77(s,4H),2.29–2.24(m,2 H),2.23(s,3H),2.03–1.89(m,4H),1.83–1.76(m,2H),1.72–1.66(m,1H),1.18(s,3H).

[0593] Example 134 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropane)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0594] Example 134, a salt containing 0.5 parts of formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 588.3 (M+H).

[0595] 1H NMR (400MHz, Methanol-d4) δ8.57 (s, 0.5H), 7.82 (dd, J = 9.4, 5.6Hz, 1H), 7.36–7 .26(m,4H),4.60(s,2H),4.43(q,J=11.4Hz,2H),3.90(d,J=13.5Hz,1H),3.78(d, J=13.4Hz,1H),2.88–2.66(m,2H),2.57(s,6H),2.22(s,3H),2.00–2.13(m,1H),1 .83–1.76(m,2H),1.69(d,J=13.1Hz,1H),1.18(s,3H),0.84(s,2H),0.68(s,2H).

[0596] Example 135 Preparation of (R)-1-(2-((1-(aminomethylene)cyclopropane)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0597] Example 135, a salt containing 0.3 parts formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 560.2 (M+H).

[0598] 1 H NMR(400MHz, Methanol-d4)δ8.43(s,0.3H),7.81(dd,J=9.5,5.6Hz,1H),7.40–7.22(m,4H),4.61(s,1H),3.89–3.44 (m,6H),2.20(s,3H),1.83–1.63(m,3H),1.37–1.21(m,1H),1.19(s,3H),0.95–0.84(m,1H),0.55(t,J=28.3Hz,4H).

[0599] Example 136 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)hexahydroazepine-4-carbonitrile

[0600] Example 136, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 655.3 (M+H).

[0601] 1 H NMR (600MHz, Methanol-d4) δ8.54(s,1H),7.69(dt,J=9.4,5.1Hz,1H),7.32(d,J=2.6Hz,1H),7.26(td,J= 9.4,6.7Hz,1H),7.14–7.07(m,1H),5.44–5.33(m,1H),4.60(s,2H),4.47–4.33(m,2H),4.23–4.15(m,1H), 4.05–3.98(m,1H),3.86–3.79(m,1H),3.43–3.36(m,2H),3.20–3.11(m,1H),2.47–2.27(m,5H),2.25–2.20 (m,2H),2.18(d,J=2.6Hz,3H),2.13–2.07(m,2H),2.02–1.93(m,3H),1.38–1.30(m,H),0.89–0.83(m,3H).

[0602] Example 137 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0603] Example 137, a salt containing 0.3 parts formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 632.3 (M+H).

[0604] 1H NMR(600MHz, Methanol-d4)δ8.54(s,0.3H),7.68(t,J=7.5Hz,1H),7.31(s,1H),7.26(td,J=9.1,4.6Hz,1H), 7.17–7.09(m,1H),5.45–5.34(m,1H),4.60(s,1H),4.46(d,J=10.6Hz,1H),4.35(d,J=11.6Hz,1H),3.93–3.7 2(m,3H),3.53–3.37(m,3H),3.18–3.12(m,1H),2.51–2.28(m,3H),2.27–2.23(m,1H),2.21(s,3H),2.15–2.0 6(m,2H),2.02–1.95(m,1H),1.87(d,J=8.9Hz,3H),1.82–1.77(m,2H),1.74–1.67(m,1H),1.20–1.12(m,3H).

[0605] Example 138 Preparation of (R)-1-(2-(((2S,4R)-1-ethyl-4-fluoropyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0606] Example 138 (a salt containing 0.1 parts formic acid) was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 606.3 (M+H).

[0607] 1H NMR(600MHz, Methanol-d4)δ8.54(s,0.1H),7.82(dd,J=9.7,5.6Hz,1H),7.34(d,J=2.4Hz,1H),7.32(d,J=2.5Hz,1H), 7.31–7.26(m,2H),5.30–5.18(m,1H),4.65–4.59(m,2H),4.53(dd,J=11.2,5.3Hz,1H),3.91(d,J=13.4Hz,1H),3.77(d, J=13.7Hz,1H),3.59–3.49(m,1H),3.47–3.39(m,1H),3.23–3.13(m,1H),2.89–2.79(m,1H),2.70–2.63(m,1H),2.41–2. 33(m,1H),2.22(s,3H),2.21–2.17(m,1H),2.12–1.99(m,2H),1.84–1.75(m,2H),1.72–1.66(m,1H),1.22–1.13(m,6H).

[0608] Example 139 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((1-(pyrrolidin-1-yl)methyl)cyclopropane)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0609] Example 139, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 614.3 (M+H).

