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HETEROCYCLIC COMPOUNDS AS KRAS INHIBITOR, AND PREPARATION THEREFOR AND USE THEREOF IN TREATMENT

20240300980 ยท 2024-09-12

    Inventors

    Cpc classification

    International classification

    Abstract

    Disclosed is a compound of formula (I) and (II) or a pharmaceutically acceptable salt, prodrug, tautomer or stereoisomer, and solvate thereof. The compound can be applied to treatment of cancers and inflammations of mammals. Further disclosed are a preparation method for the compound of formula (I) and (II) and a pharmaceutical composition containing the compound.

    ##STR00001##

    Claims

    1. A compound of formula (I) or (II), or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein the compounds of formula (I) and (II) are: ##STR00828## wherein: ##STR00829## is a 4- to 12-membered saturated or partially saturated monocyclic, bridged cyclic, or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted with one or more R.sup.1, X.sup.1 is selected from N and CR.sup.4; X.sup.2 is selected from NR.sup.4, CR.sup.4 and S(O).sub.0,1,2R.sup.4, wherein, R.sup.1 is selected from hydrogen, halogen, C.sub.1-6 alkyl optionally substituted by halogen or hydroxyl or NR.sup.1aR.sup.1b, CN, OR.sup.1a, SR.sup.1a, NR.sup.1aR.sup.1b, S(O)R.sup.1a, S(O).sub.2R.sup.1a, C(O)R.sup.1a, C(O)OR.sup.1a, NR.sup.1aC(O)R.sup.1b, C(O)NR.sup.1aR.sup.1b, S(O).sub.2N(R.sup.1aR.sup.1b).sub.2 and 5 to 6-membered heteroaryl, wherein R.sup.1a and R.sup.1b are each independently hydrogen, C.sub.1-6 alkyl, hydroxy C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl and C.sub.1-6 alkoxy C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl; R.sup.4 is selected from hydrogen, halogen, C.sub.1-6 alkyl optionally substituted by halogen or hydroxyl, CN, OR.sup.4a, SR.sup.4a, S(O)R.sup.4a, S(O).sub.2R.sup.4a, C(O)R.sup.4a, C(O)OR.sup.4a, NR.sup.4aC(O)R.sup.4b, C(O)NR.sup.4aR.sup.4b and S(O).sub.2N(R.sup.4aR.sup.4b).sub.2, wherein R.sup.4a and R.sup.4b are each independently hydrogen, C.sub.1-6 alkyl, hydroxy C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl and C.sub.1-6 alkoxy C.sub.1-6 alkyl; L is a single bond, O, S, NR.sup.La, O(CR.sup.LaR.sup.Lb).sub.t, S(CR.sup.LaR.sup.Lb).sub.t, NR.sup.Lc(CR.sup.LaR.sup.Lb).sub.t, (CR.sup.LaR.sup.Lb).sub.tO, (CR.sup.LaR.sup.Lb).sub.tS, (CR.sup.LaR.sup.Lb).sub.tNR.sup.Lc, C(O), SO.sub.2, SO, C(O)O, OC(O), C(O)NR.sup.Lc or N.sup.LcC(O), wherein R.sup.La, R.sup.Lb and R.sup.Lc are each independently hydrogen and C.sub.1-6 alkyl, or R.sup.La and R.sup.Lb connected to the same carbon atom form C.sub.3-C.sub.6 cycloalkyl with the connected carbon atom, and t is an integer from 1 to 6; R.sup.2 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted by one or more halogen, cyano, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, hydroxy C.sub.1-6 alkyl, C.sub.1-6 alkoxy C.sub.1-6 alkyl, oxo, OR.sup.2a, C(O)R.sup.2a, (CR.sup.2aR.sup.2b).sub.mOC(O)NR.sup.2cR.sup.2d, CO.sub.2R.sup.2a, CONR.sup.2cR.sup.2d, NR.sup.2cR.sup.2d, NR.sup.2cR.sup.2d, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl C.sub.1-6 alkyl, aryl, heteroaryl, and heterocyclyl, wherein R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are each independently hydrogen, C.sub.1-6 alkyl, hydroxy C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl and C.sub.1-6 alkoxy C.sub.1-6 alkyl, or R.sup.2c and R.sup.2d together with the nitrogen atom to which they are attached, form an 4 to 6-membered heterocycle, The heterocycle contains 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur as ring members, and wherein m is an integer from 1 to 6; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R.sup.8; Each R.sup.8 is independently halogen, cyano, oxo, C.sub.1-6 alkyl optionally substituted by halogen, cyano, hydroxyl or deuterium, C.sub.2-C.sub.6 alkenyl optionally substituted by hydroxyl or deuterium, C.sub.2-C.sub.6 alkynyl optionally substituted by hydroxyl or deuterium, OR.sup.8a, SR.sup.8a, S(O).sub.2R.sup.8a, P(?O)R.sup.8aR.sup.8b, NR.sup.8aR.sup.8b, C(O)NR.sup.8aR.sup.8b, optionally C.sub.3-C.sub.6 cycloalkyl substituted by halogen or C.sub.1-6 alkyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein R.sup.8a and R.sup.8b are each independently hydrogen, C.sub.1-6 alkyl substituted by halogen and C.sub.1-6 alkoxy-C.sub.1-6 alkyl-; or two R.sup.8 on the same carbon atom form C.sub.3-C.sub.8 cycloalkyl; or R.sup.8 on two adjacent carbon atoms together with their connected carbon atoms form C.sub.3-C.sub.8 cycloalkyl; Q.sup.1, Q.sup.2, and Q.sup.3 are each independently N or CR.sup.6, and M.sup.1 and M.sup.2 are each independently N or CR.sup.7, provided that at least one of Q.sup.1 and M.sup.1 is N; wherein R.sup.6 and R.sup.7 are each independently hydrogen, halogen, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl, OR.sup.6a, C(O)R.sup.6a, CO.sub.2R.sup.6a, CONR.sup.6aR.sup.6b or NR.sup.6aR.sup.6b, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl are independently substituted by one or more of oxo, halogen, hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, nitro, cyano and NR.sup.dR.sup.c, wherein R.sup.6a, R.sup.6b, R.sup.6c and R.sup.6d are each independently hydrogen, C.sub.3-6 alkyl, C.sub.1-6 alkyl, hydroxy C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl and C.sub.1-6 alkoxy C.sub.1-6 alkyl; or R.sup.7 on M.sup.2 and substituent R.sup.8 on R.sup.3 form a ring structure together with the part to which they are connected; or the substituents on Q.sup.2 and Q.sup.3 are connected to form a saturated or partially saturated 5 to 6-membered aliphatic ring, aromatic ring, or heteroaromatic ring.

    2. The compound according to claim 1, wherein ##STR00830## is ##STR00831## ##STR00832## wherein R.sup.4 is each independently selected from hydrogen, halogen, C.sub.1-6 alkyl, CN, OR.sup.4a, SR.sup.4a, S(O)R.sup.4a, S(O).sub.2R.sup.4a, C(O)R.sup.4a, C(O)OR.sup.4a, NR.sup.4aC(O)R.sup.4b, C(O)NR.sup.4aR.sup.4b and S(O).sub.2N(R.sup.4aR.sup.4b).sub.2, wherein R.sup.4a and R.sup.4b are each independently hydrogen, C.sub.1-6 alkyl and hydroxy C.sub.1-6 alkyl.

    3. The compound according to claim 1, wherein ##STR00833## is ##STR00834##

    4. The compound according to claim 1, wherein L is OCH.sub.2 or O.

    5. The compound according to claim 1, wherein L is OCH.sub.2, and R.sup.2 is a heterocyclyl that is unsubstituted or substituted by one or more of halogen, C.sub.1-6 alkyl, OR.sup.2 and (CR.sup.2aR.sup.2b).sub.mOC(O)NR.sup.2cR.sup.2a, wherein each variable is as defined for formula (I); preferably, the heterocyclyl is unsubstituted or substituted by one or more of halogen, C.sub.1-6 alkyl and OR.sup.2a; more preferably, the heterocyclyl is unsubstituted or substituted by one or two of halogen, methyl and methoxy.

    6. The compound according to claim 1, wherein L is OCH.sub.2, and R.sup.2 is a 4 to 8-membered single ring heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur as ring members, or a 6 to 12-membered bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur as ring members, wherein the single ring or bicyclic heterocyclyl is unsubstituted or substituted by one or more of halogen, C.sub.1-6 alkyl, OR.sup.2a and (CR.sup.2aR.sup.2b).sub.mOC(O)NR.sup.2cR.sup.2d, wherein each variable is defined for formula (I).

    7. The compound according to claim 6, wherein the heterocyclyl is unsubstituted or substituted by one or more halogen, C.sub.1-6 alkyl, and OR.sup.2a; more preferably, the heterocyclyl is unsubstituted or substituted by one or two halogen, methyl, and methoxy.

    8. The compound according to claim 6, wherein L is OCH.sub.2, and R.sup.2 is a monocyclic heterocyclic ring, which is azetidinyl, pyrrolidyl or piperidyl, the ring is unsubstituted or substituted by one or two halogen or C.sub.1-6 alkyl; or L is OCH.sub.2, and R.sup.2 is a bicyclic heterocycle, which is octahydropentadiene, wherein at least one carbon atom is replaced by a nitrogen atom, and one of the other carbon atoms is optionally replaced by an oxygen atom.

    9. The compound according to claim 6, wherein L is OCH.sub.2, and R.sup.2 is a bicyclic heterocyclic ring, which is tetrahydro-1H-pyrrolizinyl, tetrahydro-1H-furanopyrrolidyl, octahydrocyclopentopyrrolidyl, azabicyclo[3.1.0]hexanyl, wherein the group is unsubstituted or substituted by one or more of halogen, C.sub.1-6 alkyl, OR.sup.2a and (CR.sup.2aR.sup.2b).sub.mOC(O)NR.sup.2cR.sup.2d, each of the variables is as defined for formula (I). Preferably substituted by one or more of halogen, C.sub.1-6 alkyl and OR.sup.2a; more preferably substituted by one or two of halogen, methyl and methoxy.

    10. The compound according to claim 9, wherein the bicyclic heterocyclyl is tetrahydro-1H-pyrrolizin-7-yl, tetrahydro-1H-furano[3,4-b]pyrrole-3a-yl, tetrahydro-1H-furano[3,4-c]pyrrole-3a-yl, tetrahydro-1H-furano[3,4-b]pyrrole-6a-yl, octahydrocyclopenta[b]pyrrole-6a-yl, octahydrocyclopenta[c]pyrrole-3a-yl, octahydrocyclopenta[b]pyrrole-3a-yl, 3-azabicyclic[3.1.0]hexane-1-yl or 2-azabicyclic[3.1.0]hexane-1-yl, wherein the functional group is unsubstituted or substituted by one or more of halogen, C.sub.1-6 alkyl, OR.sup.2a, and (CR.sup.2aR.sup.2b).sub.mOC(O)NR.sup.2cR.sup.2d, wherein each variables is as defined for formula (I); preferably substituted by one or more of halogens, C.sub.1-6 alkyl, and OR.sup.2a; more preferably, substituted by one or two of halogen, methyl, and methoxy.

    11. The compound according to claim 1, wherein L-R.sup.2 is ##STR00835## ##STR00836## ##STR00837##

    12. The compound according to claim 1, wherein R.sup.3 is a. monocyclic aryl or heteroaryl, selected from phenyl, pyridyl, pyrimidinyl and pyrazinyl; b. bicyclic aryl or heteroaryl, selected from naphthyl (e.g., naphthalene-1-yl, naphthalene-2-yl, naphthalene-3-yl, naphthalene-4-yl, naphthalene-5-yl, naphthalene-6-yl, naphthalene-7-yl, naphthalene-8-yl), isoquinolinyl (e.g. isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl and isoquinoline-8-yl), tetrahydroisoquinoline (e.g., 5,6,7,8-tetrahydroisoquinoline-1-yl, 5,6,7,8-tetrahydroisoquinoline-3-yl, and 5,6,7,8-tetrahydroisoquinoline-4-yl), tetrahydrogenated naphthalene (e.g. 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-3-yl, 5,6,7,8-tetrahydronaphthalen-4-yl); c. tricyclic aryl or heteroaryl, selected from ##STR00838## the aryl or heteroaryl is substituted by 1 to 3 R.sup.8, R.sup.8 is each independently selected from: halogen, C.sub.1-6 alkyl optionally substituted by halogen, C.sub.2-C.sub.6 alkynyl, P(?O)R.sup.8aR.sup.8b, NR.sup.8aR.sup.8b, OR.sup.8a, SR.sup.8a, C.sub.3-C.sub.6 cycloalkyl optionally substituted by halogen or C.sub.1-6 alkyl, wherein R.sup.8a and R.sup.8b are each independently of hydrogen and C.sub.1-6alkyl.

    13. The compound according to claim 12, wherein R.sup.3 is a naphthalen-1-yl, and the 3 position of the naphthalen-1-yl is unsubstituted or substituted by OR.sup.8a, P(?O)R.sup.8aR.sup.8b, or NR.sup.8aR.sup.8b, wherein R.sup.8a and R.sup.8b are each independently hydrogen and C.sub.1-6 alkyl.

    14. The compound according to claim 13, wherein one or two of the positions 5, 6, 7 and 8 of the naphthalene-1-yl are substituted, the substituent group is independently selected from halogen, C.sub.1-6 alkyl optionally substituted by halogen, C.sub.2-C.sub.6 alkynyl, P(?O)R.sup.1aR.sup.8b, NR.sup.8aR.sup.8b, OR.sup.8a, SR.sup.8a, and C.sub.3-C.sub.6 cycloalkyl optionally substituted by halogen or C.sub.1-6 alkyl, wherein R.sup.8a and R.sup.8b are each independently hydrogen and C.sub.1-6alkyl.

    15. The compound according to claim 1, wherein R.sup.3 is ##STR00839## ##STR00840## ##STR00841## ##STR00842## ##STR00843## ##STR00844## ##STR00845## ##STR00846## ##STR00847## ##STR00848## ##STR00849##

    16. The compound according to claim 1, wherein the compound is a specific compound disclosed by the present invention.

    17. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1.

    18. A method for treating a cancer associated with H-ras, K-ras or N-ras inhibition, comprising administering a subject in need thereof the compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1.

    19. The method of claim 18, wherein the cancer is a cancer mediated by a G12D mutation.

    20. The method of claim 19, wherein the cancer is lung cancer, colorectal cancer or pancreatic cancer.

    Description

    DETAILED DESCRIPTION OF EMBODIMENTS

    [0082] Unless otherwise indicated, the entire disclosure of the present invention is defined by the following terms:

    [0083] The term prodrug refers to any derivative that can be converted into the corresponding active pharmaceutical compound in an organism. The prodrug of the compound described herein can easily undergo chemical changes under physiological conditions and is thus transformed into the compound of the present invention. In addition, the prodrug can be converted into the compound of the present invention in vivo by a chemical or biochemical method.

    [0084] Unless otherwise specified, the term pharmaceutically acceptable salt includes salts of acidic groups (e.g., but not limited to, potassium salt, sodium salt, magnesium salt, calcium salt, etc.) or salts of basic groups (e.g., but not limited to, formate, acetate, citrate, tartrate, methanesulfonate, malate or sulfate, hydrochloride, phosphate, nitrate, and carbonate) that can be present in the compound of the present invention.

    [0085] The term solvate refers to a complex molecular compound formed by solute molecules or ions attracting adjacent solvent molecules via intermolecular forces such as Coulomb force, van der Waals force, charge transfer force and hydrogen bond in a solution. In one embodiment, the solvent is water, that is, the compound of the present invention forms a hydrate.

    [0086] The compound of the present invention or the pharmaceutically acceptable salt thereof may contain one or more asymmetric centers, and can thus produce enantiomers, diastereomers and other stereoisomeric forms. As for the absolute stereochemical configuration of amino acids, it is defined as (R)- or (S)-configuration or as (D)- or (L)-configuration. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (?), (R)- and (S)-, or (D)- and (L)-isomers can be obtained by chiral synthesis or chiral preparation, or by resolution using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors and resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). The present invention provides pure isomers and isomer mixtures, a preparation method therefor, the use thereof, and compositions comprising same. For the sake of simplicity, it will be referred to as the compound of formula (I) and (II) hereinafter, which refers to both pure optical isomers and, if appropriate, mixtures of isomers at various ratios.

    [0087] The compound of the present invention may be present in a specific. Unless otherwise specified, the term tautomer or tautomeric form means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can quickly transform into each other. If tautomers are possible (such as in a solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also referred to as prototropic tautomers) include mutual transformation by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valencetautomers include mutual transformation by recombination of some bonding electrons.

    [0088] The term alkyl refers to alkyl selected from straight-chain and branched-chain saturated alkyl groups, which contain 1 to 18 (such as 1 to 12, further 1 to 10, and further 1 to 8 or 1 to 6 or 1 to 4) carbon atoms. Examples of alkyl (i.e. C.sub.1-6 alkyl) containing 1 to 6 carbon atoms include but are not limited to methyl, ethyl, 1-propyl or n-propyl (n-Pr), 2-propyl or isopropyl (i-Pr), 1-butyl or n-butyl (n-Bu), 2-methyl-1-propyl or isobutyl (i-Bu), 1-methylpropyl or sec-butyl (s-Bu), 1,1-dimethylethyl or tert butyl (t-Bu), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

    [0089] The term halogen in the present invention refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

    [0090] The term halogenated alkyl in the present invention refers to the alkyl in which one or more of the hydrogen is substituted by one or more halogen atoms, such as fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Examples of halogenated alkyl include halogenated C.sub.1-8 alkyl, halogenated C.sub.1-6 alkyl or halogenated C.sub.1-4 alkyl, but are not limited to CF.sub.3, CH.sub.2Cl, CH.sub.2CF.sub.3, CCl.sub.2, CF.sub.3, etc.

    [0091] The term alkenyl in the present invention refers to alkyl selected from straight-chain and branched-chain alkyl, which contain at least one C?C double bond and 2 to 18 (such as 2 to 8, further as 2 to 6) carbon atoms. Examples of alkenyl such as C.sub.2-6 alkenyl include, but are not limited to, vinyl (ethenyl or vinyl), propyl-1-enyl, propyl-2-enyl, 2-methylpropyl-1-enyl, butyl-1-enyl, butyl-2-enyl, butyl-3-enyl, butyl-1,3-dienyl, 2-methyl butyl-1,3-dienyl, hexyl-1-enyl, hexyl-2-enyl, hexyl-3-enyl, hexyl-4-enyl and hexyl-1,3-dienyl.

    [0092] The term alkynyl in the present invention refers to alkyl selected from straight-chain and branched-chain alkyl groups, which contain at least one C?C triple bond and 2 to 18 carbon atoms (such as 2 to 8, and further to 2 to 6). Examples of alkynyl groups such as C.sub.2-6 alkynyl include, but are not limited to, ethynyl, 1-propargyl, 2-propargyl (propargyl), 1-butynyl, 2-butynyl and 3-butynyl.

    [0093] The term alkoxy in the present invention refers to the alkyl as defined above, which is bonded to oxygen, and is represented by O alkyl. Examples of alkoxy groups such as C.sub.1-6 alkoxy or C.sub.1-4 alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy, etc.

    [0094] The term cycloalkyl in the present invention refers to the alkyl group selected from saturated and partially unsaturated cyclic hydrocarbons, which contains monocyclic and polycyclic (such as bicyclic and tricyclic) groups. For example, the cycloalkyl group can contain 3 to 12 carbon atoms (such as 3 to 10, further as 3 to 8, further as 3 to 6, 3 to 5, or 3 to 4). Even further, for example, the cycloalkyl group can be selected from a monocyclic group containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocycloalkyl groups include cyclopropyl, cyclopentyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, examples of saturated monocycloalkyl groups such as C.sub.3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In a preferred embodiment, the cycloalkyl is a single ring (abbreviated as C.sub.3-6 cycloalkyl) containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyl groups include those with 7 to 12 ring atoms arranged as bicyclic groups selected from [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or bridged bicyclic groups selected from bicyclic [2.2.1] heptane, bicyclic [2.2.2] octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those arranged as bicyclic cycloalkyl groups selected from the [5,6] and [6,6] ring systems, such as

    ##STR00351##

    wherein the wavy line represents the attachment point. The ring can be saturated or have at least one double bond (i.e. partially unsaturated), but not completely conjugated and not aromatic, as aromatic groups are defined in this article.

    [0095] The term aryl used alone or in combination with other terms refers to a group selected from: [0096] a. 5-membered and 6-membered carbon ring aromatic ring, such as phenyl; [0097] b. A double-ring system, such as a 7- to 12-membered double-ring system, in which at least one ring is carbon ring and aromatic, such as naphthyl; and [0098] c. A tricyclic system, such as a 10- to 15-membered tricyclic system, in which at least one ring is carbon ring and aromatic, such as fluorenyl.

    [0099] The terms aromatic ring and aryl are used interchangeably in the disclosure of the present invention. In some embodiments, monocyclic or bicyclic aromatic rings have 5 to 10 cyclic carbon atoms (i.e., C.sub.5-10 aryl). Examples of monocyclic or bicyclic aromatic rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracene, phenanthrene, etc. In some embodiments, the aromatic ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or benzene ring. In some embodiments, the aromatic ring is a benzene ring.

    [0100] The term heteroaryl in the present invention refers to a group selected from: [0101] a. 5, 6 or 7-membered aromatic single ring containing at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments containing 1 to 3 heteroatoms, and in some embodiments containing 1 to 2 heteroatoms, those heteroatoms were selected from nitrogen (N), sulfur (S), and oxygen (O) (as one or more ring atoms), with the remaining ring atoms is carbon; [0102] b. 7 to 12-membered bicycles, containing at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, those heteroatoms were selected from N, O and S (as one or more ring atoms), the remaining ring atoms are carbon, and at least one of the rings is aromatic and there is at least one heteroatom in the aromatic ring; and [0103] c. 11 to 14-membered three ring, containing at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, those heteroatoms were selected from N, O, and S (as one or more ring atoms), with the remaining ring atoms are carbon, and at least one of the rings is aromatic and there is at least one heteroatom in the aromatic ring.

    [0104] In a preferred embodiment, the heteroaryl is a 5 to 6-membered heteroaryl containing one nitrogen atom and 0 or one additional heteroatom selected from N, O and S, including, but not limited to, pyridyl, isoxazolyl and oxazolyl.

    [0105] When the total number of S and O atoms in the heteroaryl exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocyclic ring is not greater than 1. When heteroaryl contain more than one heteroatom ring member, heteroatoms can be the same or different. Nitrogen atoms in one or more rings of heteroaryl groups can be oxidized to form N-oxides.

    [0106] The terms aromatic heterocycles and heteroaryl are used interchangeably in the disclosure of this article. In some embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, of which 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, monocyclic or bicyclic aromatic heterocycles are monocycles or bicycles containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, monocyclic or bicyclic aromatic heterocycles are 5- to 6-membered heteroaryl rings, which are single rings and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, monocyclic or bicyclic aromatic heterocycles are 8- to 10-membered heteroaryl rings that are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

    [0107] Examples of heteroaromatic or mono or bicyclic aromatic heterocycles include but are not limited to (numbering from the designated priority 1 connection position) pyridinyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazolopyridyl, Isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl), tetrazolyl, thiophenyl (e.g. thiophene-2-yl, thiophene-3-yl), triazinyl, benzothiophenyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, dihydroindolyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), Quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolpyridyl (such as 1H-pyrrolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazole-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-dizolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-dizolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazolyl (such as furoxan-2-yl, furoxan-3-yl), benzofuroxanyl, benzobenzothiazolyl, benzooxazolyl, quinazolinyl, quinoxalinyl, naphthyl, furan pyridyl, benzothiazolyl (such as benzo[d]thiazole-6-yl), indazolyl (such as 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

    [0108] The term heterocyclic or heterocyclic or heterocyclic base refers to a ring selected from 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered single ring, bicyclic and tricyclic saturated ring and partially unsaturated ring, it contains at least one carbon atom and at least one heteroatom, such as 1 to 4 heteroatoms, further such as 1 to 3 heteroatoms or further such as 1 or 2 heteroatoms. These heteroatoms are selected from nitrogen (N), sulfur (S), oxygen (O), SO or SO.sub.2 (as one or more ring atoms).

    [0109] In some embodiments, the heterocyclyl is a 4, 5, 6, 7, or 8-membered single ring with at least one heteroatom selected from N, O, and S. In some preferred embodiments, the heterocyclyl is a 4-, 5-, 6-, 7- or 8-membered saturated ring containing a nitrogen heteroatom. Example heterocyclyl are azetidinyl, pyrrolyl, piperidyl, azepanyl, and azocanyl. In other embodiments, the heterocyclyl is a 5-membered, 6-membered, 7-membered, or 8-membered saturated single ring, which contains one nitrogen atom and one additional heteroatom selected from NH, O, S, SO, or SO.sub.2. The exemplary heterocyclyl is morpholine, morpholinyl, or piperazinyl ring. In some embodiments, the heterocyclyl is a 7- to 12-membered saturated bicyclic ring, which contains a nitrogen atom and 0 or 1 or 2 additional heteroatoms selected fromNH, O, S, SO or SO.sub.2. In some preferred embodiments, the heterocyclyl is a double ring bridging ring or a spirocycle.

    [0110] The term heterocycle in this article also refers to a 5-to-7-membered heterocycle that contains at least one heteroatom selected from N, O, and S, fused with a 5, 6, and/or 7-membered cycloalkyl, carbon ring aromatic ring, or heteroaromatic ring, provided that the entire ring structure is non aromatic.

    [0111] Heterocycles are not heteroaryl groups as defined in this article. In a preferred embodiment, the heterocyclic group is a 5-to-6-membered heterocyclic group consisting of one nitrogen atom and 0 or 1 additional heteroatom selected from N, O, and S, including but not limited to pyrrolyl, dihydropyridinyl, morpholine, morpholinyl, and tetrahydropyranyl.

    [0112] Examples of heterocycles include, but are not limited to (numbering starting with the connection position designated as priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidine, 2,3-pyrrolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholinyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, cyclothioethanyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridyl, tetrahydropyridyl, thiomorphinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxoheptanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolizinyl, 2-pyrrolizinyl, 3-pyrrolizinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolidyl, dithianyl, dithiolanyl, pyrazolidinyl, Imidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexanyl, tetrahydro-1H-pyrrolizin-7-yl, tetrahydro-1H-furano[3,4-b]pyrrole-3a-yl, tetrahydro-1H-furano[3,4-c]pyrrole-3a-yl, tetrahydro-1H-furano[3,4-b]pyrrole-6a-yl, octahydrocyclopentano[b]pyrrole-6a-yl, octahydrocyclopentano[c]pyrrole-3a-yl, octahydropentano[b]pyrrole-3a-yl 3-azabicyclic[3.1.0] hexan-1-yl or 2-azabicyclic[3.1.0]hexan-1-yl. The substituted heterocycles also include ring systems partially substituted by one or more oxygenyl, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

    [0113] In some embodiments, heterocyclyl is non-aromatic fused bicyclic heterocyclyl, such as the fused bicyclic heterocycles listed above, and the following non-aromatic fused bicyclic heterocyclyl.

    [0114] The term optional or optionally means that the subsequently described event or condition possibly, but not necessarily, occurs, and the description includes the case where the event or condition occurs and the case where the event or condition does not occur.

    [0115] The term substituted means that any one or more hydrogen atoms on a specific atom are replaced with a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., ?O), it is meant that two hydrogen atoms are replaced. Substitution with oxygen does not occur on aromatic groups. The term optionally substituted refers to either substituted or unsubstituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of being achievable in chemistry.

    [0116] When any variable (such as R) appears more than once in the composition or structure of a compound, the definition thereof in each case is independent. Therefore, for example, if one group is substituted with 0-2 R, the group can be optionally substituted with at most two R, and R in each case has an independent option. In addition, a combination of substituents and/or variants thereof is allowed only if such a combination produces a stable compound. The term one or more disclosed in this article. The following group substituents include, for example, 1 to 5 substituents (such as 1 to 4, further such as 1, 2 or 3), provided that the valence permits.

    [0117] Unless otherwise specified, the term heteroalkyl, by itself or in combination with another term, represents a stable linear or branched alkyl radical or its composition which consists of a certain number of carbon atoms and at least one heteroatom or heteroatom radical. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom radical is selected from C(?O)O, C(?O), C(?S), S(?O), S(?O).sub.2, C(?O)N(H), N(H), C(?NH), S(?O).sub.2N(H), and S(?O)N(H). In some embodiments, the heteroalkyl is C.sub.1-C.sub.6 heteroalkyl; and in other embodiments, the heteroalkyl is C.sub.1-C.sub.3 heteroalkyl. The heteroatom or heteroatom radical can be located in any internal position of the heteroalkyl, including the position at which the alkyl is connected to the remainder of the molecule, but the terms alkoxy, alkylamino and alkylthio (or thioalkoxy) are customary expressions and refer to alkyl groups that are connected to the remainder of the molecule via an oxygen atom, amino, or a sulfur atom, respectively. Examples of heteroalkyl include, but are not limited to, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH.sub.2(CH.sub.3).sub.2, CH.sub.2CH.sub.2OCH.sub.3, NHCH.sub.3, N(CH.sub.3).sub.2, NHCH.sub.2CH.sub.3, N(CH.sub.3)(CH.sub.2CH.sub.3), CH.sub.2CH.sub.2NHCH.sub.3, CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.3, SCH.sub.3, SCH.sub.2CH.sub.3, SCH.sub.2CH.sub.2CH.sub.3, SCH.sub.2(CH.sub.3).sub.2, CH.sub.2SCH.sub.2CH.sub.3, CH.sub.2CH.sub.2, S(?O)CH.sub.3, CH.sub.2CH.sub.2S(?O).sub.2CH.sub.3, CH?CHOCH.sub.3, CH.sub.2CH?NOCH.sub.3, and CH?CHNCCH.sub.3)CH.sub.3. At most two heteroatoms can be continuous, e.g., in CH.sub.2NHOCH.sub.3.

    [0118] Unless otherwise specified, the termalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl moieties in the present invention can be each independently substituted by one or more groups selected from the following group: hydroxyl, oxygen, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, sulfhydryl.

    Synthesis

    [0119] All suitable solvents commonly used in organic reactions can be used in the following steps of the preparation method of the present invention, e.g., but not limited to, aliphatic and aromatic, optional hydrocarbons or halogenated hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oils, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene), aliphatic and aromatic, optional alcohols (e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, and ethylene glycol), ethers (e.g., diethyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran and dioxane), esters (e.g., methyl acetate or ethyl acetate), nitriles (e.g., acetonitrile or propionitrile), ketones (e.g., acetone and butanone), amides (e.g., dimethylformamide, dimethylacetamide, and N-methylpyrrolidone), dimethyl sulfoxide, tetramethylene sulfone, hexamethylphosphoryl triamine, N,N-dimethylpropylene urea (DMPU), etc.

