PREPARATION AND APPLICATION METHOD OF HETEROCYCLIC COMPOUNDS AS KRAS INHIBITOR

Abstract

Disclosed is a compound of formula (I) 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 a pharmaceutical composition containing the compound.

##STR00001##

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein the compound of formula (I) is: ##STR01440## wherein: ring W 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.4, wherein R.sup.4 is selected from: oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, cyano, nitro, C(O)OR.sup.5, or C(O)N(R.sup.5).sub.2, among which the alkyl is unsubstituted or substituted with one or more of cyano, halo, OR.sup.5, N(R.sup.5).sub.2, or heteroaryl, wherein each R.sup.5 is independently hydrogen or alkyl; R.sup.1 is -L.sup.1-T, wherein L.sup.1 is O, S, NR.sup.a, C(O), SO.sub.2, SO, C(?NR.sup.a), C(O)O, OC(O), C(O)NR.sup.a, or NR.sup.aC(O), T is CR.sup.a?CR.sup.bR.sup.c, C?CR.sup.b, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, and each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with one or more of oxo, halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro, or NR.sup.xR.sup.y; wherein R.sup.a is hydrogen, deuterium, cyano, halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl, or heterocyclyl; R.sup.b and R.sup.c are each independently hydrogen, deuterium, cyano, halogen, C(O)OR.sup.x, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, among which each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with one or two of oxo; halogen; hydroxyl; alkyl; haloalkyl; hydroxyalkyl; alkoxy; CN; nitro; NR.sup.xR.sup.y; aryl which is unsubstituted or substituted with alkyl, hydroxyl, or halogen; heteroaryl which is unsubstituted or substituted with alkyl, hydroxyl, or halogen; or heterocyclyl which is unsubstituted or substituted with alkyl, hydroxyl, or halogen, or when T is CR.sup.a?CR.sup.bR.sup.c, R.sup.a and R.sup.b, or R.sup.a and R.sup.c, together with the carbon atom to which they are attached, form an unsaturated 5- to 8-membered ring which is unsubstituted or substituted with one or two of oxo, hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy; R.sup.x and R.sup.y are each independently hydrogen or alkyl; Q.sup.1, Q.sup.2, and Q.sup.3 are each independently N or CR.sup.11, and M.sup.1 and M.sup.2 are each independently N or CR.sup.12, provided that at least one of Q.sup.1 and M.sup.1 is N; wherein R.sup.11 and R.sup.12 are each independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, OR.sup.d, C(O)R.sup.d, CO.sub.2R.sup.d, CONR.sup.dR.sup.e, or NR.sup.dR.sup.e, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each independently substituted with one or more of oxo, halogen, hydroxyl, alkoxy, alkyl, cycloalkyl, nitro, cyano, and NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are each independently hydrogen, alkyl, C.sub.3-C.sub.6 cycloalkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl; L is a single bond, O, S, NR.sup.a, OCH.sub.2, SCH.sub.2, NR.sup.aCH.sub.2, CH.sub.2O, CH.sub.2S, CH.sub.2NR.sup.a, C(O), SO.sub.2, SO, C(O)O, OC(O), C(O)NR.sup.a, or NR.sup.aC(O); R.sup.2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each independently unsubstituted or substituted with one or more of halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, OR.sup.d, C(O)R.sup.d, CO.sub.2R.sup.d, CONR.sup.dR.sup.e, NR.sup.dR.sup.e, CH.sub.2 NR.sup.dR.sup.e, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, and heterocyclyl, wherein R.sup.d and R.sup.e are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl; R.sup.3 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that when M.sup.1, Q.sup.1, and Q.sup.2 are all N, R.sup.3 is a non-aromatic fused bicyclic group, non-aromatic fused bicyclic heterocyclyl, or bicyclic heteroaryl, R.sup.3 is unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, OR.sup.d, C(O)R.sup.d, CO.sub.2R.sup.d, CONR.sup.dR.sup.e, NR.sup.dCOR.sup.e, NR.sup.dR.sup.e, S(O).sub.2NR.sup.dR.sup.e, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each independently substituted with halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxyl, cycloalkyl, and heteroaryl, wherein R.sup.d and R.sup.e are each independently hydrogen, alkyl, C.sub.3-C.sub.6 cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl, or cycloalkyl.

2. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein L.sup.1 is C(O) or SO.sub.2, and T is CR.sup.a?CR.sup.bR.sup.c or C?CR.sup.b, wherein R.sup.a is hydrogen, deuterium, cyano, halogen, hydroxyl, or alkyl, R.sup.b and R.sup.c are each independently hydrogen; halogen; unsubstituted alkyl; alkyl substituted with hydroxyl, halogen, NR.sup.xR.sup.y or heterocyclyl; unsubstituted aryl or heteroaryl; and aryl or heteroaryl substituted with alkyl, hydroxyl or halogen, wherein R.sup.x and R.sup.y are each independently hydrogen or alkyl.

3. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein L is OCH.sub.2 or O.

4. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 3, wherein R.sup.2 is heterocyclyl, and the heterocyclyl is unsubstituted or substituted with one or more of halogen and alkyl.

5. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 4, wherein L-R.sup.2 is ##STR01441##

6. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-5, wherein R.sup.3 is aryl, and the aryl is phenyl or naphthyl which is unsubstituted or substituted with 1, 2, or 3 substituents of halogen; cyano; OR.sup.d in which R.sup.d is hydrogen, alkyl, or haloalkyl; CONR.sup.dR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen, alkyl, or cycloalkyl; NR.sup.dCOR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen or alkyl; alkyl which is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl or alkoxy; cycloalkyl which is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; NR.sup.dR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen or alkyl; or heteroaryl.

7. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-5, wherein R.sup.3 is partially hydrogenated naphthyl which is unsubstituted or substituted with hydroxyl, alkyl, hydroxyalkyl, haloalkyl or halogen.

8. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-5, wherein R.sup.3 is heteroaryl which is unsubstituted or substituted with 1, 2, or 3 substituents of oxo, halogen; cyano; OR.sup.d in which R.sup.d is hydrogen, alkyl, or haloalkyl; CONR.sup.dR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen, alkyl, or cycloalkyl; NR.sup.dCOR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen, alkyl, or alkenyl; alkyl which is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl which is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; or NR.sup.dR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen or alkyl.

9. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 8, wherein the heteroaryl is monocyclic heteroaryl selected from thiophene, thiazole, pyrazole pyridine, or pyrimidine; or bicyclic heteroaryl selected from ##STR01442## ##STR01443## in which R.sup.a and R.sup.b are independently hydrogen, halogen, or alkyl, or R.sup.a and R are connected to form a substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl, wherein the heteroaryl is unsubstituted or substituted as described above.

10. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-5, wherein R.sup.3 is non-aromatic fused bicyclic heterocyclyl which is unsubstituted or substituted with 1, 2, or 3 substituents of oxo, halogen; cyano; OR.sup.d in which R.sup.d is hydrogen, alkyl, or haloalkyl; CONR.sup.dR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen, alkyl, or cycloalkyl; NR.sup.dCOR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen, alkyl, or alkenyl; alkyl which is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl which is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; or NR.sup.dR.sup.e in which R.sup.d and R.sup.e are each independently hydrogen or alkyl.

11. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 10, wherein R.sup.3 is ##STR01444## ##STR01445## ##STR01446## ##STR01447## which is unsubstituted or substituted with 1, 2, or 3 substituents of oxo, halogen; hydroxyl, alkoxy, and alkyl; preferably, the substituent is oxo, halogen, hydroxyl, methoxy, or methyl, wherein X, Y, and Z are each independently N or CR.sup.9 in which R.sup.9 is hydrogen, hydroxyl, cyano, alkyl, haloalkyl, halogen, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl.

12. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein the compound is ##STR01448## wherein R.sup.3 is ##STR01449## ##STR01450## ##STR01451## wherein X, Y, and Z are selected from N or CR.sup.9, and R.sup.a and R.sup.b are independently hydrogen, halogen, or alkyl, or R.sup.a and R.sup.b are connected to form a substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl, and the remaining variables are as defined for formula (I).

13. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein the compound is ##STR01452## wherein L-R.sup.2 is ##STR01453## and R.sup.3 is preferably ##STR01454##

14. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein the compound is ##STR01455## wherein: R.sup.3 is ##STR01456## ##STR01457## ##STR01458## in which R.sup.a and R.sup.b are independently hydrogen, halogen, or alkyl, or R.sup.a and R.sup.b are connected to form a substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl.

15. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-14, wherein R.sup.1W is ##STR01459## in which the piperazine ring is optionally additionally substituted with one or more R.sup.4.

16. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-14, wherein R.sup.1W is ##STR01460##

17. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 15 or 16, wherein R.sup.1 is ##STR01461##

18. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein R.sup.3 is ##STR01462## ##STR01463## ##STR01464## ##STR01465## ##STR01466## ##STR01467##

19. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein R.sup.11 is hydrogen, nitro, hydroxyl, halogen, cyano, alkyl, haloalkyl, alkoxy, or alkoxyalkyl.

20. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to claim 1, wherein R.sup.12 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, heterocyclyl, C.sub.1-C.sub.6 haloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl are each unsubstituted or substituted with one or more of C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, and C.sub.3-C.sub.6 cycloalkyl, and R d is hydrogen, alkyl, C.sub.3-C.sub.6 cycloalkyl, hydroxyalkyl, or haloalkyl.