[0610] 1H NMR (600MHz, Methanol-d4) δ8.57(s,1H),7.83(dd,J=9.0,5.6Hz,1H),7.35(d,J=2.4Hz,1H),7.32(d,J=2.5Hz,1H),7.32–7.27(m,2H),4.61(s,1 H),4.53(d,J=11.6Hz,1H),4.41(d,J=11.6Hz,1H),3.91(d,J=13.5Hz,1H ),3.77(d,J=13.7Hz,1H),3.23–2.98(m,6H),2.23(s,3H),2.22–2.16(m, 1H),2.04–1.95(m,4H),1.81–1.77(m,2H),1.71–1.66(m,1H),1.36–1.30(m,1H),1.18(s,3H),0.88(s,2H),0.78(s,2H).

[0611] Example 140 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0612] Example 140, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 628.3 (M+H).

[0613] 1 H NMR(600MHz,Methanol-d4)δ8.56(s,1H),7.82(dd,J=9.0,5.6Hz,1H),7.34(d,J=2.4Hz,1H ),7.32(d,J=2.5Hz,1H),7.29(tt,J=9.1,4.1Hz,2H),4.60(s,1H),4.52(d,J=11.3Hz,1H), 4.40(d,J=11.3Hz,1H),3.89(d,J=13.5Hz,1H),3.77(d,J=13.7Hz,1H),3.02–2.62(m,6H), 2.23(s,3H),2.22–2.16(m,1H),1.85–1.49(m,10H),1.18(s,3H),0.85(s,2H),0.68(s,2H).