    [0120] The following abbreviations are used in the present invention: DCM stands for dichloromethane; CHCl.sub.3 stands for trichloromethane; EA stands for ethyl acetate; THF stands for tetrahydrofuran; MeCN stands for acetonitrile; MeOH stands for methanol; EtOH stands for ethanol; i-PrOH stands for isopropanol; PE stands for petroleum ether; toulene stands for methylbenzene; DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; DMA stands for N,N-dimethylacetamide; CDCl.sub.3 stands for deuterated chloroform; D.sub.2O stands for heavy water; (CD.sub.3).sub.2SO stands for deuterated DMSO; CD.sub.3OD stands for deuterated methanol; CuI stands for cuprous iodide; DIPEA stands for diisopropylethylamine; TEA stands for triethylamine; K.sub.2CO.sub.3 stands for potassium carbonate; Cs.sub.2CO.sub.3 stands for cesium carbonate; Na.sub.2CO.sub.3 stands for sodium carbonate; NaHCO.sub.3 stands for sodium bicarbonate; NaOH stands for sodium hydroxide; KOH stands for potassium hydroxide; LiHMDS stands for potassium hexamethyldisilazide; CDI stands for 1,1-carbonyl imidazole; MS stands for mass spectrometry; NMR stands for nuclear magnetic resonance; TFA stands for trifluoroacetic acid; BINAP stands for (2R,3S)-2,2-diphenylphosphine-1,1-binaphthyl; BOC stands for tert-butoxycarbonyl; Cbz stands for benzyloxycarbonyl; DBU stands for bicyclo-1,5-diaza-5-undecene; DCC stands for 1,3-dicyclohexylcarbodiimide; DCE stands for 1,2-dichloroethane; DMAP stands for 4-dimethylaminopyridine; dppf stands for bis(diphenylphosphino)ferrocene; LiAlH4 stands for lithium aluminium hydride; LDA stands for lithium diisopropylamide; m-CPBA stands for m-chloroperoxybenzoic acid; MTM stands for dimethyl sulfide; NBS stands for N-bromosuccinimide; NCS stands for N-chlorosuccinimide; NIS stands for N-iodosuccinimide; PCC stands for pyridinium dichromate; TBAF stands for tetrabutylamine fluoride; THP stands for tetrahydropyranyl; TMEDA stands for tetramethylethylene diamine; TMS stands for trimethylsilyl; TMP stands for 2,2,6,6-tetramethylpiperidine; Ts stands for p-toluenesulfonyl; Pd(PPh.sub.3).sub.4 stands for tetrakis(triphenylphosphine)palladium; PdCl.sub.2(dppf) stands for 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride; Pd.sub.2(dba).sub.3 stands for tris(dibenzylideneacetone)dipalladium; HOBT stands for 1-hydroxybenzotriazole; HATU stands for 2-(7-oxidobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate; TBTU stands for O-benzotriazole-N,N,N,N-tetramethyluronium tetrafluoroborate; Tf.sub.2O stands for trifluoroacetic anhydride; Pd(OAc).sub.2 stands for palladium diacetate; RuPhos stands for 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl; Pd(PPh.sub.3).sub.2Cl.sub.2 stands for bis(triphenylphosphine)palladium(II) dichloride; Sphos stands for 3,2-dicyclohexylphosphino-2,6-dimethoxybiphenyl; XantPhos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; MeONa stands for sodium methoxide; n-BuLi stands for n-butyl lithium; t-BuONa stands for sodium tert-butoxide; t-BuOK stands for potassium tert-butoxide; KSCN stands for potassium thiocyanate; CuBr stands for cuprous bromide; NaNO.sub.2 stands for sodium nitrite; urea stands for carbamide; POCl.sub.3 stands for phosphorus oxychloride; BBr.sub.3 stands for boron tribromide; NH.sub.4Cl stands for ammonium chloride; Mel stands for iodomethane; NMP stands for N-methylpyrrolidone; K.sub.3PO.sub.4 stands for potassium phosphate; column chromatography stands for column chromatography separation; Ac stands for acetyl; Bn stands for benzyl; Fmoc stands for fluorenylmethyloxycarbonyl; Cy stands for cyclohexyl; Tf stands for trifluoromethylsulfonyl; and PDC stands for pyridine dichromate.

    Synthesis Examples

    Preparation of Intermediate

    [0121] ##STR00352##

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

    [0122] The compound 1-bromo-3-chloro-2,4-difluorobenzene (5.0 g, 21.98 mmol) and furan (2.99 g, 43.97 mmol) were dissolved in anhydrous toluene (50 mL); in a nitrogen atmosphere, after the reaction liquid was cooled to ?15? C., n-BuLi (10.6 mL, 26.38 mmol) was added dropwise to the reaction liquid, and after the dropwise addition was complete, the reaction liquid was slowly heated to room temperature and reacted under stirring for 12 h; and after the reaction was complete, the reaction was quenched with saturated ammonium chloride and extracted with methyl tert-butyl ether, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, and concentrated to obtain a brown oil, which was directly used for the next step. (4.3 g, yield: 100%).

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

    [0123] The crude compound obtained from the previous step (synthesis of 8-chloro-7-fluoronaphthalen-1-ol), i.e., 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene, (4.3 g, 21.98 mmol) was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (8 mL), and the mixture was heated to 80? C. and reacted under stirring for 4 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, and concentrated to obtain a brown oil, the brown oil was placed in a refrigerator for 24 h to precipitate out a solid, which was diluted with petroleum ether, filtered, washed with petroleum ether, and dried to obtain an off-white solid. 1.3 g, yield: 30%. 1H NMR (400 MHz, CDCl3) ? 7.91 (s, 1H), 7.75 (dd, J=9.1, 5.6 Hz, 1H), 7.44-7.34 (m, 2H), 7.30 (d, J=8.7 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H).

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

    [0124] The compound 8-chloro-7-fluoronaphthalen-1-ol (1.0 g, 5.08 mmol) was dissolved in anhydrous dichloromethane (10 mL), DIEA (3.94 g, 30.51 mmol) and a molecular sieve (1 g) were added, the mixture was stirred for 10 min at room temperature and then cooled to ?40? C., and trifluoromethanesulfonic anhydride (1.86 g, 6.61 mmol) was added dropwise to the reaction liquid; after a stirred reaction was carried out for 20 min, the reaction was quenched with water and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a yellow solid. (1.65 g, yield: 98.8%). 1H NMR (400 MHz, CDCl3) ? 7.90 (d, J=8.1 Hz, 1H), 7.84 (dd, J=9.0, 5.4 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.51 (s, 1H), 7.44 (s, 1H).

    Step 4: Synthesis of 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

    [0125] The compound 8-chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (1.65 g, 5.02 mmol) and pinacol borate (2.53 g, 10.04 mmol) were dissolved in anhydrous DMF (20 mL), potassium acetate (2.44 g, 24.85 mmol) and Pd(dppf)Cl.sub.2 (366 mg, 0.50 mmol) were added, and after displacement with nitrogen, a stirred reaction was carried out in a nitrogen atmosphere for 12 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain an off-white solid. (1.25 g, yield: 82%). 1H NMR (400 MHz, CDCl3) ? 7.83 (t, J=10.4 Hz, 1H), 7.75 (dd, J=9.0, 5.5 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.50-7.44 (m, 1H), 7.32 (t, J=8.7 Hz, 1H), 1.45 (s, 12H).

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

    [0126] ##STR00353##

    Step 1: Synthesis of 8-(triisopropylsilyl) ethyne) naphthalene-1,3-diol

    [0127] The compound naphthalene-1,3-diol (10.0 g, 62.43 mmol), 2-bromoacetynyl (triisopropyl) silane (19.58 g, 74.92 mmol), dichloro (p-methylisopropyl benzene) ruthenium (II) dimer (3.82 g, 6.24 mmol), and potassium acetate (12.26 g, 124.86 mmol) were dissolved in 1,4-dioxane (120 mL), and stir for 12 hours under nitrogen atmosphere at 110? C. After the reaction is completed, the reaction was cooled to room temperature, diluted the reaction solution with ethyl acetate, filtered, washed the organic phase with water, dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA=50/1) to obtain a white like solid. (14.0 g, yield: 66%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.30 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.46 (dd, J=7.1, 1.1 Hz, 1H), 7.29 (dd, J=8.2, 7.3 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 4.91 (s, 1H), 1.25-1.14 (m, 21H).

    Step 2: Synthesis of 3-(methoxymethoxy)-8-(triisopropylsilyl) ethynyl) naphthalene-1-ol

    [0128] The compound 8-((triisopropylsilyl) ethynyl) naphthalene-1 (14 g, 41.11 mmol) was dissolved in dichloromethane (100 mL). DIEA (16.99 mL, 102.78 mmol) and bromomethyl ether (4.03 mL, 49.33 mmol) were added under ice water bath cooling and stirred for 10 minutes. After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane, the organic p by coluhase was dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA=100/1) to obtain a yellowish oil. (13.6 g, yield: 86%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.25 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.33-7.28 (m, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 5.26 (s, 2H), 3.50 (s, 3H), 1.20-1.12 (m, 21H).

    Step 3: Synthesis of 3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl) naphthalen-1-yltrifluoromethanesulfonate

    [0129] The compound 3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl) naphthalene-1-ol (13 g, 33.80 mmol) was dissolved in dichloromethane (100 mL), after the reaction was cooled to ?40? C., DIEA (13.11 g, 101.41 mmol) was added, then dripped with trifluoromethanesulfonic anhydride (14.30 g, 50.70 mmol), and then stirred for 30 minutes. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (PE/EA=20/1) to obtain yellow oil. (16.23 g, yield: 93%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.74 (dd, J=10.5, 4.3 Hz, 2H), 7.46-7.40 (m, 2H), 7.31 (d, J=2.3 Hz, 1H), 5.29 (s, 2H), 3.52 (s, 3H), 1.21-1.11 (m, 21H).

    Step 4: synthesis of triisopropyl (6-(methoxymethoxy)-8-(4-methoxymethoxy)-5-tetramethyl-1-methylidene-3-dioxoboropentane-2-yl) naphthalene-1-ethynyl) silane

    [0130] The compound 3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl) naphthalen-1-yltrifluoromethanesulfonate (16.0 g, 30.97 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (15.73 g, 61.94 mmol), potassium acetate (10.64 g, 108.40 mmol) and Pd(dppf)Cl.sub.2(2.26 g, 3.09 mmol) was dissolved in toluene (160 mL), after displacement with nitrogen, a stirred reaction was carried out in a nitrogen atmosphere at 110? C. for 12 h. After the reaction was completed, cooled to room temperature, add ethyl acetate to dilute the reaction solution, filter to remove insoluble substances, wash the organic phase with water, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain a light yellow solid. (6.2 g, yield: 41%). 1H NMR (400 MHz, CDCl3) ? 7.70-7.67 (m, 2H), 7.46 (d, J=2.1 Hz, 1H), 7.37-7.32 (m, 2H), 5.28 (s, 2H), 3.50 (s, 3H), 1.43 (s, 12H), 1.15 (s, 21H).

    Synthesis of Intermediate (1-(pyrrolidine-1-ylmethyl)cyclopropyl)methanol

    [0131] ##STR00354##

    [0132] The compound (1-(aminomethyl) cyclopropyl) methanol (500 mg, 4.94 mmol) and 1,4-dibromobutane (1.12 g, 5.19 mmol) was dissolved in acetonitrile (20 mL), then potassium carbonate (1.78 g, 12.85 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, filter off the solid, concentrate the organic phase and separate it by column chromatography (DCM/7M NH.sub.3 in MeOH=100/1) to obtain a colorless oil. (390 mg, yield: 50.8%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 3.55 (s, 2H), 2.70-2.53 (m, 6H), 1.83-1.69 (m, 4H), 0.49 (q, J=4.6 Hz, 2H), 0.36 (t, J=5.2 Hz, 2H).

    Synthesis of Intermediate 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0133] ##STR00355##

    Step 1: Synthesis of 5-(2-(2-bromo-4,5-difluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

    [0134] Compound 2-(2-bromo-4) 5-difluorophenyl) acetic acid (1.5 g, 5.98 mmol) and Meldrum's acid (947 mg, 6.57 mmol) were dissolved in acetonitrile (20 mL), DMAP (73 mg, 0.60 mmol) and DIEA (1.66 g, 12.86 mmol) were added, then pivaloyl chloride (792 mg, 6.57 mmol) was slowly dropped into the reaction solution and stirred at room temperature for 3 hours. After the reaction was finished, 1N hydrochloric acid (35 mL) was added under ice bath cooling, the solid was precipitated, filtered, the solid was washed with water, and the white solid is obtained by vacuum drying. (2.2 g, yield: 97%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 15.51 (s, 1H), 7.44 (dd, J=9.5, 7.4 Hz, 1H), 7.15 (dd, J=10.5, 8.0 Hz, 1H), 4.56 (s, 2H), 1.78 (s, 6H).

    Step 2: Synthesis of tert-butyl 4-(2-bromo-4,5-difluorophenyl)-3-oxobutanoate

    [0135] Compound of 5-(2-(2-bromo-4,5-difluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.2 g, 5.83 mmol) was dissolved in tert-butanol (20 mL) and heated to 90? C. reaction for 16 hours. After the reaction was finished, concentrated reaction solution removes the tert-butyl alcohol to give an oil which was directly used for the next step. (2.0 g, yield: 100%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.41 (dd, J=9.5, 7.5 Hz, 1H), 7.09 (dd, J=10.6, 8.1 Hz, 1H), 3.96 (s, 2H), 3.46 (s, 2H), 1.48 (s, 9H).

    Step 3: Synthesis of 4-(2-bromo-4,5-difluorophenyl)-3-oxobutanoic acid

    [0136] Compound tert-butyl 4-(2-bromo-4,5-difluorophenyl)-3-oxobutanoate 2.0 g, 5.73 mmol) was dissolved in dichloromethane (20 mL), added trifluoroacetic acid (10 mL), and stirred at room temperature for 1 hour. After the reaction was completed, concentrate the reaction solution to obtain an off-white solid. (1.6 g, yield: 100%).

    Step 4: Synthesis of 5-bromo-7,8-difluoronaphthalene-1,3-diol

    [0137] compound 4-(2-bromo-4,5-difluorophenyl)-3-oxobutanoic acid (1.6 g, 5.73 mmol) was dissolved in trifluoromethanesulfonic acid (20 mL), heated to 100? C., and stirred for 24 hours. After the reaction was completed, cooled to room temperature, slowly add the reaction solution to ice water, precipitate solids, filter to obtain crude products, and use petroleum ether to pulp and filter to obtain an off-white solid. (1.2 g, yield: 76%). .sup.1H NMR (400 MHz, DMSO) ? 10.53 (d, J=2.2 Hz, 1H), 10.14 (s, 1H), 7.94 (dd, J=10.0, 7.0 Hz, 1H), 6.90 (s, 1H), 6.66 (d, J=1.7 Hz, 1H).

    Step 5: Synthesis of 7,8-difluoronaphthalene-1,3-diol

    [0138] Compound 5-bromo-7,8-difluoronaphthalene-1,3-diol (1.2 g, 4.36 mmol) was dissolved in methanol (20 mL), 10% Pd/C (0.2 g) was added in nitrogen atmosphere, hydrogen was replaced, and the reaction was stirred at room temperature in a hydrogen atmosphere for 2 hours. After the reaction was completed, the Pd/C was removed by filtration and washed with methanol. The organic phase was concentrated to give an off-white solid. (800 mg, yield: 93%).

    Step 6: Synthesis of 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol

    [0139] Compound 7,8-difluoronaphthalene-1,3-diol (0.80 g, 4.08 mmol) was dissolved in dichloromethane (10 mL). DIEA (791 mg, 6.12 mmol) and bromomethyl ether (535 mg, 6.12 mmol) were added under ice water bath cooling and stirred for 10 minutes. After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA=100/1) to give a yellowish oil. (0.9 g, yield: 92%).

    Step 7: Synthesis of 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

    [0140] The compound 3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl) naphthalene-1-ol (0.9 g, 3.75 mmol) was dissolved in dichloromethane (10 mL), cooled to ?40? C., added DIEA (1.45 g, 11.24 mmol), then dripped with trifluoromethanesulfonic anhydride (1.59 g, 5.62 mmol), and then stirred for 30 minutes. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (PE/EA=20/1) to obtain a white solid. (1.25 g, yield: 90%). 1H NMR (400 MHz, CDCl3) ? 7.58-7.52 (m, 2H), 7.46-7.44 (m, 1H), 7.43-7.36 (m, 1H), 7.29 (d, J=2.0 Hz, 1H), 5.30 (s, 2H), 3.54 (s, 3H).

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

    [0141] Compound 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.25 g, 3.36 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (1.71 g, 6.72 mmol), potassium acetate (1.65 g, 16.80 mmol), and Pd(dppf)Cl.sub.2 (249 mg, 0.34 mmol) were dissolved in DMF (10 mL), replaced with nitrogen, and heated to 80? C. for 12 hours in a nitrogen atmosphere. After the reaction was completed, cooled to room temperature, added ethyl acetate to dilute the reaction solution, filtered to remove insoluble substances, washed the organic phase with water, dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a light yellow solid. (0.9 g, yield: 76%).

    [0142] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.49-7.44 (m, 1H), 7.44-7.41 (m, 1H), 7.41-7.38 (m, 1H), 5.29 (s, 2H), 3.51 (s, 3H), 1.45 (s, 12H).

    Synthesis of Intermediate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

    [0143] ##STR00356##

    Step 1: Synthesis of 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

    [0144] 2-(4-fluorophenyl) acetic acid (20 g, 130 mmol), Meldrum's acid (20.6 g, 143 mmol), and DMAP (1.58 g, 13 mmol) were dissolved in acetonitrile (100 mL), control temperature below 45? C., added DIPEA (36 g, 280 mmol), then added pivaloyl chloride (17.2 g, 143 mmol), stirred at room temperature for 4 hours, TLC (petroleum ether/ethyl acetate=1 bank 1) detection reaction was complete, drop 2N hydrochloric acid (100 mL) in ice bath, precipitate a large amount of yellow solid, filtrated, washed with water and dried to give a white solid. (32 g, yield: 88.1%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.45-7.32 (m, 2H), 7.16 (t, J=8.9 Hz, 2H), 4.36 (s, 2H), 1.70 (s, 6H).

    Step 2: Synthesis of tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate

    [0145] 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (32 g, 114 mmol) was dissolved in tert-butanol (300 mL) and heated to 90? C. reaction for 2 hours. The reaction was detected by TLC (petroleum ether/ethyl acetate=2-hand 1) completely, concentrated to dry, and directly used in the next reaction. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.26-7.08 (m, 4H), 3.86 (s, 2H), 3.54 (s, 2H), 1.40 (s, 9H).

    Step 3: Synthesis of 4-(4-fluorophenyl)-3-oxobutanoic acid

    [0146] tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (29 g, 114 mmol) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (150 mL) was added and reacted at room temperature for 1 hour. The reaction was detected by TLC (petroleum ether/ethyl acetate=2 Acetate) completely, concentrated to dry and directly used in the next reaction. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 11.78 (s, 1H), 7.18 (dd, J=8.6, 5.5 Hz, 2H), 7.08-7.02 (m, 2H), 3.83 (s, 2H), 3.54 (s, 2H).

    Step 4: Synthesis of 7-fluoronaphthalene-1,3-diol

    [0147] 4-(4-fluorophenyl)-3-oxobutanoic acid (22.4 g, 114 mmol) was dissolved in trifluoromethanesulfonic acid (150 mL) and reacted at room temperature for 17 hours. TLC (petroleum ether/ethyl acetate=2/1) detected that the reaction was complete, dripping into ice water, ethyl acetate extraction, concentrated to a small amount of solvent, adding petroleum ether (500 mL), precipitation of a large number of solids, filtration, drying to a yellowish solid. (19.2 g, yield: 92.3%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.18 (s, 1H), 9.48 (s, 1H), 7.63 (dd, J=9.0, 5.6 Hz, 1H), 7.56 (dd, J=10.8, 2.8 Hz, 1H), 7.24 (td, J=8.8, 2.8 Hz, 1H), 6.63 (d, J=2.1 Hz, 1H), 6.55 (d, J=2.1 Hz, 1H).

    Step 5: Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

    [0148] 7-fluoronaphthalene-1,3-diol (5 g, 27.5 mmol), (bromoacetynyl) triisopropylsilane (7.53 g, 28.8 mmol), and potassium acetate (5.39 g, 55 mmol) were dissolved in dioxane (100 mL). Ruthenium dichloride and 1-isopropyl-4-toluene dimer (1.68 g, 2.75 mmol) were added, protected by argon gas, heated to 110? C. for 20 hours, and the reaction was completely detected by TLC (petroleum ether/ethyl acetate=2/1). The reaction was cooled to room temperature, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain a black oily substance. (7.4 g, yield: 75.2%).

    Step 6: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

    [0149] 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (7.4 g, 20.6 mmol) was dissolved in dichloromethane (100 mL), DIPEA (7.99 g, 61.9 mmol) and MOMBr (2.58 g, 20.6 mmol) were added to the mixture in ice bath, reacted at room temperature for 15 minutes, TLC (petroleum ether/ethyl acetate=5 ppg) was detected completely, water was added, extracted with dichloromethane, concentrated, and purified by column chromatography to obtain a yellow solid. (4.9 g, yield: 59%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.12 (s, 1H), 7.65 (dd, J=9.1, 5.6 Hz, 1H), 7.18 (t, J=8.8 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 5.24 (s, 2H), 3.50 (s, 3H), 1.18 (d, J=5.3 Hz, 21H).

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

    [0150] 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4.9 g, 12.2 mmol) was dissolved in dichloromethane (100 mL), added DIPEA (4.7 g, 36.6 mmol), cooled to ?60? C., added trifluoromethanesulfonic anhydride (5.15 g, 18.3 mmol), reacted for 1 hour, TLC (petroleum ether/ethyl acetate=10 g) was detected completely, iced water was added, extracted with dichloromethane, concentrated, and purified by column chromatography to obtain a yellow oil. (6.0 g, yield: 92.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.70 (dd, J=9.1, 5.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.37-7.28 (m, 2H), 5.27 (s, 2H), 3.51 (s, 3H), 1.17 (d, J=6.0 Hz, 21H).

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

    [0151] 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5.0 g, 9.35 mmol), diborate pinacol ester (4.75 g, 18.7 mmol), and potassium acetate (2.75 g, 28.1 mmol) were dissolved in toluene (200 mL). [1,1-bis (diphenylphosphorus) ferrocene]palladium dichloride (684 mg, 0.935 mmol) was added, protected by argon gas, and heated to 130? C. for 5 hours. TLC (petroleum ether/ethyl acetate=5? C.) detected that the reaction was complete, cooled to room temperature, filtered, concentrated to dry, added water, extracted with ethyl acetate, concentrated and purified by column chromatography. (2.4 g, yield: 50.1%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.65 (dd, J=9.0, 5.6 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.21 (t, J=8.8 Hz, 1H), 5.26 (s, 2H), 3.50 (s, 3H), 1.43 (s, 12H), 1.15 (d, J=2.4 Hz, 21H).

    Synthesis of the intermediate 2-(4-(benzyloxy)-1,1a, 6,6a-tetrahydrocyclopropa[a]inden-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0152] ##STR00357##

    Step 1: Synthesis of 6-bromo-4-chloro-1H-indene

    [0153] Mix concentrated sulfuric acid (8 mL) with water (40 mL). Add 5-bromo-7-chloro-2,3-dihydro-1H-inden-1-ol (5 g, 20.2 mol). The reaction mixture was stirred under reflux for 12 hours. After cooled to room temperature, water (150 mL) and methyl tert-butyl ether (150 mL) were added. After shaking and delamination, the aqueous phase was extracted by methyl tert-butyl ether (50 mL). The combined organic phase was washed with saturated sodium bicarbonate solution (50 mL) and saturated salt solution (50 mL), dried with sodium sulfate and evaporated at reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether) to obtain a colorless oil (4.2 g, yield: 90%).

    Step 2: Synthesis of 4-bromo-2-chloro-1,1a, 6,6a-tetrahydrocyclopropa[a]indene

    [0154] The anhydrous dichloromethane (20 mL) solution of diethyl zinc/n-hexane (2m mL 18.3 min) was cooled in an ice water bath. A solution of Trifluoroacetic acid (2.72 mL, 36.6 mmol) in dichloromethane (20 mL) was dripped slowly. After stirring at this temperature for 20 minutes, an anhydrous dichloromethane (20 mL) solution of diiodomethane (2.96 mL, 36.6 mmol) was added. After continuing stirring for 20 minutes, a solution of anhydrous dichloromethane (10 mL) of 6-bromo-4-chloro-1H-indene (4.2 g, 18.3 mmol) slowly added dropwise. Removed the ice bath and stirred for 24 hours. Slowly added dilute hydrochloric acid (1N mL 150 min) under stirring. The mixture was extracted by petroleum ether (200 mL?2). The combined organic phase was washed with brine, dried with sodium sulfate and evaporated at reduced pressure to give a yellow oil. purified by column chromatography (silica gel, petroleum ether) to obtain 4-bromo-2-chloro-1,1a, 6,6a-tetrahydrocyclopropa[a]indene as a colorless oil (3.79 g, yield 85%).

    Step 3: Synthesis of 4-(benzyloxy)-2-chloro-1,1a, 6,6a-tetrahydrocyclopropa[a]indene

    [0155] Under nitrogen atmosphere, pour pre deoxidized 1,4-dioxane (100 mL) into a flask containing 4-bromo-2-chloro-1,1a, 6,6a-tetrahydrocyclopropane[a]indene (3.79 g, 15.6 mmol), tribenzylidene acetone dipalladium (2.75 g, 3.0 mmol), benzyl alcohol (2.05 g, 19 mmol), and cesium carbonate (7.86 g, 30 mmol). The reaction mixture was stirred at 100? C. for 15 hours. After the reaction cooled to room temperature, added methyl tert butyl ether (200 mL) and water (200 mL) for extraction. After separation, the organic phase was washed with brine (50 mL), and then dried with sodium sulfate, concentrated to obtain a viscous substance under reduced pressure. The product was obtained as a yellow solid (1.9 g, yield: 45%) through column chromatography (silica gel, ethyl acetate:petroleum ether=1:20).

    Step 4: Synthesis of 2-(4-(benzyloxy)-1,1a, 6,6a-tetrahydrocyclopropa[a]inden-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0156] Under the protection of argon gas, a mixture of 4-(benzyloxy)-2-chloro-1,1a, 6,6a-tetrahydrocyclopropa[a]indene (1.9 g, 7.0 mmol), bipinnacol borate (3.05 g, 12 mmol), tribenzylidene acetone dipalladium (1.3 g, 1.4 mmol), tricyclohexylphosphine (0.785 g, 2.8 mmol), potassium acetate (1.39 g, 14 mmol), and ethylene glycol dimethyl ether (25 mL) were heated in microwave for 2 hours at 150? C. After cooling the reaction to room temperature, add ethyl acetate (100 mL) and water (100 mL) for extraction. The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was washed with brine (30 mL), dried with sodium sulfate, and subjected to reduced pressure rotary evaporation to obtain a viscous substance. A yellow solid product (1.72 g, yield 68%) was obtained by column chromatography (silica gel, ethyl acetate:petroleum ether=1:20).

    Synthesis of Intermediate tert-butyl (1S,5R)-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0157] ##STR00358##

    Step 1: Synthesis of tert-butyl (1S,5R)-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0158] 3,8-diazabicyclo [3.2.1] oct-2-one hydrochloride (97 mg, 0.6 mmol) and potassium carbonate (165 mg, 1.2 mmol) were dissolved in tetrahydrofuran (2 mL), di-tert-butyl dicarbonate (157 mg, 0.72 mmol) was added. The mixture was stirred overnight. After the reaction was completed, the solid was filtered off, and the filtrate is concentrated before column chromatography to obtain a white solid. (116 mg, yield: 85%). MS m/z: 227.33 [M+H]+.

    Synthesis of intermediate 2-(8-methoxy-3-(methoxymethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0159] ##STR00359##

    Step 1: Synthesis of 8-bromo-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalen-1-ol

    [0160] Under argon atmosphere, 8-bromo-6-methoxymethoxy-3,4-dihydronaphthalen-1-one (146 mg, 0.5 mmol) was dissolved in methanol (2 mL), and sodium borohydride (38 mg, 1 mmol) was added at 0? C. Slowly increase the temperature to room temperature and stirred overnight. After the reaction was completed, concentrated the reaction solution under reduced pressure. Saturated ammonium chloride solution (2 mL) was added to the bottle and extracted with cyclohexane (2 mL?3). The extracted organic phase was washed with saturated salt water, dried with sodium sulfate and concentrated under reduced pressure to obtain a colorless oily product (about 150 mg). No further purification is required.

    Step 2: Synthesis of 8-bromo-1-methoxy-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalene

    [0161] Under argon atmosphere, 8-bromo-6-methoxymethoxy-1,2,3,4-tetrahydronaphthalen-1-ol (150 mg, 0.5 mmol) was dissolved in dry DMF, and sodium hydride (320 mg, 4 mmol, 60% mixed in mineral oil) and iodomethane (0.62 mL, 5 mmol) were added. The suspension was stirred at room temperature for 2 hours. After the complete conversion, concentrated the reaction solution under reduced pressure and pulped with petroleum ether, and filtered, and the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain a colorless oil 100 mg. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.16 (d, J=2.5 Hz, 1H), 6.73 (d, J=2.5 Hz, 1H), 5.12 (s, 2H), 4.39 (t, J=2.8 Hz, 1H), 3.46 (d, J=15.2 Hz, 7H), 2.92-2.73 (m, 1H), 2.65 (ddd, J=17.2, 12.1, 5.8 Hz, 1H), 2.38-2.25 (m, 1H). 1.90 (tdq, J=13.4, 8.3, 2.8 Hz, 1H), 1.70 (dh, J=13.0, 3.1 Hz, 1H), 1.49 (tt, J=13.8, 3.3 Hz, 1H).

    Step 3: Synthesis of Intermediate 2-(8-methoxy-3-(methoxymethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0162] In argon atmosphere, 8-bromo-1-methoxy-6-methoxymethoxy-1 mg (98 mg, 0.33 mmol) was dissolved in tetrahydrofuran (2 mL), and the temperature was reduced to low temperature by using dry ice ethanol bath. After that, n-butyl lithium (0.2 mL, 2.5m in THF) was added to the solution. Keep low temperature, stir for 40 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (89 mg, 0.48 mmol) was add. Then slowly warm up to room temperature. After the reaction was completed, concentrated the reaction solution under reduced pressure and pulped with petroleum ether, purified by TLC to give a colorless oil 39 mg. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.24 (d, J=2.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 5.28-5.07 (m, 2H), 4.84 (t, J=4.0 Hz, 1H), 3.52-3.35 (m, 6H), 2.87-2.58 (m, 2H), 2.15 (d, J=13.9 Hz, 1H), 1.91 (d, J=13.0 Hz, 1H). 1.78-1.61 (m, 2H), 1.43-1.26 (m, 12H).

    [0163] The preparation method of intermediate 2-(8-methoxy-3-methoxymethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl-4,4,5,5,5-tetramethyl-1,3,2-dioxabiorane was used to obtain 2-(3-methoxy-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane m/z: 334.72 [M+H].sup.+.

    ##STR00360##

    [0164] Synthesis of intermediate 2-(5-(methoxymethoxy)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:

    ##STR00361##

    Step 1: Synthesis of 5-bromo-7-(methoxymethoxy)-4-methyl-1,2-dihydronaphthalene

    [0165] MePPh3I (1.78 g, 5 mmol) was dissolved in 40 ml anhydrous tert-butyl methyl ether and t-BuOK/THF (5 ml, 5 mmol) was added in argon atmosphere, the reaction system turns orange. After the reaction system was stirred for 0.5 hour, 8-bromo-6-methoxy-3-dihydronaphthalene-1-one (284 mg, 1 mmol) was added, and the reaction system was stirred overnight at room temperature. After the reaction was completed, the reaction was quenched with 20 ml water, extracted with 100 ml ethyl acetate, the organic phase was dried by anhydrous sodium sulfate, the crude product was decompressed and removed from the solvent, and the crude product was separated by column chromatography (EA:PET/1:10) to obtain a light yellow liquid (221 mg, yield: 78%). 1H NMR (400 MHz, CDCl3) ? 7.08 (d, J=2.6 Hz, 1H), 6.79-6.69 (m, 1H), 5.91 (td, J=5.2, 1.5 Hz, 1H), 5.07 (s, 2H), 3.40 (s, 3H), 2.55 (dd, J=8.7, 6.2 Hz, 2H), 2.25 (Q, J=1.6 Hz, 3H), 1.98 (dtt, J=9.1, 5.4). 1.7 Hz, 2H).

    Step 2: Synthesis of 7-bromo-5-(methoxymethoxy)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene

    [0166] Under argon atmosphere, a diethyl zinc solution (0.23 mL, 2M in n-hexane) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (34 mg, 0.3 mmol) was added. The mixture was stirred at 0? C. for 20 minutes, followed by the addition of diiodomethane (120 mg, 0.45 mmol) to the reaction. After 20 minutes, 5-bromo-7-methoxymethoxy-4-methyl-1,2-dihydronaphthalene (42 mg, 0.15 mmol) was added to the reaction. Slowly raise the temperature to room temperature and stir overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (4 mL), extracted with ethyl acetate (3 mL?3). The organic phase was washed with brine (3 mL), then dried with sodium sulfate and concentrated under reduced pressure to give a residue which was separated by pre-TLC to give the product (20 mg, yield: 44.8%).

    Step 3: Synthesis of 2-(5-(methoxymethoxy)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0167] Compound 7-bromo-5-methoxymethoxy-7b-methyl-1a, B.sub.2Pin.sub.2 (25 mg, 0.067 mmol), KOAc (16 mg, 0.1). 16 mmol) and Pd (dppf) Cl.sub.2 (11 mg, 0.013 mmol) were dissolved in 1 ml DMF, and the reaction system was heated to 110? C. and stirred overnight under argon. After the reaction was completed, the crude product of the solvent is removed under reduced pressure, and the crude product is separated by column chromatography to obtain a colorless oil (4 mg, yield: 17%).