21. The compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-20, wherein the compound is ##STR01468## ##STR01469## ##STR01470## ##STR01471## ##STR01472## ##STR01473## ##STR01474## ##STR01475## ##STR01476## ##STR01477## ##STR01478## ##STR01479## ##STR01480## ##STR01481## ##STR01482## ##STR01483## ##STR01484## ##STR01485## ##STR01486## ##STR01487## ##STR01488## ##STR01489## ##STR01490## ##STR01491## ##STR01492## ##STR01493## ##STR01494## ##STR01495## ##STR01496## ##STR01497## ##STR01498## ##STR01499## ##STR01500## ##STR01501## ##STR01502## ##STR01503## ##STR01504## ##STR01505## ##STR01506## ##STR01507## ##STR01508## ##STR01509## ##STR01510## ##STR01511## ##STR01512## ##STR01513## ##STR01514## ##STR01515## ##STR01516## ##STR01517## ##STR01518## ##STR01519## ##STR01520## ##STR01521## ##STR01522## ##STR01523## ##STR01524## ##STR01525## ##STR01526## ##STR01527## ##STR01528## ##STR01529## ##STR01530## ##STR01531## ##STR01532## ##STR01533## ##STR01534## ##STR01535## ##STR01536## ##STR01537## ##STR01538## ##STR01539## ##STR01540## ##STR01541## ##STR01542## ##STR01543## ##STR01544## ##STR01545## ##STR01546## ##STR01547## ##STR01548## ##STR01549## ##STR01550## ##STR01551## ##STR01552## ##STR01553## ##STR01554## ##STR01555## ##STR01556## ##STR01557## ##STR01558## ##STR01559## ##STR01560## ##STR01561## ##STR01562## ##STR01563## ##STR01564## ##STR01565## ##STR01566## ##STR01567## ##STR01568## ##STR01569## ##STR01570## ##STR01571## ##STR01572## ##STR01573## ##STR01574## ##STR01575## ##STR01576## ##STR01577## ##STR01578## ##STR01579## ##STR01580## ##STR01581## ##STR01582## ##STR01583## ##STR01584## ##STR01585## ##STR01586## ##STR01587## ##STR01588## ##STR01589## ##STR01590## ##STR01591## ##STR01592## ##STR01593## ##STR01594## ##STR01595## ##STR01596## ##STR01597## ##STR01598## ##STR01599## ##STR01600## ##STR01601## ##STR01602## ##STR01603## ##STR01604## ##STR01605## ##STR01606## ##STR01607## ##STR01608## ##STR01609## ##STR01610## ##STR01611## ##STR01612## ##STR01613## ##STR01614## ##STR01615## ##STR01616## ##STR01617## ##STR01618## ##STR01619## ##STR01620## ##STR01621## ##STR01622## ##STR01623## ##STR01624## ##STR01625## ##STR01626## ##STR01627## ##STR01628## ##STR01629## ##STR01630## ##STR01631## ##STR01632## ##STR01633## ##STR01634## ##STR01635## ##STR01636## ##STR01637## ##STR01638## ##STR01639## ##STR01640## ##STR01641## ##STR01642## ##STR01643## ##STR01644## ##STR01645## ##STR01646## ##STR01647## ##STR01648## ##STR01649## ##STR01650## ##STR01651## ##STR01652## ##STR01653## ##STR01654## ##STR01655## ##STR01656## ##STR01657## ##STR01658## ##STR01659## ##STR01660## ##STR01661## ##STR01662## ##STR01663## ##STR01664## ##STR01665## ##STR01666## ##STR01667## ##STR01668## ##STR01669## ##STR01670## ##STR01671## ##STR01672## ##STR01673## ##STR01674## ##STR01675## ##STR01676## ##STR01677## ##STR01678## ##STR01679## ##STR01680## ##STR01681## ##STR01682## ##STR01683## ##STR01684## ##STR01685## ##STR01686## ##STR01687## ##STR01688## ##STR01689## ##STR01690## ##STR01691## ##STR01692## ##STR01693## ##STR01694## ##STR01695## ##STR01696## ##STR01697## ##STR01698## ##STR01699## ##STR01700## ##STR01701## ##STR01702## ##STR01703## ##STR01704## ##STR01705## ##STR01706## ##STR01707## ##STR01708## ##STR01709## ##STR01710## ##STR01711## ##STR01712## ##STR01713## ##STR01714## ##STR01715## ##STR01716## ##STR01717## ##STR01718## ##STR01719## ##STR01720## ##STR01721## ##STR01722## ##STR01723## ##STR01724## ##STR01725## ##STR01726## ##STR01727## ##STR01728## ##STR01729## ##STR01730## ##STR01731## ##STR01732## ##STR01733## ##STR01734## ##STR01735## ##STR01736## ##STR01737## ##STR01738## ##STR01739## ##STR01740## ##STR01741## ##STR01742## ##STR01743## ##STR01744## ##STR01745## ##STR01746## ##STR01747## ##STR01748## ##STR01749## ##STR01750## ##STR01751## ##STR01752## ##STR01753## ##STR01754## ##STR01755## ##STR01756## ##STR01757## ##STR01758## ##STR01759## ##STR01760## ##STR01761## ##STR01762## ##STR01763## ##STR01764## ##STR01765## ##STR01766## ##STR01767## ##STR01768## ##STR01769## ##STR01770## ##STR01771## ##STR01772## ##STR01773## ##STR01774## ##STR01775## ##STR01776## ##STR01777## ##STR01778## ##STR01779## ##STR01780## ##STR01781## ##STR01782## ##STR01783## ##STR01784## ##STR01785## ##STR01786## ##STR01787## ##STR01788## ##STR01789## ##STR01790## ##STR01791## ##STR01792## ##STR01793## ##STR01794## ##STR01795## ##STR01796## ##STR01797## ##STR01798## ##STR01799## ##STR01800## ##STR01801## ##STR01802## ##STR01803## ##STR01804## ##STR01805## ##STR01806## ##STR01807## ##STR01808## ##STR01809## ##STR01810## ##STR01811## ##STR01812## ##STR01813## ##STR01814## ##STR01815## ##STR01816## ##STR01817## ##STR01818## ##STR01819## ##STR01820## ##STR01821## ##STR01822## ##STR01823## ##STR01824## ##STR01825## ##STR01826## ##STR01827## ##STR01828## ##STR01829## ##STR01830## ##STR01831## ##STR01832## ##STR01833## ##STR01834## ##STR01835## ##STR01836## ##STR01837## ##STR01838## ##STR01839## ##STR01840## ##STR01841## ##STR01842## ##STR01843## ##STR01844## ##STR01845## ##STR01846## ##STR01847## ##STR01848## ##STR01849## ##STR01850## ##STR01851## ##STR01852## ##STR01853## ##STR01854## ##STR01855## ##STR01856## ##STR01857## ##STR01858## ##STR01859## ##STR01860## ##STR01861## ##STR01862## ##STR01863## ##STR01864## ##STR01865## ##STR01866## ##STR01867## ##STR01868## ##STR01869## ##STR01870## ##STR01871## ##STR01872## ##STR01873## ##STR01874## ##STR01875## ##STR01876## ##STR01877## ##STR01878## ##STR01879## ##STR01880## ##STR01881## ##STR01882## ##STR01883## ##STR01884## ##STR01885## ##STR01886## ##STR01887## ##STR01888## ##STR01889## ##STR01890## ##STR01891## ##STR01892## ##STR01893## ##STR01894## ##STR01895## ##STR01896## ##STR01897## ##STR01898## ##STR01899## ##STR01900## ##STR01901## ##STR01902## ##STR01903## ##STR01904## ##STR01905## ##STR01906## ##STR01907## ##STR01908## ##STR01909## ##STR01910## ##STR01911## ##STR01912## ##STR01913## ##STR01914## ##STR01915## ##STR01916## ##STR01917## ##STR01918## ##STR01919## ##STR01920## ##STR01921## ##STR01922## ##STR01923## ##STR01924## ##STR01925## ##STR01926## ##STR01927## ##STR01928## ##STR01929## ##STR01930## ##STR01931## ##STR01932## ##STR01933## ##STR01934## ##STR01935## ##STR01936## ##STR01937## ##STR01938## ##STR01939## ##STR01940## ##STR01941## ##STR01942## ##STR01943## ##STR01944## ##STR01945## ##STR01946## ##STR01947## ##STR01948## ##STR01949## ##STR01950## ##STR01951## ##STR01952## ##STR01953## ##STR01954## ##STR01955## ##STR01956## ##STR01957## ##STR01958## ##STR01959## ##STR01960## ##STR01961## ##STR01962## ##STR01963## ##STR01964## ##STR01965## ##STR01966## ##STR01967## ##STR01968## ##STR01969## ##STR01970## ##STR01971## ##STR01972## ##STR01973## ##STR01974## ##STR01975## ##STR01976##

22. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-21.

23. Use of the compound or the pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof according to any one of claims 1-21 and the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating a cancer mediated by KRAS G12C, HRAS G12C, or NRAS G12 mutation.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0100] Unless otherwise indicated, the entire disclosure of the present invention is defined by the following terms:

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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) hereinafter, which refers to both pure optical isomers and, if appropriate, mixtures of isomers at various ratios.

[0105] 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.

[0106] The alkyl, alkenyl, alkynyl, and cycloalkyl moieties can be each independently optionally substituted with one or more groups selected from hydroxyl, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, and mercapto.

[0107] Saturated or unsaturated hydrocarbon groups, such as alkyl, alkanediyl or alkenyl, including those bonded with heteroatoms, such as alkoxy, can all be individually linear or branched.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] When one variable is selected from a single bond, it means that the two groups connected thereto are directly connected. For example, when L in Ar-L-R represents a single bond, it means that the structure is actually ArR. When a substituent is vacant, it means that the substituent does not exist. For example, when L is vacant in Ar-L-R, Ar-L-R means that the structure is actually Ar.

[0112] Unless otherwise specified, the term hetero means a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical), including atoms other than carbon (C) and hydrogen (H) and radicals containing these heteroatoms, such as including oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminium (Al), boron (B), O, S, C(?O)O, C(?O), C(?S), S(?O), and S(?O)2-, as well as optionally substituted C(?O)N(H), N(H), C(?NH), S(?O)2N(H), or S(?O)N(H).

[0113] Unless otherwise specified, the term ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The ring includes both monocyclic rings and bicyclic or polycyclic systems such as spiro, fused and bridged cyclic rings. The number of atoms on a ring is usually defined as the number of the members of the ring. For example, a 5-7-membered ring refers to 5-7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Therefore, the term 5-7-membered ring includes, for example, phenyl, pyridinyl, and piperidinyl; on the other hand, the term 5-7-membered heterocycloalkyl includes pyridinyl and piperidinyl, but does not include phenyl. The term ring also includes a ring system containing at least one ring, wherein each ring independently conforms to the above definition.

[0114] 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)2-, C(?O)N(H), N(H), C(?NH), S(?O)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. Unless otherwise specified, the term heterocycloalkyl, respectively by itself or in combination with other terms, means cyclized heteroalkyl, which includes monocyclic, bicyclic and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro, bicyclic and bridged cyclic rings. In addition, in terms of heterocycloalkyl, the heteroatom can occupy the position at which the heterocycloalkyl is connected to the remainder of the molecule. In some embodiments, the heterocycloalkyl is 4- to 6-membered heterocycloalkyl; and in other embodiments, the heterocycloalkyl is 5- to 6-membered heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or oxepanyl.

[0115] The term alkoxy represents the above-mentioned alkyl with a specific number of carbon atoms connected by an oxygen bridge, and unless otherwise specified, C.sub.1-C.sub.6 alkoxy includes C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkoxy. In some embodiments, the alkoxy is C.sub.1-C.sub.3 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and pentoxy.

[0116] Unless otherwise specified, the term aryl in the present invention represents a polyunsaturated carbocyclic system, which can be a monocyclic, bicyclic or polycyclic system, in which at least one ring is aromatic, and the rings in the bicyclic and polycyclic systems are fused together. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. In some embodiments, the aryl is C.sub.6-C.sub.12 aryl; and in other embodiments, the aryl is C.sub.6-C.sub.10 aryl. Examples of aryl include, but are not limited to, phenyl and naphthyl (including 1-naphthyl, 2-naphthyl, etc.). The substituents of any of the above aryl ring systems are selected from the acceptable substituents described in the present invention.

[0117] Unless otherwise specified, the term heteroaryl in the present invention refers to aryl containing 1, 2, 3, or 4 heteroatoms independently selected from B, N, O, and S, which may be a monocyclic, bicyclic or tricyclic system, in which the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined herein), and optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, wherein p is 1 or 2). The heteroaryl group can be attached to the remainder of the molecule via a heteroatom. In some embodiments, the heteroaryl is 5- to 10-membered heteroaryl; and in other embodiments, the heteroaryl is 5- to 6-membered heteroaryl. Examples of the heteroaryl include, but are not limited to, pyrrolyl (including pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl, 6-quinolyl, etc.), pyrazinyl, purinyl, and benzoxazolyl. The substituents of any of the above heteroaryl ring systems are selected from the acceptable substituents described in the present invention.

Synthesis

[0118] 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.

[0119] 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 0-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

Synthesis of 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane

[0120] ##STR00487##

[0121] The compound 5-bromo-1,2,3,4-tetralin (5.00 g, 23.69 mmol) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bis(1,3,2-dioxaborane) (12.03 g, 47.37 mmol) was dissolved in anhydrous 1,4-dioxane (50 mL), potassium acetate (6.97 g, 71.07 mmol) and Pd(dppf)Cl.sub.2 (1.73 g, 2.37 mmol) were added, and after displacement with nitrogen, the mixture was heated to 100? C. and reacted under stirring for 16 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 light yellow oil. (5.0 g, yield: 82%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.58 (d, J=6.9 Hz, 1H), 7.11 (s, 1H), 7.08 (d, J=7.3 Hz, 1H), 3.03 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.8 Hz, 2H), 1.78 (dd, J=7.1, 4.3 Hz, 4H), 1.34 (s, 12H).

Synthesis of Intermediate 2-(4-fluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0122] ##STR00488##

[0123] The compound 5-bromo-8-fluoro-1,2,3,4-tetralin (2.00 g, 8.73 mmol) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bis(1,3,2-dioxaborane) (4.43 g, 17.46 mmol) was dissolved in anhydrous 1,4-dioxane (30 mL), potassium acetate (2.57 g, 26.19 mmol) and Pd(dppf)Cl.sub.2 (0.64 g, 0.87 mmol) were added, and after displacement with nitrogen, the mixture was heated to 100? C. and reacted under stirring for 16 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 light yellow oil. (2.1 g, yield: 87%). .sup.1H NMR (600 MHz, CDCl.sub.3) ? 7.63-7.54 (m, 1H), 6.80 (t, J=8.8 Hz, 1H), 3.03 (s, 2H), 2.71 (s, 2H), 1.82-1.72 (m, 4H), 1.33 (s, 12H).

##STR00489##

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

[0124] 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

[0125] 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%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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

[0126] 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%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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

[0127] 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%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 Intermediate (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0128] ##STR00490##

Step 1: Synthesis of 1-tert-butyl 2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate

[0129] 1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (5.8 g, 25.3 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to ?78? C., LiHMDS (1 M/L, 37.9 mmol) was added dropwise, and after 30 min, 1-bromo-3-chloropropane (19.9 g, 126 mmol) was added; and the mixture was reacted at room temperature for 2 h, and the reaction was then quenched by adding a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated and then purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain a transparent oil. (5.1 g, yield: 65.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 3.83-3.28 (m, 7H), 2.39-1.68 (m, 8H), 1.43 (d, J=13.1 Hz, 9H).

Step 2: Synthesis of methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate

[0130] 1-(tert-butyl) 2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate (1 g, 3.27 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was reacted at room temperature for 1 h, concentrated to dryness, and directly used for the next step of reaction.