[0614] Example 141 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0615] Example 141, a salt containing a formic acid, was prepared using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as starting materials, following the synthetic method of Steps B to F of Example 38. LCMS: m / z 600.3 (M+H). ...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: Among them, R1 is CR 1a or N; R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -COOalkyl, carboxyl, amino, -CONH2, -NHCOalkyl, alkyl, alkylene cyano, alkenyl and alkynyl; preferably, R 1a Selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COOC 1-6 Alkyl, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring containing at least one nitrogen atom, wherein the saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring is optionally replaced by one, two or more R 2a Preferably, R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring containing 1, 2 or 3 ring N, wherein the saturated or partially saturated monocyclic, bridged, fused or spirocyclic ring is optionally replaced by one or more R 2a Preferably, R2 is a saturated or partially saturated 3-10 membered monocyclic ring, 6-12 membered bridged ring, 4-10 membered fused ring or 5-12 membered spirocyclic ring containing 1 or 2 ring N, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring is optionally replaced by one or more R 2a substituted; preferably, R2 is a saturated or partially saturated 3, 5, 6, 7, or 8-membered monocyclic ring, a 6, 7, 8, 9, or 10-membered bridged ring, a 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or a 5, 6, 7, 8, 9, 10, 11 or 12-membered spirocyclic ring containing 1 or 2 ring N and 0, 1, 2 or 3 ring heteroatoms independently selected from O and S, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring is optionally replaced by one or more R 2a Replace; each time R 2a Each of the groups independently selected from halogen, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, amino, -CONH2, -NHCOalkyl, alkyl, alkylene cyano, alkylene alkynyl, alkylene COOalkyl, -NHCOC 1-6 alkyl, alkenyl, oxo (=O), cycloalkyl, heterocyclyl and alkynyl, optionally, the alkylene, alkyl, alkynyl, alkenyl, cycloalkyl, and heterocyclyl are substituted by one, two or more groups selected from halogen, cyano, amino, hydroxy, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, alkyl, alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted with a substituent of the alkynyl group; preferably, each R 2a Each of the following is independently selected from F, Cl, Br, I, cyano, hydroxyl, mercapto, hydroxyl C 1-6 Alkylene, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylene cyano, C 1-6 Alkylene alkynyl, C 1-6 AlkyleneCOO C 1-6 Alkyl, -NHCOC 1-6 Alkyl, C 2-6 Alkenyl, oxo (=O) and C 2-6 Alkynyl, optionally, the C 1-6 Alkylene, C 1-6 Alkyl, C 2-6 Alkynyl, and C 2-6 The alkenyl group may be replaced by one, two or more groups selected from halogen, cyano, amino, hydroxy, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted by a substituent of the alkynyl group; Y is CR x R y ,O,S,S=O,S(=O)2 or NR x , R x and R y Each occurrence is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, alkyleneaminoalkyl, aryl and alkylenearyl; preferably, R x and R y Each occurrence is independently selected from hydrogen, and C 1-6 alkyl; R3 is selected from alkyl, alkylene hydroxyl, -L-heterocyclyl, -L-aryl, -L-arylene-L-heterocyclyl, -L-heteroarylene-L-heterocyclyl, -L-heteroaryl, -L-heterocyclylene-L-OCO-N(R5)2, -L-heterocyclylene-L-NR5-CO-N(R5)2, -L-heterocyclylene-L-NR5-CO-R5, -L-cycloalkyl, -L-cycloalkylene-LN(R5)2, -L-cycloalkylene-L-heterocyclyl and -L-cycloalkylene-LN(R5)2, wherein wherein the heterocyclyl, heteroarylene, heteroaryl, and heterocyclylene groups each independently contain 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, and the alkyl, alkylhydroxy, heterocyclyl, aryl, arylene, heteroarylene, heteroaryl, heterocyclylene, cycloalkyl, and cycloalkylene groups may be optionally substituted by one, two, or more groups selected from halogen, cyano, amino, hydroxyl, hydroxyalkyl, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, alkyl, alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl substituted pyrazolyl, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 Preferably, R3 is selected from C 1-6 Alkyl, C 1-6 Alkylhydroxy, -L-(3-12 membered heterocyclyl), -L-(6-10 membered arylene), -L-(6-10 membered arylene)-L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene)-L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene), -L-(3-12 membered heterocyclyl)-L-OCO-N(R5)2, -L-(3-12 membered heterocyclyl)-L-NR5-CO-N(R5)2, -L-(3-12 membered heterocyclyl)- L-NR5-CO-R5, -L-(3-10-membered cycloalkyl), -L-(3-10-membered cycloalkylene)-LN(R5)2, -L-(3-10-membered cycloalkylene)-L-(3-12-membered heterocyclyl) and -L-(3-10-membered cycloalkylene)-LN(R5)2, wherein the 3-12-membered heterocyclyl, 3-12-membered heterocyclylene, 5-12-membered heteroarylene and 5-12-membered heteroaryl each independently contain 1, 2, or 3 heteroatoms each independently selected from N, O and S, and the C 1-6 Alkyl, C 1-6 Alkylene hydroxyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 6-10 membered arylene, 5-12 membered heteroarylene, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, 3-10 membered cycloalkyl and 3-10 membered cycloalkyl may be optionally substituted by one, two or more groups selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 Hydroxyalkyl, mercapto, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl substituted pyrazolyl, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted by a substituent of the alkynyl group; Each occurrence of L is independently selected from a covalent bond, C 1-6 Alkylene, C 1-6 Hydroxyalkylene, -C(O)C 1-6 Alkylene, -C(O)O-, -OC(O)-, C 1-6 Deuterated alkylene, C 1-6 Halogenated alkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, optionally, the C 1-6 Alkylene, C 1-6 Hydroxyalkylene, C 1-6 Deuterated alkylene, C 1-6 Halogenated alkylene, cycloalkylene, heterocyclylene, arylene and Heteroaryl is replaced by one, two or more groups selected from F, Cl, Br, I, cyano, amino, hydroxy, C 1-6 Hydroxyalkyl, mercapto, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCOC 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 substituted by a substituent of the alkynyl group; R5 is independently selected at each occurrence from hydrogen, halogen, cyano, amino, hydroxy, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH2), -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkyl, alkyl, alkylamino, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl substituted pyrazolyl, arylene C 1-6 Alkyl, aryl C 1-6 Alkylene, (C 1-6 Alkoxy) C 1-6 Alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH2NHCO C 1-6 Alkyl, C 1-6 Alkylene cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; Cy2 is an aryl group fused to Cy1, a saturated or partially unsaturated cycloalkyl group, a heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a saturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the aryl group, saturated or partially unsaturated cycloalkyl