    Synthesis of Intermediate 1-ethynyl-3-(methoxymethoxy) naphthalene

    [0168] ##STR00362##

    Step 1: Synthesis of 1-bromo-3-(methoxymethoxy) naphthalene

    [0169] 4-bromonaphthalene-2-phenol (1.0 g, 4.48 mmol) and DIEA (1.49 mL, 8.96 mmol) were dissolved in 20 ml DCM, and MOMBr (0.44 mL, 5.4 mmol) was slowly added under ice water bath. After the addition is completed, the system turns pale yellow, and the reaction system continues to be stirred for 5 minutes. After the TLC monitoring reaction is completed, add 10 ml of water to the reaction system for quenching, and then add 50 mL DCM for extraction and separation. The organic phase was dried with anhydrous sodium sulfate and the crude product of the solvent was removed under reduced pressure. The crude product was separated by column chromatography (eluent: EA:PET/1:10) to obtain a colorless oily liquid (1.1 g, yield: 91.7%). MS m/z: 267 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10-8.05 (m, 2H), 7.77 (s, 1H), 7.50-7.40 (m, 2H), 7.30 (s, 1H), 6.12 (s, 2H), 3.30 (s, 3H).

    Step 2: Synthesis of triisopropyl ((3-(methoxymethoxy) naphthalen-1-yl) ethynyl) silane

    [0170] The compound 1-bromo-3-(methoxymethoxy) naphthalene (534 mg, 2 mmol) and diethylamine (2 mL) was dissolved in 2 mL THF. After displacing argon gas, CuI and Pd(PPh.sub.3).sub.4 was added. After displacing argon gas again, 1 mL of triisopropylsilyne was added. the reaction mixture was heated to 65? C. and stir overnight. After the reaction was completed, the organic solvent was removed under reduce pressure to obtain a crude product. The crude product was separated by column chromatography (eluent: EA:PET/1:10) to obtain a colorless oily liquid (420 mg, yield: 57%). MS m/z: 369 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.31-8.15 (m, 1H), 7.97-7.65 (m, 1H), 7.50-7.40 (m, 2H), 7.30 (s, 1H), 6.12 (s, 2H), 3.30 (s, 3H), 1.50-1.40 (m, 3H), 0.97 (d, J=4.2 Hz, 18H).

    Step 3: Synthesis of 1-ethynyl-3-(methoxymethoxy) naphthalene

    [0171] The compound triisopropyl ((3-(methoxymethoxy) naphthalene-1-yl) ethynyl) silane (420 mg, 1.14 mmol) was dissolved in 3 ml DMF solvent, then CsF (866 mg, 5.70 mmol) was added and stirred at room temperature overnight under argon protection. After the reaction is completed, add 100 mL of EA and 10 mL of water for extraction. After separation, wash the organic phase twice with 10 mL of water, and wash three times with 100 mL of saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate and the crude product of the solvent was removed under reduced pressure. The crude product was purified by PLC (eluent: EA:PET/1:5) to obtain a light red oily liquid (200 mg, yield: 88%). MS m/z: 213 [M+H].sup.+.

    Synthesis of Intermediate 2-(3-ethyl-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0172] ##STR00363##

    Step 1: Synthesis of (E)-7-bromo-1-ethylidene-5-(methoxymethoxy)-2,3-dihydro-1H-indene

    [0173] EtPPh.sub.3I (2.09 g, 5 mmol) was dissolved in 40 mL anhydrous tert-butyl methyl ether and t-BuOK/THF (5 mL, 5 mmol) was added in argon atmosphere, the reaction system turns orange yellow. After the reaction system was stirred for 1 hour, the THF solution of 7-bromo-5-methoxymethoxy-2methoxy-3-dihydro-1H-indole-1-one (271 mg, 1 mmol) was added, and the reaction system was stirred overnight at room temperature. After the reaction was completed, the reaction system was quenched with 20 mL water, extracted with 100 mL ethyl acetate, the organic phase was dried by anhydrous sodium sulfate, and the crude product was decompressed to remove the solvent. The crude product was separated by column chromatography (EA:PET/1:10) to obtain a light yellow liquid (180 mg, yield: 64%). MS m/z: 283 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.01 (dd, J=5.2, 2.2 Hz, 1H), 6.82 (dd, J=12.5, 2.2 Hz, 1H), 6.74-6.63 (m, 1H), 5.07 (d, J=5.9 Hz, 2H), 3.40 (d, J=4.2 Hz, 3H), 2.86 (dd, J=9.1, 5.6 Hz, 1H). 2.77-2.64 (m, 2H), 2.60 (t, J=6.9 Hz, 1H), 1.83 (dt, J=7.3, 1.6 Hz, 1H), 1.74 (dt, J=7.0, 1.6 Hz, 2H).

    Step 2: synthesis of (E)-2-(3-ethylidene-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0174] Dissolve (E)-7-bromo-1-ethylidene-5-(methoxymethoxy)-2,3-dihydro-1H-indene (180 mg, 0.64 mmol), B.sub.2Pin.sub.2(324 mg, 1.28 mmol), KOAc (126 mg, 1.28 mmol) and Pd(dppf)Cl.sub.2(47 mg, 0.064 mmol) in 10 mL of dioxane. Run evacuating and backfilling with argon and then heat the reaction at 100? C. overnight. After completion, remove the solvent under vacuum to give crude product. The crude product was purified with column chromatography to give colorless oil (130 mg, yield: 61%). MS m/z: 331[M+H].sup.+ 0.1H NMR (400 MHz, CDCl3) ? 7.16 (d, J=2.5 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 5.13-5.03 (m, 3H), 3.40 (s, 4H), 2.95-2.75 (m, 1H), 2.72-2.61 (m, 1H), 2.17-1.91 (m, 2H), 1.84 (ddt, J=12.7, 8.0, 1.5 Hz, 1H), 1.32-1.27 (m, 1H), 1.23-1.14 (m, 5H), 0.88 (t, J=7.3 Hz, 4H)

    Step 3: synthesis of 2-(3-ethyl-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0175] Dissolve compound (E/S)-2-(3-ethylidene-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.39 mmol) in 5 mL of ethyl acetate. Add 120 mg of Pd/C (10%) and then run evacuating and backfilling with hydrogen. The reaction was stirred at room temperature overnight. After completion, filter the reaction mixture. The solvent was removed under vacuum to leave pasty solid (100 mg, yield: 80%). MS m/z: 331[M+H]+. 1H NMR (400 MHz, CDCl3) ? 7.16 (d, J=2.5 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 6.02 (s, 2H), 3.40 (s, 3H), 3.33-3.22 (m, 2H), 2.72-2.61 (m, 1H), 2.17-1.52 (m, 6H), 1.25 (s, 12H), 0.88 (t, J=7.3 Hz, 3H)

    Example 1: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl naphthalen-2-ol

    [0176] ##STR00364##

    Step 1: synthesis of 2-chloro-3-fluoro-5-iodopyridin-4-amine

    [0177] 2-chloro-3-fluoropyridin-4-amine (4.22 g, 28.80 mmol) was dissolved in acetonitrile (50 mL). NIS (7.77 g, 34.55 mmol) and p-toluene sulfonic acid (248 mg, 1.44 mmol) were added in. The reaction was heated at 70? C. for 16 hours. After completion, the reaction was cooled to room temperature. Water was added to dilute the reaction mixture. Solid precipitated. Solid was collected by filtering. Solid was eluted with saturated aqueous Na2S2O3 and water successively and then dried in vacuum to give the target compound which was used in next step directly. (7.5 g, yield: 98%). 1H NMR (400 MHz, CDCl3) ? 8.17 (s, 1H), 4.83 (s, 2H).

    Step 2: synthesis of 4-amino-6-chloro-5-fluoronicotinonitrile

    [0178] Dissolve 2-chloro-3-fluoro-5-iodopyridin-4-amine (7.7 g, 28.26 mmol) and Zn(CN)2 (4.32 g, 36.74 mmol) in DMF (150 mL). Add Pd(PH3)4 (1.63 g, 1.41 mmol) and 4 ? molecular sieves (2.5 g). Run evacuating and backfilling with nitrogen. Heat and stir the reaction at 100? C. for 3 hours under nitrogen atmosphere. After completion, remove solid by filtering. Let the filtrate cooled to room temperature and add 300 mL of water to dilute the reaction solution. Solid precipitated. Filter the mixture and elute the solid by water. Solid was dried in vacuum to give the crude product which was used directly in next step. (4.85 g, yield: 100%). 1H NMR (400 MHz, DMSO) ? 8.20 (s, 1H), 7.66 (s, 2H).

    Step 3: synthesis of 4-amino-6-chloro-5-fluoronicotinic acid

    [0179] Dissolve 4-amino-6-chloro-5-fluoronicotinonitrile (4.85 g, 28.26 mmol) in 50% H2SO4 (50 mL). Heat the mixture at 120? C. and stirred it for 6 hours. After completion, let the mixture cooled to room temperature. Poured the mixture into ice slowly. Solid precipitated. Filter and elute the solid with water. Dissolve the solid with ethyl acetate and wash the solution with saturated aqueous solidum carbonate. The aqueous layer was treated with 10% aqueous hydrochloric acid to pH 2-3. Solid precipitated. Collected the solid by filtering and dried the solid under vacuum to give off-white solid. (4.62 g, yield: 85.8%). 1H NMR (400 MHz, DMSO) ? 8.36 (s, 1H), 7.59 (s, 2H).

    Step 4: synthesis of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one

    [0180] A mixture of 4-amino-6-chloro-5-fluoronicotinic acid and POCl3 (50 mL) was heated at 90? C. and stirred for 4 hours. After completion, the mixture was cooled to room temperature and then concentrated. The resulting oil was dissolved in anhydrous THF (20 mL). The solution was added dropwise to a solution of ammonium thiocyanate (3.67 g, 48.28 mmol) in THF (80 mL). The mixture was stirred at room temperature for 24 hours. Added water and extract the mixture with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and then concentrated to give yellow solid. 10 mL of ethyl acetate was added. Solid was crushed and collected by filtering to give light yellow solid. (4.52 g, yield: 80.8%). 1H NMR (400 MHz, DMSO) ? 13.29 (s, 1H), 12.85 (s, 1H), 8.64 (s, 1H).

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

    [0181] Dissolve 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (4.52 g, 19.51 mmol) in anhydrous DMF (50 mL). Add sodium methoxide (1.06 g, 19.51 mmol). After stirring at room temperature for 10 min, add methyl iodide (2.77 g, 1.21 mL, 19.51 mmol) and stir the reaction at room temperature for 2 hours. After completion, add cooled water. Solid precipitated. Collected the solid by filtering and elute the solid by water. Drying in vacuum gave yellow solid (3.0 g, yield: 66%). 1H NMR (400 MHz, DMSO) ? 13.24 (s, 1H), 8.81 (s, 1H), 2.62 (s, 3H).

    Step 6: synthesis of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

    [0182] Dissolve 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (420 mg, 1.71 mmol) in POCl3 (4 mL) and then add DIEA (442 mg, 3.42 mmol). Heat the reaction at 90? C. for 3 hours. After completion, cool the reaction to room temperature. Run concentration to remove excess POCl3. Dissolve the residue in ethyl acetate, wash the solution by water and brine successively. Dry the organic layer with sodium sulfate and the concentrate it to give crude product which was used directly in next step. (450 mg, yield: 100%).

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

    [0183] Dissolve 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (120 mg, 0.46 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (107 mg, 0.50 mmol) in anhydrous DMF (5 mL). Add DIEA (89 mg, 0.69 mmol) with cooling by ice-water bath. The reaction was stirred in ice-water batch for 30 min. After completion, add water to dilute the reaction. Extract the reaction with ethyl acetate. The organic layer was washed with brine twice and then dried over sodium sulfate. Concentration gave yellow solid. Used petroleum ether to wash the solid and run filtering and drying under vacuum to give light yellow solid. (200 mg, yield: 99%). 1H NMR (400 MHz, CDCl3) ? 8.71 (s, 1H), 4.57-4.28 (m, 4H), 3.65 (s, 2H), 2.62 (s, 3H), 2.08-1.84 (m, 4H), 1.69 (d, J=7.4 Hz, 2H), 1.52 (s, 9H).

    Step 8: synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0184] Dissolve tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.45 mmol) in DCM (10 mL). Cooled the solution in ice-water bath to 0? C.-10? C., then add 85% m-CPBA (116 mg, 0.54 mmol). The reaction was stirred at 0? C.-10? C. for 20 min. After completion, quench the reaction by adding saturated aqueous sodium thiosulfate. Use DCM to extract the reaction. The organic layer was washed with saturated aqueous sodium bicarbonate and brine successively and dried over sodium sulfate. Concentration gave light yellow solid which was used directly in next step. (200 mg, yield: 99%). 1H NMR (400 MHz, CDCl3) ? 8.91 (s, 1H), 4.77-4.35 (m, 4H), 3.77 (s, 2H), 2.98 (s, 3H), 2.08-1.84 (m, 4H), 1.69 (d, J=7.4 Hz, 2H), 1.52 (s, 9H).

    Step 9: synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)Cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0185] Dissolve tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.44 mol) and (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (82 mg, 0.53 mmol) in anhydrous toluene (5 mL). Add sodium tert-butoxide (55 mg, 0.57 mmol) under cooling with ice-water bath. Stir the reaction in ice-water bath for 30 min. After completion, quench the reaction by adding ice-water. Use ethyl acetate to extract the reaction. The organic layer was dried over sodium sulfate and then concentrated. Isolation with column chromatography gave off-white solid. (150 mg, yield: 62.5%)

    Step 10: synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0186] Add tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.09 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (57 mg, 0.11 mmol) and cesium carbonate (74 mg, 0.23 mmol) into 1,4-dioxane/water=5/1 (3 mL). Add Pd(dppf)Cl.sub.2 (13 mg, 0.02 mmol), run evacuating and backfilling with argon for 3 times. Heat the reaction at 100? C. for 8 hours. After completion, cooled the reaction to room temperature and add water. Use ethyl acetate to extract the reaction. The organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC gave off-white solid. (35 mg, yield: 42%)

    Step 11: synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol

    [0187] Dissolve tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.04 mmol) in DMF (3 mL). Add CsF (30 mg, 0.20 mmol). Stir the reaction at room temperature for 2 hours. After completion, add water and extract the reaction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was dissolved in acetonitrile (0.5 mL). Then 4M HCl in 1,4-dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 30 min. After completion, saturated aqueous sodium bicarbonate was added carefully to adjust pH to 7. Use DCM to run extraction. The organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC (DCM/MeOH(7N NH.sub.3)=10/1) gave light yellow solid (15 mg, yield: 64%). MS m/z: 597.6 [M+H]+

    [0188] The compounds of Examples 2-77 were prepared by preparation method 1.

    TABLE-US-00001 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H] 2 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2- ol [00365]embedded image 602.2 3 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethyl-6- fluoronaphthalen-2- ol [00366]embedded image 601 4 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethylnaphthalen-2-ol [00367]embedded image 583 5 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5, 6-difluoronaphthalen- 2-ol [00368]embedded image 591 6 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- fluoronaphthalen-2-ol [00369]embedded image 573.6 7 1-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7- yl)isoquinolin-3- amine [00370]embedded image 555.6 8 6-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-4- methyl-5- (trifluoromethyl) pyridin-2-amine [00371]embedded image 587 9 6-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- cyclopropyl-4- methylpyridin-2- amine [00372]embedded image 559 10 3-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- chloro-4- cyclopropylphenol [00373]embedded image 579 11 4-(4-((1R,5S)-8-oxa- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynylnaphthalen-2- ol [00374]embedded image 584.6 12 4-(4-((1R,5S)-8-oxa- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2- ol [00375]embedded image 602.2 13 4-(4-((1R,5S)-8-oxa- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethyl-6- fluoronaphthalen-2- ol [00376]embedded image 606.2 14 4-(4-((1R,5S)-8-oxa- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethylnaphthalen-2-ol [00377]embedded image 588.3 15 4-(4-((1R,5S)-8-oxa- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- fluoronaphthalen-2- ol [00378]embedded image 578.3 16 4-(4-((1R,5S)-8-oxa- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2- ol [00379]embedded image 596.2 17 4-(4-((1R,5S)-3-thia- 8-azabicyclo[3.2.1] octan-8-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2- ol [00380]embedded image 618.6 18 (1R,5S)-8-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-4- yl)-3-thia-8- azabicyclo[3.2.1] octane 3-oxide [00381]embedded image 634.3 19 (1R,5S)-8-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-4- yl)-3-thia-8- azabicyclo[3.2.1] octane 3,3-dioxide [00382]embedded image 650.3 20 4-(4-((1R,5S)-8- thia-3-azabicyclo [3.2.1]octan-3-yl)- 8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-7- yl)-5- ethynylnaphthalen- 2-ol [00383]embedded image 600.7 21 4-(4-((1R,5S)-8-thia- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2- ol [00384]embedded image 618 22 (1R,5S,8R)-3-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)- 8-thia-3-azabicyclo [3.2.1]octane 8-oxide [00385]embedded image 634 23 (1R,5S)-3-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-8- thia-3-azabicyclo[3.2.1] octane 8,8-dioxide [00386]embedded image 650 24 4-(4-((1R,5S)-8-thia-3- azabicyclo[3.2.1]octan- 3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl- 6-fluoronaphthalen-2-ol [00387]embedded image 622 25 4-(4-((1R,5S)-8-thia-3- azabicyclo[3.2.1]octan- 3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethylnaphthalen-2-ol [00388]embedded image 604.7 26 4-(4-((1R,5S)-8-thia-3- azabicyclo[3.2.1]octan- 3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- fluoronaphthalen-2-ol [00389]embedded image 594.6 27 4-(4-((1R,5S)-8-thia- 3-azabicyclo[3.2.1] octan-3-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2- ol [00390]embedded image 612 28 (1R,5S,8R)-3-(7-(7,8- difluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-8- thia-3-azabicyclo [3.2.1]octane 8-oxide [00391]embedded image 628.2 29 (1R,5S)-3-(7-(7,8- difluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-4-yl)-8- thia-3-azabicyclo [3.2.1 ]octane 8,8- dioxide [00392]embedded image 644.2 30 4-(4-((1R,5S)-8,8- difluoro-3- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00393]embedded image 636.6 31 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethyl-6- fluoronaphthalen-2-ol [00394]embedded image 640.6 32 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynylnaphthalen-2- ol [00395]embedded image 618.6 33 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2- ol [00396]embedded image 630 34 5-ethynyl-6-fluoro-4- (8-fluoro-4-((1R,5S, 8R)-8-fluoro-3- azabicyclo [3.2.1]octan-3-yl)-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-ol [00397]embedded image 618 35 5-ethyl-6-fluoro-4-(8- fluoro-4-((1R,5S,8R)- 8-fluoro-3-azabicyclo [3.2.1]octan-3-yl)-2- (((2R,7aS)-- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-ol [00398]embedded image 622 36 5-ethynyl-4-(8-fluoro- 4-((1R,5S,8R)-8-fluoro- 3-azabicyclo[3.2.1] octan-3-yl)-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-ol [00399]embedded image 600 37 5,6-difluoro-4-(8-fluoro- 4-((1R,5S,8R)-8-fluoro- 3-azabicyclo[3.2.1] octan-3-yl)-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-ol [00400]embedded image 612 38 1-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-7,8- difluoroisoquinolin-3- amine [00401]embedded image 595.25 39 1-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-8- chloro-7- fluoroisoquinolin-3- amine [00402]embedded image 611.22 40 1-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-8- ethynyl-7- fluoroisoquinolin-3- amine [00403]embedded image 601.26 41 6-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-4- methyl-5- (trifluoromethyl) pyridin-2-amine [00404]embedded image 591.25 42 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-amine [00405]embedded image 558.27 43 4-(4-(3,9-diazabicyclo [3.3.1]nonan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00406]embedded image 615.26 44 4-(4-(3,9-diazabicyclo [3.3.1]nonan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynylnaphthalen-2-ol [00407]embedded image 597.2 45 4-(4-(3,6-diazabicyclo [3.1.1]heptan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00408]embedded image 587.23 46 4-(4-(2,5-diazabicyclo [2.2.2]octan-2-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00409]embedded image 601.25 47 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(1,8- diazaspiro[4.5]decan- 8-yl)pyrido[4,3-d] pyrimidin-7-yl) naphthalen-2-ol [00410]embedded image 629.28 48 5-ethynyl-4-(8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-4-(1,8- diazaspiro[4.5]decan- 8-yl)pyrido[4,3-d] pyrimidin-7-yl) naphthalen-2-ol [00411]embedded image 611.7 49 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-(1- thia-8- azaspiro[4.5]decan-8- yl)pyrido[4,3-d] pyrimidin-7- yl)naphthalen-2-ol [00412]embedded image 646.24 50 8-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1- thia-8-azaspiro[4.5] decane 1,1-dioxide [00413]embedded image 678.23 51 4-(4-(3- aminopyrrolidin-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00414]embedded image 575.23 52 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-(octahydro- 6H-pyrrolo[3,4-b] pyridin-6-yl)pyrido[4,3- d]pyrimidin-7- yl)naphthalen-2-ol [00415]embedded image 615.26 53 5-ethynyl-4-(8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-(octahydro- 6H-pyrrolo[3,4-b] pyridin-6-yl)pyrido[4,3- d]pyrimidin-7- yl)naphthalen-2-ol [00416]embedded image 597.6 54 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4- (hexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)pyrido [4,3-d]pyrimidin-7-yl) naphthalen-2-ol [00417]embedded image 601.25 55 4-(4-((3S,4S)-4-amino- 3-methyl-2-oxa-8- azaspiro[4.5]decan-8- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00418]embedded image 659.29 56 4-(4-((3S,4S)-4-amino- 3-methyl-2-oxa-8- azaspiro[4.5]decan-8- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynylnaphthalen-2-ol [00419]embedded image 641.7 57 4-(4-((3S,4S)-4-amino- 3-methyl-2-oxa-8- azaspiro[4.5]decan-8- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2-ol [00420]embedded image 653.6 58 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-(3- (methylamino)pyrrolidin- 1-yl)pyrido[4,3-d] pyrimidin-7- yl)naphthalen-2-ol [00421]embedded image 589.4 59 N-(1-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl) pyrrolidin-3-yl) methanesulfonamide [00422]embedded image 653.21 60 (1R,5S,8R)-3-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan- 8-ol [00423]embedded image 616.25 61 (1R,5S,8R)-3-(7-(8- ethynyl-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3- azabicyclo[3.2.1] octan-8-ol [00424]embedded image 598.26 62 (1R,5S,8S)-3-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3- azabicyclo[3.2.1] octane-8-carbonitrile [00425]embedded image 625.25 63 4-(4-((1R,5S,8R)-8- amino-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00426]embedded image 615.26 64 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1R,5S, 8R)-8-(methylthio)-3- azabicyclo[3.2.1]octan- 3-yl)pyrido[4,3-d] pyrimidin-7-yl) naphthalen-2-ol [00427]embedded image 646.24 65 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1R,5S, 8R)-8-(methylsulfinyl)- 3-azabicyclo[3.2.1] octan-3-yl)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-ol [00428]embedded image 662.23 66 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1R,5S, 8R)-8-(methylsulfonyl)- 3-azabicyclo[3.2.1] octan-3-yl)pyrido[4,3- d]pyrimidin-7-yl) naphthalen-2-ol [00429]embedded image 678.23 67 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1R,5S, 8R)-8- ((trifluoromethyl) sulfonyl)-3- azabicyclo[3.2.1] octan-3-yl)pyrido[4,3- d]pyrimidin-7- yl)naphthalen-2-ol [00430]embedded image 732.20 68 1-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-4- yl)piperidine-4- carbonitrile [00431]embedded image 599.23 69 1-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-4-yl) azetidine-3- carbonitrile [00432]embedded image 571.20 70 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4- (2,6-diazaspiro[3.3] heptan-2-yl)pyrido[4,3- d]pyrimidin-7- yl)naphthalen-2-ol [00433]embedded image 587.23 71 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4- (quinuclidin-4-yl) pyrido[4,3-d] pyrimidin-7-yl) naphthalen-2-ol [00434]embedded image 600.25 72 6-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- cyclopropyl-4- methylpyridin-2-amine [00435]embedded image 563.30 73 2-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1, 1a, 6,6a- tetrahydrocyclopropa [a]inden-4-ol [00436]embedded image 561.4 74 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan-3-yl)-8- fluoro-2-((1- methylhexahydrocyclo- penta[b]pyrrol-3a(1H)- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00437]embedded image 597.4 75 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-methyltetrahydro- 1H-furo[3,4-b]pyrrol- 3a(4H)-yl)methoxy) pyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00438]embedded image 599.4 76 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan- 3-yl)-8-fluoro-2-((3- methyl-3-azabicyclo [3.1.0]hexan-1- yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00439]embedded image 569.4 77 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((2-methyl-2- azabicyclo[3.1.0]hexan- 1-yl)methoxy)pyrido [4,3-d]pyrimidin-7-yl)- 5-ethynyl-6- fluoronaphthalen-2-ol [00440]embedded image 569.4

    Example 78: synthesis of 4-(4-((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

    [0189] ##STR00441## ##STR00442##

    Step 1: synthesis of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

    [0190] Add 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500 mg, 1.89 mmol), tert-butyl (1S,5R)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (826 mg, 2.46 mmol), potassium carbonate (653 mg, 4.73 mmol) and Pd(dppf)Cl.sub.2 (138 mg, 0.19 mmol) to 1,4-dioxane/water=5/1 (10 mL). Run evacuating and backfilling with argon. Heat the reaction at 100? C. and stir for 12 hours. After completion, cool the reaction to room temperature, add water, use ethyl acetate to run extraction. The organic layer was dried over sodium sulfate and concentrated. Purification by prep-TLC gave off-white solid (300 mg, yield: 36.3%). MS m/z: 437 [M+H]+.

    Step 2: synthesis of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

    [0191] Dissolve tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (300 mg, 0.69 mmol) in DCM (10 mL), add m-CPBA (168 mg, 0.82 mmol, 85%) with cooling by ice-water bath. Stir the reaction in ice-water bath for 10 min. After completion, the reaction was quenched by addition of saturated aqueous sodium thiosulfate. The reaction was extracted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate. Concentration gave off-white solid which was used directly in next step (310 mg, yield: 99%).

    Step 3: synthesis of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

    [0192] Dissolve tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (310 mg, 0.68 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (142 mg, 0.89 mmol) in anhydrous toluene (10 mL). Add sodium tert-butoxide (79 mg, 0.82 mmol) under cooling with ice-water bath. Stir the reaction for 30 min under cooling with ice-water bath. After completion, add cooled water to quench the reaction. The reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification with column chromatography gave off-white solid (243 mg, yield: 64%). MS m/z: 548 [M+H]+

    Step 4: synthesis of tert-butyl (1S,5R)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

    [0193] Dissolve tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (50 mg, 0.09 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46 mg, 0.13 mmol), cesium carbonate (82 mg, 0.25 mmol) and Pd(dppf)Cl.sub.2 (8 mg, 0.01 mmol) in 1,4-dioxane/water=5/1 (3 mL). Run evacuating and backfilling with nitrogen, heat the reaction at 100? C. and stir for 12 hours. After completion, the reaction was cooled to room temperature and water was added. Ethyl acetate was used for extraction, the organic layer was dried over sodium sulfate and concentrated. Purification by prep-TLC gave off-white solid (30 mg, yield: 44%). MS m/z: 736 [M+H]+

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

    [0194] Dissolve tert-butyl (1S,5R)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (30 mg, 0.04 mmol) in methanol (5 mL). Add 10% Pd\C (50 mg) under nitrogen atmosphere. Run evacuating and backfilling with hydrogen. Stir the reaction at room temperature for 3 hours. After completion, remove Pd\C by filtering. The following concentration gave off-white solid which was used directly in next step (30 mg, yield: 100%). MS m/z: 738 [M+H]+

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

    [0195] Dissolve tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.04 mmol) in acetonitrile (1 mL). Then add a solution of HCl in 1,4-dioxane (1 mL, 4 M). Stir the reaction at room temperature for 30 min. After completion, add aqueous sodium bicarbonate carefully to adjust pH to 7. The mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC (DCM/MeOH(7N NH.sub.3)=10/1) gave light yellow solid (15 mg, yield: 62%). MS m/z: 594 [M+H].sup.+.

    [0196] The compounds of Examples 79-88 were prepared by preparation method 78.

    TABLE-US-00002 m/z: Ex. Compound name Structural formula ES.sup.+[M + H] 79 4-(4-((1R,5S)-8- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin- 7a(5H)-yl)methoxy) pyrido[4,3-d] pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2- ol [00443]embedded image 600.2 80 4-(4-((1R,5S)-8- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin- 7a(5H)-yl)methoxy) pyrido[4,3-d] pyrimidin-7-yl)-5- ethyl-6- fluoronaphthalen-2- ol [00444]embedded image 604.2 81 4-(4-((1R,5S)-8- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-7- yl)-5-ethylnaphthalen- 2-ol [00445]embedded image 586.3 82 4-(4-((1R,5S)-8- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-7- yl)-5- fluoronaphthalen-2- ol [00446]embedded image 576.6 83 4-(4-((1R,5S)-8- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido [4,3-d]pyrimidin-7- yl)-5- ethynylnaphthalen- 2-ol [00447]embedded image 582.4 84 1-(3-(7-(8-ethynyl- 7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin- 4-yl) pyrrolidin-1-yl)-2- hydroxyethan-1-one [00448]embedded image 618.4 85 1-(3-(7-(7,8-difluoro- 3-hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-4-yl) pyrrolidin-1-yl)-2- hydroxyethan-1-one [00449]embedded image 612.3 86 1-(3-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1H- pyrrol-1-yl)-2- hydroxyethan-1-one [00450]embedded image 614.3 87 1-(4-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1H- pyrazol-1-yl)-2- hydroxyethan-1-one [00451]embedded image 615.3 88 1-(4-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1H- imidazol-1-yl)-2- hydroxyethan-1-one [00452]embedded image 615.3

    Example 89: synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol

    [0197] ##STR00453##

    Step 1: synthesis of 2-amino-4-bromo-3-fluorobenzamide

    [0198] Dissolve 2-amino-4-bromo-3-fluorobenzoic acid (5.0 g, 20 mmol) in 50 mL DMF, add TBTU (16.0 g, 50 mmol), NH.sub.4Cl (27.0 g, 50 mmol) and DIEA (14 mL, 80 mmol) at room temperature in one portion. The reaction was stirred at room temperature for 3 hours. After completion, add 300 mL of water into the reaction. Much solid precipitated. When there is no more solid precipitated, collect the light yellow solid by filtering and use the product directly in next step (3.7 g, yield: 74%). 1HNMR (400 MHz, DMSO) ? 7.92 (s, 2H), 7.66 (s, 1H), 6.94 (s, 1H), 6.25 (s, 2H).

    Step 2: synthesis of 7-bromo-8-fluoroquinazoline-2,4-diol

    [0199] Dissolve 2-amino-4-bromo-3-fluorobenzamide (3.6 g, 14.4 mmol) in 40 mL of DMF, add CDI (9.3 g, 57.7 mmol) and K.sub.2CO.sub.3 (8.0 g, 50 mmol) in one portion at room temperature. The reaction was heated at 80? C. and stirred overnight. After completion, add 300 mL of water into the reaction. Much solid precipitated. When there is no more solid precipitating, collect the light yellow solid by filtering and use the product directly in next step (3.9 g, yield: 90%). 1HNMR (400 MHz, DMSO) ? 11.34 (s, 1H), 11.40 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H).

    Step 3: synthesis of 7-bromo-2,4-dichloro-8-fluoroquinazoline

    [0200] Dissolve 7-bromo-8-fluoroquinazoline-2,4-diol (3.9 g, 14 mmol) in 50 mL of POCl3, add 5 mL of N,N-diethyl aniline at room temperature. The reaction was heated at 110? C. and stirred overnight. After completion, solvent was removed under vacuum to give crude product. The crude product was purified with column chromatography (PE) to give yellow solid (2.62 g, 60%). 1HNMR (400 MHz, CDCl3) ? 8.12 (s, 1H), 7.93 (s, 1H).

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

    [0201] 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.0 g, 3.38 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (789 mg, 3.72 mmol) were added to anhydrous DMF (10 mL). DIEA (655 mg, 0.83 mL, 5.07 mmol) was added with ice-water bath. The reaction was stirred in ice-water bath for 30 min. After completion, water was added and ethyl acetate was used to extract the reaction. The organic layer was washed with brine twice, dried over sodium sulfate and concentrated to give light yellow solid. Washing with PE, filtering and dried in vacuum gave light yellow solid (1.5 g, yield: 94%). 1H NMR (400 MHz, CDCl3) ? 7.57-7.42 (m, 2H), 4.37 (s, 4H), 3.68 (d, J=71.0 Hz, 2H), 1.99-1.88 (m, 2H), 1.73 (s, 2H), 1.52 (s, 9H).