Step 3: Synthesis of methyl tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate

[0131] 2-(3-chloropropyl) methyl pyrrolidine-2-carboxylate (670 mg, 3.27 mmol) was dissolved in methanol (10 mL), potassium carbonate (1.35 g, 9.81 mmol), potassium iodide (670 mg, 0.327 mmol) was added, the mixture was reacted at room temperature for 2 h, the solid was filtered out, and the filtrate was concentrated and then purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain a transparent oil. (400 mg, yield: 72.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 3.72 (s, 3H), 3.21-3.11 (m, 2H), 2.64 (d, J=10.2 Hz, 2H), 2.38-2.24 (m, 2H), 1.86-1.76 (m, 4H), 1.72-1.66 (m, 2H).

Step 4: Synthesis of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0132] Methyl tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (400 mg, 2.37 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminium tetrahydride (270 mg, 7.10 mmol) was added in portions under ice bath condition, after 1 h, TLC (petroleum ether/ethyl acetate=10/1) detected that the reaction was complete, sodium sulfate decahydrate was added, the solid was filtered out, and the filtrate was concentrated to obtain a transparent oil. (290 mg, yield: 87%). .sup.1H NMR (400 MHz, MeOD) ? 3.36-3.28 (m, 2H), 2.96 (dt, J=10.4, 6.1 Hz, 2H), 2.64 (ddd, J=10.5, 7.3, 6.0 Hz, 2H), 1.97-1.81 (m, 4H), 1.73 (dt, J=12.6, 6.8 Hz, 2H), 1.64-1.52 (m, 2H).

Synthesis of Intermediate tert-butyl (1R,5R)2,6-diazabicyclo[3.2.0]heptane-2-carboxylate

[0133] ##STR00491##

Step 1: Synthesis of (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

[0134] (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (1.31 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL), sodium hydroxide (0.80 g, 20 mmol) and Boc anhydride (3.30 g, 15 mmol) were added, the mixture was stirred at room temperature for 15 h and extracted with ethyl acetate, and the aqueous layer was adjusted to pH=2.0 with 1N hydrochloric acid, extracted with ethyl acetate, and concentrated to obtain a white solid. (1.5 g, yield: 65%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.82 (s, 1H), 4.25 (s, 1H), 3.62 (q, J=9.3 Hz, 1H), 3.48 (s, 1H), 2.12 (dd, J=8.9, 4.5 Hz, 1H), 1.94 (ddd, J=10.0, 6.7, 3.3 Hz, 1H), 1.51 (s, 9H).

Step 2: Synthesis of tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0135] (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 6.5 mmol) was dissolved in tetrahydrofuran (20 mL), borane dimethyl sulfide (2 M/L, 14.3 mmol) was added, the mixture was heated to reflux for 3 h and cooled to room temperature, methanol was added dropwise to quench the reaction, and after concentration, the reaction product was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain a transparent oil. (1.2 g, yield: 85.7%). 1H NMR (400 MHz, MeOD) ? 4.42-4.21 (m, 1H), 3.66 (d, J=8.8 Hz, 2H), 3.52-3.35 (m, 3H), 2.19-2.04 (m, 1H), 1.90-1.74 (m, 1H), 1.47 (s, 9H).

Step 3: Synthesis of tert-butyl (2R,3S)3-(methylsulfonyloxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate

[0136] Tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.16 g, 5.3 mmol) was dissolved in dichloromethane (20 mL), triethylamine (2.26 g, 22.4 mmol) and methylsulfonyl chloride (1.83 g, 16 mmol) were added under ice bath condition, the mixture was reacted at room temperature for 2 h, ice water was added, and the mixture was extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and then directly used for the next step of reaction.

Step 4: Synthesis of tert-butyl (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate

[0137] Tert-butyl (2R,3S)3-(methylsulfonyloxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (2.0 g, 5.3 mmol) was dissolved in toluene (20 mL), benzylamine (1.71 g, 16 mmol) was added, the mixture was heated to 110? C., reacted for 15 h, and cooled to room temperature, the solid was filtered out, and the filtrate was concentrated and then purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain a light yellow oil. (890 mg, yield: 58%). .sup.1H NMR (400 MHz, MeOD) ? 7.42-7.18 (m, 5H), 4.31-4.15 (m, 1H), 3.99 (d, J=5.0 Hz, 1H), 3.67 (d, J=14.7 Hz, 4H), 3.18 (dd, J=6.4, 4.3 Hz, 2H), 1.69-1.53 (m, 2H), 1.44 (d, J=15.2 Hz, 9H).

Step 5: Synthesis of tert-butyl (1R,5R)2,6-diazabicyclo[3.2.0]heptane-2-carboxylate

[0138] Tert-butyl (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (145 mg, 0.5 mmol) was dissolved in methanol (20 mL), palladium on carbon (10%, 100 mg) was added, the mixture was reacted under the pressure of a hydrogen balloon for 20 h and filtered, and the filtrate was concentrated to obtain a transparent solid. (90 mg, yield: 90.3%). .sup.1H NMR (400 MHz, MeOD) ? 4.11 (dd, J=10.7, 6.0 Hz, 1H), 3.92 (s, 1H), 3.72 (td, J=10.8, 6.9 Hz, 2H), 3.44-3.33 (m, 2H), 2.07 (tt, J=16.0, 7.9 Hz, 2H), 1.47 (d, J=4.2 Hz, 12H).

Example 1: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0139] ##STR00492##

Step 1: 2-chloro-3-fluoro-5-iodopyridine-4-amine

[0140] The compound 2-chloro-3-fluoropyridine-4-amine (4.22 g, 28.80 mmol) was dissolved in acetonitrile (50 mL), NIS (7.77 g, 34.55 mmol) and p-methylbenzenesulfonic acid (248 mg, 1.44 mmol) were then added, and the mixture was heated to 70? C. and reacted under stirring for 16 h. After the reaction was complete, the reaction liquid was cooled to room temperature and diluted with water, whereby a solid precipitated out, which was filtered out and washed with a saturated sodium thiosulfate aqueous solution and with water and dried in vacuo to obtain the target compound, which was directly used in the next step. (7.5 g, yield: 98%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.17 (s, 1H), 4.83 (s, 2H).

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

[0141] The compound 2-chloro-3-fluoro-5-iodopyridine-4-amine (7.7 g, 28.26 mmol) and Zn(CN).sub.2 (4.32 g, 36.74 mmol) were dissolved in anhydrous DMF (150 mL), Pd(PPh.sub.3).sub.4 (1.63 g, 1.41 mmol) and a 4A molecular sieve (2.5 g) were then added, and after displacement with nitrogen, the mixture was heated to 100? C. in a nitrogen atmosphere and reacted under stirring for 3 h. After the reaction was complete, the reaction product was filtered to remove solids, the solution was cooled to room temperature, 300 mL of water was added to dilute the reaction liquid, whereby a solid precipitated out, and after filtration, the solid was washed with water and dried in vacuo to obtain a crude product, which was directly used in the next step. (4.85 g, yield: 100%). .sup.1H NMR (400 MHz, DMSO) ? 8.20 (s, 1H), 7.66 (s, 2H).

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

[0142] The compound 4-amino-6-chloro-5-fluoronicotinonitrile (4.85 g, 28.26 mmol) was dissolved in 50% H.sub.2SO.sub.4 (50 mL), and the mixture was heated to 120? C. and reacted under stirring for 6 h. After the reaction was complete, the reaction product was cooled to room temperature, the reaction liquid was slowly poured onto crushed ice, whereby a solid precipitated out, and after filtration, the solid was washed with water. The solid was dissolved with ethyl acetate and washed by adding a saturated sodium carbonate aqueous solution, an aqueous phase was collected, the aqueous phase was adjusted to pH 2-3 with 10% hydrochloric acid, whereby a solid precipitated out, and after filtration, the solid was dried in vacuo to obtain an off-white solid. (4.62 g, yield: 85.8%). .sup.1H NMR (400 MHz, DMSO) ? 8.36 (s, 1H), 7.59 (s, 2H).

Step 4: Synthesis of 7-chloro-8-fluoro-4-hydroxypyridino[4,3-d]pyrimidine-2(1H)-thione

[0143] The compound 4-amino-6-chloro-5-fluoronicotinic acid was added to a reaction flask, POCl.sub.3 (50 mL) was then added, and the mixture was heated to 90? C. and reacted under stirring for 4 h. After the reaction was complete, the reaction product was cooled to room temperature, the reaction liquid was concentrated to obtain an oil, and the oil was dissolved in anhydrous tetrahydrofuran (20 mL), then added dropwise to ammonium thiocyanate (3.67 g, 48.28 mmol) in tetrahydrofuran (80 mL), and reacted under stirring at room temperature 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 a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain a yellow solid. 10 ml of ethyl acetate was then added for pulping and filtered to obtain a light yellow solid. (4.52 g, yield: 80.8%). .sup.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)pyridino[4,3-d]pyrimidin-4-ol

[0144] The compound 7-chloro-8-fluoro-4-hydroxypyridino[4,3-d]pyrimidine-2(1H)-thione (4.52 g, 19.51 mmol) was dissolved in anhydrous DMF (50 mL), sodium methoxide (1.06 g, 19.51 mmol) was then added, the mixture was stirred at room temperature for 10 min, iodomethane (2.77 g, 1.21 mL, 19.51 mmol) was added dropwise, and the mixture was reacted at room temperature under stirring for 2 h. After the reaction was complete, the reaction liquid was diluted by adding cold water, whereby a solid precipitated out, and after filtration, the solid was washed with water and dried in vacuo to obtain a yellow solid. (3.0 g, yield: 66%). .sup.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)pyridino[4,3-d]pyrimidine

[0145] The compound 7-chloro-8-fluoro-2-(methylthio)pyridino[4,3-d]pyrimidin-4-ol (420 mg, 1.71 mmol) was dissolved in phosphorus oxychloride (4 mL), DIEA (442 mg, 3.42 mmol) was then added, and the mixture was heated to 90? C. and reacted for 3 h. After the reaction was complete, the reaction product was cooled to room temperature and concentrated to remove excess phosphorus oxychloride. The product was then dissolved in ethyl acetate and washed sequentially with a saturated aqueous NaCl solution and water, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a crude product, which was directly used for the next step. (450 mg, yield: 100%).

Step 7: Synthesis of tert-butyl (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0146] The compound 4,7-dichloro-8-fluoro-2-(methylthio)pyridino[4,3-d]pyrimidine (450 mg, 1.71 mmol) was dissolved in anhydrous DMF (10 mL), and DIEA (1.10 g, 8.55 mmol) and (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (339 mg, 1.71 mmol) were added under ice-water bath cooling condition; and after stirring for 10 min under ice-water bath cooling condition, di-tert butyl dicarbonate (747 mg, 3.42 mmol) was added, and the mixture was reacted at room temperature under stirring for 16 h. After the reaction was complete, the reaction liquid was diluted by adding 100 mL of cold water under stirring 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. (710 mg, yield: 91.6%). .sup.1H NMR (600 MHz, CDCl.sub.3) ? 8.80 (s, 1H), 4.62 (s, 1H), 4.45 (dd, J=13.9, 3.5 Hz, 1H), 4.28 (d, J=12.8 Hz, 1H), 4.08 (s, 1H), 3.84 (s, 1H), 3.66 (d, J=8.6 Hz, 1H), 3.39 (s, 1H), 2.87-2.74 (m, 1H), 2.69 (dd, J=16.8, 5.9 Hz, 1H), 2.64 (s, 3H), 1.51 (s, 9H).

Step 8: Synthesis of tert-butyl (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0147] The compound tert-butyl (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (700 mg, 1.55 mmol) was dissolved in dichloromethane (10 mL), 85% m-chloroperoxybenzoic acid (378 mg, 1.86 mmol) was added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 30 min. After the reaction was complete, the reaction was quenched by using a saturated sodium thiosulfate solution and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and a table salt aqueous solution, dried with anhydrous sodium sulfate and concentrated to obtain a crude product, which was directly used for the next step. (725 mg, yield: 100%).

Step 9: Synthesis of tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0148] The compound tert-butyl (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (725 mg, 1.55 mmol) was dissolved in anhydrous toluene (10 mL), (S)-(1-methylpyrrolidin-2-yl)methanol (0.31 g, 2.71 mmol) was then added, sodium tert-butoxide (0.30 g, 3.09 mmol) was added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 30 min. After the reaction was complete, the reaction was quenched with cold 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 an off-white solid. (510 mg, yield: 63%).

Step 10: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0149] The compound tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (40 mg, 0.08 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (30 mg, 0.12 mmol) were dissolved in 1,4-dioxane/water=5/1 (3 mL), cesium carbonate (76 mg, 0.23 mmol) and Pd(PPh.sub.3).sub.4 (45 mg, 0.04 mmol) were added, and after displacement with nitrogen, the mixture was heated to 95? C. in a nitrogen atmosphere and reacted under stirring for 1 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 TLC to obtain an off-white solid. (20 mg, yield: 42%).