group, heteroaryl group or heterocycloalkyl group may be optionally substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents, optionally, the alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents are substituted by 1, 2, 3 or more halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Cy2 is a 6-10 membered aryl group fused to Cy1, a saturated or partially unsaturated 3-10 membered cycloalkyl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 5-10 membered saturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5-10 membered partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the aryl group, saturated or partially unsaturated cycloalkyl group, heteroaryl group, heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more groups selected from F, Cl, Br, I, C 1-6 Alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 Substituted by a heteroaryl substituent, optionally, the C 1-6 Alkyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 Heteroaryl is substituted by 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 Alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 Preferably, Cy2 is substituted by a heteroaryl substituent; since in represents the connection site with R4, Indicates the fusion position of Cy2 and Cy1; q is 0, 1, or 2; R a Each occurrence is independently selected from hydrogen, halogen, alkyl, alkynyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, aryl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the alkyl, alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, aryl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, and heteroaryl are substituted by 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 Alkyl, hydroxyl, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 When R2 contains two ring N atoms, Cy2 is And R a When H, R4 is R3 is When Cy2 is And R a When H, R4 is R3 is When with R b Connected When it is a double bond, R b Each occurrence is independently O, S or C(R5)2; when b Connected When it is a single bond, R b Each occurrence is independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkyleneamino, cycloalkyl, heterocyclyl, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, alkylenehydroxy, aryl, alkynyl, alkenyl, and heteroaryl, preferably, R b Each occurrence is independently selected from hydrogen, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, cyano, amino, amino C 1-6 Alkyl, C 1-6 Alkyleneamino, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, and C 5-10 heteroaryl; R c Selected from H, C 1-6 Alkyl, -CN, -≡-R ca , -CONH2 and -OCONH2; when R2 contains 2 ring N atoms, and when R c C 1-6 When alkyl or H, R1 is N, R4 is When R2 contains 2 ring N atoms, when R c When H, R1 is CR 1a , R 1a for When CN, R4 is R3 is R ca Each time it appears, each R ca are each independently selected from hydrogen, amino, hydroxy, halogen, cyano, -CONH2, -NHC(O)C 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyleneamino, C 1-6 Alkylene NHC 1-6 Alkyl, C 1-6 Alkylene hydroxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkynyl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R ca Each time it appears, each R ca Each independently selected from hydrogen, amino, hydroxy, F, Cl, Br, I, cyano, -CONH2, -NHC(O)C 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyleneamino, C 1-6 Alkylene NHC 1-6 Alkyl, C 1-6 Alkylene hydroxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, optionally, the C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl is substituted by 1, 2, 3 or more groups selected from F, Cl, Br, I, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R ca Each time it appears, each R ca each independently selected from hydrogen, -CH3, -C(CH3)3, -C(CH3)2OH, -CH(CH3)OH, -C2H5, -C3H7, -C4H9, -CH2OH, -C2H4OH, -C3H6OH, -CH2NH2, -CH2NHCH3, and cyclopropyl; When R2 is R4 is And when R ca When it is hydrogen, R d When Y is O, R3 is not R d Each occurrence is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, mercapto, hydroxyalkylene, carboxyl, oxo, alkoxy, amino, -CONH2, -NHC(O)alkyl, alkyl, C 1-6 Alkylene cyano, -CO-alkyl, alkylamino, alkyleneamino, alkyleneNHalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, alkenyl and alkynyl, optionally, the alkyl, alkylene, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R d Each occurrence is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, mercapto, hydroxyl C 1-6 Alkylene, carboxyl, oxo, C 1-6 Alkoxy, amino, -CONH2, -NHC(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylene cyano, -CO-C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkyleneamino, C 1-6 Alkylene NH alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 5-10 Heteroaryl, C 2-6 Alkenyl and C 2-6 Alkynyl, optionally, the C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl is substituted by 1, 2, 3 or more groups selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 substituted by a heteroaryl substituent; R4 is selected from 0, 1, 2, 3, 4, 5, or more R 4a Substituted aryl and heteroaryl, the heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, R4 is selected from 0, 1, 2, 3, 4, 5 or more R 4a substituted 6-12 membered aryl and 5-12 membered heteroaryl, wherein the 5-12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, R4 is selected from 0, 1, 2, 3, 4, 5 or more R 4a substituted phenyl, naphthyl, 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; R 4a Each occurrence is independently selected from halogen, alkynyl, alkenyl, alkynylenealkyl, alkenylenealkyl, alkylenecyano, alkoxy, -OH, -SH, -NH2, -NH-R 4c 、-CN、-CO-alkyl、-CON(R 4c )2, alkyl-CO-NR 4c -, alkyl, haloalkyl, haloalkoxy, alkylamino, alkyleneamino, cycloalkyl, cycloalkylenealkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylenealkyl, optionally, the alkynyl, alkenyl, alkynylene, Alkenylene, alkylene, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylene may be substituted by one or more radicals selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, R 4a Each occurrence is independently selected from C 1-6 Alkyl, F, Cl, Br, I, C 2-6 Alkynyl, C 2-6 Alkenyl, C 2-6 Alkynylidene C 1-6 Alkyl, C 2-6 Alkenylene C 1-6 Alkyl, C 1-6 Alkylene cyano, C 1-6 Alkoxy, -OH, -SH, -NH2, -NH-R 4c 、-CN、-CO 1-6 Alkyl, -CON(R 4c )2、C 1-6 Alkyl-CO-NR 4c -、Halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyleneamino, 3-10 membered cycloalkyl, 3-10 membered cycloalkylene C 1-6 Alkyl, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkylene C 1-6 Alkyl, optionally, the C 2-6 Alkynyl, C 2-6 Alkenyl, C 2-6 Alkynylidene, C 2-6 Alkenylene, C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-10 Heterocycloalkyl and C 3-10 Heterocycloalkylene is replaced by one or more selected from halogen, alkyl, hydroxy, cyano, amino, -CONH2, -NHCOC 1-6 Alkyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylene hydroxyl, C 6-10 Aryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, and C 5-10 substituted by a heteroaryl substituent; R 4c Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, hydroxyalkylene, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, alkyl, C 1-6 alkylene cyano, alkenyl, and alkynyl groups; The compound of formula I is not:

2. A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: Among them, R1 is CR 1a or N; R 1a independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, -CONH2, amino, -NHCOC 1-6 Alkyl, alkyl, C 1-4 alkylcyano, alkenyl, and alkynyl groups; R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing at least one N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally replaced by one or more R 2a Replace; each time R 2a When it appears, each R 2a are independently selected from halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, carbonyl, amino, -CONH2-NHCOC 1-6 Alkyl, alkyl, C 1-4 Alkyl cyano, alkenyl and alkynyl; preferably, R2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing 1 ring N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally replaced by one or more R 2a substituted; preferably, R2 is a saturated or partially saturated 3, 5, 6, 7, or 8-membered monocyclic ring, a 6, 7, 8, 9, or 10-membered bridged ring, a 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or a 5, 6, 7, 8, 9, 10, 11 or 12-membered spirocyclic ring containing 1 ring N and 0, 1, 2 or 3 ring heteroatoms independently selected from O and S, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring is optionally substituted with one or more R2a; each R 2a When it appears, each R 2a are independently selected from halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COOalkyl, carboxyl, oxo, -NH2, -CONH2, -NHC(O)C 1-6 Alkyl, alkyl, C 1-4 alkylcyano, alkenyl, and alkynyl groups; Y is -CR x R y -, -O-, -S-, -S=O-, -S(=O)2- or -NR x -, R x and R y are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, alkylaminoalkyl, aryl, and alkylaryl; R3 is each independently selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, heterocyclic group, -LN(R5)2, -L-NHC(=NH)NH2, -LC(O)N(R5)2, -L-NR5C(O)-aryl, -LC 1-6 Haloalkyl, -L-OR5, -L-heterocyclyl, -L- Aryl, -L-heteroaryl, -L-cycloalkyl, nitrogen-saturated or partially saturated monocyclic or fused rings, and oxygen-saturated or partially saturated monocyclic or fused rings, wherein the heteroaryl, aryl, saturated or partially saturated monocyclic or fused ring portion and the heterocyclyl portion of -L-heterocyclyl and the cycloalkyl portion of -L-cycloalkyl may be optionally substituted with one or more R5; Each L is independently selected from C 1-6 Alkylene, C 1-6 hydroxyalkyl and heteroaryl groups; Each occurrence of R5 is independently selected from hydrogen, halogen, cyano, hydroxyl, thiol, hydroxymethyl, ester, carboxyl, carbonyl, -NH2, -CONH2, -NHC(O)C 1-6 Alkyl, alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl substituted pyrazolyl, aryl C 1-4 Alkyl, (C 1-4 Alkoxy) C 1-4 Alkyl-, (C 1-4 alkyl)C(=O)-, (C 1-4 haloalkyl)C(=O)-, -CH2NHCO C 1-6 Alkyl, C 1-4 Alkyl cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; Cy2 is fused with Cy1, and Cy2 is an aryl group or a 5-7 membered heteroaryl group containing 1 or 2 heteroatoms, a 5-7 membered saturated heterocycloalkyl group or a 5-7 membered unsaturated heterocycloalkyl group; and when Cy2 is an aryl group or a pyridyl group, it has the structural formula R a Each time it appears, each R a independently selected from hydrogen, halo, alkyl, alkynyl, hydroxyl, cyano, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkyl hydroxyl, aryl, C 2-4 Alkynyl, C 2-6 Alkenyl, cycloalkyl, heterocyclyl, heteroaryl; R c Selected from -CN, -≡-R ca 、 R ca Each time it appears, each R ca independently selected from hydrogen, halogen, cyano, -COO-alkyl, -NHC(O)C 1-6 Alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkyl hydroxyl, aryl, C 2-4 Alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl; Each time R d Each of the groups independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, oxo, oxyalkyl, amino, -CONH2, -NHC(O)C 1-6 Alkyl, alkyl, C 1-4 alkylcyano, alkenyl, and alkynyl groups; R4 is selected from 1, 2, or 3 R 4a or 1, 2 or 3 Rs 4b substituted phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered heterocyclic group, benzo 5-6 membered cycloalkenyl group and benzo 5-6 membered heteroaryl group; each R 4a independently selected from halo, -OH, -SH, -NH2, -CN, -CO-alkyl, -CON(R 4c )2、C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkyl C 1-4 Alkyl; each R 4b Each independently selected from halogen, -OH, -SH, -NH2, -NO2, -CN, -CO-alkyl, -CON(R 4c )2, triazole, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl cyanide, di-C 1-6 Alkylamino, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkylthio, di(halogenated C 1-6 Alkyl)amino; R 4c Each time it appears, each R 4c Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, amino, -CONH2, -NHCOC 1-6 Alkyl, alkyl, C 1-4 Alkylcyano, alkenyl and alkynyl, or two R attached to the same C atom 4c Formation = O; When R4 is When m is an integer from 0 to 6, each time R 4a When it appears, each R 4a Independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogen, -OH, -SH, -CN, -COR5, -CON(R5)2, -OCON(R5)2 and -≡-R ca ; Each time R ca When it appears, each R ca independently selected from hydrogen, halogen, -CN, -COO-alkyl, -CONH2, -NHCOC 1-6 Alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkyl hydroxyl, aryl, C 2-4 Alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl; Each occurrence of R6 is independently selected from H and C 1-4 alkyl; Preferably, the compound of formula I is not:

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: R4 is selected from 4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: R2 is selected from 5. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: R3 is selected from C 1-6 alkyl, Where n = 0, 1, 2 or 3; each time R 3b When present, independently selected from a covalent bond, -COC 1-6 Alkylene, C 1-6 Alkylene, C 1-6 Deuterated alkylene, cycloalkylene, C 1-6 Haloalkylene, heterocyclylene, arylene, and heteroarylene; and Each time R 3c When it appears, each R 3c independently selected from hydrogen, deuterium atoms, halogen groups, C 1-6 Alkyl, -CONH2, -NHCOC 1-6 Alkyl, C 1-6 Alkyl-NHCOC 1-6 Alkyl, hydroxy, amino, hydroxyalkylene, cyano, alkylamino, haloalkyl, C 1-6 Alkoxy.

6. The compound according to claim 1 or 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: R3 is selected from 7. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: Selected from Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is a formate salt of the compound, preferably the formate salt contains 0.1-3 moles of formate ions per mole of the compound, preferably the formate salt contains 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2 or 3 moles of formate ions per mole of the compound.

8. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: The compound is selected from Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is a formate salt of the compound, preferably the formate salt contains 0.1-3 moles of formate ions per mole of the compound, preferably the formate salt contains 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2 or 3 moles of formate ions per mole of the compound.

9. A method for preparing the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, characterized in that: include: Scheme a): Under the action of base and DMF, nitrogen-containing heterocyclic ring R2 and intermediate compound Selective nucleophilic substitution to obtain compounds Then, the allylamine containing R4 group and the methyl ester compound III-4 are subjected to amine ester exchange under the action of LiHMDS to obtain Amide compounds Then, a nucleophile having the formula HY-R3 is used to replace the chlorine in the amide compound III-5 and introduce a substituent -Y-R3 in the presence of cesium carbonate and 1,4-dioxane as a solvent to obtain a compound Subsequently, compound III-6 is subjected to a Heck reaction in the presence of a palladium catalyst and an organic base to obtain an intermediate compound containing an exocyclic double bond, and then the intermediate compound containing an exocyclic double bond is deprotected to obtain a compound of formula I; and / or scheme b): Alternatively, the intermediate compound After mixing with PyBOP, DIEA and nitrogen-containing heterocyclic compound R2, the reaction is carried out to obtain compound Then the allylamine containing R4 group and the chloride IV-4 are subjected to substitution reaction under K2CO3 and acetonitrile heating to obtain compound Then use palladium catalyst to carry out Heck reaction ring closure to obtain exocyclic double bond compound Then, the sulfide compound is oxidized with IV-6 by m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of formula HY-R3 in the presence of cesium carbonate and 1,4-dioxane as solvent to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce a substituent -Y-R3 to obtain an intermediate compound, which is then deprotected to obtain the target compound. and / or scheme c): the intermediate compound After mixing with PyBOP, DIEA and nitrogen-containing heterocyclic ring R2, the reaction is carried out to obtain compound Then, a palladium catalyst is used to perform Heck reaction to obtain an intracyclic double bond compound. Then, the Chan-Lam coupling reaction is used to couple the R4 group to V-6 to obtain Subsequently, the sulfoxide is obtained by oxidation of the sulfide compound and V-7 with m-CPBA, and then reacted with a nucleophile of the structural formula HY-R3 in the solvent conditions of cesium carbonate and 1,4-dioxane to replace the sulfoxide group of the sulfoxide pyrimidine compound and introduce the substituent -Y-R3 to obtain an intermediate compound, which can be obtained by deprotection in step H. And / or scheme d): using phosphorus oxychloride to convert the intermediate compound After chlorination of the hydroxyl group, a nucleophilic reaction with the nitrogen-containing heterocyclic ring R2 is performed to obtain Then based on Suzuki The coupling reaction introduces a methyl group to prepare the compound Then, a Suzuki coupling or Stille coupling reaction is used to prepare a compound containing R4. Then, selenium dioxide is used to oxidize the methyl group to obtain the aldehyde Then, dimethyl (1-diazo-2-oxopropyl)phosphonate reagent (Ohira-Bestman reagent) and aldehyde VI-5 were reacted with potassium carbonate and methanol to generate alkyne. Then, the sulfoxide compound VI-6 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of the formula HY-R3 in a solvent containing LiHMDS and THF to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce a substituent -Y-R3 to obtain an intermediate compound, which is then deprotected to obtain the compound and / or option e): Will The intermediate oxime was prepared under the action of hydroxylamine hydrochloride and potassium carbonate. The intermediate oxime VII-1 is then dehydrated under the action of acetic anhydride to form a cyano group get Then, the sulfoxide compound VII-2 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophilic reagent of the formula HY-R3. Subsequently, under the conditions of a solvent containing LiHMDS and THF, the sulfoxide group of the sulfoxide pyrimidine compound is replaced and a substituent -Y-R3 is introduced to obtain an intermediate compound. The intermediate compound is deprotected to obtain the compound And / or scheme f): At low temperature, in anhydrous THF of LiHMDS, capture The terminal alkyne's H then reacts with an electrophilic reagent containing an R group to form a substituted alkynyl compound Then, the sulfide compound VII-2 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of the formula HY-R3. Subsequently, in a solvent containing LiHMDS and THF, the sulfoxide group of the sulfoxide pyrimidine compound is replaced and a substituent -Y-R3 is introduced to obtain an intermediate compound. The intermediate compound is deprotected to obtain the compound; And / or, Scheme g): using trifluoroethyl trifluoromethanesulfonate and an intermediate compound Under the action of DMF and base, the intermediate compound is generated Then, the Rca-substituted acetylene reagent was used for coupling reaction under palladium catalysis to obtain the compound The nitrogen-containing heterocyclic ring R2 reacts with compound VIII-2 under the action of a base to undergo nucleophilic substitution reaction. Compound VIII-3 should be obtained Then, a borate or boric acid containing an R4 group, or an organic tin reagent, is reacted with chloropyridine VI-3 under the catalysis of a palladium reagent to undergo Suzuki coupling or Stille coupling reaction to obtain a compound containing R4. Then, the sulfoxide compound VIII-4 is oxidized with m-CPBA to obtain a sulfoxide, which is then reacted with a nucleophile of the formula HY-R3 in a solvent containing LiHMDS and THF to replace the sulfoxide group of the sulfoxide pyrimidine compound to introduce a substituent -Y-R3 to obtain an intermediate compound, which is then deprotected to obtain the compound Wherein, R2 is as defined in any one of claims 1 to 6, the compound containing nitrogen heterocyclic ring R2 is preferably a heterocyclic compound containing piperazine, bridged ring piperazine, morpholinyl, or piperidinyl; the organic base is preferably triethylamine; and the electrophilic reagent is preferably deuterated water, halogenated hydrocarbon, aldehyde, or ketone compound.