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

    [0202] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (220 mg, 1.38 mmol) was dissolved in anhydrous THF (5 mL). With cooling by ice-water bath, 60% NaH (51 mg, 1.27 mmol) was added, the reaction was stirred in ice-water bath for 20 min. tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.06 mmol) was added. The stirring was kept for 4 more hours. After completion, the reaction was quenched by adding cooled water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification with column chromatography gave off-white solid (260 mg, yield: 41%). 1H NMR (400 MHz, CDCl3) ? 7.41 (d, J=9.1 Hz, 1H), 7.32-7.27 (m, 1H), 5.28 (d, J=52 Hz, 1H), 4.33 (s, 4H), 4.24 (d, J=10.3 Hz, 1H), 4.12 (d, J=10.3 Hz, 1H), 3.54 (s, 2H), 3.20 (d, J=28.1 Hz, 3H), 3.03-2.93 (m, 1H), 2.33-2.11 (m, 3H), 1.76 (d, J=7.2 Hz, 2H), 1.63 (s, 2H), 1.51 (s, 9H).

    Step 6: synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0203] tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.10 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (65 mg, 0.13 mmol), cesium carbonate (82 mg, 0.25 mmol) and Pd(dppf)Cl.sub.2 (8 mg, 0.01 mmol) were added to 1,4-dioxane/water=5/1 (3 mL). Run evacuating and backfilling with nitrogen, heat the reaction at 100? C. for 12 hours. After completion, cooled the reaction to room temperature, add water and extract the reaction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification with TLC gave off-white solid (20 mg, yield: 23%). 1H NMR (400 MHz, CDCl3) ? 7.80 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.48 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.24-7.19 (m, 1H), 7.15 (d, J=2.6 Hz, 1H), 5.31 (s, 3H), 4.36 (s, 4H), 4.06 (s, 2H), 3.52 (s, 3H), 3.31-3.17 (m, 2H), 3.05-2.90 (m, 1H), 2.23 (s, 3H), 1.94 (d, J=31.1 Hz, 8H), 1.51 (d, J=3.3 Hz, 9H), 1.25 (d, J=5.3 Hz, 21H).

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

    [0204] tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.02 mmol) was dissolved in DMF (3 mL). CsF (17 mg, 0.11 mmol) was added and the mixture was stirred at room temperature for 2 hours. After completion, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was dissolved in acetonitrile (0.5 mL), 4M HCl in 1,4-dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 30 min. After completion, saturated aqueous sodium bicarbonate was carefully added to adjust pH to 7. The mixture was extracted with DCM, the organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC (DCM/MeOH (7N NH.sub.3)=10/1) gave light yellow solid (8 mg, yield: 61%). 1H NMR (400 MHz, CDCl3) ? 7.75 (d, J=8.2 Hz, 1H), 7.52 (dd, J=12.8, 6.0 Hz, 2H), 7.35-7.24 (m, 3H), 7.19-7.08 (m, 2H), 5.37 (t, J=29.1 Hz, 1H), 4.46 (s, 2H), 4.35 (s, 1H), 3.81 (s, 2H), 3.76-3.65 (m, 4H), 3.10 (dd, J=14.7, 7.4 Hz, 2H), 2.45-2.17 (m, 11H). MS m/z: 582.6 [M+H]+

    Example 90: synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,8-diazaspiro[4,5]decan-8-yl)quinazolin-7-yl)naphthalen-2-ol

    [0205] ##STR00454##

    Step 1: synthesis of tert-butyl 8-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate

    [0206] 7-bromo-2,4-dichloro-8-fluoroquinazoline (150 mg, 0.51 mmol) custom-character tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate (128 mg, 0.53 mmol) was dissolved in DMF (3 mL). With cooling by ice-water bath, DIEA (98 mg, 0.76 mmol) was added. The reaction was stirred in ice-water bath for 15 min. After completion, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine twice, dried over sodium sulfate and concentrated to give light yellow solid. Solid was washed with PE and dried in vacuo to give light yellow solid (240 mg, yield: 95%). 1H NMR (400 MHz, CDCl3) ? 7.64-7.42 (m, 2H), 4.44 (s, 2H), 3.47 (s, 2H), 3.26 (t, J=13.0 Hz, 2H), 2.98 (d, J=13.7 Hz, 1H), 2.76 (s, 1H), 2.04 (d, J=29.8 Hz, 2H), 1.84 (dd, J=13.6, 6.8 Hz, 2H), 1.55-1.53 (m, 2H), 1.48-1.34 (m, 9H).

    Step 2: synthesis of tert-butyl 8-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate

    [0207] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (84 mg, 0.53 mmol) was dissolved in anhydrous THF (5 mL). With ice-water bath cooling, 60% NaH (21 mg, 0.53 mmol) was added. The reaction was stirred in ice-water bath for 20 min. tert-butyl 8-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate (240 mg, 0.48 mmol) was added and the stirring was kept for 4 hours more. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification with column chromatography gave off-white solid (160 mg, yield: 54%). 1H NMR (400 MHz, MeOD) ? 7.68 (d, J=8.0 Hz, 1H), 7.47-7.43 (m, 1H), 5.33 (d, J=54.0 Hz, 1H), 4.53-4.47 (m, 2H), 4.34-4.19 (m, 2H), 3.46 (t, J=6.7 Hz, 2H), 3.39-3.31 (m, 4H), 3.08-3.04 (m, 1H), 2.93-2.86 (m, 1H), 2.77-2.72 (m, 1H), 2.45-1.78 (m, 11H), 1.53 (d, J=13.0 Hz, 2H), 1.39 (d, J=33.8 Hz, 9H).

    Step 3: synthesis of tert-butyl 8-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate

    [0208] tert-butyl 8-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate (50 mg, 0.08 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (50 mg, 0.10 mmol), cesium carbonate (50 mg, 0.15 mmol) and Pd(dppf)Cl.sub.2 (9 mg, 0.01 mmol) was added to 1,4-dioxane/water=5/1(3 mL). Run evacuating and backfilling with nitrogen, the reaction was stirred at 100? C. in nitrogen atmosphere for 12 hours. After completion, the reaction was cooled to room temperature. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC gave off-white solid (55 mg, yield: 59%). MS m/z: 928 [M+H]+

    Step 4: synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,8-diazaspiro[4.5]decan-8-yl)quinazolin-7-yl)naphthalen-2-ol

    [0209] tert-butyl 8-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate (50 mg, 0.05 mmol) was dissolve in DMF (3 mL). CsF (41 mg, 0.27 mmol) was added and the reaction was stirred at room temperature for 2 hours. After completion, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium sulfate and concentrated. The crude product was dissolved in acetonitrile (2 mL). 4M HCl in 1,4-dioxane (1 mL) was added, the mixture was stirred at room temperature for 30 min. After completion, saturated aqueous sodium bicarbonate was added carefully to adjust pH to 7. The mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. Pre-TLC (DCM/MeOH(7N NH.sub.3)=10/1) gave light yellow solid (25 mg, yield: 74%). MS m/z: 628.64 [M+H]+

    [0210] The compounds of Examples 91-156 were prepared by the preparation method for Example 89

    TABLE-US-00003 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 91 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)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00455]embedded image .sup.1H NMR (400 MHZ, MeOD) ? 7.85 (dd, J = 8.4, 4.6 Hz, 2H), 7.31 (d, J = 2.6 Hz, 3H), 7.09 (s, 1H), 5.48 (d, J = 53.2 Hz, 1H), 4.75- 4.46 (m, 4H), 4.05 (s, 2H), 3.90-3.63 (m, 5H), 2.79 (s, 1H), 2.67-2.43 (m, 2H), 2.38- 2.20 (m, 4H), 2.07 (s, 5H). MS m/z: 600.62 92 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)quinazolin- 7-yl)-5-ethyl-6- fluoronaphthalen-2-ol [00456]embedded image 604.28 93 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)quinazolin- 7-yl)-5- ethylnaphthalen-2-ol [00457]embedded image 586 94 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)quinazolin- 7-yl)-5,6- difluoronaphthalen- 2-ol [00458]embedded image 594.24 95 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)quinazolin- 7-yl)-5- fluoronaphthalen-2- ol [00459]embedded image 576.25 96 ((3R,7aR)-7a-(((4- ((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8- fluoroquinazolin-2- yl)oxy)methyl) hexahydro-1H- pyrrolizin-3- yl)methyl dimethylcarbamate [00460]embedded image 683.31 97 ((3R,7aR)-7a-(((4- ((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-7-(8- ethyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8- fluoroquinazolin-2- yl)oxy)methyl) hexahydro-1H- pyrrolizin-3-yl) methyl dimethylcarbamate [00461]embedded image 687.34 98 ((3R,7aR)-7a-(((4- ((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-7-(8- ethynyl-7- fluoronaphthalen-1- yl)-8- fluoroquinazolin-2- yl)oxy)methyl) hexahydro-1H- pyrrolizin-3-yl) methyl dimethylcarbamate [00462]embedded image 667.31 99 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00463]embedded image 596.28 100 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)quinazolin- 7-yl)-5-ethyl-6- fluoronaphthalen-2-ol [00464]embedded image 600.31 101 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)quinazolin- 7-yl)-5,6- difluoronaphthalen-2- ol [00465]embedded image 590.27 102 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)quinazolin- 7-yl)-5- fluoronaphthalen-2-ol [00466]embedded image 572.28 103 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)quinazolin- 7-yl)-5- ethynylnaphthalen-2-ol [00467]embedded image 578.29 104 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-8-fluoro-2- ((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)quinazolin- 7-yl)-5-ethylnaphthalen- 2-ol [00468]embedded image 582.32 105 4-(4-(3,9-diazabicyclo [3.3.1]nonan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00469]embedded image 614.27 106 4-(4-(3,9-diazabicyclo [3.3.1]nonan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5- ethynylnaphthalen-2-ol [00470]embedded image 596 107 4-(4-(3,6-diazabicyclo [3.1.1 ]heptan-3-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00471]embedded image 586.24 108 4-(4-(2,5-diazabicyclo [2.2.2]octan-2-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00472]embedded image 600.25 109 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-(1-thia-8- azaspiro[4.5]decan-8- yl)quinazolin-7- yl)naphthalen-2-ol [00473]embedded image 645.24 110 8-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 4-yl)-1-thia-8-azaspiro [4.5]decane 1,1- dioxide [00474]embedded image 677.23 111 4-(4-(3- aminopyrrolidin-1-yl)- 8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00475]embedded image 574.24 112 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4- (octahydro- 6H-pyrrolo[3,4-b] pyridin-6-yl) quinazolin-7-yl) naphthalen-2-ol [00476]embedded image 614.27 113 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4- (hexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl) quinazolin-7-yl) naphthalen-2-ol [00477]embedded image 600.25 114 4-(4-((3S,4S)-4-amino- 3-methyl-2-oxa-8- azaspiro[4.5]decan-8- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00478]embedded image 658.29 115 4-(4-((3S,4S)-4-amino- 3-methyl-2-oxa-8- azaspiro[4.5]decan-8- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5- ethynylnaphthalen-2-ol [00479]embedded image 640.3 116 4-(4-(3-aminopyrrolidin- 1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00480]embedded image 574.24 117 N-(1-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 4-yl)pyrrolidin-3- yl)methanesulfonamide [00481]embedded image 652.21 118 (1R,5S,8R)-3-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 4-yl)-3-azabicyclo [3.2.1]octan-8-ol [00482]embedded image 615.25 119 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00483]embedded image 635.64 120 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethyl-6- fluoronaphthalen-2-ol [00484]embedded image 639 121 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5- ethynylnaphthalen-2-ol [00485]embedded image 617 122 4-(4-((1R,5S)-8,8- difluoro-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5,6- difluoronaphthalen-2-ol [00486]embedded image 629 123 5-ethynyl-6-fluoro-4- (8-fluoro-4-((1R,5S, 8R)-8-fluoro-3- azabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin-7- yl)naphthalen-2-ol [00487]embedded image 617 124 5-ethyl-6-fluoro-4-(8- fluoro-4-((1R,5S, 8R)-8-fluoro-3- azabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)naphthalen-2-ol [00488]embedded image 621 125 5-ethynyl-4-(8-fluoro- 4-((1R,5S,8R)-8- fluoro-3-azabicyclo [3.2.1]octan-3-yl)-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 7-yl)naphthalen-2-ol [00489]embedded image 599 126 5,6-difluoro-4-(8- fluoro-4-((1R,5S,8R)- 8-fluoro-3-azabicyclo [3.2.1]octan-3-yl)-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 7-yl)naphthalen-2-ol [00490]embedded image 611 127 (1R,5S,8S)-3-(7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen- 1-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 4-yl)-3-azabicyclo [3.2.1 ]octane-8- carbonitrile [00491]embedded image 624.25 128 4-(4-((1R,5S,8R)-8- amino-3-azabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00492]embedded image 614.6 129 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1R, 5S,8R)-8-(methylthio)- 3-azabicyclo[3.2.1] octan-3-yl)quinazolin- 7-yl)naphthalen-2-ol [00493]embedded image 645.24 130 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-4-((1R,5S, 8R)-8-(methylsulfinyl)- 3-azabicyclo[3.2.1] octan-3-yl)quinazolin- 7-yl)naphthalen-2-ol [00494]embedded image 661.24 131 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-4-((1R,5S, 8R)-8-(methylsulfonyl)- 3-azabicyclo[3.2.1] octan-3-yl)quinazolin- 7-yl)naphthalen-2-ol [00495]embedded image 677.23 132 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-((1R,5S, 8R)-8-((trifluoromethyl) sulfonyl)-3-azabicyclo [3.2.1]octan-3-yl) quinazolin-7-yl) naphthalen-2-ol [00496]embedded image 731.20 133 1-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 4-yl)piperidine-4- carbonitrile [00497]embedded image 598.24 134 1-(7-(8-ethynyl-7- fluoro-3- hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 4-yl)azetidine-3- carbonitrile [00498]embedded image 570.20 135 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)-4-(2,6- diazaspiro[3.3]heptan- 2-yl)quinazolin-7- yl)naphthalen-2-ol [00499]embedded image 586.24 136 5-ethynyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-4- (quinuclidin-4- yl)quinazolin-7- yl)naphthalen-2-ol [00500]embedded image 599.26 137 4-(4-((1R,5S)-8- azabicyclo[3.2.1] octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00501]embedded image 599.26 138 4-(4-((1R,5S)-8- azabicyclo[3.2.1]octan- 3-yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin-7- yl)-5- ethynylnaphthalen-2-ol [00502]embedded image 581 139 6-(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)quinazolin- 7-yl)-5-cyclopropyl-4- methylpyridin-2-amine [00503]embedded image 562.30 140 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3- d]pyrimidin-7-yl)-5- ethynyl-6- fluoronaphthalen-2-ol [00504]embedded image 583.26 141 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R,7aS)- 2-fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3- d]pyrimidin-7-yl)-5- ethyl-6-fluoronaphthalen- 2-ol [00505]embedded image 587.29 142 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[2,3- d]pyrimidin-7-yl)-5,6- difluoronaphthalen-2-ol [00506]embedded image 577.25 143 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[2,3- d]pyrimidin-7-yl)-5- fluoronaphthalen-2-ol [00507]embedded image 559.26 144 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[2,3- d]pyrimidin-7-yl)-5- ethynylnaphthalen-2-ol [00508]embedded image 565.26 145 ((3R,7aR)-7a-(((4-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen-1- yl)pyrido[2,3-d] pyrimidin-2-yl)oxy) methyl)hexahydro-1H- pyrrolizin-3-yl)methyl dimethylcarbamate [00509]embedded image 666.31 146 ((3R,7aR)-7a-(((4-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-7-(8- ethyl-7-fluoro-3- hydroxynaphthalen-1- yl)pyrido[2,3-d] pyrimidin-2-yl)oxy) methyl)hexahydro-1H- pyrrolizin-3-yl)methyl dimethylcarbamate [00510]embedded image 670.34 147 ((3R,7aR)-7a-(((4-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-7-(8- ethynyl-7- fluoronaphthalen-1-yl) pyrido[2,3-d] pyrimidin-2-yl)oxy) methyl)hexahydro-1H- pyrrolizin-3-yl)methyl dimethylcarbamate [00511]embedded image 650.32 148 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00512]embedded image 582.26 149 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5-ethyl-6- fluoronaphthalen-2-ol [00513]embedded image 586.29 150 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 7-yl)-5,6- difluoronaphthalen-2-ol [00514]embedded image 576.25 151 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 7-yl)-5- fluoronaphthalen-2-ol [00515]embedded image 558.26 152 4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1] octan-3-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)quinazolin- 7-yl)-5- ethynylnaphthalen-2-ol [00516]embedded image 564.27 153 ((3R,7aR)-7a-(((4-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3- hydroxynaphthalen-1- yl)quinazolin-2-yl) oxy)methyl)hexahydro- 1H-pyrrolizin-3-yl) methyl dimethylcarbamate [00517]embedded image 665.32 154 ((3R,7aR)-7a-(((4-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-7-(8- ethyl-7-fluoro-3- hydroxynaphthalen-1- yl)quinazolin-2-yl) oxy)methyl)hexahydro- 1H-pyrrolizin-3-yl) methyl dimethylcarbamate [00518]embedded image 669.36 155 ((3R,7aR)-7a-(((4-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-7-(8- ethynyl-7- fluoronaphthalen-1- yl)quinazolin-2-yl)oxy) methyl)hexahydro-1H- pyrrolizin-3-yl)methyl dimethylcarbamate [00519]embedded image 649.32 156 2-(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)quinazolin- 7-yl)-1,1a,6,6a- tetrahydrocyclopropa [a]inden-4-ol [00520]embedded image 560.4

    Example 157: synthesis of 4-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol

    [0211] ##STR00521##

    Step 1: synthesis of (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

    [0212] Dissolve compound 7-bromo-2,4-dichloro-8-fluoroquinazoline (200 mg, 0.68 mmol) and (1R,5S)-8-oxa-3-azabicyclic [3.2.1] octane hydrochloride (112 mg, 0.74 mmol) in anhydrous DMF (5 mL), then add DIEA (262 mg, 2.03 mmol) and stir at room temperature for 1 hour. After completion, dilute the reaction solution with ice water, solid precipitated. Solid was collected with filtering and dried in vacuum to give off-white solid (250 mg, yield: 100%). 1H NMR (400 MHz, CDCl3) ? 7.56-7.44 (m, 2H), 4.47 (d, J=2.0 Hz, 2H), 4.34 (d, J=12.8 Hz, 2H), 3.69 (d, J=11.8 Hz, 2H), 2.06-1.91 (m, 2H), 1.87-1.76 (m, 2H).

    Step 2: synthesis of (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

    [0213] Dissolve compound (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methanol (139 mg, 0.87 mmol) in anhydrous THF (5 ml), with ice water bath cooling, 60% NaH (34 mg, 0.81 mmol) was added, and stir for 15 minutes under ice water bath cooling Then, compound (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-8-oxa-3-azabicyclic [3.2.1] octane (250 mg, 0.67 mmol) was added to the reaction solution, and stirred for 4 hours under ice water bath cooling After the reaction is completed, ice water is added for quenching reaction, extracted with ethyl acetate. The organic layer is washed with brine, dried with sodium sulfate and concentrated. Pre-TLC purification gave white solid (162 mg, yield: 49%). 1H NMR (400 MHz, CDCl3) ? 7.41 (dd, J=9.1, 1.3 Hz, 1H), 7.32-7.27 (m, 1H), 5.30 (dd, J=34.3, 19.6 Hz, 1H), 4.44 (d, J=1.9 Hz, 2H), 4.32-4.19 (m, 3H), 4.12 (d, J=10.3 Hz, 1H), 3.61 (ddd, J=12.9, 5.0, 1.9 Hz, 2H), 3.22 (dd, J=27.4, 14.3 Hz, 3H), 3.03-2.91 (m, 1H), 2.35-2.11 (m, 3H), 2.04-1.77 (m, 7H).

    Step 3: synthesis of (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

    [0214] (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (30 mg, 0.06 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (33 mg, 0.07 mmol), cesium carbonate (50 mg, 0.15 mmol) and Pd(dppf)Cl.sub.2(9 mg, 0.01 mmol) were added to 1,4-dioxane/custom-character=5/1 (3 mL). Run evacuating and backfilling with nitrogen, the reaction was stirred at 100? C. for 12 hours. After completion, the reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Prep-TLC gave off-white solid (40 mg, yield: 83.6%). MS m/z: 783.7 [M+H]+

    Step 4: synthesis of (1R,5S)-3-(7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

    [0215] (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (40 mg, 0.05 mmol) was added in DMF (3 mL). CsF (39 mg, 0.26 mmol) was added. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was used directly in next step (32 mg, yield: 100%).

    Step 5: synthesis of 4-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol

    [0216] (1R,5S)-3-(7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (32 mg, 0.05 mmol) was dissolved in acetonitrile (1 mL). 4N HCl in 1,4-dioxane (1 mL) was added. Three reaction was stirred at room temperature for 1 hours. After completion, carefully add saturated aqueous sodium bicarbonate to adjust pH to 7. Run extraction with DCM, the organic layer was dried over sodium sulfate and concentrated. Prep-TLC purification gave off-white solid (18 mg, yield: 61%). 1H NMR (400 MHz, CDCl3) ? 7.69 (d, J=8.2 Hz, 1H), 7.46 (t, J=6.8 Hz, 1H), 7.30-7.20 (m, 4H), 7.06 (dd, J=15.0, 7.1 Hz, 1H), 5.39 (d, J=11.3 Hz, 0.5H), 5.27 (d, J=13.6 Hz, 0.5H), 4.44-4.20 (m, 6H), 3.63-3.56 (m, 2H), 3.40-3.33 (m, 2H), 3.27-3.12 (m, 1H), 3.08-2.98 (m, 2H), 2.41 (d, J=2.8 Hz, 1H), 2.31-2.09 (m, 3H), 2.07-1.73 (m, 5H). MS m/z: 583.57 [M+H]+.

    [0217] The compounds of Examples 158-169 were prepared by the preparation method for Example 157

    TABLE-US-00004 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 158 4-(4-((1R,5S)-8-thia-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00522]embedded image 617 159 (1R,5S,8R)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-8-thia-3- azabicyclo[3.2.1]octane 8-oxide [00523]embedded image 633 160 (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-8-thia-3- azabicyclo[3.2.1]octane 8,8-dioxide [00524]embedded image 649 161 4-(4-((1R,5S)-8-thia-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol [00525]embedded image 621.7 162 (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-8-thia-3- azabicyclo[3.2.1]octane 8-oxide [00526]embedded image 637 163 (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-thia- 3-azabicyclo[3.2.1]octane 8,8-dioxide [00527]embedded image 653 164 4-(4-((1R,5S)-8-thia-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6- difluoronaphthalen-2-ol [00528]embedded image 611 165 (1R,5S,8R)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-thia- 3-azabicyclo[3.2.1]octane 8-oxide [00529]embedded image 627 166 (1R,5S)-3-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-thia- 3-azabicyclo[3.2.1]octane 8,8-dioxide [00530]embedded image 643 167 4-(4-((1R,5S)-8-thia-3-azabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5- fluoronaphthalen-2-ol [00531]embedded image 593 168 (1R,5S,8R)-3-(8-fluoro-7-(8-fluoro-3- hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-8-thia-3- azabicyclo[3.2.1]octane 8-oxide [00532]embedded image 609 169 (1R,5S)-3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen- 1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-8-thia-3- azabicyclo[3.2.1]octane 8,8-dioxide [00533]embedded image 625

    Example 170: synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-carbonitrile

    [0218] ##STR00534##

    Step 1: synthesis of methyl 4-bromo-2-(2-cyanoacetamido)benzoate

    [0219] methyl 2-amino-4-bromobenzoate (10 g, 43.47 mmol) and cyanoacetic acid (4.44 g, 52.16 mmol) were dissolve in DCM (100 mL). With ice-water bath cooling, EDCI (12.5 g, 65.10 mmol) was added. The reaction was stirred in ice-water bath for 1 hours. After completion, water was added and the mixture was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give target compound (12.9 g, yield: 100%). 1HNMR (400 MHz, CDCl3) ? 11.73 (s, 1H), 8.88 (d, J=1.5 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 1.8 Hz, 1H), 3.97 (s, 3H), 3.61 (s, 2H).

    Step 2: synthesis of 7-bromo-2,4-dihydroxyquinoline-3-carbonitrile

    [0220] methyl 4-bromo-2-(2-cyanoacetamido)benzoate (12.9 g, 43.42 mmol) was dissolved in anhydrous methanol (100 mL). With ice-water bath cooling, a solution of 30% sodium methoxide (11.73 g, 65.13 mmol) was added. The reaction was stirred in ice-water bath for 30 min. After completion, the reaction was treated with 10% aqueous HCl to adjust pH to 2-3. 100 mL of water was added. The precipitated solid was collected by filtering and dried under vacuum to give off-white solid (11.18 g, yield: 97%). 1HNMR (400 MHz, DMSO) ? 11.62 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.37 (dd, J=8.6, 1.8 Hz, 1H).

    Step 3: synthesis of 7-bromo-2,4-dichloroquinoline-3-carbonitrile

    [0221] 7-bromo-2,4-dihydroxyquinoline-3-carbonitrile (11.0 g, 41.50 mmol) was dissolve in acetonitrile (10 mL) and POCl3 (40 mL). The reaction was heated at 90? C. and stirred for 16 hours. After completion, the reaction was cooled to room temperature and concentrated to give light yellow solid which was used directly in next step (12.53 g, yield: 100%). 1HNMR (400 MHz, CDCl3) ? 8.28 (d, J=1.8 Hz, 1H), 8.13 (d, J=8.9 Hz, 1H), 7.87 (dd, J=9.0, 1.9 Hz, 1H).

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

    [0222] 7-bromo-2,4-dichloroquinoline-3-carbonitrile (5.00 g, 16.56 mmol) was dissolved in anhydrous DMF (50 mL). With ice-water bath cooling, DIEA (12.84 g, 16.42 mL, 99.36 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.87 g, 18.22 mmol) were added successively. The reaction was stirred in ice-water bath for 10 min. After completion, 100 mL of cooled water was added under stirring. The solid was collected by filtering and eluted with water. Drying under vacuum gave light yellow solid which was used directly in next step (7.2 g, yield: 88.59%). 1HNMR (400 MHz, CDCl3) ? 8.18 (d, J=1.9 Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 7.67 (dd, J=9.0, 2.0 Hz, 1H), 4.43 (s, 2H), 3.90 (d, J=49.2 Hz, 2H), 3.41 (s, 2H), 2.24-2.06 (m, 4H), 1.53 (s, 9H).

    Step 5: synthesis of tert-butyl (1R,5S)-3-(7-bromo-3-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0223] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (44 mg, 0.27 mmol) was dissolved in anhydrous THF (3 ml). With ice-water bath cooling, 60% NaH (11 mg, 0.27 mmol) was added. The reaction was stirred in ice-water bath for 15 min. tert-butyl (1R,5S)-3-(7-bromo-2-chloro-3-cyanoquinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.21 mmol) was added. The stirring was kept in ice-water bath for 4 hours. After completion, the reaction was quenched by addition of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification with prep-TLC gave off-white solid (120 mg, yield: 95%). 1HNMR (400 MHz, CDCl3) ? 7.95 (dd, J=9.4, 5.5 Hz, 2H), 7.47 (dd, J=8.9, 2.0 Hz, 1H), 5.37 (d, J=52.7 Hz, 1H), 4.34 (d, J=41.9 Hz, 4H), 3.90 (s, 1H), 3.76-3.62 (m, 1H), 3.28 (s, 5H), 3.03 (s, 1H), 2.13 (dd, J=34.9, 7.1 Hz, 10H), 1.52 (s, 9H).

    Step 6: synthesis of tert-butyl (1R,5S)-3-(7-(8-chloro-7-fluoronaphthalen-1-yl)-3-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0224] tert-butyl (1R,5S)-3-(7-bromo-3-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.08 mmol), 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31 mg, 0.10 mmol), cesium carbonate (68 mg, 0.21 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol) were added to 1,4-dioxane/water=5/1(3 mL). Run evacuating and backfilling with nitrogen. The reaction was heated at 100? C. under nitrogen atmosphere for 6 hours. After completion, the reaction was cooled to room temperature. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC gave off-white solid (43 mg, yield: 73%).

    Step 7: synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-carbonitrile

    [0225] tert-butyl (1R,5S)-3-(7-(8-chloro-7-fluoronaphthalen-1-yl)-3-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (43 mg, 0.06 mmol) was dissolved in (3 mL). TFA (1 mL) was added. The reaction was stirred at room temperature for 1 hour. After completion, the reaction solution was concentrated. Then, saturated aqueous sodium bicarbonate and water were added. The organic layer was separated out, dried over sodium sulfate and concentrated. Purification with prep-TLC gave off-white solid (30 mg, yield: 81%). 1H NMR (400 MHz, CDCl3) ? 8.12 (d, J=8.6 Hz, 1H), 7.95-7.85 (m, 2H), 7.76 (s, 1H), 7.56-7.49 (m, 1H), 7.46 (t, J=6.4 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 5.37 (d, J=45.4 Hz, 1H), 4.32 (d, J=12.0 Hz, 2H), 3.95-3.74 (m, 2H), 3.70 (s, 2H), 3.50 (ddd, J=31.9, 21.2, 11.7 Hz, 6H), 3.25 (s, 1H), 3.03 (s, 1H), 2.44-2.14 (m, 5H), 2.12-2.06 (m, 3H). MS m/z: 600.5 [M+H]+

    [0226] The compounds of Examples 171-198 were prepared by the preparation method for Example 170

    TABLE-US-00005 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 171 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00535]embedded image 606.7 172 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00536]embedded image 610.7 173 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00537]embedded image 588.7 174 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00538]embedded image 592.7 175 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8- difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00539]embedded image 600.6 176 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00540]embedded image 582.6 177 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00541]embedded image 624.6 178 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00542]embedded image 628.7 179 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8- difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00543]embedded image 618.6 180 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00544]embedded image 600.6 181 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00545]embedded image 610 182 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [00546]embedded image 606 183 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3-(trifluoromethyl)quinolin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol [00547]embedded image 649 184 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3-(trifluoromethyl)quinolin-7-yl)-5- ethynylnaphthalen-2-ol [00548]embedded image 631 185 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)-3-(trifluoromethyl)quinolin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol [00549]embedded image 667 186 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)-3-(trifluoromethyl)quinolin-7-yl)- 5-ethyl-6-fluoronaphthalen-2-ol [00550]embedded image 671 187 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)-3-(trifluoromethyl)quinolin-7-yl)- 5,6-difluoronaphthalen-2-ol [00551]embedded image 661 188 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00552]embedded image 607 189 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00553]embedded image 607 190 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00554]embedded image 611 191 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00555]embedded image 625.6 192 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00556]embedded image 629 193 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8- difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00557]embedded image 619.6 194 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-carbonitrile [00558]embedded image 601.6 195 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3-(trifluoromethyl)-1,6-naphthyridin-7- yl)-5-ethynyl-6-fluoronaphthalen-2-ol [00559]embedded image 650 196 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)-3-(trifluoromethyl)-1,6- naphthyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [00560]embedded image 668 197 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)-3-(trifluoromethyl)-1,6- naphthyridin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [00561]embedded image 672 198 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)-3-(trifluoromethyl)-1,6- naphthyridin-7-yl)-5,6-difluoronaphthalen-2-ol [00562]embedded image 662

    Example 199: synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[3,2-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol

    [0227] ##STR00563##

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

    [0228] A solution of 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine (0.72 g, 3.4 mmol) in DMF (15 mL) was cooled in ice-water bath. DIEA (1.0 mL, 6.1 mmol) was added dropwise followed by addition of tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The reaction was stirred at this temperature for 2 hours. Ethyl acetate (120 mL) and water (100 mL) were added. After shaking and separation, the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (40 mL?3) and brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified with column chromatography (silica gel,ethyl acetate:PE=1:4) to give light brown solid (1.25 g, yield: 90%).