Step 11: Synthesis of 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0150] The compound tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (20 mg, 0.03 mmoL) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated, then dissolved in dichloromethane, adjusted to pH 8-9 with a saturated sodium carbonate solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a crude product, which was directly used for the next step. (14 mg, yield: 98%).

Step 12: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0151] The compound 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (14 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), DIEA (5 mg, 0.03 mmol) and acryloyl chloride (3 mg, 0.03 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 5 min. After the reaction was complete, the reaction was quenched with saturated sodium carbonate and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (10 mg, yield: 62%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.10 (s, 1H), 7.26-7.21 (dd, m, 3H), 6.62-6.57 (m, 1H), 6.48-6.31 (m, 1H), 5.83 (dd, J=19.7, 11.2 Hz, 1H), 5.02 (s, 2H), 4.62-4.58 (m, 1H), 4.49-4.44 (m, 3H), 4.10 (d, J=12.0 Hz, 1H), 3.87-3.83 (m, 2H), 3.65 (dd, J=13.5, 6.8 Hz, 1H), 3.57-3.51 (m, 2H), 3.34-3.31 (m, 1H), 3.14-2.95 (m, 2H), 2.87-2.83 (m, 6H), 2.75-2.71 (m, 1H), 2.62 (t, J=5.7 Hz, 3H), 2.30-2.25 (m, 2H), 2.16-2.11 (m, 2H). MS m/z: 570.75 [M+H].sup.+

Example 2: Synthesis of (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0152] ##STR00493##

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

[0153] The compound tert-butyl (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.21 mmol) was dissolved in anhydrous toluene (3 mL), and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (46 mg, 0.32 mmol) and sodium tert-butoxide (31 mg, 0.32 mmol) were added under ice-water bath cooling condition and reacted under stirring and ice-water bath cooling conditions for 3 h; and after the reaction was complete, the reaction was quenched with cold water and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and separated by column chromatography to obtain an off-white solid. (55 mg, yield: 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.82 (s, 1H), 4.75 (dt, J=23.5, 12.9 Hz, 3H), 4.58 (s, 1H), 4.31 (d, J=11.7 Hz, 1H), 4.18-3.88 (m, 4H), 3.82 (t, J=10.1 Hz, 1H), 3.37 (s, 1H), 3.23 (dd, J=16.7, 8.9 Hz, 1H), 3.01 (s, 2H), 2.80 (dd, J=16.7, 3.9 Hz, 1H), 2.55-2.37 (m, 2H), 2.34-2.21 (m, 3H), 2.15 (dt, J=13.5, 6.8 Hz, 2H), 2.02 (dd, J=11.3, 6.9 Hz, 2H), 1.49 (s, 9H).

Step 2: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0154] The compound tert-butyl (S)-4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (57 mg, 0.10 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (33 mg, 0.13 mmol) were dissolved in 1,4-dioxane/water=5/1 (3 mL), cesium carbonate (102 mg, 0.31 mmol) and Pd(PPh.sub.3).sub.4 (60 mg, 0.05 mmol) were added, and after displacement with nitrogen, the mixture was heated to 95? C. in a nitrogen atmosphere and reacted under stirring for 1 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 TLC to obtain an off-white solid. (38 mg, yield: 57%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.09 (s, 1H), 7.26-7.21 (m, 3H), 4.82 (s, 2H), 4.73-4.57 (m, 2H), 4.41-4.38 (m, 1H), 3.98-3.92 (m, 4H), 3.87-3.82 (m, 1H), 3.47-3.40 (m, 2H), 3.23-3.20 (m, 1H), 3.00 (s, 2H), 2.87 (t, J=6.2 Hz, 2H), 2.63-2.61 (m, 2H), 2.54-2.38 (m, 2H), 2.38-2.20 (m, 2H), 2.14 (s, 2H), 2.03-1.98 (m, 2H), 1.81 (d, J=6.1 Hz, 2H), 1.73-1.71 (m, 2H), 1.50 (s, 9H).

Step 3: Synthesis of (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0155] The compound tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (38 mg, 0.06 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated, then dissolved in dichloromethane, adjusted to pH 8-9 with saturated sodium carbonate and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a crude product, which was directly used for the next step. (32 mg, yield: 100%).

Step 4: Synthesis of (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0156] The compound (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), DIEA (5 mg, 0.033 mmol) and acryloyl chloride (3 mg, 0.03 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 5 min. After the reaction was complete, the reaction was quenched with saturated sodium carbonate and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (8 mg, yield: 49%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.13 (s, 1H), 7.21 (d, J=3.8 Hz, 3H), 6.56 (s, 1H), 6.38 (d, J=15.4 Hz, 1H), 5.82 (d, J=9.6 Hz, 1H), 4.82 (s, 2H), 4.62 (d, J=14.6 Hz, 1H), 4.47 (d, J=11.3 Hz, 1H), 4.25-4.22 (m, 1H), 3.93 (s, 4H), 3.66 (d, J=4.6 Hz, 1H), 3.35 (dd, J=16.9, 7.6 Hz, 1H), 3.15-2.94 (m, 4H), 2.87 (t, J=6.1 Hz, 2H), 2.63 (d, J=5.9 Hz, 2H), 2.45 (ddd, J=26.5, 13.0, 6.6 Hz, 2H), 2.28 (dd, J=16.8, 8.4 Hz, 2H), 2.18-2.11 (m, 2H), 2.06-1.99 (m, 2H), 1.81 (d, J=6.4 Hz, 2H), 1.73 (d, J=6.2 Hz, 2H). MS m/z: 596.68 [M+H].sup.+

Example 3: Synthesis of (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0157] ##STR00494##

[0158] The compound (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.03 mmol) and 2-fluoroacrylic acid (4 mg, 0.04 mmol) were dissolved in dichloromethane (3 mL), HATU (16 mg, 0.04 mmol) was added, the mixture was cooled to 0-10? C. in an ice-water bath, DIEA (6 mg, 0.04 mmol) was then added, and the mixture was reacted at 0-10? C. under stirring for 4 h. After the reaction was complete, the reaction liquid was diluted 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 to obtain an off-white solid. (8 mg, yield: 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.14 (s, 1H), 7.26-7.22 (m, 3H), 5.60-5.38 (m, 1H), 5.28 (dd, J=16.8 Hz, 1H), 4.82 (s, 2H), 4.62 (d, J=14.6 Hz, 1H), 4.47 (d, J=11.3 Hz, 1H), 4.25-4.22 (m, 1H), 3.93 (s, 4H), 3.66 (d, J=4.6 Hz, 1H), 3.35 (dd, J=16.9, 7.6 Hz, 1H), 3.15-2.94 (m, 4H), 2.87 (t, J=6.1 Hz, 2H), 2.63 (d, J=5.9 Hz, 2H), 2.45 (ddd, J=26.5, 13.0, 6.6 Hz, 2H), 2.28 (dd, J=16.8, 8.4 Hz, 2H), 2.18-2.11 (m, 2H), 2.06-1.99 (m, 2H), 1.81 (d, J=6.4 Hz, 2H), 1.73 (d, J=6.2 Hz, 2H) MS m/z: 614.6 [M+H].sup.+

[0159] The compounds of Examples 4-48 were prepared by preparation method 1

TABLE-US-00001 Ex. Compound name Structural formula m/z: ES+[M + H] 4 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00495] 588.2 5 2-((S)-1-acryloyl-4-(8-fluoro-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00496] 588.2 6 2-((S)-4-((8-fluoro-2-(((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile [00497] 606.2 7 2-((S)-1-acryloyl-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00498] 614.7 8 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00499] 632.7 9 1-((1R,5R)-6-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00500] 543 10 2-fluoro-1-((1R,5R)-6-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00501] 561.6 11 1-((1R,5R)-6-(8-fluoro-2-(((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00502] 561.6 12 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5, 6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00503] 579.6 13 1-((1R,5R)-6-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00504] 569.3 14 2-fluoro-1-((1R,5R)-6-(8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00505] 587.7 15 1-(((1R,5R)-6-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00506] 587.7 16 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00507] 605.6 17 2-((S)-1-acryloyl-4-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00508] 588 18 2-((S)-4-((8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile [00509] 606 19 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(4- fluoro-5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00510] 606 20 2-((S)-4-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(4-fluoro- 5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile [00511] 624 21 (S)-2-(1-acryloyl-4-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00512] 614 22 (S)-2-(4-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H))-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile [00513] 23 2-((2S)-1-acryloyl-4-(8-fluoro-7-(4-fluoro- 5,6,7,8-tetrahydronaphthalen-1-yl)-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00514] 632 24 2-((2S)-4-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00515] 650 25 1-((1R,5R)-6-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00516] 561.6 26 2-fluoro-1-(((1R,5R)-6-(8-fluoro-7-(4-fluoro- 5,6,7,8-tetrahydronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00517] 579.6 27 1-((1R,5R)-6-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(4-fluoro- 5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00518] 579.2 28 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(4- fluoro-5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00519] 597.2 29 1-(((1R,5R)-6-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00520] 587 30 2-fluoro-1-(((1R,5R)-6-(8-fluoro-7-(4-fluoro- 5,6,7,8-tetrahydronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00521] 605 31 1-(((1R,5R)-6-(8-fluoro-7-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00522] 605.6 32 2-fluoro-1-(((1R,5R)-6-(8-fluoro-7-(4-fluoro- 5,6,7,8-tetrahydronaphthalen-1-yl)-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00523] 623.2 33 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00524] 571.3 34 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00525] 589 35 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00526] 589 36 2-((S)-4-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile [00527] 607 37 (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00528] 597.3 38 (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile [00529] 615 39 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00530] 615 40 2-((S)-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00531] 633 41 1-((1R,5R)-6-(8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00532] 544.6 42 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7]-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00533] 562 43 1-((1R,5R)-6-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00534] 562 44 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00535] 580 45 1-((1R,5R)-6-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00536] 570 46 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy))-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[4,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00537] 588 47 1-(((1R,5R)-6-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00538] 588 48 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[4,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00539] 606

Example 49: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0160] ##STR00540##

Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(thiochroman-8-yl)-1,3,2-dioxolane

[0161] 8-bromo-thiochroman (114 mg, 0.5 mmol), bis(pinacolato)diboron (279 mg, 1.1 mmol), Pd(dppf)Cl.sub.2 (37 mg, 0.05 mmol) and potassium acetate (147 mg, 1.5 mmol) were added to a round-bottomed flask. After displacement with nitrogen, anhydrous 1,4-dioxane (5 mL) which had been deoxidized in advance was added. The resulting suspension was stirred at 100? C. for 16 h. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After layering, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=1:40) to obtain a colorless viscous material. (42 mg, 0.152 mmol, yield: 30%)

Step 2: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiocyano-8)pyridinyl[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0162] Tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (52 mg, 0.1 mmol), 4,4,5,5-tetramethyl-2-(thiochroman-8-yl)-1,3,2-dioxolane (42 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.4 mmol) and cesium carbonate (98 mg, 0.3 mmol) were added to a round-bottomed flask. After displacement with nitrogen, 1,4-dioxane (2 mL) and water (0.4 mL) which had been deoxidized in advance was added. The reaction liquid was stirred at 100? C. for 3 h. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and layering, the aqueous phase was extracted with ethyl acetate (10 mL?2). The combined organic phases were washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining brown viscous material was purified by prep-TLC (silica gel, methanol:dichloromethane=1:9) to obtain a light yellow solid. (32 mg, 0.05 mmol, yield: 50%) MS m/z: 634.7 [M+H].sup.+.

Step 3: Synthesis of 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0163] Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiocyano-8)pyridinyl[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (32 mg, 0.05 mmol) in dichloromethane (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. Dichloromethane (7 mL) was added and concentration in vacuo was performed. Dichloromethane (5 mL) was added to the resulting residue, concentration was performed again, and this process was repeated once. The resulting yellow solid was directly used for the next step.

Step 4: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0164] A solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) was added dropwise to a solution of 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.05 mL, 0.35 mmol) in dichloromethane (2 mL) at room temperature. The reaction liquid was stirred at room temperature for 15 min. Dichloromethane (20 mL) and a saturated sodium carbonate aqueous solution (20 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation to obtain a viscous material. Purification by prep-TLC (methanol:dichloromethane=1:8) gave a white solid (17 mg, overall yield over two steps: 57%). MS m/z: 588.6 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) ? 9.11 (s, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.16-7.12 (m, 2H), 6.66-6.56 (m, 1H), 6.42 (d, J=16 Hz, 1H), 5.86 (d, J=12 Hz, 1H), 5.10-4.98 (m, 2H), 4.65-4.60 (m, 1H), 4.52-4.40 (m, 2H), 4.10-4.07 (m, 1H), 3.85-3.81 (m, 1H), 3.72-3.25 (m, 4H), 3.06-2.78 (m, 10H), 2.32-1.98 (m, 3H), 1.80-1.55 (m, 3H).