10. The preparation method according to claim 9, characterized in that include: described It is prepared by a method comprising the following steps: Methyl orotate reacts with halogen X' to produce Then, phosphorus oxyhalide and DIEA are used to halogenate the hydroxyl group to obtain III-3; preferably, the halogen X' is bromine, and the phosphorus oxyhalide is phosphorus oxychloride; more preferably, the III-3 is and / or, It is prepared by a method comprising the following steps: Will Reaction with S-methylisothiourea sulfate to obtain Then, a substitution reaction is carried out with an N-halogenated succinimide containing a halogen X' to obtain compound IV-3; preferably, the IV-1 is ethyl chloroacetoacetate, the N-halogenated succinimide is N-bromosuccinimide (NBS); more preferably, the IV-3 is and / or, It is prepared by a method comprising the following steps: Diethyl oxaloacetate sodium salt With S-methylisothiourea sulfate Under strong alkaline conditions, the reaction Then, N-halogenated succinimide is used for halogenation reaction to obtain Then, V-3 is subjected to an amide condensation reaction with allylamine to obtain V-4; preferably, the N-halosuccinimide is N-bromosuccinimide (NBS); more preferably, V-4 is 11. A pharmaceutical composition, characterized in that Comprising a therapeutically effective amount of the compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, and a pharmaceutically acceptable excipient.

12. Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for inhibiting the activity of a KRas mutant protein, preferably, in the preparation of a medicament for inhibiting the activity of KRas G12D.

13. Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating KRas mutant protein-related cancers, preferably in the preparation of a medicament for treating KRas G12D-related cancers.

14. The use according to claim 13, characterized in that The KRas mutant protein-related cancer is selected from: Non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer, and pancreatic cancer; bronchial cancer, alveolar cancer, sarcoma, lymphoma, bronchial adenoma, chondroma, hamartoma, and mesothelioma; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vipoma, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal Kaposi's sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal hamartoma, large intestinal villous adenoma, and large intestinal leiomyoma; heart sarcoma, cardiac angiosarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, cardiac fibroma, cardiac rhabdomyoma, cardiac lipoma, and cardiac teratoma; hepatocellular carcinoma or hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, and hepatic hemangioma; gallbladder cancer, bile duct cancer, and ampullary carcinoma; Wilms' tumor, Wilms' tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratocarcinoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular fibroma, testicular adenomatoid tumor, and testicular lipoma; Osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, reticulocyte sarcoma, benign enchondroma, malignant giant cell tumor, chordoma, chondroblastoma, osteochondroma, osteochondral exostosis, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; osteoma, xanthomas, hemangiomas, granulomas, osteitis deformans, meningioma, glioma, meningiosarcoma, astrocytoma, medulloblastoma, ependymoma, glioma, germ cell tumor, pinealoma, neurilemoma, oligodendroglioma, glioblastoma multiforme, retinoblastoma, glioma, congenital tumors, meningioma, spinal neurofibroma, sarcoma; endometrial carcinoma, serous cyst Adenocarcinoma, mucinous cystadenocarcinoma, granulosa-theca cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube carcinoma; acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; malignant melanoma of the skin, Kaposi's sarcoma of the skin, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, nevus of the skin with dysplasia, skin lipoma, skin hematoma One or more of: ductal carcinoma, dermatofibroma, skin keloid, psoriasis; adrenal neuroblastoma.

15. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or the pharmaceutical composition according to claim 9, for inhibiting the activity of a KRas mutant protein, preferably, for inhibiting the activity of KRas G12D.

16. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or the pharmaceutical composition according to claim 9, for use in treating KRas mutant protein-related cancers, preferably for treating KRas G12D-related cancers.

17. The compound for use according to claim 16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein: The KRas mutant protein-related cancer is selected from non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer and pancreatic cancer; bronchial cancer, alveolar cancer, sarcoma, lymphoma, bronchial adenoma, chondroma hamartoma, mesothelioma; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vipoma, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal Kaposi's sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal hamartoma, large intestinal villous adenoma, large intestinal intestinal leiomyomas; cardiac sarcoma, cardiac angiosarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, cardiac fibroma, cardiac rhabdomyoma, cardiac lipoma, and cardiac teratoma; hepatocellular carcinoma or hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, and hepatic hemangioma; gallbladder cancer, bile duct cancer, and ampullary carcinoma; Wilms' tumor, Wilms' tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratocarcinoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular fibroma, testicular adenomatoid tumor, and testicular lipoma; Osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, reticulum cell sarcoma, benign chondroma, malignant giant cell tumor chordoma, chondroblastoma, osteochondroma, osteocartilaginous exostosis, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; osteoma, xanthomas, hemangiomas, granulomas, osteitis deformans, meningioma, glioma, meningiosarcoma, brain astrocytoma, medulloblastoma, ependymoma, glioma, germ cell tumor, pinealoma, neurilemoma, oligodendroglioma, glioblastoma multiforme, retinoblastoma, glioma, congenital tumors, Meningioma, spinal neurofibroma, sarcoma; endometrial cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-theca cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; one or more of the following: malignant melanoma of the skin, Kaposi's sarcoma of the skin, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, dysplastic nevus of the skin, skin lipoma, skin hemangioma, dermatofibroma, skin keloid, psoriasis; adrenal neuroblastoma.

18. A method for treating a disease responsive to inhibition of KRas mutant protein activity, comprising administering to a subject suffering from the disease a therapeutically effective amount of the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or the pharmaceutical composition of claim 9.

19. A method for treating KRas mutant protein-related cancer, comprising administering to a subject suffering from the KRas mutant protein-related cancer a therapeutically effective amount of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or the pharmaceutical composition of claim 9, wherein preferably, the KRas mutant protein-related cancer is KRas G12D-related cancer.

20. The method according to claim 19, wherein The KRas mutant protein-related cancer is selected from the group consisting of: non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer and pancreatic cancer; bronchial cancer, alveolar cancer, sarcoma, lymphoma, bronchial adenoma, chondroma hamartoma, mesothelioma; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vipoma, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal Kaposi's sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal hamartoma, large intestinal villous adenoma, large intestinal intestinal leiomyomas; cardiac sarcoma, cardiac angiosarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, cardiac fibroma, cardiac rhabdomyoma, cardiac lipoma, and cardiac teratoma; hepatocellular carcinoma or hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, and hepatic hemangioma; gallbladder cancer, bile duct cancer, and ampullary carcinoma; Wilms' tumor, Wilms' tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratocarcinoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular fibroma, testicular adenomatoid tumor, and testicular lipoma; Osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, reticulocyte sarcoma, benign enchondroma, malignant giant cell tumor, chordoma, chondroblastoma, osteochondroma, osteochondral exostosis, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; osteoma, xanthomas, hemangiomas, granulomas, osteitis deformans, meningioma, glioma, meningiosarcoma, astrocytoma, medulloblastoma, ependymoma, glioma, germ cell tumor, pinealoma, neurilemoma, oligodendroglioma, glioblastoma multiforme, retinoblastoma, glioma, congenital tumors, meningioma, spinal neurofibroma, sarcoma; endometrial carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa cell-theca cell tumor , malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; malignant melanoma of the skin, Kaposi's sarcoma of the skin, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, dysplastic nevus of the skin, skin lipoma, skin hemangioma, skin fibroma, skin keloid, psoriasis; one or more of adrenal neuroblastoma.