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

    [0229] In ice-water bath, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.525 g, 3.3 mmol) in anhydrous THF (30 mL) was added sodium hydride in portions (77 mg, 3.2 mmol). The reaction was stirred at room temperature for 40 min and then cooled in ice-water bath. tert-butyl (1R,5S)-3-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.25 g, 2.75 mmol) was added. The ice-water bath was removed, the stirring was kept for 6 hours. The reaction was quenched by addition of water (100 mL). Ethyl acetate (100 mL) was added. After shaking and separation, the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The leaving paste was purified with column chromatography (silica gel, methanol:DCM=1:20) to give tert-butyl (1R,5S)-3-(7-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as yellow solid (0.95 g, yield: 60%).

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

    [0230] Under argon, a mixture of tert-butyl (1R,5S)-3-(7-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (131 mg, 0.374 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Pd(dppf)Cl.sub.2 (15 mg, 0.02 mmol) and potassium carbonate (58 mg, 0.42 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was stirred at 90? C. for 4 hours. Ethyl acetate (20 mL) and water (20 mL) were added. After shaking and separation, the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified with column chromatography (silica gel, methanol:DCM=1:20) to give light brown solid (75 mg, yield: 50%). MS m/z: 721.4 [M+H]+

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

    [0231] In ice-water bath, to a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy) naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.104 mmol) in acetonitrile (1.5 mL) was added a solution of HCl in 1,4-dioxane (4 M, 3 mL). The reaction was stirred at this temperature for 0.5 hour. The solution was concentrated under vacuum. DCM (20 mL) and saturated aqueous saturated sodium carbonate (10 mL) were added for extraction. The organic layer was washed with water (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified with prep-TLC (ammonia:methanol:DCM=1:10:80) to give yellow solid (29 mg, yield: 48%). MS m/z: 577.4 [M+H].sup.+. 1H NMR (400 MHz, DMSO) ? 8.21 (s, 1H), 8.08 (s, 1H), 7.66-7.56 (m, 1H), 7.46-7.35 (m, 1H), 7.34-7.31 (m, 1H), 7.23 (d, J=2.0 Hz, 1H), 5.44-5.20 (m, 1H), 4.69-4.54 (m, 2H), 4.40-4.20 (m, 2H), 3.80-3.54 (m, 4H), 3.27-3.12 (m, 3H), 3.08-2.94 (m, 1H), 2.41-2.09 (m, 3H), 2.07-1.66 (m, 7H)

    [0232] The compounds of Examples 200 and 201 were prepared by the preparation method for Example

    TABLE-US-00006 m/z: Ex. Compound name Structural formula ES.sup.+[M + H] 200 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[3,2-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00564]embedded image 583.4 201 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[3,2-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol [00565]embedded image 587.4

    Example 202: synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0233] ##STR00566##

    Step 1: synthesis of tert-butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

    [0234] 1-(tert-butyl) 4-methyl 3-oxopiperidine-1,4-dicarboxylate (20 g, 77.73 mmol) was dissolved in an aqueous solution (160 mL). 30% sodium methoxide solution (42.0 g, 233.20 mmol) and thiourea (8.88 g, 116.60 mmol) were added, the reaction was heated at 80? C. for 2 hours. After completion, the reaction was cooled to room temperature, iodomethane was added dropwise (13.79 g, 6.10 mL, 97.17 mmol) to the reaction solution. The reaction was stirred for 1 hour at room temperature. After completion, concentrate the reaction solution, dissolve the residue in water, adjust the pH to 6-7 with glacial acetic acid. Solid precipitated. Filtering gave white solid. (22 g, yield: 95%). 1H NMR (400 MHz, CDCl3) ? 11.40 (s, 1H), 4.33 (s, 2H), 3.60 (t, J=5.5 Hz, 2H), 2.56 (s, 5H), 1.49 (s, 9H).

    Step 2: synthesis of 2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

    [0235] tert-butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (22 g, 73.98 mmol) was dissolved in DCM (200 mL). TFA (50 mL) was added. The reaction was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated. The leaving residue was extracted with saturated aqueous sodium bicarbonate and DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give crude product which was used directly in next step (14.6 g, yield: 100%).

    Step 3: synthesis of benzyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

    [0236] 2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (14.5 g, 73.51 mmol) was dissolved in anhydrous THF (150 mL). With ice-water bath cooling, TEA (15.37 mL, 110.26 mmol) was added, following by adding benzyl chloroformate (13.79 g, 80.86 mmol) dropwise. The reaction was stirred in ice-water bath for 1 hour. After completion, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Column chromatography purification gave target compound (24 g, yield: 98.5%).

    Step 4: synthesis of benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

    [0237] benzyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (24.0 g, 72.42 mmol) was dissolved in DCM (300 mL). With ice-water bath cooling, DIEA (14.04 g, 108.63 mmol) was added following by adding trifluoromethanesulfonic anhydride (22.48 g, 79.66 mol) dropwise. After addition, the reaction was stirred in ice-water bath for 1 hour. After completion, the reaction mixture was concentrated and the resulting oil was used directly in next step.

    Step 5: synthesis of benzyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

    [0238] benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (72.42 mmol) was dissolved in anhydrous DMF (300 mL). DIEA (14.04 g, 108.63 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.38 g, 72.42 mmol) were added. The reaction was stirred in ice-water bath for 30 min. Brine was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography gave off-white solid (26.6 g, yield: 70%). 1H NMR (400 MHz, CDCl3) ? 7.36 (d, J=9.9 Hz, 5H), 5.17 (s, 2H), 4.54 (s, 2H), 4.29 (s, 2H), 3.78 (s, 2H), 3.61 (d, J=4.8 Hz, 2H), 3.21 (s, 2H), 2.62 (s, 2H), 2.49 (s, 3H), 1.85 (dd, J=43.2, 5.8 Hz, 4H), 1.49 (s, 9H).

    Step 6: synthesis of benzyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

    [0239] benzyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (26.6 g, 50.60 mmol) was dissolved in DCM (200 mL). With ice-water bath cooling, 85% m-CPBA (12.32 g, 60.72 mmol) was added. The reaction was stirred in ice-water bath for 30 min. After completion, saturated aqueous sodium thiosulfate was added to quench the reaction. Use DCM to run extraction, the organic layer was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and off-white solid (27.4 g, yield: 100%). 1H NMR (400 MHz, CDCl3) ? 7.37 (s, 5H), 5.19 (s, 2H), 4.71 (s, 2H), 4.31 (s, 2H), 3.92 (s, 2H), 3.65 (s, 2H), 3.30-3.27 (m, 2H), 2.88 (s, 3H), 2.72 (s, 2H), 2.02-1.85 (m, 2H), 1.75 (d, J=7.4 Hz, 2H), 1.49 (s, 9H).

    Step 7: synthesis of benzyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

    [0240] benzyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (2.0 g, 3.69 mmol) was dissolved in anhydrous toluene (20 mL). With ice-water bath cooling, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.76 g, 4.80 mmol) was added. Then sodium tert-butoxide (0.53 g, 5.54 mmol) was added in portions. The reaction was stirred in ice-water bath for 20 min. After completion, the reaction was quenched by addition of water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification with column chromatography gave off-white solid (1.53 g, yield: 65%). 1H NMR (300 MHz, CDCl3) ? 7.38 (s, 5H), 5.26 (d, J=38.3 Hz, 3H), 4.55 (s, 2H), 4.29 (s, 2H), 4.14-3.91 (m, 2H), 3.82 (d, J=12.8 Hz, 2H), 3.63 (s, 2H), 3.34-3.05 (m, 5H), 3.03-2.87 (m, 1H), 2.63 (s, 2H), 2.13 (s, 3H), 1.87 (ddd, J=23.6, 10.7, 6.0 Hz, 7H), 1.51 (s, 9H).

    Step 8: synthesis of tert-butyl (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0241] benzyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.53 g, 2.40 mmol) was dissolved in methanol (30 mL) and NH.sub.3/methanol (6M, 4 mL). Under nitrogen atmosphere, 10% wet Pd/C (300 mg) was added. The flask was evacuated and backfilled with hydrogen. The reaction was stirred at room temperature for 5 hours. After completion, the mixture was filtered through celite and eluted with methanol. The combined filtrates were concentrated to give off-white solid (1.1 g, yield: 91%). 1H NMR (300 MHz, CDCl3) ? 5.38-5.11 (m, 1H), 4.29 (s, 2H), 4.06 (t, J=8.7 Hz, 1H), 3.94 (t, J=5.0 Hz, 2H), 3.85 (d, J=12.1 Hz, 2H), 3.31-3.09 (m, 5H), 3.09-2.91 (m, 3H), 2.69-2.51 (m, 2H), 2.37-2.06 (m, 3H), 1.89 (dt, J=11.8, 8.1 Hz, 8H), 1.51 (s, 9H).

    Step 9: synthesis of tert-butyl (1R,5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0242] tert-butyl (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.10 mmol) and 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (46 mg, 0.12 mmol) were dissolved in anhydrous toluene (5 mL). Cesium carbonate (93 mg, 0.25 mmol), RuPhos (5 mg, 0.01 mmol) and Pd2(dba)3 (10 mg, 0.0 mmol) were added. Run evacuating and backfilling with nitrogen for three times. The reaction was heated at 100? C. for 12 hours. After completion, the reaction was cooled to room temperature and diluted with EA. The mixture was filtered and the filtrate was concentrated. The residue was purified with column chromatography to give off-white solid (30 mg, yield: 34%).

    Step 10: synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0243] tert-butyl (1R,5S)-3-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.06 mmol) was dissolved in DMF (3 mL). CsF (42 mg, 0.28 mmol) was added. The reaction was stirred at room temperature for 2 hours. After completion, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give crude product. This product was dissolved in acetonitrile (2 mL). Then 4M HCl in 1,4-dioxane (1 mL) was added. The reaction was stirred at room temperature for 30 min. After completion, saturated aqueous sodium bicarbonate was added carefully to adjust pH to 7. The mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. Purification with prep-TLC (DCM/MeOH(7N NH.sub.3)=10/1) gave light yellow solid (20 mg, yield: 60%). MS m/z: 587.6 [M+H]+

    [0244] The compounds of Examples 203-211 were prepared by the preparation method for Example 202

    TABLE-US-00007 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H] 203 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5,8- dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [00567]embedded image 591.7 204 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5,8- dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)-5,6-difluoronaphthalen-2-ol [00568]embedded image 581.6 205 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5,8- dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)-5-fluoronaphthalen-2-ol [00569]embedded image 562.6 206 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5,8- dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)-5-ethynylnaphthalen-2-ol [00570]embedded image 569.7 207 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5,8- dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)-5-ethylnaphthalen-2-ol [00571]embedded image 573.3 208 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5,8- dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)-5-chloro-6-fluoronaphthalen-2-ol [00572]embedded image 597 209 ((3R,7aR)-7a-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl)oxy)methyl)hexahydro- 1H-pyrrolizin-3-yl)methyl dimethylcarbamate [00573]embedded image 670 210 ((3R,7aR)-7a-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl)oxy)methyl)hexahydro- 1H-pyrrolizin-3-yl)methyl dimethylcarbamate [00574]embedded image 674 211 ((2R,7aS)-7a-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoronaphthalen-1-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)methyl dimethylcarbamate [00575]embedded image 654

    Example 212: synthesis of 4-(4-(3-(2-aminopropan-2-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0245] ##STR00576##

    Step 1: synthesis of tert-butyl (2-(1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)azetidin-3-yl)propan-2-yl)carbamate

    [0246] tert-butyl (2-(azetidin-3-yl)propan-2-yl)carbamate (107 mg, 0.5 mmol) and 7-bromo-2,4-dichloro-8-fluoroquinazoline (167 mg, 0.55 mmol) were dissolved in DMF (1.5 mL). DIEA (193 mg. 0.75 mmol) was added. Run evacuating and backfilling with nitrogen, the reaction was stirred at room temperature overnight. After completion, the mixture was concentrated in high vacuo and then purified with prep-TLC to give off-white solid (112 mg, yield: 47.5%). MS m/z: 473.44, 475.45 [M+H]+

    Step 2: synthesis of tert-butyl (2-(1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)quinazolin-4-yl)azetidin-3-yl) propan-2-yl)carbamate

    [0247] Under nitrogen atmosphere, tert-butyl (2-(1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)azetidin-3-yl)propan-2-yl)carbamate (110 mg, 0.24 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (56 mg, 0.36 mmol) were dissolved in 1,4-dioxane (1 mL) and DCM (1 mL). NaH (15 mg, 0.36 mmol, 60% in mineral oil) was added at 0? C. The reaction was allowed to warm to room temperature gradually. After completion, the reaction was quenched by addition of saturated aqueous NH.sub.4Cl (2 mL) and extracted with DCM (2 mL?3). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification with prep-TLC gave light yellow solid (92 mg, yield: 42.9%). MS m/z: 596.62, 598.66 [M+H].sup.+.

    Step 3: synthesis of tert-butyl (2-(1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-3-yl)propan-2-yl)carbamate

    [0248] Under nitrogen atmosphere, tert-butyl (2-(1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-3-yl)propan-2-yl)carbamate (92 mg, 0.15 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (118 mg, 0.23 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.8 mL). CataCXium A Pd G4 (11 mg, 0.015 mmol), potassium phosphate (97 mg, 0.45 mmol) were added. The reaction was warm up to 70? C. gradually. After completion, saturated aqueous NH.sub.4Cl (3 mL) was added to quench the reaction. Ethyl acetate (2 mL?3) was used for extraction. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification with prep-TLC gave light yellow solid (77 mg, yield: 56.9%).

    Step 4: synthesis of tert-butyl (2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)propan-2-yl)carbamate

    [0249] tert-butyl (2-(1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-3-yl)propan-2-yl)carbamate (77 mg, 0.086 mmol) was dissolved in THF (1 mL) and TBAF (0.21 mmol, 1M in THF) was added. Run evacuating and backfilling with nitrogen, the reaction was stirred at room temperature overnight. After completion, the mixture was concentrated. Purification with prep-TLC gave white solid (56 mg, yield: 91%). MS m/z: 746.96 [M+H]+

    Step 5: synthesis of 4-(4-(3-(2-aminopropan-2-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0250] At 0? C., tert-butyl (2-(1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)propan-2-yl)carbamate (56 mg, 0.077 mmol) was dissolved in acetonitrile (1 mL). HCl (1 mL, 4M in 1,4-dioxane) was added. The mixture was allowed to warm to room temperature and stirred overnight. After completion, the mixture was concentrated. HCl was neutralized with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2 mL?3). The combined organics were washed with brine, dried over sodium sulfate and concentrated. Purification with prep-TLC gave white solid (38 mg, yield: 81.9%). MS m/z: 602.79 [M+H]+

    [0251] The compounds of Examples 213-219 were prepared by the preparation method for Example 212

    TABLE-US-00008 m/z: Ex. Compound name Structural formula ES.sup.+[M + H] 213 4-(4-(3-(1-aminoethyl)azetidin-1-yl)- 8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol [00577]embedded image 588.70 214 3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin- 4-yl)-3,8-diazabicyclo[3.2.1]octan-2-one [00578]embedded image 614.67 215 1-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin- 4-yl)azetidine-3-carboxamide [00579]embedded image 588.3 216 5-ethynyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(1,6- diazaspiro[3.3]heptan- 6-yl)quinazolin-7- yl)naphthalen-2-ol [00580]embedded image 586.4 217 4-(4-(3-amino-3-methylazetidin- 1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7- yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00581]embedded image 574.4 218 5-ethynyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (3-methyl-3-(methylamino)azetidin- 1-yl)quinazolin-7- yl)naphthalen-2-ol [00582]embedded image 588.4 219 4-(4-(cyclopropyl(2-(methyl- amino)ethyl)amino)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol [00583]embedded image 603.4

    Example 220: synthesis of 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol

    [0252] ##STR00584##

    Step 1: synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

    [0253] 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (5.0 g, 23.1 mmol) was dissolved in 50 mL of POCl.sub.3. 5 mL of N,N-diethyl aniline was added at room temperature. The reaction was heated at 110? C. at stirred overnight. After completion, the reaction mixture was treated with vacuum to remove organic solvents. The leaving crude product was purified with column chromatography (DCM) to give off-white solid (5.28 g, yield: 91%). MS m/z: 252[M+H]+

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

    [0254] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 10 mmol) was dissolved in 50 mL of anhydrous THF, followed by addition of DIEA (2.8 ml, 20 mmol). In ice-water bath, tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.23 g, 10.5 mmol) was added. The reaction was stirred for 2 h. After completion, solvent was removed under vacuum to give crude product. This crude product was dissolved in 200 mL of ethyl acetate. The solution was washed with 50 mL of brine. The organic layer was dried over sodium sulfate and concentrated. The product was triturated in PE (200 mL) for 1 h. Filtering gave white solid (4.0 g, yield: 93%). MS m/z: 428[M+H]+

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

    [0255] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (482 mg, 3.03 mmol) was dissolved in anhydrous THF (10 mL). With ice-water bath cooling, 60% NaH (51 mg, 1.27 mmol) was added. The reaction was stirred in ice-water bath for 30 min. tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 2.33 mmol) was added. The stirred was kept overnight. After completion, the reaction was quenched by addition of cooled water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification with column chromatography gave off-white solid (700 mg, yield: 55%).

    Step 4: synthesis of tert-butyl (1R,5S)-3-(7-(3-ethyl-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-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

    [0256] tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.13 mmol), 2-(3-ethyl-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (55 mg, 0.1 mmol) and Cs.sub.2CO.sub.3 (65.16 mg, 0.2 mmol) were dissolved in 5 mL/1 mL of 1,4-dioxane/water. After evacuation and backfilling with argon, Pd(PPh.sub.3).sub.4 (57.18 mg, 0.05 mmol) was added. After further evacuation and backfilling with argon, the reaction was heated at 100? C. overnight. After completion, solvent was removed in vacuo to give crude product. This crude product was purified with prep-TLC to give target compound as light yellow solid (59 mg, yield: 82%). MS m/z: 721[M+H]+

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

    [0257] tert-butyl (1R,5S)-3-(7-(3-ethyl-6-(methoxymethoxy)-2,3-dihydro-1H-inden-4-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 was dissolved in 5 mL of HCl/dioxane (4M/L). The reaction was stirred at room temperature for 2 h. After completion, the reaction mixture was treated with vacuum to remove organic solvents. 100 mL of DCM was added to dissolve the residue. The solution was neutralized and washed with 10 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to give crude product. This crude product was purified with prep-TLC to give target compound as off-white solid (35 mg, yield: 48%). MS m/z: 577 [M+H].sup.+. 1H NMR (400 MHz, DMSO) ? 9.31 (s, 1H), 9.07 (s, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.9 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 5.33 (d, J=9.0 Hz, 1H), 5.21 (s, 1H), 4.49 (d, J=12.3 Hz, 2H), 4.27 (d, J=12.1 Hz, 1H), 4.11 (d, J=10.4 Hz, 1H), 4.02 (d, J=10.4 Hz, 1H), 3.65 (d, J=12.1 Hz, 1H), 3.50 (t, J=14.2 Hz, 1H), 3.16-3.05 (m, 1H), 3.01 (s, 1H), 2.94-2.72 (m, 3H), 2.24-1.92 (m, 4H), 1.93-1.71 (m, 3H), 1.63 (s, 3H), 1.24 (s, 2H), 1.11-0.92 (m, 3H), 0.53 (t, J=7.3 Hz, 3H).

    TABLE-US-00009 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 221 1.sup.st eluting isomer (R)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol or (S)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol [00585]embedded image 577.2 Column: Chiralcel OJ-3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp .: 35? C. ABPR: 2000 psi or [00586]embedded image 222 2.sup.nd eluting isomer, (S)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol or (R)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol [00587]embedded image 577.2 Column: Chiralcel OJ-3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi or [00588]embedded image 223 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-methyl-2,3-dihydro-1H- inden-5-ol [00589]embedded image 563.4 224 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-methyl-5,6,7,8- tetrahydronaphthalen-2-ol [00590]embedded image 577.2 225 1.sup.st eluting isomer (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol or (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol [00591]embedded image 577.2 Column: Chiralcel OJ-3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi or [00592]embedded image 226 2nd eluting isomer, (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol or (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol [00593]embedded image 577.2 Column: Chiralcel OJ-3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi or [00594]embedded image 227 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00595]embedded image 591.4 228 1.sup.st eluting isomer (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol or (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol [00596]embedded image 591.4 Column: Chiralcel OJ-3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi or [00597]embedded image 229 1.sup.st eluting isomer (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol or (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol [00598]embedded image 591.4 Column: Chiralcel OJ-3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi or [00599]embedded image 230 (R)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol, S-axial chirality isomer [00600]embedded image 577.2 231 (S)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol S-axial chirality isomer [00601]embedded image 577.2 232 (R)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol R-axial chirality isomer [00602]embedded image 577.2 233 (S)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol R-axial chirality isomer [00603]embedded image 577.2 234 (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol S-axial chirality isomer [00604]embedded image 577.2 235 (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol S-axial chirality isomer [00605]embedded image 577.2 236 (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol R-axial chirality isomer [00606]embedded image 577.2 237 (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol R-axial chirality isomer [00607]embedded image 577.2 238 (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol S-axial chirality isomer [00608]embedded image 591.4 239 (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol S-axial chirality isomer [00609]embedded image 591.4 240 (R)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol R-axial chirality isomer [00610]embedded image 591.4 241 (S)-4-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol, R-axial chirality isomer [00611]embedded image 591.4 242 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-propyl-2,3-dihydro-1H- inden-5-ol [00612]embedded image 591.5 243 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-3-ethyl-2,3- dihydrobenzofuran-6-ol [00613]embedded image 579.4 244 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-3-ethylbenzofuran-6-ol [00614]embedded image 577.4 245 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-3-ol [00615]embedded image 561.4 246 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1a,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalen-5-ol [00616]embedded image 575.4 247 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-ethynyl-2,3-dihydro-1H- inden-5-ol [00617]embedded image 573.4 248 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-5,6,7,8- tetrahydronaphthalen-2-ol [00618]embedded image 587.4 249 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-hydroxy-3,4- dihydronaphthalen-1(2H)-one [00619]embedded image 577.4 250 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-hydroxy-2,3-dihydro-1H- inden-1-one [00620]embedded image 562.4 251 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-hydroxythiochromane 1- oxide [00621]embedded image 597.4 252 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-hydroxy-2,3- dihydrobenzo[b]thiophene 1-oxide [00622]embedded image 573.3 253 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-methylene-5,6,7,8- tetrahydronaphthalen-2-ol [00623]embedded image 575.4 254 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,5-dimethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00624]embedded image 591.4 255 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-2,3- dihydrospiro[cyclopropane-1,1-inden]-5-ol [00625]embedded image 575.4 256 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-3,4-dihydro-2H- spiro[cyclopropane-1,1-naphthalen]-6-ol [00626]embedded image 589.4 257 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-(2,2,2-trifluoroethyl)-2,3- dihydro-1H-inden-5-ol [00627]embedded image 631.4 258 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-(2,2-difluoroethyl)-2,3- dihydro-1H-inden-5-ol [00628]embedded image 613.4 259 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-(2-fluoroethyl)-2,3- dihydro-1H-inden-5-ol [00629]embedded image 595.4 260 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-(trifluoromethyl)-5,6,7,8- tetrahydronaphthalen-2-ol [00630]embedded image 631.4 261 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-(difluoromethyl)-5,6,7,8- tetrahydronaphthalen-2-ol [00631]embedded image 613.4 262 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-(fluoromethyl)-5,6,7,8- tetrahydronaphthalen-2-ol [00632]embedded image 595.4 263 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-ethyl-5-hydroxy-1,3- dihydro-2H-inden-2-one [00633]embedded image 591.4 264 (Z)-7-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-1-ethylidene-5-hydroxy-1,3-dihydro-2H- inden-2-one [00634]embedded image 589.4 265 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1 -(hydroxymethyl)-2,3- dihydro-1H-inden-5-ol [00635]embedded image 579.4 266 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-2-methyl-2,3-dihydro-1H- inden-5-ol [00636]embedded image 563.4 267 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-cyclopropyl-2,3-dihydro- 1H-inden-5-ol [00637]embedded image 589.3 268 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-isopropyl-2,3-dihydro- 1H-inden-5-ol [00638]embedded image 591.3 269 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-methoxy-2,3-dihydro-1H- inden-5-ol [00639]embedded image 579.28 270 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-methoxy-5,6,7,8- tetrahydronaphthalen-2-ol [00640]embedded image 593.4 271 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5,6,7,8- tetrahydronaphthalen-2-ol [00641]embedded image 563.6 272 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-fluoro-5,6,7,8- tetrahydronaphthalen-2-ol [00642]embedded image 581.4 273 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-hydroxy-2-methyl-3,4- dihydroisoquinolin-1(2H)-one [00643]embedded image 592.4 274 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-((2-methyl-2- azabicyclo[2.2.1]heptan-1- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol [00644]embedded image 583.4 275 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((3R)-3-fluoro-1- azabicyclo[2.2.1]heptan-7- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol [00645]embedded image 587.3 276 4-(2-((1-azabicyclo[2.2.1]heptan-7- yl)methoxy)-4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalen-2-ol [00646]embedded image 569.4 277 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-((6-methyl-6- azabicyclo[3.2.1]octan-5- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol [00647]embedded image 597.4

    Example 278: Synthesis of 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-ethyl-1H-benzo[d]imidazol-5-ol

    [0258] ##STR00648##

    Step 1: Synthesis of N-(2-bromo-4-methoxy-6-nitrophenyl)-2,2,2-trifluoroacetamide

    [0259] 2-Bromo-4-methoxy-6-nitroaniline (2 g, 8.1 mmol) in TFAA (20 mL) was stirred at 18? C. for 1 h. After the reaction was complete, the mixture was concentrated, diluted with sat. NaHCO.sub.3 and extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate and concentrated to obtain a yellow solid. (2.8 g, yield: 100%).

    Step 2: Synthesis of N-(2-bromo-4-methoxy-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide

    [0260] N-(2-bromo-4-methoxy-6-nitrophenyl)-2,2,2-trifluoroacetamide (2.8 g, 8.1 mmol) in THF (50 mL) at 0? C., was added NaH (356 mg, 8.9 mmol) portion wise. The mixture was stirred at 0? C. for 15 min. EtI (2.5 g, 16.2 mmol) was then added to the reaction liquid, the mixture was heated to 60? C. and reacted under stirring for 20 h. After the reaction was complete, the mixture was quenched by sat. NH.sub.4Cl and extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain a yellow solid. (1.7 g, yield: 56%).

    Step 3: Synthesis of 2-bromo-N-ethyl-4-methoxy-6-nitroaniline

    [0261] N-(2-bromo-4-methoxy-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide (1.7 g, 4.6 mmol) and LiOH.Math.H.sub.2O (966 mg, 23 mmol) were stirred in MeOH/H.sub.2O/THF (10 mL/5 mL/10 mL) at room temperature for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate and sat. NaCl, concentrated to obtain a yellow solid. (1 g, yield: 79%).

    Step 4: Synthesis of 6-bromo-N1-ethyl-4-methoxybenzene-1,2-diamine

    [0262] 2-Bromo-N-ethyl-4-methoxy-6-nitroaniline (1 g, 3.6 mmol) and Fe powder (613 mg, 10.9 mmol) in AcOH (10 mL) were stirred at 60? C. for 2 h. After the reaction was complete, the mixture was filtered and concentrated, then dissolved in ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to obtain a yellow solid. (780 mg, yield: 88%).

    Step 5: Synthesis of 7-bromo-1-ethyl-5-methoxy-1H-benzo[d]imidazole

    [0263] 6-Bromo-N1-ethyl-4-methoxybenzene-1,2-diamine (780 mg, 3.2 mmol), trimethyl orthoformate (1.01 g, 9.6 mmol) and TsOH (55 mg, 0.32 mmol) in THF (10 mL) were stirred at 70? C. for 1 h. After the reaction was complete, the mixture was concentrated, then dissolved in ethyl acetate and saturated sodium bicarbonate. The organic phase was dried with anhydrous sodium sulfate, concentrated to obtain a yellow solid. (700 mg, yield: 86%).

    Step 6: Synthesis of 7-bromo-1-ethyl-1H-benzo[d]imidazol-5-ol

    [0264] Compound 7-bromo-1-ethyl-5-methoxy-1H-benzo [d] imidazole (700 mg, 2.7 mmol) in anhydrous DCM (25 mL) at 0? C., was added BBr.sub.3 (27 mL, 27 mmol, 1M), and stirred for 1 hour under ice water bath cooling. After the reaction was completed, the reaction solution was poured into saturated aqueous solution of sodium bicarbonate to quench the reaction. The mixture was extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, concentrated to obtain the crude product. (660 mg, yield: 100%). .sup.1H NMR (400 MHz, DMSO) ? 9.48 (s, 1H), 8.19 (s, 1H), 7.06-6.89 (m, 2H), 4.44 (d, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).

    Step 7: Synthesis of 1-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-5-ol

    [0265] A solution of 7-bromo-1-ethyl-1H-benzo[d]imidazol-5-ol (200 mg, 0.83 mmol), B.sub.2Pin.sub.2(316 mg, 1.24 mmol), KOAc (244 mg, 2.5 mmol), PCy.sub.3 (46 mg, 0.16 mmol) and Pd(OAc).sub.2 (19 mg, 0.08 mmol) in DMSO (5 mL) was stirred under N.sub.2 at 100? C. for 16h. After the reaction was complete, the mixture was extracted with ethyl acetate and H.sub.2O. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain a brown solid. (84 mg, yield: 35%). .sup.1H NMR (400 MHz, DMSO) ? 9.05 (s, 1H), 8.10 (s, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 4.50 (q, J=7.0 Hz, 2H), 1.35 (s, 12H), 1.28 (t, J=7.1 Hz, 3H).

    Step 8 to step 9: Synthesis of 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-ethyl-1H-benzo[d]imidazol-5-ol

    [0266] Using the method from step 4 to step 5 in the synthesis of Example 220, a yellow solid was obtained. (5 mg, two-step overall yield: 3%). .sup.1H NMR (400 MHz, DMSO) ? 9.12 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.11 (s, 1H), 6.80 (s, 1H), 5.35 (s, 1H), 5.22 (s, 1H), 4.41 (d, J=11.5 Hz, 2H), 4.12 (d, J=10.1 Hz, 1H), 4.02 (d, J=10.2 Hz, 1H), 3.87 (d, J=7.2 Hz, 1H), 3.72-3.50 (m, 3H), 3.05 (d, J=30.5 Hz, 2H), 2.83 (s, 1H), 2.20-1.93 (m, 2H), 1.81 (d, J=36.3 Hz, 2H), 1.60 (s, 2H), 1.23 (s, 2H), 0.92-0.71 (m, 3H).

    [0267] Example 267 was obtained by using the method of Example 266.

    TABLE-US-00010 Ex. Compound name Structural formula m/z: ES.sup.+ [M + H].sup.+ 279 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-methyl-1H-benzo[d]imidazol- 5-ol [00649]embedded image 563.4

    Example 280: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-methoxy-5,6,7,8-tetrahydronaphthalen-2-ol

    [0268] ##STR00650##

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

    [0269] A solution of 2-(8-methoxy-3-(methoxymethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20 mg, 0.057 mmol), tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34 mg, 0.057 mmol) in 1,4-dioxane (0.8 mL) and H.sub.2O (0.2 mL), was added cataCXium A Pd G4 (8 mg, 0.01 mmol) and K.sub.3PO.sub.4(36 mg, 0.16 mmol). The mixture was stirred under N.sub.2 at 70? C. overnight. After the reaction was complete, the mixture was concentrated and purified by prep-TLC to give a white solid (29 mg, yield: 69%). MS m/z: 736.69 [M+H].sup.+.

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

    [0270] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methoxy-3-(methoxymethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29 mg, 0.039 mmol) was stirred in DCM (0.5 mL) and TFA (0.5 mL) under N.sub.2 for 1h. The mixture was concentrated, extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated and purified by prep-TLC to obtain a yellow solid. (1 mg, yield: 4.8%). MS m/z: 592.4 [M+H].sup.+.

    Example 281: Synthesis of 7-(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)quinazolin-7-yl)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-5-ol

    [0271] ##STR00651##

    Step 1: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-(methoxymethoxy)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-7-Vi)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0272] A solution of 2-(5-(methoxymethoxy)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4 mg, 0.0116 mmol), tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7 mg, 0.0116 mmol) in 1,4-dioxane (0.8 mL) and H.sub.2O (0.2 mL), was added cataCXium A Pd G4 (2 mg, 0.002 mmol) and K.sub.3PO.sub.4(7 mg, 0.033 mmol). The mixture was stirred under N.sub.2 at 70? C. overnight. After the reaction was complete, the mixture was concentrated and purified by prep-TLC to give a white solid (4.2 mg, yield: 50%).