Example 50: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0165] ##STR00541##

Step 1: Synthesis of 2-(isochroman-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane

[0166] 5-bromoisochroman (198 mg, 0.93 mmol), bis(pinacolato)diboron (709 mg, 2.8 mmol), Pd(dppf)Cl.sub.2 (102 mg, 0.14 mmol) and potassium acetate (274 mg, 2.8 mmol) were added to a round-bottomed flask. After displacement with nitrogen, anhydrous 1,4-dioxane (10 mL) which had been deoxidized in advance was added. The resulting suspension was stirred at 100? C. for 16 h. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After layering, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=1:30) to obtain a colorless oil. (196 mg, 0.754 mmol, yield: 81%)

Step 2: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0167] Tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (55 mg, 0.106 mmol), 2-(isochroman-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane (52 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (49 mg, 0.0424 mmol) and cesium carbonate (104 mg, 0.32 mmol) were added to a round-bottomed flask. After displacement with nitrogen, 1,4-dioxane (2 mL) and water (0.4 mL) which had been deoxidized in advance was added. The reaction liquid was stirred at 100? C. for 3 h. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and layering, the aqueous phase was extracted with ethyl acetate (10 mL?2). The combined organic phases were washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining brown viscous material was purified by prep-TLC (silica gel, methanol:dichloromethane=1:9) to obtain a light yellow powder. (16 mg, 0.0259 mmol, yield: 24%) MS m/z: 618.7 [M+H].sup.+.

Step 3: Synthesis of 2-((S)-4-(8-fluoro-7-(isochroman-5-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0168] Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (16 mg, 0.0259 mmol) in dichloromethane (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. Dichloromethane (7 mL) was added and concentration in vacuo was performed. Dichloromethane (5 mL) was added to the resulting residue, concentration was performed again, and this process was repeated once. The resulting yellow solid was directly used for the next step.

Step 4: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0169] A solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) was added dropwise to a solution of 2-((S)-4-(8-fluoro-7-(isochroman-5-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.06 mL, 0.42 mmol) in dichloromethane (2 mL) at room temperature. The reaction liquid was stirred at room temperature for 15 min. Dichloromethane (20 mL) and a saturated sodium carbonate aqueous solution (20 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation to obtain a viscous material. Purification by prep-TLC (methanol:dichloromethane=1:9) gave a white solid (3 mg, 0.0052 mmol, overall yield over two steps: 20%). MS m/z: 572.7 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) ? 9.11 (s, 1H), 7.34-7.32 (m, 2H), 7.13 (d, J=4.0 Hz, 1H), 6.66-6.56 (m, 1H), 6.42 (d, J=16 Hz, 1H), 5.86 (d, J=12 Hz, 1H), 5.10-4.98 (m, 2H), 4.89 (s, 2H), 4.56-4.40 (m, 3H), 4.10-4.14 (m, 1H), 3.94 (t, J=8.0 Hz, 2H), 3.85-3.81 (m, 1H), 3.72-3.25 (m, 2H), 3.06-3.00 (m, 1H), 2.80-2.52 (m, 7H), 2.32-1.98 (m, 3H), 1.80-1.55 (m, 3H).

Example 51: Synthesis of 2-((S)-1-acryloyl-4-(7-(benzo[b]thien-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0170] ##STR00542##

Step 1: Synthesis of 2-(benzothien-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane

[0171] 7-bromobenzo[b]thiophene (150 mg, 0.7 mmol), bis(pinacolato)diboron (533 mg, 2.1 mmol), Pd(dppf)Cl.sub.2 (102 mg, 0.14 mmol) and potassium acetate (206 mg, 2.1 mmol) were added to a round-bottomed flask. After displacement with nitrogen, anhydrous 1,4-dioxane (5 mL) which had been deoxidized in advance was added. The resulting suspension was stirred at 100? C. for 16 h. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After layering, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=1:40) to obtain a colorless viscous material. (160 mg, 0.615 mmol, yield: 99%)

Step 2: Synthesis of tert-butyl (S)-4-(7-(benzothien-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0172] Tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (26 mg, 0.05 mmol), 2-(benzothien-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane (26 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cesium carbonate (29 mg, 0.15 mmol) were added to a round-bottomed flask. After displacement with nitrogen, 1,4-dioxane (2 mL) and water (0.4 mL) which had been deoxidized in advance was added. The reaction liquid was stirred at 100? C. for 3 h. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and layering, the aqueous phase was extracted with ethyl acetate (10 mL?2). The combined organic phases were washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining brown viscous material was purified by prep-TLC (silica gel, methanol:dichloromethane=1:9) to obtain a light yellow solid. (16 mg, 0.0259 mmol, yield: 52%) MS m/z: 618.7 [M+H].sup.+.

Step 3: Synthesis of 2-((S)-4-(7-(benzo[b]thien-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0173] Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (S)-4-(7-(benzothien-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (16 mg, 0.0259 mmol) in dichloromethane (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. Dichloromethane (10 mL) was added and concentration in vacuo was performed. Dichloromethane (5 mL) was added to the resulting residue, concentration was performed again, and this process was repeated once. The resulting yellow solid was directly used for the next step.

Step 4: Synthesis of 2-((S)-1-acryloyl-4-(7-(benzo[b]thien-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0174] A solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) was added dropwise to a solution of 2-((S)-4-(7-(benzo[b]thien-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.06 mL, 0.42 mmol) in dichloromethane (2 mL) at room temperature. The reaction liquid was stirred at room temperature for 15 min. Dichloromethane (20 mL) and a saturated sodium carbonate aqueous solution (20 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation to obtain a viscous material. Purification by prep-TLC (methanol:dichloromethane=1:8) gave a light yellow powder (10 mg, 0.0175 mmol, overall yield over two steps: 67%). MS m/z: 572.6 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) ? 9.24 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.45 (d, J=4.0 Hz, 1H), 6.66-6.56 (m, 1H), 6.40 (d, J=16 Hz, 1H), 5.86 (d, J=12 Hz, 1H), 5.10-4.98 (m, 2H), 4.67-4.65 (m, 1H), 4.57-4.49 (m, 2H), 4.10-4.14 (m, 1H), 3.89-3.85 (m, 1H), 3.70-3.30 (m, 2H), 2.86 (s, 3H), 2.75-2.65 (m, 1H), 2.32-1.70 (m, 8H).

Example 52: Synthesis of 2-((2S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0175] ##STR00543##

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

[0176] 2-Bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene (180 mg, 0.86 mmol), bis(pinacolato)diboron (655 mg, 2.58 mmol), Pd(dppf)Cl.sub.2 (126 mg, 0.172 mmol) and potassium acetate (253 mg, 2.58 mmol) were added to a round-bottomed flask. After displacement with nitrogen, anhydrous 1,4-dioxane (6 mL) which had been deoxidized in advance was added. The resulting suspension was stirred at 100? C. for 16 h. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After layering, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=1:40) to obtain a colorless viscous material. (101 mg, 0.395 mmol, yield: 46%)

Step 2: Synthesis of tert-butyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0177] Tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (30 mg, 0.058 mmol), 4,4,5,5-tetramethyl-2-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)-1,3,2-dioxolane (26 mg, 0.104 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol) and cesium carbonate (57 mg, 0.174 mmol) were added to a round-bottomed flask. After displacement with nitrogen, 1,4-dioxane (2 mL) and water (0.4 mL) which had been deoxidized in advance was added. The reaction liquid was stirred at 100? C. for 3 h. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and layering, the aqueous phase was extracted with ethyl acetate (10 mL?2). The combined organic phases were washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining brown viscous material was purified by prep-TLC (silica gel, methanol:dichloromethane=1:9) to obtain a light yellow solid. (15 mg, 0.0244 mmol, yield: 42%) MS m/z: 614.7 [M+H].sup.+.

Step 3: Synthesis of 2-((2S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0178] Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (15 mg, 0.0244 mmol) in dichloromethane (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. Dichloromethane (10 mL) was added and concentration in vacuo was performed. Dichloromethane (5 mL) was added to the resulting residue, concentration was performed again, and this process was repeated once. The resulting yellow solid was directly used for the next step.

Step 4: Synthesis of 2-((2S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0179] A solution of acryloyl chloride (0.005 mL, 0.061 mmol) in dichloromethane (1 mL) was added dropwise to a solution of 2-((2S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (2 mL) at room temperature. The reaction liquid was stirred at room temperature for 15 min. Dichloromethane (20 mL) and a saturated sodium carbonate aqueous solution (20 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation to obtain a viscous material. Purification by prep-TLC (methanol:dichloromethane=1:8) gave a light yellow powder (10 mg, 0.0176 mmol, overall yield over two steps: 72%). MS m/z: 568.6 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) ? 9.09 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.37-7.35 (m, 2H), 6.66-6.56 (m, 1H), 6.42 (d, J=16 Hz, 1H), 5.86 (d, J=12 Hz, 1H), 5.04-4.98 (m, 2H), 4.61-4.45 (m, 3H), 4.11-4.07 (m, 1H), 3.81-3.76 (m, 1H), 3.60-3.38 (m, 1H), 3.34-3.24 (m, 2H), 3.06-2.97 (m, 2H), 2.83 (s, 3H), 2.75-2.70 (m, 1H), 2.48-2.44 (m, 1H), 2.32-1.80 (m, 8H), 1.10-1.04 (m, 1H), 0.15-0.11 (m, 1H).

[0180] The compounds of Examples 53-72 were prepared b preparation method 1

TABLE-US-00002 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 53 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(thiochroman-8-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00544] 606.6 54 2-((S)-1-acryloyl-4-(8-fluoro-7-(5- fluorothiochroman-8-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00545] 606.6 55 2-((2S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00546] 586.7 56 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-((1aS,6aS)- 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00547] 568.7 57 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00548] 586.7 58 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-((1aR,6aR)- 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00549] 568.7 59 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-((1aR,6aR)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00550] 586.7 60 2-((2S)-1-acryloyl-4-(8-fluoro-7-(2-methyl-2,3- dihydro-1H-inden-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00551] 570.3 61 2-((2S)-1-acryloyl-4-(8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00552] 594.3 62 2-((2S)-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00553] 612.3 63 2-((S)-1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-((1aS,6aS)- 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00554] 594.3 64 2-((S)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00555] 612.3 65 2-((S)-1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H-yl)methoxy)-7-((1aR,6aR)- 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00556] 594.3 66 2-((S)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-((1aR,6aR)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00557] 612.3 67 2-(((2S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]indan-2- yl)pyridinyl[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00558] 612.3 68 2-((2S)-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]indan-2- yl)pyridinyl[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00559] 630.3 69 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]indan-2- yl)pyridinyl[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00560] 612.3 70 2-((S)-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]indan-2- yl)pyridinyl[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00561] 630.3 71 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(((1aR,6aR)-1,1a,6,6a- tetrahydrocyclopropa[a]indan-2- yl)pyridinyl[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00562] 612.3 72 2-((S)-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)-7-((1aR,6aR)-1,1a,6,6a- tetrahydrocyclopropa[a]indan-2- yl)pyridinyl[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00563] 630.3

Example 73: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0181] ##STR00564##

Step 1: Synthesis of tert-butyl (S)-4-(7-bromo-2-chloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0182] The compound 7-bromo-2,4-dichloroquinazoline (200 mg, 0.72 mmol) was dissolved in DMF (5 mL), and DIEA (465 mg, 3.60 mmol) and (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (142 mg, 0.72 mmol) were then added and reacted at room temperature under stirring for 30 min. Di-tert butyl dicarbonate (472 mg, 2.16 mmol) was then added, and the mixture was heated to 60? C. and reacted under stirring for 16 h. After the reaction was complete, the reaction liquid was diluted by adding 20 mL of cold water under stirring 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. (200 mg, yield: 60%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.06 (d, J=1.9 Hz, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.60 (dd, J=8.9, 1.9 Hz, 1H), 4.68 (s, 1H), 4.37 (d, J=13.3 Hz, 1H), 4.27 (d, J=11.7 Hz, 1H), 4.15 (d, J=7.1 Hz, 1H), 3.71 (dd, J=13.6, 3.7 Hz, 1H), 3.59-3.48 (m, 1H), 3.42 (s, 1H), 2.87 (s, 1H), 2.75 (s, 1H), 1.54 (s, 9H).

Step 2: Synthesis of tert-butyl (S)-4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0183] The compound (S)-(1-methylpyrrolidin-2-yl)methanol (149 mg, 1.29 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), 60% NaH (52 mg, 1.29 mmol) was added under ice-water bath cooling condition and reacted at room temperature under stirring for 20 min, and tert-butyl (S)-4-(7-bromo-2-chloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.43 mmol) was added and reacted at room temperature under stirring for 1 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. (200 mg, yield: 85%)

Step 3: Synthesis of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-cyanomethyl)piperazine-1-carboxylate

[0184] The compound tert-butyl (S)-4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (30 mg, 0.06 mmol) and 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (19 mg, 0.07) were dissolved in dioxane/water=5/1 (3 mL), cesium carbonate (54 mg, 0.17 mmol) and Pd(PPh.sub.3).sub.4 (30 mg, 0.03 mmol) were then added, and after displacement with nitrogen, the mixture was heated to 90? C. and reacted under stirring for 1 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 TLC to obtain an off-white solid. (28 mg, yield: 80%).