    Step 2: Synthesis of 7-(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)quinazolin-7-yl)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropane[a]naphthalen-5-ol

    [0273] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-(methoxymethoxy)-7b-methyl-1a, 2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-7-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.2 mg, 0.005 mmol) was stirred in CH.sub.3CN (0.5 mL) and HCl/dioxane (1 mL, 4M) under N.sub.2 for 8h. The mixture was concentrated, extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated and purified by prep-TLC to obtain a yellow solid. (1 mg, yield: 35%). MS m/z: 588.3 [M+H].sup.+.

    Example 282: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol

    [0274] ##STR00652##

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

    [0275] A solution of 2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (40 mg, 0.125 mmol), tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.125 mmol) in 1,4-dioxane (2 mL) and H.sub.2O (0.5 mL), was added cataCXium ANP G4 (18 mg, 0.025 mmol) and K.sub.3PO.sub.4 (80 mg, 0.375 mmol). The mixture was stirred under N.sub.2 at 70? C. overnight. After the reaction was complete, the mixture was concentrated and purified by prep-TLC to give a white solid (69 mg, yield: 76%). MS m/z: 720.65 [M+H].sup.+.

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

    [0276] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-CH-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.04 mmol) was stirred in CH.sub.3CN (1 mL) and HCl/dioxane (1 mL, 4M) under N.sub.2 for 1h. The mixture was concentrated, extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated and purified by prep-TLC to obtain a yellow solid. (18 mg, yield: 76%). MS m/z: 576.7 [M+H].sup.+.

    [0277] Examples 271-292 were obtained by using the method of Example 270.

    TABLE-US-00011 Ex. Compound name Structural formula m/z: ES.sup.+ [M + H].sup.+ 283 7-(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)quinazolin-7-yl)-1- ethyl-2,3-dihydro-1H-inden-5-ol [00653]embedded image 576.5 284 7-(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)quinazolin-7-yl)-1- ethyl-2,3-dihydro-1H-inden-5-ol, epimer-1 [00654]embedded image 576.5 Column: Chiralcel OJ- 3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi 285 7-(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)quinazolin-7-yl)-1- ethyl-2,3-dihydro-1H-inden-5-ol, epimer-2 [00655]embedded image 576.5 Column: Chiralcel OJ- 3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi 286 7-(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)quinazolin-7-yl)-1- methyl-2,3-dihydro-1H-inden-5-ol [00656]embedded image 562.3 287 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)quinazolin-7-yl)-5- methyl-5,6,7,8-tetrahydronaphthalen-2-ol, epimer- 1 [00657]embedded image 576.7 288 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)quinazolin-7-yl)-5- methyl-5,6,7,8-tetrahydronaphthalen-2-ol, epimer-2 [00658]embedded image 576.7 289 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)quinazolin-7-yl)-5- ethyl-5,6,7,8-tetrahydronaphthalen-2-ol [00659]embedded image 590.3 290 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)quinazolin-7-yl)-5- ethyl-5,6,7,8-tetrahydronaphthalen-2-ol, epimer-1 [00660]embedded image 590.3 Column: Chiralcel OJ- 3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi 291 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)quinazolin-7-yl)-5- ethyl-5,6,7,8-tetrahydronaphthalen-2-ol, epimer-2 [00661]embedded image 590.3 Column: Chiralcel OJ- 3, 150 ? 4.6 mm I.D., 3 um Mobile phase: A: CO2/B: IPA (0.1% IPAm, v/v Flow rate 2.5 mL/min Column temp.: 35? C. ABPR: 2000 psi 292 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)quinazolin-7-yl)-3- ethyl-2,3-dihydrobenzofuran-6-ol [00662]embedded image 578.4 293 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)quinazolin-7-yl)-3- ethylbenzofuran-6-ol [00663]embedded image 576.4 294 5-(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)quinazolin-7-yl)- 1,1a,6,6a-tetrahydrocyclopropa[a]inden-3-ol [00664]embedded image 560.4 295 7-(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)quinazolin-7-yl)- 1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen- 5-ol [00665]embedded image 574.4 296 8-(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)quinazolin-7-yl)-6- hydroxy-3,4-dihydronaphthalen-1(2H)-one [00666]embedded image 576.4 297 7-(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)quinazolin-7-yl)-5- hydroxy-2,3-dihydro-1H-inden-1-one [00667]embedded image 561.4 298 7-(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)quinazolin-7-yl)-1- methoxy-2,3-dihydro-1H-inden-5-ol [00668]embedded image 578.4 299 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1,1-dimethyl-2,3-dihydro-1H- inden-5-ol [00669]embedded image 577.4 300 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-1,3-dihydrospiro[cyclopropane- 1,2-inden]-6-ol [00670]embedded image 575.4 301 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol [00671]embedded image 610.3 302 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol [00672]embedded image 610.3 303 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7- yl)-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol [00673]embedded image 624.3 304 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7- yl)-1-methyl-2,3-dihydro-1H-inden-5-ol [00674]embedded image 596.3

    Example 305: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7,8-dihydronaphthalen-2-ol

    [0278] ##STR00675##

    [0279] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methoxy-3-(methoxymethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (17 mg, 0.023 mmol) was stirred in CH.sub.3CN (1 mL) and HCl/dioxane (1 mL, 4M) under N.sub.2 for 1h. The mixture was concentrated, extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated and purified by prep-TLC to obtain a yellow solid. (11 mg, yield: 87%). MS m/z: 560.9 [M+H].sup.+.

    [0280] Example 293 was obtained by using the method of Example 294.

    TABLE-US-00012 Ex. Compound name Structural formula m/z: ES.sup.+[M + H].sup.+ 306 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)quinazolin-7-yl)-1H-inden-6-ol [00676]embedded image 546.3

    Example 307: Synthesis of acetoxymethyl (1R,5S)-3-(7-(3-ethyl-6-hydroxy-2,3-dihydro-1H-inden-4-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

    [0281] ##STR00677##

    [0282] Compound 7-(4-((R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol (29 mg, 0.05 mmol) and DIEA (0.025 mL, 0.15 mmol) in DCM (1.5 mL) at ?40? C., was added ((chlorocarbonyl)oxy)methyl acetate (9.2 mg, 0.06 mmol) in DCM (0.5 mL) dropwise. The mixture was stirred at ?40? C. for 15 m.sup.2. Then, warm to room temperature and diluted with DCM, concentrated, purified by prep-TLC (MeOH:DCM=1:10) to give a yellow solid (4.5 mg, 0.0065 mmol, 13% yield). MS m/z: 693.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) ? 9.31 (s, 1H), 9.07 (s, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.9 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 5.84 (s, 2H), 5.33 (d, J=9.0 Hz, 1H), 5.21 (s, 1H), 4.49 (m, 2H), 4.27 (d, J=12.1 Hz, 1H), 4.11 (d, J=10.4 Hz, 1H), 4.02 (d, J=10.4 Hz, 1H), 3.65 (d, J=12.1 Hz, 1H), 3.50 (t, J=14.2 Hz, 1H), 3.16-3.05 (m, 1H), 3.01 (s, 1H), 2.94-2.72 (m, 3H), 2.24-1.92 (m, 7H), 1.93-1.71 (m, 3H), 1.63 (s, 3H), 1.24 (s, 2H), 1.11-0.92 (m, 3H), 0.53 (t, J=7.3 Hz, 3H).

    [0283] Examples 296-314 were obtained by using the method of Example 295.

    TABLE-US-00013 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 308 (decanoyloxy)methyl (1R,5S)-3-(7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00678]embedded image 828.5 309 (palmitoyloxy)methyl (1R,5S)-3-(7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00679]embedded image 911.6 310 acetoxymethyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00680]embedded image 716.4 311 (decanoyloxy)methyl (1R,5S)-3-(7-(3-ethyl-6-hydroxy- 2,3-dihydro-1H-inden-4-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 [00681]embedded image 805.6 312 (decanoyloxy)methyl (1R,5S)-3-(7-(3-ethyl-6-hydroxy- 2,3-dihydro-1H-inden-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00682]embedded image 804.6 313 (palmitoyloxy)methyl (1R,5S)-3-(7-(3-ethyl-6- hydroxy-2,3-dihydro-1H-inden-4-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 [00683]embedded image 889.7 314 (palmitoyloxy)methyl (1R,5S)-3-(7-(3-ethyl-6- hydroxy-2,3-dihydro-1H-inden-4-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00684]embedded image 888.7 315 acetoxymethyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00685]embedded image 693.3 316 acetoxymethyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [00686]embedded image 692.8 317 (decanoyloxy)methyl (1R,5S)-3-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8- tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00687]embedded image 805.5 318 (decanoyloxy)methyl (1R,5S)-3-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00688]embedded image 804.5 319 (palmitoyloxy)methyl (1R,5S)-3-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8- tetrahydronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00689]embedded image 889.4 320 (palmitoyloxy)methyl (1R,5S)-3-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00690]embedded image 888.4 321 acetoxymethyl (1R,5S)-3-(7-(8-ethyl-3-hydroxy- 5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00691]embedded image 707.4 322 (decanoyloxy)methyl (1R,5S)-3-(7-(8-ethyl-3-hydroxy- 5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00692]embedded image 819.6 323 (palmitoyloxy)methyl (1R,5S)-3-(7-(8-ethyl-3- hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00693]embedded image 903.7 324 acetoxymethyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (6-hydroxy-3-methyl-2,3-dihydro-1H-inden-4- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00694]embedded image 679.4 325 (decanoyloxy)methyl (1R,5S)-3-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(6-hydroxy-3-methyl-2,3-dihydro-1H- inden-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00695]embedded image 791.5 326 (palmitoyloxy)methyl (1R,5S)-3-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(6-hydroxy-3-methyl-2,3-dihydro-1H- inden-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00696]embedded image 875.6

    Example 327: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0284] ##STR00697##

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

    [0285] Cyclopropanol (99 mg, 1.68 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0? C., KHMDS (1 M/L, 1.7 ml) was added dropwise, and after 30 min, tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.337 mmol) was added; and the mixture was reacted at room temperature for 1 h, and the reaction was then quenched by adding a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated and then purified by prep-TLC to obtain a white solid (210 mg, yield: 95%). MS m/z: 632.22 [M+H].sup.+.

    Step 2: Synthesis of tert-butyl (1R,5S)-3-(8-cyclopropoxy-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0286] Compound tert-butyl (1R,5S)-3-(7-bromo-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.11 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (73 mg, 0.14 mmol), Potassium carbonate (31 mg, 0.22 mmol) and Pd (dppf) Cl.sub.2 (8 mg, 0.01 mmol) were stirred in 1,4-dioxane/water=5/1 (6 mL) under nitrogen atmosphere at 100? C. for 12 hours. After the reaction was completed, cooled to room temperature, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-TLC to obtain a white solid. (33 mg, yield: 36%). MS m/z: 938.5 [M+H].sup.+.

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

    [0287] Compound tert-butyl (1R,5S)-3-(8-cyclopropoxy-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.031 mmol) was stirred in HCl/dioxane (5 mL, 4M) for 1h. The mixture was concentrated, extracted with DCM and saturated sodium bicarbonate. The organic phase was dried with anhydrous sodium sulfate, concentrated and purified by prep-TLC to obtain a yellow solid. (15 mg, yield: 80%). MS m/z: 638.3 [M+H].sup.+.

    [0288] Examples 316-322 were obtained by using the method of Example 315.

    TABLE-US-00014 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 328 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-8-ol [00698]embedded image 597.4 329 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- chloro-8-cyclopropoxy-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)naphthalen-2-ol [00699]embedded image 630.4 330 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- chloro-8-cyclopropoxy-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00700]embedded image 672.4 331 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00701]embedded image 714.3 332 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-8-ol [00702]embedded image 599.4 333 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [00703]embedded image 681.4 334 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00704]embedded image 639.4

    Example 335: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-7-yl)-5-ethynyl-6-fluoronanhthalen-2-ol

    [0289] ##STR00705##

    Step 1: Synthesis of 2-acetamido-4-bromo-3-fluorobenzoic acid

    [0290] Compound 2-amino-4-bromo-3-fluorobenzoic acid (1 g, 4.27 mmol) was stirred in acetic anhydride (10 mL) at 80? C. for 5h. The mixture was concentrated to obtain a white solid. (1.2 g, yield: 100%). .sup.1HNMR (400 MHz, CDCl.sub.3) ? 7.86 (dd, J=8.2, 1.6 Hz, 1H), 7.68 (dd, J=8.5, 5.9 Hz, 1H), 2.54 (s, 3H).

    Step 2: Synthesis of methyl 2-acetamido-4-bromo-3-fluorobenzoate

    [0291] Compound 2-acetamido-4-bromo-3-fluorobenzoic acid (200 mg, 0.8 mmol), EDCI (183 mg, 0.96 mmol) and DMAP (4.88 mg, 0.04 mmol) were stirred in DCM (10 mL) and MeOH (1 mL) at room temperature for 10 h. The mixture was extracted with DCM and H.sub.2O, concentrated and purified by column chromatography to obtain a white solid. (200 mg, yield: 86.5%). .sup.1HNMR (400 MHz, CDCl.sub.3) ? 8.98 (s, 1H), 7.62 (dd, J=8.6, 1.6 Hz, 1H), 7.44 (dd, J=8.6, 6.1 Hz, 1H), 3.92 (s, 3H), 2.25 (s, 3H).

    Step 3: Synthesis of 7-bromo-8-fluoroquinoline-2,4(1H,3H)-dione

    [0292] KHMDS (12.4 mL, 12.4 mmol) in a single-mouth bottle was added methyl 2-acetamido-4-bromo-3-fluorobenzoate (1.2 g, 4.1 mmol) in THF under Ar at ?78? C. The mixture was stirred at room temperature for 1 h, then the reaction liquid was poured onto crushed ice. White solid was precipitated out when pH was adjusted to 2.0 with 6N HCl. It was filtered and dried to give a white solid. (800 mg, yield: 75.4%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.71 (s, 1H), 11.42 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.39 (t, J=7.3 Hz, 1H), 5.80 (s, 1H).

    Step 4: Synthesis of 7-bromo-8-fluoro-3-nitroquinoline-2,4(1H,3H)-dione

    [0293] Compound 7-bromo-8-fluoroquinoline-2,4(1H,3H)-dione (280 mg, 1.08 mmol) in AcOH (10 mL), was added concentrated nitric acid (201 mg, 2.17 mmol). The mixture was stirred at 80? C. for 1 h, then the reaction liquid was poured onto crushed ice, extracted with EA, concentrated to give a yellow solid. (200 mg, yield: 60.9%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.66 (s, 1H), 7.73 (dd, J=8.8, 1.4 Hz, 1H), 7.45 (dd, J=8.7, 6.1 Hz, 1H).

    Step 5: Synthesis of 7-bromo-2,4-dichloro-8-fluoro-3-nitroquinoline

    [0294] Compound 7-bromo-8-fluoro-3-nitroquinoline-2,4(1H,3H)-dione (200 mg, 0.66 mmol) and DIPEA (170 mg, 1.32 mmol) were stirred in POCl.sub.3 (10 mL) at 100? C. for 10 h. The mixture was concentrated, extracted with EA and H.sub.2O, concentrated and purified by column chromatography to obtain a yellow solid. (100 mg, yield: 44.6%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.22 (dd, J=9.1, 6.3 Hz, 1H), 8.11 (dd, J=9.1, 1.4 Hz, 1H).

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

    [0295] Compound 7-bromo-2,4-dichloro-8-fluoro-3-nitroquinoline (50 mg, 0.147 mmol) in DMF (10 mL), was added DIPEA (28.5 mg, 0.22 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31.2 mg, 0.147 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by prep-TLC to obtain a light yellow solid. (36 mg, yield: 47.5%).

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

    [0296] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (14.4 mg, 0.09 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), 60% NaH (3.3 mg, 0.84 mmol) was added under ice-water bath cooling condition and reacted at 0? C. under stirring for 30 min, and tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-3-nitroquinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36 mg, 0.07 mmol) was added. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a yellow solid. (35 mg, yield: 78.6%). MS m/z: 638.1 [M+H].sup.+.

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

    [0297] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3-nitroquinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.313 mmol) in EtOH (10 mL) and H.sub.2O (2 mL) was added iron powder (87.7 mg, 1.56 mmol) and AcOH (131.5 mg, 2.19 mmol). The mixture was stirred at room temperature for 2 h. The reaction was filtered, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain a yellow solid. (150 mg, yield: 78.9%).

    Step 9: Synthesis of tert-butyl (1R,5S)-3-(7-bromo-3,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0298] Compound tert-butyl (1R,5S)-3-(3-amino-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.247 mmol) in pyridine hydrogen fluoride (5 mL) at 0? C., was added NaNO.sub.2 (22 mg, 0.321 mmol). The mixture was stirred at 80? C. for 10 h. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (100 mg, yield: 66.7%).

    Step 10: Synthesis of tert-butyl (1R,5S)-3-(3,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0299] Compound tert-butyl (1R,5S)-3-(7-bromo-3,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.163 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (125.8 mg, 0.245 mmol) and Cs.sub.2CO.sub.3 (159 mg, 0.489 mmol) were dissolved in 1,4-dioxane and water (3 ml, 5/1), and after displacement with nitrogen, Pd(dppf)Cl.sub.2 (11.9 mg, 0.0163 mmol) was added. The reaction system was stirred at 100? C. for 12 h. After the reaction was complete, the reaction system was extracted with ethyl acetate and separated, the organic phase was dried, and the solvent was then removed under reduced pressure to obtain a crude product. The crude product was separated by prep-TLC to obtain a white solid (80 mg, yield: 53.7%). MS m/z: 917.5 [M+H]+

    Step 11: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0300] Compound tert-butyl (1R,5S)-3-(3,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.087 mmol) and CsF (66 mg, 0.435 mmol) in DMF (3 mL) were stirred at room temperature for 2 h. After the reaction was complete, the reaction was diluted with water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to give the crude product. Then the crude product was dissolved with CH.sub.3CN (2 mL), HCl/1,4-dioxane (4M, 1 mL) was added and stirred at room temperature for 30 min. After the reaction was complete, pH of the solution was adjusted to 7 with saturated sodium bicarbonate aqueous solution, extracted with DCM, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH(7N NH.sub.3)=10/1) to give a yellow solid (25 mg, yield: 46.6%). MS m/z: 617.2 [M+H].sup.+

    Example 336: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahvdro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-(methylthio)naphthalen-2-ol

    [0301] ##STR00706## ##STR00707##

    Step 1: Synthesis of (Z)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime

    [0302] Compound 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (2.1 g, 11.9 mmol), O-methylhydroxylamine hydrochloride (1.19 g, 14.3 mmol) and pyridine (1.41 g, 17.8 mmol) were stirred EtOH (50 mL) at room temperature for 5 h. The mixture was concentrated, diluted with water and extracted with DCM, concentrated to obtain a brown oil, used directly in the next step. .sup.1HNMR (400 MHz, CDCl.sub.3) ? 7.92 (d, J=8.8 Hz, 1H), 6.75 (dd, J=8.8, 2.7 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 3.96 (s, 3H), 3.81 (s, 3H), 2.71 (t, J=6.4 Hz, 4H), 1.88-1.78 (m, 2H).

    Step 2: Synthesis of (Z)-8-chloro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime

    [0303] Compound (Z)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime (2.0 g, 9.74 mmol) and NCS (1.56 g, 11.7 mmol) in AcOH (50 mL) was added Pd(OAc).sub.2 (218 mg, 0.97 mmol) under Ar. The mixture was stirred at 90? C. for 1 h. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow oil. (2 g, yield: 85.8%). .sup.1HNMR (400 MHz, CDCl.sub.3) ? 6.86 (d, J=2.6 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 4.01 (s, 3H), 3.79 (s, 3H), 2.74 (t, J=6.9 Hz, 2H), 2.64-2.53 (m, 2H), 1.79-1.67 (m, 2H).

    Step 3: Synthesis of 8-chloro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

    [0304] Compound (Z)-8-chloro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime (7.6 g, 31.7 mmol) was stirred in 1,4-dioxane (100 mL) and 6N HCl (100 mL) at 90? C. for 2 h. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (6.0 g, yield: 90.9%). .sup.1HNMR (400 MHz, CDCl.sub.3) ? 6.86 (d, J=2.6 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 3.85 (d, J=6.0 Hz, 3H), 2.93 (t, J=6.1 Hz, 2H), 2.70-2.59 (m, 2H), 2.12-2.01 (m, 2H).

    Step 4: Synthesis of 8-chloro-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

    [0305] Compound 8-chloro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (5.8 g, 27.5 mmol) in MeOH (150 mL) was added Selecetfluor (11.7 g, 33.0 mmol) and concentrated sulfuric acid (0.5 mL). The mixture was stirred at 50? C. for 5 h. The solution was concentrated, diluted with water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (5.2 g, yield: 82.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.90 (d, J=2.5 Hz, 1H), 6.64 (dd, J=2.5, 1.1 Hz, 1H), 5.04 (ddd, J=48.7, 11.8, 4.9 Hz, 1H), 3.86 (s, 3H), 3.11 (dt, J=6.6, 4.1 Hz, 2H), 2.50 (ddt, J=13.0, 8.3, 4.8 Hz, 1H), 2.41-2.26 (m, 1H).

    Step 5: Synthesis of 2-bromo-8-chloro-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

    [0306] Compound 8-chloro-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (5.2 g, 22.8 mmol) in CH.sub.3CN (100 mL), was added pyridinium tribromide (8.02 g, 25 mmol) under Ar. The mixture was stirred at 60? C. for 1 h. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (6.8 g, yield: 97.1%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.96 (d, J=2.5 Hz, 1H), 6.66 (dd, J=2.4, 1.1 Hz, 1H), 3.32 (ddd, J=17.4, 12.2, 5.0 Hz, 1H), 3.13-3.02 (m, 1H), 2.84-2.75 (m, 1H), 2.66-2.54 (m, 1H).

    Step 6: Synthesis of 8-chloro-2-fluoro-6-methoxynaphthalen-1-ol

    [0307] Compound 2-bromo-8-chloro-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (6.6 g, 21.5 mmol) and LiBr (4.1 g, 47.2 mmol) were stirred in DMF (100 mL) at 100? C. for 1 h. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (4.6 g, yield: 94.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.30 (dd, J=10.0, 9.0 Hz, 1H), 7.25-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.01 (d, J=2.5 Hz, 1H), 3.89 (s, 3H).

    Step 7: Synthesis of 8-chloro-2-fluoro-6-methoxynaphthalen-1-yl trifluoromethanesulfonate

    [0308] Compound 8-chloro-2-fluoro-6-methoxynaphthalen-1-ol (250 mg, 1.1 mmol) in DCM at ?60? C. under Ar, was added DIPEA (426 mg, 3.3 mmol) and trifluoromethanesulfonic anhydride (467 mg, 1.65 mmol). The mixture was stirred at room temperature for 10 h. The solution was poured into ice water, extracted with DCM, concentrated and separated by column chromatography to obtain a light yellow solid. (350 mg, yield: 89.7%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.75 (dd, J=9.2, 5.2 Hz, 1H), 7.42-7.35 (m, 2H), 7.09 (d, J=2.5 Hz, 1H), 3.92 (s, 3H).

    Step 8: Synthesis of 8-chloro-2-fluoro-6-hydroxynaphthalen-1-yl trifluoromethanesulfonate

    [0309] Compound 8-chloro-2-fluoro-6-methoxynaphthalen-1-yl trifluoromethanesulfonate (50 mg, 0.139 mmol) in DCM (20 mL) was added BBr.sub.3 (0.418 mL, 0.418 mmol) at 0? C. The mixture was stirred at room temperature for 10 h. The solution was poured into ice water, extracted with DCM, concentrated and separated by column chromatography to obtain a light yellow solid. (40 mg, yield: 83.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.70 (dd, J=9.2, 5.2 Hz, 1H), 7.44-7.32 (m, 2H), 7.14 (d, J=2.4 Hz, 1H).

    Step 9: Synthesis of 8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

    [0310] Compound 8-chloro-2-fluoro-6-hydroxynaphthalen-1-yl trifluoromethanesulfonate (40 mg, 0.116 mmol) in DCM (10 mL) at 0? C., was added DIPEA (44.8 mg, 0.348 mmol) and MOMBr (21.7 mg, 0.174 mmol). The mixture was stirred at room temperature for 10 min. The solution was poured into ice water, extracted with DCM, concentrated and separated by column chromatography to obtain a light yellow solid. (40 mg, yield: 88.9%). .sup.1H NMR (400 MHz, CDCl.sub.3)) ? 7.77 (dd, J=9.2, 5.2 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43-7.33 (m, 2H), 5.28 (s, 2H), 3.52 (s, 3H).

    Step 10: Synthesis of 2-((8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)thio)ethyl 3-ethylheptanoate

    [0311] Compound 8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (40 mg, 0.102 mmol), 2-mercaptoethyl 3-ethylheptanoate (45 mg, 0.204 mmol), Pd.sub.2(dba).sub.3 (4.7 mg, 0.005 mmol), Xantphos (5.95 mg, 0.01 mmol) and DIPEA (39.8 mg, 0.308 mmol) were stirred in 1,4-dioxane (10 mL) at 100? C. for 15 h under Ar. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (20 mg, yield: 42.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.72 (dd, J=9.0, 5.7 Hz, 1H), 7.47-7.41 (m, 1H), 7.34 (d, J=2.6 Hz, 2H), 5.27 (s, 2H), 3.94 (dd, J=5.9, 2.5 Hz, 2H), 3.52 (s, 3H), 3.14 (t, J=7.4 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H), 1.50 (d, J=5.7 Hz, 1H), 1.25 (m, 8H), 0.88-0.80 (m, 6H).

    Step 11: Synthesis of (8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)(methyl)sulfane

    [0312] Compound 2-((8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)thio)ethyl 3-ethylheptanoate (100 mg, 0.219 mmol) in THF (10 mL) at 0? C., was added t-BuONa (31.5 mg, 0.328 mmol). The mixture was stirred at room temperature for 1 h, then Mel (31.5 mg, 0.328 mmol) was added at 0? C. The mixture was stirred at room temperature for 2 h. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (45 mg, yield: 71.7%).

    Step 12: Synthesis of 2-(7-fluoro-3-(methoxymethoxy)-8-(methylthio)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0313] Compound (8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)(methyl)sulfane (45 mg, 0.157 mmol), B.sub.2Pin.sub.2 (59.8 g, 0.235 mmol), Pd.sub.2(dba).sub.3 (14.3 mg, 0.0157 mmol), Sphos (10.4 mg, 0.0254 mmol) and KOAc (46.2 mg, 0.471 mmol) were stirred in 1,4-dioxane (10 mL) at 110? C. for 12 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was concentrated and separated by column chromatography to obtain a white solid. (45 mg, yield: 76.2%).

    Step 13: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(methylthio)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0314] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.336 mmol), 2-(7-fluoro-3-(methoxymethoxy)-8-(methylthio)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (190 mg, 0.504 mmol), Cs.sub.2CO.sub.3 (328 mg, 1.008 mmol) and Pd(dppf)Cl.sub.2 (24.6 mg, 0.0336 mmol) were stirred in 1,4-dioxane/H.sub.2O (15 mL, 5/1) at 100? C. for 12 h under N.sub.2. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by prep-TLC to obtain a white solid. (90 mg, yield: 35%). MS m/z: 765.3 [M+H].sup.+

    Step 14: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-(methylthio)naphthalen-2-ol

    [0315] Compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(methylthio)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 0.117 mmol) was stirred in CH.sub.3CN (3 mL) and HCl/1,4-dioxane (1 mL, 4M) at room temperature for 30 min. After the reaction was complete, pH of the reaction liquid was adjusted to 7 with a saturated sodium bicarbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC (DCM/MeOH(7N NH.sub.3)=10/1) to obtain a yellow solid. (30 mg, yield: 41%). MS m/z: 622.2 [M+H].sup.+

    Example 337: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-(methylsulfonyl)napthalen-2-ol

    [0316] ##STR00708##

    Step 1: Synthesis of 8-chloro-2-fluoro-6-(methoxymethoxy)-1-(methylsulfonyl)naphthalene

    [0317] Compound (8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)(methyl)sulfane (200 mg, 0.697 mmol) in DCM (10 mL) at 0? C.-10? C., was added 85% m-CPBA (708 mg, 3.48 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction was quenched by saturated sodium thiosulfate solution and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate, dried with anhydrous sodium sulfate and concentrated to obtain a yellow solid, which was directly used for the next step.

    Step 2: Synthesis of 2-(7-fluoro-3-(methoxymethoxy)-8-(methylsulfonyl)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [0318] Compound 8-chloro-2-fluoro-6-(methoxymethoxy)-1-(methylsulfonyl)naphthalene (50 mg, 0.157 mmol), B.sub.2Pin.sub.2 (59.8 g, 0.235 mmol), Pd.sub.2(dba).sub.3 (14.3 mg, 0.0157 mmol), Sphos (10.4 mg, 0.0254 mmol) and KOAc (46.2 mg, 0.471 mmol) were stirred in 1,4-dioxane (10 mL) under Ar at 110? C. for 12 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a white solid. (47 mg, yield: 73.0%).

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

    [0319] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.336 mmol), 2-(7-fluoro-3-(methoxymethoxy)-8-(methylsulfonyl)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (206.6 mg, 0.504 mmol), C.sub.s2CO.sub.3 (328 mg, 1.008 mmol) and Pd(dppf)Cl.sub.2 (24.6 mg, 0.0336 mmol) were stirred in 1,4-dioxane/H.sub.2O (15 mL, 5/1) under N.sub.2 at 100? C. for 12 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by prep-TLC to obtain a white solid. (95 mg, yield: 36.2%). MS m/z: 780.3 [M+H].sup.+

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

    [0320] Compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(methylsulfonyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (95 mg, 0.122 mmol) was stirred in CH.sub.3CN (3 mL) and 1,4-dioxane (1 mL, 4M) at room temperature for 30 min. After the reaction was complete, pH of the reaction liquid was adjusted to 7 with a saturated sodium bicarbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC (DCM/MeOH(7N NH.sub.3)=10/1) to obtain a yellow solid. (35 mg, yield: 45.4%). MS m/z: 654.7 [M+H].sup.+

    Example 338: Synthesis of (8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahvdro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)dimethylphosphine oxide

    [0321] ##STR00709##

    Step 1: Synthesis of (8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)dimethylphosphine oxide

    [0322] Compound 8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (40 mg, 0.102 mmol), dimethylphosphine oxide (15.9 mg, 0.204 mmol), Pd.sub.2(dba).sub.3 (4.7 mg, 0.005 mmol), Xantphos (5.95 mg, 0.01 mmol) and DIPEA (39.8 mg, 0.308 mmol) were stirred in 1,4-dioxane (10 mL) under Ar at 100? C. for 15 h. The solution was poured into ice water, extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a light yellow solid. (25 mg, yield: 78.1%).

    Step 2: Synthesis of (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)dimethylphosphine oxide

    [0323] Compound (8-chloro-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)dimethylphosphine oxide (49.7 mg, 0.157 mmol), B.sub.2Pin.sub.2 (59.8 g, 0.235 mmol), Pd.sub.2(dba).sub.3 (14.3 mg, 0.0157 mmol), Sphos (10.4 mg, 0.0254 mmol) and KOAc (46.2 mg, 0.471 mmol) were stirred in 1,4-dioxane (10 mL) under Ar at 110? C. for 12 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, concentrated and separated by column chromatography to obtain a white solid. (48 mg, yield: 75.0%).

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

    [0324] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.336 mmol), (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)dimethylphosphine oxide (205.6 mg, 0.504 mmol), Cs.sub.2CO.sub.3 (328 mg, 1.008 mmol) and Pd(dppf)Cl.sub.2 (24.6 mg, 0.0336 mmol) were stirred in 1,4-dioxane/H.sub.2O (15 mL, 5/1) under N.sub.2 at 100? C. for 12 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by prep-TLC to obtain a white solid. (98 mg, yield: 36.7%). MS m/z: 796.3 [M+H].sup.+

    Step 4: Synthesis of (8-(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)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)dimethylphosphine oxide

    [0325] Compound tert-butyl (1R,5S)-3-(7-(8-(dimethylphosphoryl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (98 mg, 0.123 mmol) was stirred in CH.sub.3CN (3 mL) and HCl/1,4-dioxane (1 mL, 4M) at room temperature for 30 min. After the reaction was complete, pH of the reaction liquid was adjusted to 7 with a saturated sodium bicarbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC (DCM/MeOH(7N NH.sub.3)=10/1) to obtain a yellow solid. (35 mg, yield: 43.7%). MS m/z: 652.2 [M+H].sup.+

    Example 339: Synthesis of 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-ethynylisoquinolin-6-ol

    [0326] ##STR00710## ##STR00711##

    Step 1: Synthesis of 8-bromoisoquinolin-6-yl pivalate

    [0327] Compound 8-bromoisoquinolin-6-ol (1.13 g, 5.04 mmol) and DIEA (1.3 g, 10.08 mmol) in DCM (20 mL) at 0? C., was added pivaloyl chloride (608 mg, 5.04 mmol) dropwise. The mixture was stirred at 0? C. for 15 min. After the reaction was complete, the mixture was concentrated, diluted with water and extracted with ethyl acetate, and the organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to obtain a yellow oil. (1.32 g, yield: 84.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.62 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 7.72 (d, J=5.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.62 (s, 1H), 1.41 (s, 9H).