[0185] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.96 (dd, J=8.2, 1.1 Hz, 1H), 7.90 (dd, J=8.1, 1.1 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.75 (t, J=1.7 Hz, 1H), 7.60-7.52 (m, 2H), 7.45 (dd, J=5.6, 2.7 Hz, 1H), 7.33 (dd, J=8.5, 1.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 4.86 (d, J=5.8 Hz, 1H), 4.71 (s, 1H), 4.57 (d, J=11.5 Hz, 1H), 4.47-4.25 (m, 2H), 4.15 (s, 1H), 3.64-3.22 (m, 4H), 3.01-2.55 (m, 6H), 2.25 (d, J=6.3 Hz, 1H), 2.18-1.89 (m, 3H), 1.54 (s, 9H).

Step 4: Synthesis of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0186] The compound tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-cyanomethyl)piperazine-1-carboxylate (28 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated, then dissolved in dichloromethane, adjusted to pH 8-9 with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a crude product, which was directly used for the next step. (23 mg, yield: 100%).

Step 5: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0187] The compound 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (23 mg, 0.04 mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (8 mg, 0.06 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 5 min. After the reaction was complete, the reaction was quenched with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by TLC to obtain an off-white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.96-7.74 (m, 4H), 7.54 (d, J=7.1 Hz, 2H), 7.43 (d, J=4.9 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 6.70-6.61 (m, 1H), 6.49-6.32 (m, 1H), 5.84 (d, J=10.5 Hz, 1H), 5.42-5.34 (m, 1H), 5.13-5.06 (m, 1H), 4.71-4.67 (m, 1H), 4.55-4.31 (m, 2H), 3.89-3.43 (m, 4H), 3.10-2.88 (m, 6H), 2.33 (s, 2H), 2.21-1.96 (m, 4H). MS m/z: 581.58 [M+H].sup.+

Example 74: Synthesis of 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2-ylacetonitrile

[0188] ##STR00565##

Step 1: Synthesis of compound 2-amino-3-fluoro-4-bromobenzamide

[0189] The compound 2-amino-3-fluoro-4-bromobenzoic acid (5.0 g, 20 mmol) was dissolved in 50 ml of DMF, stirred and dissolved, TBTU (16.0 g, 50 mmol), NH.sub.4Cl (27.0 g, 50 mmol), and DIEA (14 ml, 80 mmol) were added in one portion at room temperature, and the reaction system was stirred at room temperature for 3 h. After the reaction was complete, about 300 ml of water was added to the reaction system, and a large amount of solid was precipitated. When no more solid was precipitated, suction filtration gave a light yellow solid, which was directly used for the next step. (3.7 g, yield: 74%). .sup.1H NMR (400 MHz, DMSO) ? 7.92 (s, 2H), 7.66 (s, 1H), 6.94 (s, 1H), 6.25 (s, 2H).

Step 2: Synthesis of Compound 7-bromo-8-fluoroquinazolin-2,4-diol

[0190] The compound 2-amino-4-bromo-5-chlorobenzamide (3.6 g, 14.4 mmol) was dissolved in 40 ml of DMF, stirred and dissolved, CDI (9.3 g, 57.7 mmol) and K.sub.2CO.sub.3 (8.0 g, 50 mmol) were added then dropwise in one portion at room temperature, and the reaction system was heated to 80? C. and stirred overnight. After the reaction was complete, about 300 ml of water was added to the reaction system, and a large amount of solid was precipitated. When no more solid was precipitated, suction filtration gave a light yellow solid, which was directly used for the next step. (3.9 g, yield: 90%). .sup.1H NMR (400 MHz, DMSO) ? 11.34 (s, 1H), 11.40 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H).

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

[0191] The compound 7-bromo-6-chloroquinazolin-2,4-diol (3.9 g, 14 mmol) was dissolved in 50 ml of POCl.sub.3, and about 5 ml of N,N-diethylaniline was added at room temperature. The reaction system was heated to 110? C. and stirred overnight. After the reaction was complete, the reaction system was placed under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated by column chromatography (petroleum ether) to obtain a yellow solid. (2.62 g, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.12 (s, 1H), 7.93 (s, 1H).

Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0192] The compound 7-bromo-2,4,6-trichloroquinazoline (312 mg, 1 mmol) and DIEA (0.6 ml, 3.5 mmol) were dissolved in 10 ml of DMF, and 2-cyanopiperazine (198 mg, 1 mmol) was added in portions under ice-water bath condition. The reaction was stirred and returned to room temperature, the reaction was monitored complete by TLC, and Boc.sub.2O (0.6 ml, 2.5 mmol) was then added, and the reaction was stirred at room temperature for 2 h; and after the reaction was complete, about 70 ml of a saturated sodium chloride solution was added to the reaction system, and extraction was performed with ethyl acetate for separation. After the organic phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a light yellow solid which was directly used for the next reaction. (450 mg, yield 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.14 (s, 1H), 7.95 (s, 1H), 3.5 (m, 1H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.73 (m, 1H), 2.48 (m, 1H), 1.42 (s, 9H).

Step 5: Synthesis of tert-butyl (S)-4-(7-bromo-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0193] (S)-(1-methylpyrrolidin-2-yl)methanol (173 mg, 1.5 mmol) was dissolved in ultradry THF (15 mL), 60% sodium hydride (36 mg, 1.5 mmol) was added under ice-water bath condition and stirred 30 min, the compound tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (250 mg, 0.5 mmol) was then added, and the reaction system was stirred at room temperature for one hour. After the reaction was complete, water was added to the reaction system to quench the reaction, ethyl acetate was used for extraction and separation, and the organic phase was then dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain a light yellow solid. (133 mg, yield: 50%).

Step 6: Synthesis of tert-butyl (S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid

[0194] The compound tert-butyl (S)-4-(7-bromo-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (43 mg, 0.17 mmol) and Cs.sub.2CO.sub.3 (72 mg, 0.22 mmol) were dissolved in a hybrid solvent of 1,4-dioxane and water (4 ml/1 ml), and after displacement with nitrogen, a Pd(PPh.sub.3).sub.4 catalyst (13 mg, 0.01 mmol) was added. The reaction system was stirred at 90? C. for 1 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 column chromatography to obtain a light yellow solid (50 mg, yield: 80%).

Step 7: Synthesis of 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2-ylacetonitrile

[0195] The compound tert-butyl (S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid (31 mg, 0.1 mmol) was dissolved in a hybrid solvent of DCM and CF.sub.3COOH (3 ml/1 ml) and stirred at room temperature for 1 h; after the reaction was complete, the organic solvent was removed from the reaction system under reduced pressure, dichloromethane was added for dissolution, the system was then spin-dried again, and the same operation was repeated again. The resulting crude product, which was directly used for the next reaction, was dissolved in 3 ml of ultradry dichloromethane, triethylamine (0.1 ml, 0.5 mmol) and acryloyl chloride (0.05 ml, 0.2 mmol) were added, and the reaction system was stirred at room temperature for 1 h. After the reaction was complete, the reaction system was spin-dried, ethyl acetate was added for dissolution, the organic phase was neutralized with a saturated sodium carbonate solution, extracted and separated, the organic phase was then dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was separated by PLC to obtain an off-white solid. (10 mg, yield: 34%).sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.29 (s, 1H), 8.23 (s, 1H), 7.27 (m, 1H), 7.21 (m, 1H), 7.02 (m, 1H), 6.62 (m, 1H), 6.04 (m, 1H), 5.58 (m, 1H), 3.65-3.40 (m, 3H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.85 (m, 1H), 2.75-2.70 (m, 5H), 2.50-2.30 (m, 3H), 2.26 (s, 3H), 1.74-1.41 (m, 8H). MS m/z: 585.27 [M+H].sup.+

Example 75: Synthesis of 2-((S)-1-acryloyl-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0196] ##STR00566##

Step 1: Synthesis of compound 2-amino-4-bromo-5-chlorobenzamide

[0197] The compound 2-amino-4-bromo-5-chlorobenzoic acid (5.0 g, 20 mmol) was dissolved in 50 ml of DMF, stirred and dissolved, TBTU (16.0 g, 50 mmol), NH.sub.4Cl (27.0 g, 50 mmol), and DIEA (14 ml, 80 mmol) were added in one portion at room temperature, and the reaction system was stirred at room temperature for 3 h. After the reaction was complete, about 300 ml of water was added to the reaction system, and a large amount of solid was precipitated. When no more solid was precipitated, suction filtration gave a light yellow solid, which was directly used for the next step. (3.6 g, yield: 72%). .sup.1H NMR (400 MHz, DMSO) ? 7.90 (s, 2H), 7.68 (s, 1H), 6.96 (s, 1H), 6.27 (s, 2H).

Step 2: Synthesis of Compound 7-bromo-6-chloroquinazolin-2,4-diol

[0198] The compound 2-amino-4-bromo-5-chlorobenzamide (3.6 g, 14.4 mmol) was dissolved in 40 ml of DMF, stirred and dissolved, CDI (9.3 g, 57.7 mmol) and K.sub.2CO.sub.3 (8.0 g, 50 mmol) were added then dropwise in one portion at room temperature, and the reaction system was heated to 80? C. and stirred overnight. After the reaction was complete, about 300 ml of water was added to the reaction system, and a large amount of solid was precipitated. When no more solid was precipitated, suction filtration gave a light yellow solid, which was directly used for the next step. (3.9 g, yield: 90%). .sup.1H NMR (400 MHz, DMSO) ? 11.34 (s, 1H), 11.40 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H).

Step 3: Synthesis of Compound 7-bromo-2,4,6-trichloroquinazoline

[0199] The compound 7-bromo-6-chloroquinazolin-2,4-diol (3.9 g, 14 mmol) was dissolved in 50 ml of POCl.sub.3, and about 5 ml of N,N-diethylaniline was added at room temperature. The reaction system was heated to 110? C. and stirred overnight. After the reaction was complete, the reaction system was placed under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated by column chromatography (petroleum ether) to obtain a yellow solid. (2.62 g, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.12 (s, 1H), 7.93 (s, 1H).

Step 4: Synthesis of Compound tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0200] The compound 7-bromo-2,4,6-trichloroquinazoline (312 mg, 1 mmol) and DIEA (0.6 ml, 3.5 mmol) were dissolved in 10 ml of DMF, and 2-cyanopiperazine (198 mg, 1 mmol) was added in portions under ice-water bath condition. The reaction was stirred and returned to room temperature, the reaction was monitored complete by TLC, and Boc.sub.2O (0.6 ml, 2.5 mmol) was then added, and the reaction was stirred at room temperature for 2 h; and after the reaction was complete, about 70 ml of a saturated sodium chloride solution was added to the reaction system, and extraction was performed with ethyl acetate for separation. After the organic phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a light yellow solid which was directly used for the next reaction. (450 mg, yield 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.14 (s, 1H), 7.95 (s, 1H), 3.5 (m, 1H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.73 (m, 1H), 2.48 (m, 1H), 1.42 (s, 9H).

Step 5: Synthesis of tert-butyl (S)-4-(7-bromo-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0201] (S)-(1-methylpyrrolidin-2-yl)methanol (173 mg, 1.5 mmol) was dissolved in ultradry THF (15 mL), 60% sodium hydride (36 mg, 1.5 mmol) was added under ice-water bath condition and stirred 30 min, the compound tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (250 mg, 0.5 mmol) was then added, and the reaction system was stirred at room temperature for one hour. After the reaction was complete, water was added to the reaction system to quench the reaction, ethyl acetate was used for extraction and separation, and the organic phase was then dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain a light yellow solid. (150 mg, yield: 52%).

Step 6: Synthesis of tert-butyl (S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid

[0202] The compound tert-butyl (S)-4-(7-bromo-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (43 mg, 0.17 mmol) and Cs.sub.2CO.sub.3 (72 mg, 0.22 mmol) were dissolved in a hybrid solvent of 1,4-dioxane and water (4 ml/1 ml), and after displacement with nitrogen, a Pd(PPh.sub.3).sub.4 catalyst (13 mg, 0.01 mmol) was added. The reaction system was stirred at 90? C. for 1 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 column chromatography to obtain a light yellow solid (62 mg, yield: 89%).