    Step 2: Synthesis of 8-bromo-6-(pivaloyloxy)isoquinoline 2-oxide

    [0328] Compound 8-bromoisoquinolin-6-yl pivalate (1.32 g, 4.28 mmol) in DCM (30 mL) at 0? C., was added 85% m-CPBA (2.18 g, 10.71 mmol) portionwise. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction was quenched by saturated sodium sulfite solution and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and brine, dried with anhydrous sodium sulfate and concentrated to obtain a white solid. (1.4 g, yield: 100%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.23 (s, 1H), 8.26 (d, J=6.6 Hz, 1H), 7.72-7.66 (m, 2H), 7.58 (s, 1H), 1.40 (s, 9H).

    Step 3: Synthesis of 1,8-dibromoisoquinolin-6-yl pivalate

    [0329] Compound 8-bromo-6-(pivaloyloxy)isoquinoline 2-oxide (1.4 g, 4.31 mmol) in DCM (40 mL) at 0? C., was added POBr.sub.3 (3.71 g, 12.96 mmol) and DMF (0.5 mL, 6.46 mmol) dropwise. The mixture was stirred at 0? C. for 30 min. After the reaction was complete, the solution was poured into saturated sodium bicarbonate and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (PE/EA=20/1) to obtain a yellow solid. (360 mg, yield: 21.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.31 (d, J=4.6 Hz, 1H), 7.83 (dd, J=15.6, 2.2 Hz, 1H), 7.70-7.58 (m, 2H), 1.40 (s, 9H).

    Step 4: Synthesis of 8-bromo-1-((triisopropylsilyl)ethynyl)isoquinolin-6-yl pivalate

    [0330] Compound 1,8-dibromoisoquinolin-6-yl pivalate (100 mg, 0.26 mmol) in THF/iPr.sub.2NH=1/1(5 mL) was added CuI (3 mg, 0.013 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (4 mg, 0.005 mmol) and (triisopropylsilyl)acetylene (52 mg, 0.28 mmol). The mixture was stirred at 60? C. for 2 h under N.sub.2. After the reaction was complete, the solution was concentrated and separated by prep-TLC (PE/EA=10/1) to obtain a white solid. (65 mg, yield: 51.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.57 (d, J=4.6 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=4.6 Hz, 1H), 7.64 (s, 1H), 1.40 (s, 9H), 1.21 (d, J=6.5 Hz, 21H).

    Step 5: Synthesis of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((triisopropylsilyl)ethynyl)isoquinolin-6-ol

    [0331] Compound 8-bromo-1-((triisopropylsilyl)ethynyl)isoquinolin-6-yl pivalate (30 mg, 0.06 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (3 mg, 0.003 mmol), TEA (31 mg, 0.307 mmol) and pinacolborane (24 mg, 0.184 mmol) were stirred in dichloroethane (5 mL) at 90? C. for 6 h under N.sub.2. After the reaction was complete, the solution was concentrated and separated by prep-TLC (PE/EA=10/1) to obtain a yellow solid. (18 mg, yield: 65.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.59 (d, J=5.3 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 1.42 (s, 12H), 1.16 (d, J=7.4 Hz, 21H).

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

    [0332] Compound tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (14 mg, 0.025 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((triisopropylsilyl)ethynyl)isoquinolin-6-ol (15 mg, 0.033 mmol), Cs.sub.2CO.sub.3 (16 mg, 0.05 mmol) and Pd(PPh.sub.3).sub.4(14 mg, 0.013 mmol) were stirred in 1,4-dioxane/H.sub.2O (3 mL, 511) at 100? C. for 4 h under N.sub.2. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by prep-TLC (DCM/MeOH=1511) to obtain a white solid. (17 mg, yield: 79%).

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

    [0333] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-H-pyrrolizin-7a(5H)-yl)methoxy)-7-(6-hydroxy-1-((triisopropylsilyl)ethynyl)isoquinolin-8-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16 mg, 0.019 mmol) and CsF (15 mg, 0.095 mmol) were stirred in DMF (3 mL) at room temperature for 4 h. After the reaction was complete detected by TLC, the reaction liquid was diluted with brine and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated to obtain a white solid. Then, the solid was stirred in CH.sub.3CN (3 mL) and HCl/1,4-dioxane (1 mL, 4N) at room temperature for 30 min. After the reaction was complete, pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH(7N NH.sub.3)=15/1) to give a white solid (7 mg, yield: 62.9%). MS m/z: 584.6 [M+H].sup.+

    [0334] Examples 328-350 were obtained by using the method of Example 327.

    TABLE-US-00015 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 340 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- ethylisoquinolin-6-ol [00712]embedded image 588.6 341 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- (methylthio)isoquinolin-6-ol [00713]embedded image 605.2 342 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- methoxyisoquinolin-6-ol [00714]embedded image 590.2 343 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- methylisoquinolin-6-ol [00715]embedded image 574.6 344 8-(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)quinazolin-7-yl)-1- ethylisoquinolin-6-ol [00716]embedded image 587.7 345 8-(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)quinazolin-7-yl)-1- ethynylisoquinolin-6-ol [00717]embedded image 583.7 346 8-(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)quinazolin-7-yl)-1- (methylthio)isoquinolin-6-ol [00718]embedded image 605.7 347 8-(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)quinazolin-7-yl)-1- methoxyisoquinolin-6-ol [00719]embedded image 589.6 348 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3- ethylbenzo[b]thiophen-6-ol [00720]embedded image 593.2 349 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3- ethylimidazo[1,5-a]pyridin-7-ol [00721]embedded image 577.2 350 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3- ethylimidazo[1,2-a]pyridin-7-ol [00722]embedded image 577.2 351 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3- ethylindolizin-7-ol [00723]embedded image 576.2 352 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- ethylindolizin-6-ol [00724]embedded image 576.2 353 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- ethylimidazo[1,5-a]pyridin-6-ol [00725]embedded image 577.2 354 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- (methylthio)-2,3-dihydro-1H-inden-5-ol [00726]embedded image 595.2 355 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- ethyl-1,1a,6,6a-tetrahydrocyclopropa[a]inden-3-ol [00727]embedded image 589.7 356 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- methylisochroman-6-ol [00728]embedded image 579.7 357 tert-butyl (3-((1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2- hydroxypropyl)carbamate [00729]embedded image 750.4 358 N-(3-((1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2- hydroxypropyl)acetamide [00730]embedded image 692.8 359 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- methyl-1,2,3,4-tetrahydroquinolin-6-ol [00731]embedded image 578.6 360 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- fluoro-5-(methylthio)naphthalen-2-ol [00732]embedded image 623.7 361 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- fluoro-5-(methylsulfinyl)naphthalen-2-ol [00733]embedded image 639.4 362 (8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2- fluoro-6-hydroxynaphthalen-1-yl)dimethylphosphine oxide [00734]embedded image 653.6

    Example 363: Synthesis of 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)ethynyl)naphthalen-2-ol

    [0335] ##STR00735## ##STR00736##

    Step 1: Synthesis of 7-bromo-2,4-dichloro-8-fluoroquinazoline

    [0336] Compound 7-bromo-8-fluoroquinazoline-2,4-diol (4.3 g, 20 mmol) in POCl.sub.3 (50 ml) was added N,N-diethylaniline (5 ml) at room temperature. The resulting suspension was stirred at 110? C. overnight. After the reaction was complete, the reaction liquid was concentrated and purified by column chromatography (petroleum ether) to obtain a yellow solid. (3.8 g, yield: 75%). .sup.1HNMR (400 MHz, CDCl.sub.3) ? 8.12 (s, 1H), 7.93 (s, 1H).

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

    [0337] Compound 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.0 g, 3.38 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 13.9 mmol) in DMF (40 mL) at 0? C. was added DIEA (4.6 mL, 27.8 mmol). The resulting suspension was stirred at 0? C. for 30 min. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to obtain a light yellow solid, washed with petroleum ether, filtered and dried in vacuum to obtain a light yellow solid. (5.3 g, yield: 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.57-7.42 (m, 2H), 4.37 (s, 4H), 3.68 (d, J=71.0 Hz, 2H), 1.99-1.88 (m, 2H), 1.73 (s, 2H), 1.52 (s, 9H).

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

    [0338] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.45 g, 9.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), 60% NaH (336 mg, 8.4 mmol) was added under ice-water bath cooling condition and reacted under stirring for 30 min, and tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.0 g, 7 mmol) was added and reacted under stirring for 4 h. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain an off-white solid. (2.9 g, yield: 41%).

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

    [0339] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (53 mg, 0.1 mmol), ethynyl-3-(methoxymethoxy) naphthalene (60 mg, 0.25 mmol), CuI (4 mg, 0.02 mmol) and Pd(PPh.sub.3).sub.4 were stirred in TEA/THF (2 ml/2 ml) under Ar at 75? C. overnight. After the reaction was complete, the mixture was concentrated and separated by prep-TLC to obtain an yellow solid. (35 mg, yield: 20%). MS m/z: 726 [M+H].sup.+.

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

    [0340] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-H-pyrrolizin-7a(5H)-yl)methoxy)-7-((3-(methoxymethoxy)naphthalen-1-yl)ethynyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was stirred in HCl/1,4-dioxane (5 mL, 4M) at room temperature for 2h. After the reaction was complete, the mixture was concentrated, diluted with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by prep-TLC to obtain a yellow solid. (25 mg, yield: 48%). MS m/z: 582 [M+H]+.

    [0341] Examples 352-356 were obtained by using the method of Example 351

    TABLE-US-00016 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H] 364 8-((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)quinazolin-7- yl)ethynyl)naphthalen-1-ol [00737]embedded image 582 365 1-((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)quinazolin-7- yl)ethynyl)naphthalen-2-ol [00738]embedded image 582 366 8-((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)quinazolin-7-yl)ethynyl)-7- fluoronaphthalene-1,3-diol [00739]embedded image 616 367 5-((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)quinazolin-7-yl)ethynyl)-6- fluoronaphthalen-2-ol [00740]embedded image 600.6 368 5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)ethynyl)-6-fluoronaphthalen-2-ol [00741]embedded image 601.6

    Example 369: Synthesis of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

    [0342] ##STR00742## ##STR00743##

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

    [0343] The compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (1.0 g, 2.37 mmol) was dissolved in DMF (10 mL), DIEA (460 mg, 3.55 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (553 mg, 2.60 mmol) were added under ice-water bath cooling condition. After stirring for 10 min under ice-water bath cooling condition, the reaction liquid was diluted with brine, filtered and the solid was washed with water, dried to give a yellow solid. (1.4 g, yield: 98%). .sup.1H NMR (400 MHz, DMSO) ? 8.34 (s, 1H), 4.36 (d, J=12.5 Hz, 2H), 4.24 (s, 2H), 3.62 (d, J=12.4 Hz, 2H), 1.77 (s, 2H), 1.60 (d, J=7.6 Hz, 2H), 1.46 (s, 9H).

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

    [0344] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (484 mg, 3.04 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), 60% NaH (113 mg, 2.81 mmol) was added under ice-water bath cooling condition and reacted at 0? C. under stirring for 20 min, and tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 2.34 mmol) was added and reacted at room temperature under stirring for 8 h. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain an off-white solid. (500 mg, yield: 30%). (H NMR (400 MHz, CDCl.sub.3) ? 8.09 (s, 1H), 5.28 (d, J=54.4 Hz, 1H), 4.22 (dd, J=43.6, 33.5 Hz, 6H), 3.57 (d, J=47.0 Hz, 2H), 3.20 (d, J=26.7 Hz, 3H), 2.98 (s, 1H), 2.37-2.07 (m, 3H), 1.93 (s, 5H), 1.80-1.59 (m, 4H), 1.52 (s, 9H).

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

    [0345] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.104 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2(2 mg, 0.002 mmol), CuI (1 mg, 0.005 mmol) in diisopropylamine/THF=1/1(3 mL) was added acetylene triisopropylsilane (23 mg, 0.13 mmol). The mixture was stirred under N.sub.2 at 50? C. for 2 h. After the reaction was complete, the mixture was concentrated, purified by prep-TLC (DCM/MeOH=15/1) to give a white solid (60 mg, yield: 74%). (H NMR (400 MHz, CDCl.sub.3) ? 7.71 (s, 1H), 5.28 (d, J=53.3 Hz, 1H), 4.22 (dd, J=44.6, 34.5 Hz, 7H), 3.58 (d, J=84.3 Hz, 3H), 3.23 (s, 4H), 2.37-2.09 (m, 3H), 1.92 (s, 5H), 1.63 (s, 4H), 1.52 (s, 8H), 1.17 (s, 21H).

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

    [0346] Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-((triisopropylsilyl)ethynyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.08 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32 mg, 0.10 mmol), Pd(dppf)Cl.sub.2 (12 mg, 0.02 mmol) and K.sub.2CO.sub.3 (22 mg, 0.15 mmol) were stirred in 1,4-dioxane/H.sub.2O (3 mL, 5/1) under N.sub.2 at 100? C. for 4 h. After the reaction was complete, the reaction product was cooled to room temperature, the reaction liquid was diluted by adding water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by prep-TLC (DCM/MeOH=15/1) to obtain an off-white solid. (53 mg, yield: 78%). MS m/z: 882.9 [M+H].sup.+

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

    [0347] Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-6-((triisopropylsilyl)ethynyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (53 mg, 0.06 mmol) and CsF (46 mg, 0.30 mmol) were stirred in DMF (3 mL) at room temperature for 6 h. After the reaction was completed by TLC, the reaction solution was diluted with salt water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain a white-like solid. (43 mg, yield: 100%). MS m/z: 726.7 [M+H].sup.+.

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

    [0348] Compound tert-butyl (1R,5S)-3-(6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (43 mg, 0.06 mmol) was stirred in CH.sub.3CN (1 mL) and HCl/1,4-dioxane (1 mL, 4N) at room temperature for 30 min. After the reaction was complete, pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH(7N NH.sub.3)=15/1) to give a white solid (20 mg, yield: 62.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.82 (d, J=7.4 Hz, 1H), 7.73-7.57 (m, 1H), 7.33 (dt, J=15.3, 7.7 Hz, 2H), 7.24-7.07 (m, 3H), 5.21 (dd, J=54.6, 12.7 Hz, 1H), 4.61-4.06 (m, 4H), 3.80-3.11 (m, 7H), 2.99 (s, 1H), 2.75 (s, 1H), 2.45-2.06 (m, 3H), 2.04-1.82 (m, 3H), 1.75-1.48 (m, 4H). MS m/z: 582.6 [M+H].sup.+.

    [0349] Examples 358-366 were obtained by using the method of Example 357.

    TABLE-US-00017 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 370 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)- 5,6,7,8-tetrahydronaphthalen-2-ol [00744]embedded image 585.6 371 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1- ethyl-2,3-dihydro-1H-inden-5-ol [00745]embedded image 600.7 372 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6- ethyl-1,1a,6,6a-tetrahydrocyclopropa[a]inden-3-ol [00746]embedded image 612.7 373 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol [00747]embedded image 624.6 374 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5- methyl-5,6,7,8-tetrahydronaphthalen-2-ol [00748]embedded image 600.7 375 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1- ethylisoquinolin-6-ol [00749]embedded image 611.7 376 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)-6-(1H-pyrazol-4-yl)quinazolin-7- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol [00750]embedded image 642.7 377 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)-6-(1H-pyrazol-4-yl)quinazolin-7- yl)naphthalen-2-ol [00751]embedded image 624.7 378 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-6-yl)propanenitrile [00752]embedded image 653.7

    Example 379: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2 fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-6-yl)-5-ethynyl-6 fluoronaphthalen-2-ol

    [0350] ##STR00753## ##STR00754##

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

    [0351] Compound 7-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (4.58 g, 20 mmol) was dissolved in 100 ml TFA, SiHEt.sub.3 (8.4 ml, 50 mmol) was added at room temperature, and the reaction system was stirred overnight. After the reaction was complete, the crude product was obtained by concentration, purified by spectrum (eluent: Petroleum ether/EA=10/1) to obtain a colorless oil (4.1 g, yield: 95%). MS m/z: 215 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-D6) ? 7.14 (m, 1H), 6.80 (t, 1H, J=1.3 Hz), 2.85-2.80 (m, 4H), 2.02-1.92 (in, 2H).

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

    [0352] Compound 4-bromo-5-fluoro-2,3-dihydro-1H-indene (4.1 g, 19 mmol) in concentrated sulfuric acid (40 ml) at 0? C., was added KNO.sub.3 (2.3 g. 22.8 mmol) slowly, and stirred for 30 min. After the reaction was completed, the reaction system was slowly poured onto ice, with a large amount of solid precipitated, extracted with 200 ml EA, and the organic phase was washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, it was concentrated to obtain the crude product, purified by column chromatography to obtain a white solid (3.9 g, yield: 79%). MS m/z: 260 [M+H].sup.+. MS m/z: 215 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-D6) ? 7.61 (m, 1H), 2.85-2.80 (m, 4H), 2.02-1.92 (m, 2H).

    Step 3: Synthesis of 7-bromo-6-fluoro-2,3-dihydro-1H-inden-5-amine

    [0353] Compound 4-bromo-5-fluoro-6-nitro-2,3-dihydro-1H-indene (3.9 g, 15 mmol) and Fe powder (1.85 g, 33 mmol) were stirred in AcOH (50 ml) under Ar at room temperature overnight. After the reaction was completed, the reaction system was neutralized with a saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate and concentrated to give a light yellow solid (2.3 g, yield: 67%). The light yellow solid was directly used for the next reaction without any further treatment. MS m/z: 230 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-D6) ? 6.33 (m, 1H), 5.32 (m, 4H) 2.85-2.80 (m, 4H), 2.02-1.92 (m, 2H).

    Step 4: Synthesis of 7-bromo-6-fluoro-4-iodo-2,3-dihydro-1H-inden-5-amine

    [0354] Compound 7-bromo-6-fluoro-2,3-dihydro-1H-inden-5-amine (2.3 g, 10 mmol) and NIS (2.7 g, 12 mmol) were stirred in 20 ml DMF at 70? C. overnight. After the reaction was completed, the mixture was concentrated, diluted with 200 ml EA, the organic phase was washed by 100 ml water and 100 ml brine for three times, dried with anhydrous sodium sulfate and concentrated to give a yellow solid (2.1 g, yield: 60%). MS m/z: 355[M+H].sup.+.

    Step 5: Synthesis of 5-amino-7-bromo-6-fluoro-2,3-dihydro-1H-indene-4-carbonitrile

    [0355] Compound 7-bromo-6-fluoro-4-iodo-2,3-dihydro-1H-inden-5-amine (2.1 g, 6 mmol), Zn(CN).sub.2 (914 mg, 7.8 mmol), 4 ? molecular sieve (100 mg) and Pd(PPh.sub.3).sub.4(693 mg, 0.6 mmol) were stirred in 10 ml DMF under Ar at 100? C. overnight. After the reaction was completed, the mixture was concentrated, purified by column chromatography to give a yellow solid (581 mg, yield: 38%). MS m/z: 255[M+H].sup.+.

    Step 6: Synthesis of 5-amino-7-bromo-6-fluoro-2,3-dihydro-1H-indene-4-carboxamide

    [0356] Compound 5-amino-7-bromo-6-fluoro-2,3-dihydro-1H-indene-4-carbonitrile (581 mg, 2.28 mmol) and t-BuOK (1.3 g, 11.4 mmol) were stirred in t-BuOH at 70? C. overnight. After the reaction was completed, the mixture was concentrated, extracted with DCM/H.sub.2O, the organic phase was dried with anhydrous sodium sulfate and concentrated to give a white solid (546 mg, yield: 88%). MS m/z: 273[M+H].sup.+.

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

    [0357] Compound 5-amino-7-bromo-6-fluoro-2,3-dihydro-1H-indene-4-carboxamide (546 mg, 2 mmol), CDI (1.3 g, 8 mmol) and K.sub.2CO.sub.3 (1.1 g, 8 mmol) were stirred in 10 ml DMF at 80? C. overnight. After the reaction was completed, the mixture was diluted with 100 ml Saturated sodium chloride solution, extracted with 500 ml EA, the organic phase was dried with anhydrous sodium sulfate and concentrated to give a white solid, the white solid was directly used for the next reaction without any further treatment.

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

    [0358] Compound 6-bromo-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline-1,3-diol (obtained last step) in POCl.sub.3 (10 ml) was added N,N-diethylaniline (1 ml) at room temperature. The resulting suspension was refluxed overnight. After the reaction was complete, the reaction liquid was concentrated and purified by column chromatography (DCM) to obtain a yellow solid. (510 mg, yield: 76%). MS m/z: 336[M+H].sup.+.

    Step 9: Synthesis of tert-butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0359] Compound 6-bromo-1,3-dichloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline (510 mg, 1.52 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (354 mg, 1.67 mmol) in DMF (10 mL) at 0? C. was added DIEA (0.43 mL, 3 mmol). The resulting suspension was stirred at 0? C. for 30 min. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to obtain a light yellow solid, washed with petroleum ether, filtered and dried in vacuum to obtain a light yellow solid. (715 mg, yield: 92%). MS m/z: 511[M+H].sup.+.

    Step 10: Synthesis of tert-butyl (1R,5S)-3-(6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0360] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (315 mg, 1.98 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), 60% NaH (73 mg, 1.8 mmol) was added under ice-water bath cooling condition and reacted under stirring for 30 min, and tert-butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (510 mg, 1.52 mmol) was added and reacted under stirring overnight. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain an off-white solid. (626 mg, yield: 65%). MS m/z: 634[M+H].sup.+.

    Step 11: Synthesis of tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0361] Compound tert-butyl (1R,5S)-3-(6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (63 mg, 0.10 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (70 mg, 0.13 mmol) and Cs.sub.2CO.sub.3 (82 mg, 0.25 mmol) were dissolved in 1,4-dioxane and water (3 ml, 5/1), and after displacement with nitrogen, Pd(dppf)Cl.sub.2 (8 mg, 0.01 mmol) was added. The reaction system was stirred at 100? C. for 12 h. After the reaction was complete, the reaction system was cooled to room temperature, diluted with water, extracted with ethyl acetate and separated, the organic phase was dried with anhydrous sodium sulfate, and the solvent was then removed under reduced pressure to obtain a crude product. The crude product was separated by prep-TLC to obtain a white solid (30 mg, yield: 33%). MS m/z: 940 [M+H].sup.+.

    Step 12: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0362] Compound tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.032 mmol) and CsF (15 mg, 0.095 mmol) in DMF (3 mL) were stirred at room temperature for 4 h. After the reaction was complete by TLC, the reaction was diluted with brine, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated to give a white solid. Then the crude product was dissolved with CH.sub.3CN (3 mL), HCl/1,4-dioxane (4M, 1 mL) was added and stirred at room temperature for 30 min. After the reaction was complete, pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH(7N NH.sub.3)=15/1) to give a yellow solid (18 mg, yield: 88%). MS m/z: 640 [M+H].sup.+.

    [0363] Examples 368-371 were obtained by using the method of Example 367.

    TABLE-US-00018 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H] 380 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H- cyclopenta[f]quinazolin-6-yl)-5,6- difluoronaphthalen-2-ol [00755]embedded image 634 381 7-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H- cyclopenta[f]quinazolin-6-yl)-1-ethyl-2,3-dihydro- 1H-inden-5-ol [00756]embedded image 616 382 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H- cyclopenta[f]quinazolin-6-yl)-5-methyl-5,6,7,8- tetrahydronaphthalen-2-ol [00757]embedded image 616.5 383 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-7H- cyclopenta[f]quinazolin-6-yl)-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00758]embedded image 630.5

    Example 384: Synthesis of 4-(9-((2R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)furo[2,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0364] ##STR00759##

    [0365] Step 1 to step 4: white solid was obtained by using the synthetic method from steps 9 to 12 of example 367. (1.1 mg, 0.0056 mmol, total yield: 12%). MS m/z: 622.4 [M+H].sup.+.

    [0366] Examples 373-376 were obtained by using the method of Example 372.

    TABLE-US-00019 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 385 7-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)furo[2,3-f]quinazolin-4-yl)-1-methyl-2,3- dihydro-1H-inden-5-ol [00760]embedded image 584.4 386 7-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)furo[2,3-f]quinazolin-4-yl)-1-ethyl-2,3- dihydro-1H-inden-5-ol [00761]embedded image 597.4 387 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)furo[2,3-f]quinazolin-4-yl)-5-methyl- 5,6,7,8-tetrahydronaphthalen-2-ol [00762]embedded image 598.4 388 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)furo[2,3-f]quinazolin-4-yl)-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00763]embedded image 612.4

    Example 389: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4-yl)naphthalen-2-ol

    [0367] ##STR00764## ##STR00765##

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

    [0368] Compound 3-bromo-4-fluorobenzene-1,2-diol (1.0 g, 4.83 mmol), Cs.sub.2CO.sub.3 (3.96 g, 12.08 mmol) and CH.sub.2I.sub.2(1.42 g, 5.31 mmol) were stirred in DMA (20 mL) at 60? C. for 12 h. After the reaction was completed, cooled to room temperature, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated, purified by column chromatography (PE/EA=10/1) to obtain a white solid. (0.82 g, yield: 77.5%).

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

    [0369] Compound 4-bromo-5-fluorobenzo[d][1,3]dioxole (0.82 g, 3.74 mmol) in AcOH (10 ml) at 0? C., was added KNO.sub.3 (378 mg, 3.74 mmol) slowly, and stirred for 1 h. After the reaction was completed, the reaction system was slowly poured onto ice, extracted with EA, and the organic phase was washed with saturated sodium carbonate. After drying with anhydrous sodium sulfate, it was concentrated to obtain the crude product, purified by column chromatography (PE/EA=5/1) to obtain a yellow solid (0.8 g, yield: 81%).

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

    [0370] Compound 4-bromo-5-fluoro-6-nitrobenzo[d][1,3]dioxole (0.8 g, 3.03 mmol) and Fe powder (0.38 g, 6.67 mmol) were stirred in AcOH (50 ml) under Ar at room temperature overnight. After the reaction was completed, the reaction system was neutralized with a saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate and concentrated to give a light yellow solid (0.6 g, yield: 84.6%). The light yellow solid was directly used for the next reaction without any further treatment.

    Step 4: Synthesis of 7-Bromo-6-fluorobenzo[d][1,3]dioxocyclopenten-5-[di (t-butoxycarbonyl)] amine

    [0371] Compound 7-bromo-6-fluorobenzo[d][1,3]dioxol-5-amine (0.6 g, 2.56 mmol), Boc.sub.2O (1.4 g, 6.41 mmol) and DMAP (16 mg, 0.13 mmol) were stirred in THF (10 mL) at 60? C. for 12 h. After the reaction was completed, the mixture was concentrated, beating with MeOH to give a white solid (1.0 g, yield: 89.8%).

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

    [0372] Compound 7-Bromo-6-fluorobenzo [d][1,3]dioxocyclopenten-5-[di (t-butoxycarbonyl)] amine (1.0 g, 2.3 mmol) in THF (10 mL) at ?70? C., was added to a solution of LDA (2.3 mL, 4.6 mmol, 2M) in THF (20 mL). The mixture was stirred at ?70? C. for 2 h. After the reaction was completed, the mixture was quenched by sat. NH.sub.4Cl and extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, used directly in the next step. (1 g, yield: 100%).

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

    [0373] Compound tert-butyl 7-bromo-5-((tert-butoxycarbonyl)amino)-6-fluorobenzo[d][1,3]dioxole-4-carboxylate (1 g, 2.3 mmol) was stirred in DCM (15 ml) and TFA (5 mL) at room temperature for 3 h. After the reaction was completed, the mixture was concentrated to give the crude product, used directly in the next step.

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

    [0374] Compound 5-amino-7-bromo-6-fluorobenzo[d][1,3]dioxole-4-carboxylic acid (0.64 g, 2.30 mmol) was stirred in SOC.sub.2 (5 mL) at 50? C. for 3 h. After the reaction was completed, the mixture was concentrated, diluted with acetone (10 mL) and it was added to a solution of NH.sub.4SCN (0.53 g, 6.91 mmol) in acetone (10 mL). The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to give the crude product, used directly in the next step. (0.5 g, yield: 68%).

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

    [0375] Compound 4-bromo-5-fluoro-7-mercapto-[1,3]dioxolo[4,5-f]quinazolin-9(8H)-one (0.5 g, 1.57 mmol), MeONa/MeOH (1 mL, 40%) and Mel (245 mg, 1.72 mmol) were stirred in MeOH (10 mL) at room temperature for 1 h. After the reaction was completed, the mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated, purified by column chromatography to give a yellow solid (0.5 g, yield: 95%).

    Step 9: Synthesis of tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0376] Compound 4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxolo[4,5-f]quinazolin-9(8H)-one (500 mg, 1.5 mmol), DIEA (291 mg, 2.25 mmol) and POCl.sub.3 (277 mg, 1.8 mmol) were stirred in CH.sub.3CN (10 mL) at 80? C. for 1.5 h. After the reaction was completed, the mixture was cooled to 0-10? C., DIEA (291 mg, 2.25 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (319 mg, 1.5 mmol) were added and stirred at room temperature for 30 min. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to give a yellow solid, beating with PE to give an off-white solid. (720 mg, yield: 91%). MS m/z: 527.4 [M+H].sup.+

    Step 10: Synthesis of tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(methylsulfinyl)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0377] Compound tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.33 mmol) and m-CPBA (275 mg, 1.59 mmol, 85%) were stirred in DCM (10 mL) under ice bath cooling for 30 min. After the reaction was complete, the reaction was quenched by using a saturated sodium bisulfite solution and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and brine, dried with anhydrous sodium sulfate and concentrated to obtain an off-white solid, which was directly used for the next step. (721 mg, yield: 100%).

    Step 11: Synthesis of tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0378] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (275 mg, 1.32 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), 60% NaH (39 mg, 1.59 mmol) was added under ice-water bath cooling condition and reacted at room temperature under stirring for 20 min, and tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(methylsulfinyl)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720 mg, 1.72 mmol) was added and reacted at room temperature under stirring for 8 h. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain an off-white solid. (450 mg, yield: 53.1%). MS m/z: 838.4 [M+H].sup.+.

    Step 12: Synthesis of tert-butyl (1R,5S)-3-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methoxymethoxy)naphthalen-1-yl)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0379] Compound tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.047 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18 mg, 0.056 mmol), Cs.sub.2CO.sub.3 (31 mg, 0.094 mmol) and Pd(PPh.sub.3).sub.4 (27 mg, 0.023 mmol) were stirred in 1,4-dioxane/H.sub.2O (5 ml/1 ml) under Ar at 100? C. for 4 h. After the reaction was complete, the mixture was concentrated to give the crude product, purified by prep-TLC to give an off-white solid. (25 mg, yield: 71.3%). MS m/z: 746.8 [M+H].sup.+.

    Step 13: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4-yl)naphthalen-2-ol

    [0380] Compound tert-butyl (1R,5S)-3-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methoxymethoxy)naphthalen-1-yl)-[1,3]dioxolo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.034 mmol) was stirred in CH.sub.3CN (2 mL) and HCl/1,4-dioxane (1 mL, 4N) at room temperature for 30 min. After the reaction was complete, pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH (7N NH.sub.3)=15/1) to give a white solid (14 mg, yield: 69.4%). MS m/z: 602.6 [M+H].sup.+

    [0381] Examples 378-385 were obtained by using the method of Example 377.