Step 7: Synthesis of 2-((S)-1-acryloyl-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0203] The compound tert-butyl (S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid (62 mg, 0.1 mmol) was dissolved in a hybrid solvent of DCM and CF.sub.3COOH (3 ml/1 ml) and stirred at room temperature for 1 h; after the reaction was complete, the organic solvent was removed from the reaction system under reduced pressure, dichloromethane was added for dissolution, the system was then spin-dried again, and the same operation was repeated again. The resulting crude product, which was directly used for the next reaction, was dissolved in 3 ml of ultradry dichloromethane, triethylamine (0.1 ml, 0.5 mmol) and acryloyl chloride (0.05 ml, 0.2 mmol) were added, and the reaction system was stirred at room temperature for 1 h. After the reaction was complete, the reaction system was spin-dried, ethyl acetate was added for dissolution, the organic phase was neutralized with a saturated sodium carbonate solution, extracted and separated, the organic phase was then dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was separated by PLC to obtain an off-white solid. (20 mg, yield: 34%).sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.29 (s, 1H), 8.23 (s, 1H), 7.27 (m, 1H), 7.21 (m, 1H), 7.02 (m, 1H), 6.62 (m, 1H), 6.04 (m, 1H), 5.58 (m, 1H), 3.65-3.40 (m, 3H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.85 (m, 1H), 2.75-2.70 (m, 5H), 2.50-2.30 (m, 3H), 2.26 (s, 3H), 1.74-1.41 (m, 8H). MS m/z: 585.27 [M+H].sup.+

Example 76: Synthesis of 1-(4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0204] ##STR00567##

Step 1: Synthesis of tert-butyl 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0205] The compound tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (56 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (43 mg, 0.17 mmol) and Cs2CO3 (72 mg, 0.22 mmol) was dissolved in a hybrid solvent of 1,4-dioxane and water (4 ml/1 ml), and after displacement with nitrogen, a Pd(PPh3)4 catalyst (13 mg, 0.01 mmol) was added. The reaction system was stirred at 90? C. for 1 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 column chromatography to obtain a light yellow solid (33 mg, yield: 50%).

Step 2: Synthesis of 1-(4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0206] The compound tert-butyl 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate (33 mg, 0.05 mmol) was dissolved in a hybrid solvent of DCM and CF3COOH (3 ml/1 ml) and stirred at room temperature for 1 h; after the reaction was complete, the organic solvent was removed from the reaction system under reduced pressure, dichloromethane was added for dissolution, the system was then spin-dried again, and the same operation was repeated again. The resulting crude product, which was directly used for the next reaction, was dissolved in 3 ml of ultradry dichloromethane, triethylamine (0.1 ml, 0.5 mmol) and acryloyl chloride (0.05 ml, 0.2 mmol) were added, and the reaction system was stirred at room temperature for 1 h. After the reaction was complete, the reaction system was spin-dried, ethyl acetate was added for dissolution, the organic phase was neutralized with a saturated sodium carbonate solution, extracted and separated, the organic phase was then dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was separated by PLC to obtain an off-white solid. (8 mg, yield: 28%) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.00 (s, 1H), 7.27 (m, 1H), 7.11 (m, 1H), 7.02 (m, 1H), 6.62 (m, 1H), 6.04 (m, 1H), 5.58 (m, 1H), 3.65-3.40 (m, 2H), 3.38-3.13 (m, 4H), 2.85 (m, 1H), 2.75-2.70 (m, 5H), 2.50-2.30 (m, 3H), 2.26 (s, 3H), 1.74-1.41 (m, 8H). MS m/z: 585.27 [M+H]+

Example 77: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0207] ##STR00568##

Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2,7-dichloropyridino[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0208] The compound 2,4,7-trichloropyridino[2,3-d]pyrimidine (200 mg, 0.85 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (552 mg, 4.27 mmol) and (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (169 mg, 0.85 mmol) were added under ice-water bath cooling condition, the mixture was reacted under stirring and ice-water bath cooling conditions for 10 min, di-tert butyl dicarbonate (372 g, 1.70 mmol) was then added, and the mixture was heated to 40? C. and reacted under stirring for 3 h. After the reaction was complete, the reaction product was cooled to room temperature, the reaction liquid was diluted by adding a saturated aqueous NaCl solution 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 light yellow solid. (335 mg, yield: 93%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.18 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 4.65 (s, 1H), 4.47 (dd, J=13.9, 3.0 Hz, 1H), 4.30 (d, J=12.0 Hz, 1H), 4.12 (d, J=7.1 Hz, 1H), 3.82 (d, J=12.2 Hz, 1H), 3.69 (s, 1H), 3.54 (s, 1H), 3.02-2.87 (m, 1H), 2.80 (d, J=13.8 Hz, 1H), 1.52 (s, 9H).

Step 2: Synthesis of tert-butyl (S)-4-(7-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0209] The compound tert-butyl (S)-2-(cyanomethyl)-4-(2,7-dichloropyridino[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.24 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (82 mg, 0.71 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), DIEA (92 mg, 0.71 mmol) was added, and the mixture was heated to 80? C. and reacted under stirring for 16 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, separated and purified by TLC to obtain an off-white solid. (70 mg, yield: 59%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.14 (d, J=8.6 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 5.04 (s, 1H), 4.82 (s, 1H), 4.61 (s, 1H), 4.45 (d, J=13.9 Hz, 1H), 4.21 (d, J=12.6 Hz, 1H), 4.07 (s, 1H), 3.73 (d, J=10.6 Hz, 2H), 3.64-3.47 (m, 2H), 3.45-3.25 (m, 2H), 2.95 (s, 3H), 2.86-2.61 (m, 3H), 2.28 (s, 2H), 2.10 (d, J=21.3 Hz, 2H), 1.51 (s, 9H).

Step 3: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0210] The compound tert-butyl (S)-4-(7-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (30 mg, 0.06 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (19 mg, 0.07 mmol) were dissolved in 1,4-dioxane/water=5/1 (3 mL), cesium carbonate (59 mg, 0.18 mmol) and Pd(PPh.sub.3).sub.4 (35 mg, 0.03 mmol) were added, and after displacement with nitrogen, the mixture was heated to 95? C. in a nitrogen atmosphere and reacted under stirring for 1 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 TLC to obtain an off-white solid. (27 mg, yield: 75%). MS m/z: 598.84 [M+H].sup.+.

Step 4: Synthesis of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0211] The compound tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (27 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated, a saturated sodium carbonate aqueous solution and dichloromethane were added, the mixture was extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a crude product, which was directly used for the next step.

Step 5: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0212] The compound 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (22 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL), and DIEA (8 mg, 0.06 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added under ice-water bath cooling condition and reacted under stirring and ice-water bath cooling conditions for 5 m. After the reaction was complete, the reaction was quenched by adding saturated sodium carbonate and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (18 mg, yield: 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.24 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.22-7.16 (m, 3H), 6.59 (s, 1H), 6.41 (d, J=16.3 Hz, 1H), 5.84 (d, J=11.7 Hz, 1H), 5.02 (s, 2H), 4.84 (d, J=11.2 Hz, 1H), 4.47 (d, J=14.0 Hz, 1H), 4.37-4.34 (m, 1H), 3.84 (d, J=10.3 Hz, 1H), 3.77-3.49 (m, 4H), 3.08 (ddd, J=16.9, 11.4, 7.7 Hz, 2H), 2.97 (s, 3H), 2.89-2.73 (m, 6H), 2.42-2.17 (m, 4H), 2.09-2.03 (m, 4H). MS m/z: 552.64 [M+H].sup.+.