    TABLE-US-00020 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 390 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-5,6,7,8-tetrahydronaphthalen-2-ol [00766]embedded image 606.6 391 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol [00767]embedded image 620.7 392 8-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-1-methylisochroman-6-ol [00768]embedded image 622.7 393 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-5-ethynyl-6-fluoronaphthalen-2-ol [00769]embedded image 644.6 394 7-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol [00770]embedded image 620.7 395 8-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-1-ethylisoquinolin-6-ol [00771]embedded image 631.7 396 5-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-3-ethylimidazo[1,5-a]pyridin-7-ol [00772]embedded image 620.6 397 5-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-[1,3]dioxolo[4,5-f]quinazolin-4- yl)-3-ethylindolizin-7-ol [00773]embedded image 619.6

    Example 398: Synthesis of 4-C.SUB.1.-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0382] ##STR00774## ##STR00775## ##STR00776##

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

    [0383] Compound 2,6-dichloropyridin-4-amine (5 g, 30.5 mmol) and selectfluor (11.3 g, 33.5 mmol) were stirred in MeOH/1H.sub.2O (50 mL/10 mL) at 50? C. for 24 h. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, and the organic phase was washed with brine, dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a white solid. (2.5 g, yield: 45%).

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

    [0384] Compound 2,6-dichloro-3-fluoropyridin-4-amine (2.5 g, 13.8 mmol), BOC.sub.2O (7.53 g, 34.5 mmol) and DMAP (84 mg, 0.7 mmol) were stirred in THF (25 mL) at 60? C. for 12 h. After the reaction was complete, the reaction liquid was concentrated, beating with MeOH to give a white solid. (5.1 g, yield: 97%).

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

    [0385] Compound 3-fluoro-4-[di (t-butoxycarbonyl) amino]-2,6-dichloropyridine (5.1 g, 13.6 mmol) in THF (10 mL) at ?70? C., was added to a solution of LDA (20.5 mL, 40.9 mmol, 2M) in THF (80 mL). The mixture was stirred at ?70? C. for 2 h. After the reaction was completed, the mixture was quenched by sat. NH.sub.4Cl and extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, used directly in the next step. (5.2 g, yield: 100%).

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

    [0386] Compound tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (5.2 g, 13.6 mmol) was stirred in concentrated hydrochloric acid (13 ml) and 1,4-dioxane (42 mL) at room temperature for 18 h. After the reaction was completed, the mixture was concentrated to give the crude product, used directly in the next step. (3 g, yield: 100%).

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

    [0387] Compound 4-amino-2,6-dichloro-5-fluoronicotinic acid (3 g, 13.6 mmol) was stirred in SOC.sub.2 (30 mL) at 50? C. for 3 h. After the reaction was completed, the mixture was concentrated, diluted with acetone (10 mL) and it was added to a solution of NH.sub.4SCN (3.1 g, 40.8 mmol) in acetone (40 mL). The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated to give the crude product, used directly in the next step. (3.6 g, yield: 100%).

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

    [0388] Compound 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (3.6 g, 13.6 mmol), NaOH (272 mL, 27.2 mmol, 0.1M) and Mel (3.9 g, 27.2 mmol) were stirred in MeOH (272 mL) at room temperature for 1 h. After the reaction was completed, the mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated, purified by column chromatography to give a yellow solid (1.7 g, yield: 45%).

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

    [0389] Compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1 g, 3.6 mmol), Zn(CN).sub.2 (626 mg, 5.4 mmol), DPPF (199 mg, 0.36 mmol) and Pd.sub.2dba.sub.3 (330 mg, 0.36 mmol) were stirred in 5 ml DMF under N.sub.2 at 90? C. for 8 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, concentrated, purified by column chromatography to give a yellow solid (750 mg, yield: 78%).

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

    [0390] Compound 7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidine-5-carbonitrile (750 mg, 2.8 mmol) in POCl.sub.3 (9 ml) was added N,N-diethylaniline (1 ml) at room temperature. The resulting suspension was stirred at 110? C. overnight. After the reaction was complete, the reaction liquid was concentrated to obtain the crude product, used directly in the next step. (800 mg, yield: 100%).

    Step 9: Synthesis of (4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)methanamine

    [0391] Compound 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-5-carbonitrile (800 mg, 2.8 mmol) and NaBH.sub.4 (106 mg, 2.8 mmol) were stirred in THF (10 mL) at room temperature for 5 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, used directly in the next step. (810 mg, yield: 100%).

    Step 10: Synthesis of 1,6-dichloro-5-fluoro-3-(methylthio)imidazo[1,5:1,21pyrido[4,3-d]pyrimidine

    [0392] Compound (4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)methanamine (810 mg, 2.8 mmol) was stirred in anhydrous ethyl formate (10 mL) at 65? C. for 3 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with DCM, then POCl.sub.3 (638 mg, 4.2 mmol) and TEA (848 mg, 8.4 mmol) were added and stirred at room temperature for 2 h. After the reaction was complete, the reaction liquid was diluted with water and extracted with DCM, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a light yellow solid. (470 mg, yield: 56%).

    Step 11: Synthesis of tert-butyl (1R,5S)-3-(6-chloro-5-fluoro-3-(methylthio)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0393] Compound 1,6-dichloro-5-fluoro-3-(methylthio)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidine (470 mg, 1.6 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (360 mg, 1.7 mmol) in anhydrous DMF (8 mL) under ice bath cooling, was added DIEA (310 mg, 2.4 mmol) and stirred for 30 min. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to obtain a light yellow solid, washed with PE, filtered, dried to give a light yellow solid (510 mg, yield: 69%).

    Step 12: Synthesis of tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-3-(methylthio)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0394] Compound tert-butyl (1R,5S)-3-(6-chloro-5-fluoro-3-(methylthio)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (48 mg, 0.1 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (57 mg, 0.11 mmol) and Cs.sub.2CO.sub.3 (74 mg, 0.23 mmol) were dissolved in 1,4-dioxane and water (3 ml, 5/1), and after displacement with nitrogen, Pd(dppf)Cl.sub.2 (13 mg, 0.02 mmol) was added. The reaction system was stirred at 100? C. for 5 h. After the reaction was complete, the reaction system was cooled to room temperature, diluted with water, extracted with ethyl acetate and separated, the organic phase was dried with anhydrous sodium sulfate, and the solvent was then removed under reduced pressure to obtain a crude product. The crude product was separated by prep-TLC to obtain an off-white solid (32 mg, yield: 43%).

    Step 13: Synthesis of tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-3-(methylsulfinyl)imidazo[1,5:1,2pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0395] Compound tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-3-(methylthio)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (32 mg, 0.043 mmol) and 85% m-CPBA (11 mg, 0.052 mmol) were stirred in DCM (2 mL) at 0? C.-10? C. for 20 min. After the reaction was complete, the reaction was quenched by saturated sodium thiosulfate solution and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and brine, dried with anhydrous sodium sulfate and concentrated to obtain a yellow solid, which was directly used for the next step. (32 mg, yield: 100%).

    Step 14: Synthesis of tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0396] Compound tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-3-(methylsulfinyl)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (32 mg, 0.042 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (7 mg, 0.046 mmol) in anhydrous toluene (2 mL) under ice bath cooling, was added t-BuNa (5 mg, 0.05 mmol). The mixture was stirred for 30 min under ice bath cooling. After the reaction was complete, the reaction was quenched with cold water and extracted with EA, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by prep-TLC to obtain an off-white solid. (25 mg, yield: 69%).

    Step 15: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0397] Compound tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.03 mmol) and CsF (30 mg, 0.20 mmol) in DMF (1 mL) were stirred at room temperature for 2 h. After the reaction was complete, the reaction was diluted with water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to give the crude product. Then the crude product was dissolved with CH.sub.3CN (0.5 mL), HCl/1,4-dioxane (4M, 0.5 mL) was added and stirred at room temperature for 30 min. After the reaction was complete, pH of the solution was adjusted to 7 with saturated sodium bicarbonate aqueous solution, extracted with DCM, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH(7N NH.sub.3)=10/1) to give a yellow solid (13 mg, yield: 70%). .sup.1H NMR (400 MHz, Chloroform) ? 8.69 (d, J=2.9 Hz, 1H), 8.26 (s, 1H), 7.85 (d, J=0.6 Hz, 1H), 7.68 (ddd, J=15.0, 10.0, 3.0 Hz, 1H), 7.57 (t, J=3.0 Hz, 1H), 6.89 (dd, J=15.9, 15.0 Hz, 1H), 5.17-4.87 (m, 2H), 4.87-4.77 (m, 2H), 4.49 (q, J=24.8 Hz, 2H), 3.84-3.75 (m, 2H), 3.59 (ddd, J=50.4, 24.7, 14.9 Hz, 1H), 3.37-3.18 (m, 4H), 2.65-2.18 (m, 3H), 2.15-2.00 (m, 2H), 1.76-1.63 (m, 2H), 1.51 (ddd, J=26.0, 13.9, 12.0 Hz, 1H), 1.43-1.19 (m, 4H), 1.06 (s, 1H).

    Example 399: Synthesis of 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0398] ##STR00777## ##STR00778##

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

    [0399] Compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1 g, 3.6 mmol), PMBNH.sub.2 (1.5 g, 10.7 mmol) and Cs.sub.2CO.sub.3 (3.5 g, 10.7 mmol) were stirred in DMA (5 mL) at 100? C. for 24 h. After the reaction was complete, the reaction liquid was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a yellow solid. (1.1 g, yield: 81%).

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

    [0400] Compound 7-chloro-8-fluoro-5-((4-methoxybenzyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.1 g, 2.9 mmol) and N,N-diethylaniline (1 ml) were stirred in POCl.sub.3 (9 ml) at 110? C. overnight. After the reaction was complete, the reaction liquid was concentrated to give the crude product, used directly to the next step. (1.2 g, yield: 100%).

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

    [0401] Compound 4,7-dichloro-8-fluoro-N-(4-methoxybenzyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine (1.2 g, 2.9 mmol) was stirred in TFA (10 mL) at room temperature for 5 h. After the reaction was complete, the reaction liquid was concentrated, extracted with ethyl acetate and saturated sodium bicarbonate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to give the crude product, used directly to the next step. (805 mg, yield: 100%).

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

    [0402] Compound 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine (805 mg, 2.9 mmol) was stirred in i-PrOH (10 mL) and HBr (1 mL) at 90? C. for 3 h. After the reaction was complete, the reaction liquid was cooled to room temperature, concentrated, extracted with DCM and sodium bicarbonate, the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by column chromatography to give a yellow solid (610 mg, yield: 70%).

    Steps 5-9: Synthesis of 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0403] Yellow solid (13 mg) was obtained by using the method from step 11 to step 15 of example 387. .sup.1H NMR (400 MHz, Chloroform) ? 8.69 (d, J=2.9 Hz, 1H), 7.98 (d, J=15.0 Hz, 1H), 7.68 (ddd, J=15.0, 10.0, 3.0 Hz, 1H), 7.57 (t, J=3.0 Hz, 1H), 7.45 (d, J=15.0 Hz, 1H), 6.89 (dd, J=16.0, 15.1 Hz, 1H), 5.82 (tt, J=13.9, 8.4 Hz, 1H), 5.64 (tt, J=13.7, 8.3 Hz, 1H), 5.11 (dd, J=24.8, 11.1 Hz, 2H), 5.00 (s, 1H), 4.56 (d, J=24.9 Hz, 1H), 4.26 (d, J=24.7 Hz, 1H), 3.95-3.71 (m, 3H), 3.34-3.15 (m, 3H), 3.01-2.82 (m, 2H), 2.65 (ddd, J=50.4, 24.7, 8.3 Hz, 1H), 2.21-2.05 (m, 2H), 1.91 (ddd, J=50.4, 24.8, 13.8 Hz, 1H), 1.78-1.63 (m, 2H), 1.57-1.18 (m, 5H), 1.05 (s, 1H).

    Example 400: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3-methyl-3H-imidazo[4,5-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0404] ##STR00779## ##STR00780##

    Step 1: Synthesis of 7-bromo-5-fluoro-1-methyl-1H-benzo[d]imidazole-4-carbonitrile

    [0405] Compound 7-bromo-5-fluoro-1H-benzo[d]imidazole-4-carbonitrile (1 g, 4.1 mmol), Mel (1.16 g, 8.2 mmol) and (2.67 g, 8.2 mmol) were stirred in DMF (10 mL) at room temperature for 24 h. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to give the crude product, used directly to the next step. (1.1 g, yield: 100%).

    Step 2: Synthesis of 5-azido-7-bromo-1-methyl-1H-benzo[d]imidazole-4-carbonitrile

    [0406] Compound 7-bromo-5-fluoro-1-methyl-1H-benzo[d]imidazole-4-carbonitrile (1.1 g, 4.1 mmol) and NaN.sub.3 (320 mg, 4.9 mmol) were stirred in DMA (10 mL) at 90? C. for 8 h. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a yellow solid. (750 mg, yield: 63%).

    Step 3: Synthesis of 5-amino-7-bromo-1-methyl-1H-benzo[d]imidazole-4-carbonitrile

    [0407] Compound 5-azido-7-bromo-1-methyl-1H-benzo[d]imidazole-4-carbonitrile (750 mg, 2.7 mmol) in THF (20 mL) under ice bath cooling was added NaBH.sub.4 (103 mg, 2.7 mmol). The mixture was stirred at room temperature for 5 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a yellow solid. (620 mg, yield: 91%).

    Step 4: Synthesis of 5-amino-7-bromo-1-methyl-1H-benzo[d]imidazole-4-carboxamide

    [0408] Compound 5-amino-7-bromo-1-methyl-1H-benzo[d]imidazole-4-carbonitrile (620 mg, 2.5 mmol) in DMSO (10 mL) under ice bath cooling was added K.sub.2CO.sub.3(1 g, 7.5 mmol) and H.sub.2O.sub.2(2 mL). The mixture was stirred at room temperature for 5 h. After the reaction was complete, the reaction was diluted with cold water, and solid was precipitated out. The mixture was filtered, washed with water, dried in vacuum to give a yellow solid. (640 mg, yield: 96%).

    Step 5: Synthesis of 4-bromo-3-methyl-3,6-dihydro-7H-imidazo[4,5-f]quinazoline-7,9(8H)-dione

    [0409] Compound 5-amino-7-bromo-1-methyl-1H-benzo[d]imidazole-4-carboxamide (640 mg, 2.4 mmol), K.sub.2CO.sub.3 (662 mg, 4.8 mmol) and CDI (778 mg, 4.8 mmol) were stirred in DMF (10 mL) at 90? C. for 4 h. After the reaction was complete, the reaction was diluted with water, extracted with ethyl acetate, pH of the water phase was adjusted to 2-3 with 10% HCl, and solid was precipitated out. The mixture was filtered, dried in vacuum to give a yellow solid. (620 mg, yield: 88%).

    Step 6: Synthesis of 4-bromo-7,9-dichloro-3-methyl-3H-imidazo[4,5-f]quinazoline

    [0410] Compound 4-bromo-3-methyl-3,6-dihydro-7H-imidazo[4,5-f]quinazoline-7,9(8H)-dione (620 mg, 2.1 mmol) and N,N-diethylaniline (1 ml) were stirred in POCl.sub.3 (9 ml) at 110? C. overnight. After the reaction was complete, the reaction liquid was concentrated, purified by column chromatography (PE) to give a yellow solid. (530 mg, 76%).

    Step 7: Synthesis of tert-butyl (1R,5S)-3-(4-bromo-7-chloro-3-methyl-3H-imidazo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0411] Compound 4-bromo-7,9-dichloro-3-methyl-3H-imidazo[4,5-f]quinazoline (530 mg, 1.6 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (360 mg, 1.7 mmol) in anhydrous DMF (8 mL) under ice bath cooling, was added DIEA (310 mg, 2.4 mmol) and stirred for 30 min. After the reaction was complete, the reaction liquid was diluted with water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated to obtain a light yellow solid, washed with PE, filtered, dried to give a light yellow solid (570 mg, yield: 70%).

    Step 8: Synthesis of tert-butyl (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3-methyl-3H-imidazo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0412] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (220 mg, 1.38 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), 60% NaH (51 mg, 1.27 mmol) was added under ice-water bath cooling condition and reacted under stirring for 20 min, and tert-butyl (1R,5S)-3-(4-bromo-7-chloro-3-methyl-3H-imidazo[4,5-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (570 mg, 1.1 mmol) was added and reacted under stirring for 4 h. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain an off-white solid. (360 mg, yield: 51%).

    Steps 9 to 10: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3-methyl-3H-imidazo[4,5-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

    [0413] Yellow solid was obtained by using the synthetic method from steps 6 to 7 of example 327. (15 mg, 0.0056 mmol, total yield: 4.8%). .sup.1H NMR (400 MHz, Chloroform) ? 8.56 (s, 1H), 8.05 (s, 1H), 7.85-7.77 (m, 2H), 7.49 (t, J=3.0 Hz, 1H), 7.32 (dd, J=16.0, 3.0 Hz, 1H), 6.90 (ddd, J=15.8, 15.2, 2.9 Hz, 1H), 5.40 (p, J=4.7 Hz, 1H), 5.21 (p, J=4.7 Hz, 1H), 5.02 (s, 1H), 4.57-4.38 (m, 3H), 4.23 (d, J=24.7 Hz, 1H), 3.92-3.73 (m, 7H), 3.32-3.07 (m, 2H), 2.90 (ddd, J=50.4, 24.8, 4.7 Hz, 1H), 2.70 (dt, J=24.6, 12.1 Hz, 1H), 2.50-2.34 (m, 2H), 2.13 (ddd, J=50.4, 24.8, 4.6 Hz, 1H), 1.91-1.75 (m, 2H), 1.68-1.43 (m, 2H), 1.33-1.19 (m, 3H), 1.02 (s, 1H).

    Example 401: Synthesis of 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)naphthalen-2-ol

    [0414] ##STR00781## ##STR00782##

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

    [0415] Compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.71 mmol), 2-aminoethan-1-ol (66 mg, 1.07 mmol) and Cs.sub.2CO.sub.3 (698 mg, 2.14 mmol) were stirred in DMA (10 mL) at 100? C. for 12 h. After the reaction was completed, cooled to room temperature, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, used directly in the next step. (160 mg, yield: 73.5%). MS m/z: 305.6 [M+H].sup.+

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

    [0416] Compound 7-chloro-8-fluoro-5-((2-hydroxyethyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (160 mg, 0.53 mmol) in CHCl.sub.3 (6 mL), was added SOCl.sub.2 (2 mL) and stirred at 70? C. for 12 h. After the reaction was completed, the mixture was concentrated, diluted with saturated sodium bicarbonate aqueous solution, filtered to obtained the solid, washed with water, dried to give an off-white solid (130 mg, yield: 86.3%). MS m/z: 287 [M+H].sup.+

    Step 3: Synthesis of tert-butyl (1R,5S)-3-(5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0417] Compound 5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-ol (120 mg, 0.42 mmol), DIEA (81 mg, 0.63 mmol) and POCl.sub.3 (77 mg, 0.50 mmol) were stirred in CH.sub.3CN (10 ml) at 80? C. for 1.5 h. After the reaction was complete, DIEA (81 mg, 0.63 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (89 mg, 0.42 mmol) were added to the mixture under 0-10? C., stirred at room temperature for 30 min. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, concentrated to give a yellow solid, beating with petroleum ether to give a white solid (160 mg, yield: 81.9%).

    Step 4: Synthesis of tert-butyl (1R,5S)-3-(5-chloro-6-fluoro-8-(methylsulfinyl)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0418] Compound tert-butyl (1R,5S)-3-(5-chloro-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.33 mmol) in DCM (10 mL) at 0? C., was added 85% m-CPBA (102 mg, 0.50 mmol) and stirred for 30 min. After the reaction was complete, the reaction was quenched by saturated sodium bisulfite solution and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and brine, dried with anhydrous sodium sulfate and concentrated to obtain a white solid, used directly in the next step (165 mg, yield: 100%).

    Step 5: Synthesis of tert-butyl (1R,5S)-3-(5-chloro-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0419] The compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (67 mg, 0.42 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), 60% NaH (10 mg, 0.39 mmol) was added under ice-water bath cooling condition and reacted under stirring for 20 min, and tert-butyl (1R,5S)-3-(5-chloro-6-fluoro-8-(methylsulfinyl)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.32 mmol) was added and reacted under stirring at room temperature for 8 h. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (DCM/MeOH=30/1) to obtain an off-white solid. (100 mg, yield: 52.5%).

    Step 6: Synthesis of tert-butyl (1R,5S)-3-(6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-(methoxymethoxy)naphthalen-1-yl)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

    [0420] Compound tert-butyl (1R,5S)-3-(5-chloro-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.03 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13 mg, 0.04 mmol), Cs.sub.2CO.sub.3 (22 mg, 0.07 mmol) and Pd(PPh.sub.3).sub.4 (20 mg, 0.02 mmol) were stirred in 1,4-dioxane/H.sub.2O (5 ml/1 ml) under Ar at 100? C. for 4 h. After the reaction was complete, the mixture was concentrated to give the crude product, purified by prep-TLC to give an light yellow solid. (20 mg, yield: 79.6%). MS m/z: 744.3 [M+H].sup.+.

    Step 7: Synthesis of 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)naphthalen-2-ol

    [0421] Compound tert-butyl (1R,5S)-3-(6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-(methoxymethoxy)naphthalen-1-yl)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.026 mmol) was stirred in CH.sub.3CN (2 mL) and HCl/dioxane (1 mL, 4M) for 30 min at room temperature. After the reaction was complete, pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, purified by prep-TLC (DCM/MeOH(7N NH.sub.3)=15/1) to give a white solid (10 mg, yield: 62.02%). MS m/z: 600.6 [M+H].sup.+

    [0422] Examples 390-426 were obtained by using the method of Example 386, 387, 388, 389.

    TABLE-US-00021 m/z: ES.sup.+ Ex. Compound name Structural formula [M + H].sup.+ 402 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [00783]embedded image 642.7 403 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol [00784]embedded image 646.7 404 8-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-1-ethynylisoquinolin-6-ol [00785]embedded image 625.7 405 8-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-1-ethylisoquinolin-6-ol [00786]embedded image 629.7 406 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-5,6,7,8-tetrahydronaphthalen-2-ol [00787]embedded image 604.7 407 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2- ol [00788]embedded image 618.7 408 7-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol [00789]embedded image 618.7 409 5-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-6-ethyl-1,1a,6,6a- tetrahydrocyclopropa[a]inden-3-ol [00790]embedded image 630.7 410 8-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-1-methylisochroman-6-ol [00791]embedded image 620.7 411 5-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-3-ethylimidazo[1,5-a]pyridin-7-ol [00792]embedded image 618.7 412 5-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3-dihydroimidazo[1,2:1,2]pyrido[4,3- d]pyrimidin-5-yl)-3-ethylindolizin-7-ol [00793]embedded image 617.7 413 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)imidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)- 5-ethyl-6-fluoronaphthalen-2-ol [00794]embedded image 644.72 414 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)imidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)- 5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol [00795]embedded image 616.7 415 7-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro- 8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)imidazo[1,2:1,2]pyrido[4,3-d]pyrimidin-5-yl)- 1-ethyl-2,3-dihydro-1H-inden-5-ol [00796]embedded image 616.7 416 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-6-yl)- 5-ethyl-6-fluoronaphthalen-2-ol [00797]embedded image 644.7 417 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-6-yl)- 5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol [00798]embedded image 616.7 418 7-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)imidazo[1,5:1,2]pyrido[4,3-d]pyrimidin-6-yl)- 1-ethyl-2,3-dihydro-1H-inden-5-ol [00799]embedded image 616.7 419 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6,7,8- tetrahydronaphthalen-2-ol [00800]embedded image 563.6 420 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)quinazolin-7-yl)-5,6,7,8-tetrahydronaphthalen- 2-ol [00801]embedded image 562.6 421 4-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl- 5,6,7,8-tetrahydronaphthalen-2-ol [00802]embedded image 593.7 422 4-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl- 5,6,7,8-tetrahydronaphthalen-2-ol [00803]embedded image 607.7 423 7-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-ethyl- 2,3-dihydro-1H-inden-5-ol [00804]embedded image 593.7 424 8-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1- ethynylisoquinolin-6-ol [00805]embedded image 600.6 425 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- (methylsulfonyl)naphthalen-2-ol [00806]embedded image 637.7 426 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)- 5,6,7,8-tetrahydronaphthalen-2-ol [00807]embedded image 609.7 427 4-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-methyl-5,6,7,8- tetrahydronaphthalen-2-ol [00808]embedded image 592.7 428 4-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00809]embedded image 606.7 429 7-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-1-ethyl-2,3-dihydro- 1H-inden-5-ol [00810]embedded image 592.7 430 4-(4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol [00811]embedded image 616.7 431 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5-methyl- 5,6,7,8-tetrahydronaphthalen-2-ol [00812]embedded image 594.7 432 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00813]embedded image 608.7 433 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-1-methyl-2,3- dihydro-1H-inden-5-ol [00814]embedded image 580.4 434 7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,6-naphthyridin-7-yl)-1-ethyl-2,3- dihydro-1H-inden-5-ol [00815]embedded image 593.4 435 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1a,2,3,7b- tetrahydro-1H-cyclopropa[a]naphthalen-6-ol [00816]embedded image 575.6 436 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,8-dimethyl- 5,6,7,8-tetrahydronaphthalen-2-ol [00817]embedded image 591.7 437 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)quinazolin-7-yl)-1a,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalen-6-ol [00818]embedded image 574.7 438 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)quinazolin-7-yl)-5,8-dimethyl-5,6,7,8- tetrahydronaphthalen-2-ol [00819]embedded image 590.7 439 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, S-axis chiral isomer [00820]embedded image 597.4 440 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, R-axis chiral isomer [00821]embedded image 597.4 441 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, S-axis chiral isomer [00822]embedded image 601.5 442 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, R-axis chiral isomer [00823]embedded image 601.5 443 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)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol, R-axis chiral isomer [00824]embedded image 600.4 444 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)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol, S-axis chiral isomer [00825]embedded image 600.4 445 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)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2- ol, R-axis chiral isomer [00826]embedded image 604.4 446 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)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2- ol, S-axis chiral isomer [00827]embedded image 604.4

    Cell Activity Experiment

    1. Cells

    [0423]

    TABLE-US-00022 Cell line Culture medium formula Cell mutation site AGS F12K + 10% FBS KRAS.sup.G12D

    [0424] The above cells were cultured in a complete medium containing 10% fetal bovine serum, 100 IU/mL penicillin and 100 jag/mL streptomycin, in the aseptic incubator with 95% relative humidity and 5% CO.sub.2 concentration.

    2. Reagents: F12K, D-PBS, FBS, Penicillin Streptomycin, Tryple, MTT (5 mg/mL)

    Experimental Method

    1. Compound Preparation

    [0425] Appropriate amount of compound powder was weighed in a 1.5 mL centrifuge tube, then the corresponding volume of dimethyl sulfoxide (DMSO) was added to form a 20 mM reserve solution. The solution was packed separately and stored in a refrigerator at ?20? C. away from light.

    2. Tumor Cell Culture

    [0426] The cells were inoculated in a cell culture bottle, added an appropriate amount of complete medium, and cultured in a sterile incubator. When the degree of cell confluence reached more than 80%, subculture was carried out.

    3. Detection of Cell Proliferation In Vitro by MTT/MTS Method

    [0427] The adherent cells in logarithmic growth phase were digested by trypsin or the suspension cells were collected by centrifugation and counted. 90 ?L cell suspension was inoculated into 96-well plate according to the cell inoculation density of 1000 cells per well, and 10 ?L of 10-fold final concentration compound diluted by culture medium was added 24 hours later. Compared with the hole with the same volume of 5% DMSO as control, the final concentration of DMSO was 0.5%. After 3 days of drug treatment, the cell viability was detected by MTT. The specific methods are as follows: 10 ?L MTT per well was added into the incubator for 4 hours, the supernatant was discarded and 150 ?L DMSO was added to dissolve the crystal methylazan, and the absorbance of 490 nM was detected by enzyme labeling instrument, or 10 ?L MITS per well was added to the incubator for 4 hours, and 490 nM absorbance was detected directly by enzyme labeling instrument. GraphPad Prism 6 software makes dose-effect curve and calculates IC50.

    [0428] The IC50 values of formula (I) and (11) compound activity data are shown in Table 1:

    TABLE-US-00023 Ex No. AGS IC.sub.50((nM) Ex No. AGS IC.sub.50((nM) 1 8.1 2 3.0 3 4.5 4 11 5 3.8 6 14 7 2584 8 >1000 9 >1000 10 17 11 390 12 316 13 320 14 330 15 320 16 315 17 4134 18 >1000 19 >1000 20 271 21 269 22 3948 23 6952 24 280 25 290 26 300 27 295 28 >1000 29 >2500 30 >2500 31 >2500 32 >2500 33 >2500 34 >2500 35 >2500 36 >2500 37 >2500 38 >2500 39 >2500 40 >2500 41 >2500 42 109 43 31 44 47 45 39 46 13 47 4535 48 5158 49 >10000 50 >10000 51 1655 52 >2500 53 >2500 54 >2500 55 >2500 56 >2500 57 >2500 58 >2500 59 >2500 60 >2500 61 >2500 62 >2500 63 1575 64 >10000 65 >10000 66 >10000 67 >10000 68 1288 69 411 70 >2500 71 >2500 72 >2500 73 16.9 74 >2500 75 >2500 76 >2500 77 >2500 78 >2500 79 >2500 80 >2500 81 >2500 82 >2500 83 >2500 84 >10000 85 >1000 86 >10000 87 >10000 88 >10000 89 1.5 90 8922 91 1.3 92 2.7 93 10.1 94 1.5 95 13.5 96 7.9 97 18 98 129 99 8.8 100 21 101 9.4 102 33 103 29 104 57 105 80 106 120 107 105 108 40.5 109 >2500 110 >2500 111 >2500 112 >2500 113 >2500 114 >2500 115 >2500 116 >2500 117 >2500 118 >2500 119 >2500 120 >2500 121 >2500 122 >2500 123 >2500 124 >2500 125 >2500 126 >2500 127 >2500 128 >2500 129 >2500 130 >2500 131 >2500 132 >2500 133 >2500 134 586 135 1202 136 >2500 137 >2500 138 >2500 139 >2500 140 >2500 141 >2500 142 >2500 143 >2500 144 >2500 145 >2500 146 >2500 147 >2500 148 318 149 320 150 330 151 335 152 318 153 190 154 195 155 215 156 40 157 330 158 235 159 >2500 160 >2500 161 236 162 >2500 163 >2500 164 300 165 >2500 166 >2500 167 310 168 >2500 169 >2500 170 1040 171 1238 172 1230 173 1450 174 1460 175 1330 176 1344 177 530 178 535 179 550 180 556 181 536 182 533 183 >2500 184 >2500 185 1350 186 1420 187 1410 188 1550 189 152 190 150 191 120 192 121 193 125 194 150 195 >2500 196 >2500 197 >2500 198 >2500 199 >2500 200 >2500 201 >2500 202 7.5 203 17 204 11 205 18 206 20 207 25 208 20 209 35 210 65 211 55 212 419 213 >2500 214 >10000 215 >2500 216 3482 217 835 218 980 219 >2500 220 5.0 221 875 222 2.5 223 14 224 4.8 225 668 226 2.4 227 5.0 228 1090 229 2.5 242 34 243 18 244 59 245 25 246 109 247 6.1 248 6.7 249 >2500 250 >2500 251 >2500 252 >2500 253 42 254 462 255 157 256 303 257 1848 258 >10000 259 2630 260 417 261 1930 262 305 263 >10000 264 >10000 265 >10000 266 52 267 1049 268 3997 269 30 270 20 271 11 272 70 273 >2500 274 275 276 277 278 >10000 279 >10000 280 281 537 282 15 283 14 284 2200 285 7.0 286 29 287 2137 288 7.2 289 15 290 3406 291 7.2 292 40 293 121 294 65 295 183 296 >2500 297 >2500 298 299 945 300 177 301 28 302 22 303 22 304 35 305 102 306 366 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 230 328 8906 329 260 330 195 331 823 332 >2500 333 455 334 125 335 20.7 336 9.9 337 338 339 15 340 20 341 25 342 343 17 344 35 345 346 347 348 85 349 350 351 30 352 353 354 25 355 20 356 21 357 358 359 35 360 10 361 362 363 753 364 811 365 3638 366 2100 367 194 368 55 369 180 370 130 371 85 372 65 373 30 374 32 375 376 100 377 120 378 160 379 90 380 95 381 75 382 45 383 50 384 212 385 459 386 508 387 481 388 493 389 180 390 150 391 100 392 110 393 70 394 75 395 396 397 70 398 50 399 65 400 >2500 401 100 402 56 403 60 404 405 406 120 407 35 408 41 409 45 410 75 411 412 35 413 414 45 415 60 416 28 417 35 418 75 419 14 420 60 421 26 422 35 423 55 424 30 425 426 15 427 55 428 70 429 75 430 35