[0213] The compounds of Examples 78-614 were prepared by preparation method 2

TABLE-US-00003 Ex. Compound name Structural formula m/z: ES.sup.+ [M + H] 78 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00569] 599.2 79 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl]methoxy))quinazolin-4-yl)piperazin-2-yl)acetonitrile [00570] 599.2 80 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-2-yl)methoxy)quinazolin- 4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00571] 617.2 81 (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl piperazin-2-yl)acetonitrile [00572] 607 82 (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00573] 625.2 83 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- (((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00574] 625.2 84 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00575] 643.2 85 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00576] 554.2 86 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00577] 572.2 87 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00578] 572.2 88 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00579] 590.2 89 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00580] 580.2 90 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00581] 598.2 91 1-(((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00582] 598.2 92 1-(((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00583] 616.2 93 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00584] 599.2 94 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00585] 617.2 95 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00586] 617.2 96 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00587] 635 97 (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00588] 625.2 98 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00589] 643 99 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00590] 643 100 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00591] 661 101 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00592] 572.2 102 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2- en-1-one [00593] 590.2 103 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00594] 590.2 104 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00595] 608.2 105 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00596] 598.23 106 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00597] 616.2 107 1-(((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H]- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00598] 616.2 108 1-(((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H]- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00599] 634.2 109 (S)-2-(1-acryloyl-4-(2-((2-methyl-1,2,3,4- tetrahydroisoquinolin-5-yl)oxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00600] 599.6 110 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00601] 551.3 111 2-((S)-1-(2-fluoroacryloyl)-4-(2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00602] 569.3 112 2-((S)-1-acryloyl-4-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00603] 569.3 113 2-((S)-4-(2-(((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1)- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00604] 587 114 (S)-2-(1-acryloyl-4-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00605] 577.3 115 (S)-2-(1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00606] 595.3 116 2-((2S)-1-acryloyl-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-ylquinazolin-4- ylpiperazin-2-ylacetonitrile [00607] 595.3 117 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00608] 613.3 118 1-((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7]-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00609] 524.3 119 2-fluoro-1-(((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7]-(5,6,7,8-tetrahydronaphthalen-1)- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00610] 542.3 120 1-((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00611] 542.4 121 2-fluoro-1-(((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7)((5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00612] 560 122 1-(1R,5R)-6-(2-(tetrahydro-1H-pyrolizin-7a(5H)- yl)methoxy)-7)((5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00613] 550 123 2-fluoro-1-(((1R,5R)-6-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy))-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00614] 568 124 1-(((1R,5R)-6-(2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)- 7)((tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00615] 568 125 2-fluoro-1-(((1R,5R)-6-(2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00616] 586 126 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl]) piperazin-2-yl)acetonitrile [00617] 582.2 127 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00618] 600.2 128 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy))quinazolin-4-yl)piperazin-2-yl)acetonitrile [00619] 600 129 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2--2-yl)methoxy)quinazolin- 4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00620] 618 130 (S)-2-(1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00621] 608 131 (S)-2-(4-(7-(5-chloroisoquinolin-4-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00622] 626 132 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00623] 626 133 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-2-(((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00624] 644 134 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl]-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00625] 555 135 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl]-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00626] 572 136 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00627] 573 137 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00628] 591 138 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00629] 581 139 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00630] 599 140 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00631] 599 141 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00632] 617 142 2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00633] 552 143 2-((S)-1-(2-fluoroacryloyl)-4-(2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)quinazolin-4-yl)piperazin- 2-yl)acetonitrile [00634] 570 144 2-((S)-1-acryloyl-4-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00635] 570 145 2-((S)-4-(2-(((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy))-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00636] 588 146 (S)-2-(1-acryloyl-4-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00637] 578 147 (S)-2-(1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00638] 596 148 2-((2S)-1-acryloyl-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy)- 7)-(5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4- ylpiperazin-2-yl)acetonitrile [00639] 596 149 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00640] 614 150 1-((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7)-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00641] 525 151 2-fluoro-1-(((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy]-7)-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00642] 543 152 1-(((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7)((5,6,7,8- tetrahydroisoquinoline-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00643] 543 153 2-fluoro-1-(((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7)((5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00644] 561 154 1-((1R,5R)-6-(2-(((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00645] 551 155 2-fluoro-1-(((1R,5R)-6-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy))-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00646] 569 156 1-(((1R,5R)-6-(2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00647] 569.3 157 2-fluoro-1-(((1R,5R)-6-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00648] 587 158 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-8- fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00649] 600.2 159 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-8-fluoro-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00650] 618.2 160 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-8- fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- (yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00651] 618.2 161 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-8-fluoro-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00652] 636.2 162 (S)-2-(1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00653] 626.2 163 (S)-2-(4-(7-(5-chloroisoquinolin-4-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00654] 644 164 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-8- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H))-yl)methoxy)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00655] 644 165 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-8-fluoro-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00656] 662 166 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00657] 573 167 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2- en-1-one [00658] 591.2 168 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8-fluoro- 2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00659] 591 169 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8-fluoro- 2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00660] 609 170 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8)-fluoro- 2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00661] 599 171 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8)-fluoro- 2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00662] 617 172 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8)-fluoro- 2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00663] 617 173 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-8)-fluoro- 2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00664] 635 174 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)quinazolin-4-yl)piperazin- 2-yl)acetonitrile [00665] 570 175 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl))quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00666] 588 176 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00667] 588 177 2-((S)-4-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00668] 606 178 (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00669] 596 179 (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00670] 614 180 2-((2S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00671] 614 181 2-((2S)-4-(8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00672] 632.4 182 1-((1R,5R)-6-(8-fluoro-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00673] 543.2 183 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00674] 561 184 1-((1R,5R)-6-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00675] 561 185 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00676] 579 186 1-((1R,5R)-6-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00677] 569 187 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy))-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00678] 587 188 1-(((1R,5R)-6-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00679] 587 189 2-fluoro-1-(((1R,5R)-6-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00680] 605 190 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6- fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00681] 600.2 191 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00682] 618.2 192 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6- fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- (yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00683] 618.2 193 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00684] 636.2 194 (S)-2-(1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00685] 626.2 195 (S)-2-(4-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00686] 644.3 196 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H))-yl)methoxy)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00687] 644.3 197 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00688] 662.3 198 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00689] 573.2 199 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2- en-1-one [00690] 591.2 200 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro- 2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00691] 591 201 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro- 2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00692] 609 202 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00693] 599.2 203 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00694] 617.2 204 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro- 2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00695] 617.2 205 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6-fluoro- 2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00696] 635 206 2-((S)-1-acryloyl-4-(6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)quinazolin-4-yl)piperazin- 2-yl)acetonitrile [00697] 570 207 2-((S)-4-(6-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00698] 588 208 2-((S)-1-acryloyl-4-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00699] 588 209 2-((S)-4-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00700] 606 210 (S)-2-(1-acryloyl-4-(6-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00701] 596 211 (S)-2-(4-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00702] 614 212 2-((S)-1-acryloyl-4-(6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00703] 614 213 2-((2S)-4-(6-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00704] 632 214 1-((1R,5R)-6-(6-fluoro-2-((((S)-1-methylpyrrolidin-2- yl]methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00705] 543 215 2-fluoro-1-(((1R,5R)-6-(6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00706] 561 216 1-((1R,5R)-6-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00707] 561 217 2-fluoro-1-(((1R,5R)-6-(6-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00708] 579 218 1-((1R,5R)-6-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00709] 569 219 2-fluoro-1-(((1R,5R)-6-(6-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00710] 587 220 1-(((1R,5R)-6-(6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00711] 587 221 2-fluoro-1-(((1R,5R)-6-(6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00712] 605 222 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00713] 618 223 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00714] 636 224 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidon-2- yl)methoxy)quinazolin-4-ylpiperazin-2-yl)acetonitrile [00715] 636 225 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00716] 654 226 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00717] 644 227 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00718] 662 228 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00719] 662 229 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00720] 680 230 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00721] 591 231 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00722] 609 232 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00723] 609 233 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00724] 627 234 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00725] 617 235 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00726] 635 236 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00727] 635 237 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-6,8- difluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00728] 653 238 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00729] 588 239 2-((2S)-4-(6,8-difluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00730] 606 240 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00731] 606 241 2-((2S)-4-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00732] 624 242 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7)((5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00733] 614 243 2-((2S)-4-(6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00734] 632 244 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00735] 632 245 2-((2S)-4-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [00736] 650 246 1-((1R,5R)-6-(6,8-difluoro-2-(((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00737] 561 247 1-((1R,5R)-6-(6,8-difluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00738] 579 248 1-((1R,5R)-6-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00739] 579 249 1-((1R,5R)-6-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00740] 597 250 1-(((1R,5R)-6-(6,8-difluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy))-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00741] 587 251 1-((1R,5R)-6-(6,8-difluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00742] 605 252 1-(((1R,5R)-6-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00743] 605 253 1-(((1R,5R)-6-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1- one [00744] 623 254 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00745] 582 255 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00746] 600 256 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl]methoxy))pyridino[2,3-d]pyrimidin-4-yl)piperazin- 2-yl)acetonitrile [00747] 600 257 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00748] 618.2 258 (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00749] 608 259 (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00750] 626 260 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- (((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00751] 626 261 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy]pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00752] 644 262 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2--2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00753] 555 263 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2--2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)-2- fluoroprop-2-en-1-one [00754] 573.2 264 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00755] 573.2 265 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00756] 591 266 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00757] 581 267 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00758] 599 268 1-(((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00759] 599 269 1-(((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00760] 617 270 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00761] 600.5 271 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00762] 618 272 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidine-2- acyl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin- 2-yl)acetonitrile [00763] 618 273 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00764] 636 274 (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00765] 626 275 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00766] 644 276 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00767] 644 277 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00768] 662 278 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2--2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00769] 573 279 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)-2- fluoroprop-2-en-1-one [00770] 591 280 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00771] 591 281 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl))methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00772] 609 282 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00773] 599 283 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00774] 617 284 1-(((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00775] 617 285 1-(((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00776] 635 286 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00777] 552 287 2-((S)-1-(2-fluoroacryloyl)-4-(2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00778] 570 288 2-((S)-1-acryloyl-4-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00779] 570 289 2-((S)-4-(2-(((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1)- yl)pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00780] 588 290 (S)-2-(1-acryloyl-4-(2-(((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy))-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00781] 578 291 (S)-2-(1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00782] 596 292 2-((2S)-1-acryloyl-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00783] 596 293 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00784] 614 294 1-(((R), 5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7]-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00785] 525 295 2-fluoro-1-(((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7)-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00786] 543 296 1-((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00787] 543 297 2-fluoro-1-(((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00788] 561 298 1-((1R,5R)-6-(2-(((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7)((5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00789] 551 299 2-fluoro-1-(((1R,5R)-6-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy))-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00790] 569 300 1-(((1R,5R)-6-(2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00791] 569 301 2-fluoro-1-(((1R,5R)-6-(2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00792] 587 302 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00793] 583 303 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00794] 601 304 2-((S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy))pyridino[2,3-d]pyrimidin-4-yl)piperazin- 2-yl)acetonitrile [00795] 601 305 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00796] 619 306 (S)-2-(1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00797] 609 307 (S)-2-(4-(7-(5-chloroisoquinolin-4-yl)-2-(((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [00798] 627 308 2-((2S)-1-acryloyl-4-(7-(5-chloroisoquinolin-4-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00799] 627 309 2-((2S)-4-(7-(5-chloroisoquinolin-4-yl)-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00800] 645 310 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2-(((S)-1- methylpyrrolidin-2--2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00801] 556 311 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2-(((S)-1- methylpyrrolidin-2--2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)-2- fluoroprop-2-en-1-one [00802] 574 312 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00803] 574 313 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00804] 592 314 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00805] 582 315 1-(((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00806] 600 316 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00807] 600 317 1-((1R,5R)-6-(7-(5-chloroisoquinolin-4-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)-2-fluoroprop-2-en-1-one [00808] 618 318 2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00809] 553 319 2-((S)-1-(2-fluoroacryloyl)-4-(2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)pyridino[2,3-d]pyrimidin- 4-yl)piperazin-2-yl)acetonitrile [00810] 571 320 2-((S)-1-acryloyl-4-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00811] 571 321 2-((S)-4-(2-(((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[2,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [00812] 589 322 (S)-2-(1-acryloyl-4-(2-(((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy))-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00813] 579 323 (S)-2-(1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00814] 597 324 2-((2S)-1-acryloyl-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00815] 597 325 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [00816] 615 326 1-((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7)-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00817] 526 327 2-fluoro-1-(((1R,5R)-6-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7)-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00818] 544 328 1-(((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinoline-4-yl)pyridino[2,3-d]pyrimidin- 4-yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00819] 544 329 2-fluoro-1-(((1R,5R)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00820] 562 330 1-((1R,5R)-6-(2-(((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00821] 552 331 2-fluoro-1-(((1R,5R)-6-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy))-7-(5,6,7,8-tetrahydroisoquinolin- 4-yl)pyridinyl[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00822] 570 332 1-(((1R,5R)-6-(2-(((((2R)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00823] 570 333 2-fluoro-1-(((1R,5R)-6-(2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydroisoquinolin-4-yl)pyridino[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00824] 588 334 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-6- fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00825] 600 335 (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-6- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00826] 626 336 1-((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-6-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00827] 555 337 1-(((1R,5R)-6-(7-(8-chloronaphthalen-1-yl)-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00828] 599 338 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-6-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00829] 618 339 (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00830] 644 340 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-6- fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00831] 591 341 1-((1R,5R)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-6- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00832] 617 342 2-((S)-1-acryloyl-4-(6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00833] 570 343 (S)-2-(1-acryloyl-4-(6-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00834] 596 344 1-((1R,5R)-6-(6-fluoro-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7]-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00835] 543 345 1-((1R,5R)-6-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00836] 569 346 2-((S)-1-acryloyl-4-(6-chloro-7-(8-chloronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00837] 582 347 (S)-2-(1-acryloyl-4-(6-chloro-7-(8-chloronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [00838] 642 348 1-((1R,5R)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((S)-1-methylpyrrolidin-2--2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00839] 589 349 1-(((1R,5R)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)- 2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00840] 615 350 2-((S)-1-acryloyl-4-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl))methoxy)pyridino[2,3-d]pyrimidin-4-yl)piperazin- 2-yl)acetonitrile [00841] 634 351 (S)-2-(1-acryloyl-4-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00842] 660 352 1-((1R,5R)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00843] 607 353 1-((1R,5R)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyridino[2,3-d]pyrimidin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00844] 633 354 2-((S)-1-acryloyl-4-(6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00845] 586 355 (S)-2-(1-acryloyl-4-(6-chloro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[2,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [00846] 612 356 1-((1R,5R)-6-(6-chloro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00847] 559 357 1-((1R,5R)-6-(6-chloro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)pyridino[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00848] 585 358 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8- fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00849] 599.23 359 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00850] 617.22 360 2-((S)-1-acryloyl-4-(8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2- ylacetonitrile [00851] 587.29 361 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8- fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- (yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00852] 617.22 362 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-8-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00853] 635.21 363 (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalene)-1-yl)quinazolin-4-ylpiperazin- 2-yl)acetonitrile [00854] 594.31 364 (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00855] 625.24 365 (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1- yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00856] 643.23 366 2-((2S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00857] 613.3 367 2-((2S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H))-yl)methoxy)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00858] 643.23 368 2-((2S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen- 1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00859] 661.22 369 1-((1R,5S)-6-(8-fluoro-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00860] 542.29 370 1-((1R,5S)-6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00861] 572.22 371 1-((1R,5S)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8- fluoro-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00862] 590.21 372 1-((1R,5S)-6-(8-fluoro-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00863] 568.3 373 1-((1R,5S)-6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00864] 598.23 374 1-((1R,5S)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00865] 616.22 375 1-(((1R,5S)-6-(2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy]]-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-8-fluoro-quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00866] 586.29 376 1-(((1R,5S)-6-(8-fluoro-7-(8-chloronaphthalen-1-yl)-8- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00867] 616.22 377 1-(((1R,5S)-6-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00868] 634.21 378 1-((1R,5S)-6-(2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)8-fluoro-quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00869] 560.28 379 1-((1R,5S)-6-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00870] 590.21 380 1-(((1R,5S)-6-(8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00871] 608.2 381 1-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en- 1-one [00872] 544.3 382 1-((S)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00873] 574.23 383 1-((S)-4-(8-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00874] 592.22 384 (S)-1-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2- en-1-one [00875] 570.32 385 (S)-1-(4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00876] 600.25 386 (S)-1-(4-(8-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00877] 618.24 387 1-((3S)-4-(8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00878] 588.31 388 1-((3S)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00879] 617.24 389 1-((3S)-4-(8-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H))-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00880] 635.23 390 1-((S)-4-(8-fluoro--2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00881] 561.29 391 1-((S)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00882] 591.22 392 1-((S)-4-(8-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00883] 609.21 393 2-((S)-1-acryloyl-4-(6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)piperazin-2- yl)acetonitrile [00884] 569.29 394 2-((S)-1-acryloyl-4-(6-fluoro-7-(8-chloronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00885] 616.22 395 2-((S)-1-acryloyl-4-(6-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00886] 634.21 396 2-((S)-1-acryloyl-4-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2- ylacetonitrile [00887] 604.28 397 2-((S)-1-acryloyl-4-(6-fluoro-7-(8-chloronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- (yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00888] 634.21 398 2-((S)-1-acryloyl-4-(6-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- ylpiperazin-2-yl)acetonitrile [00889] 652.2 399 (S)-2-(1-acryloyl-4-(6-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00890] 611.3 400 1-((1R,5S)-6-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)--2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00891] 642.23 401 1-((1R,5S)-6-(6-fluoro-7-(8-chloro-7-fluoronaphthalen- 1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00892] 660.22 402 1-(((1R,5S)-6-(6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy]]- 7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00893] 630.29 403 1-(((1R,5S)-6-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00894] 660.22 404 1-(((1R,5S)-6-(6-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00895] 688.21 405 1-((1R,5S)-6-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00896] 559.28 406 1-(((1R,5S)-6-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00897] 572.22 407 1-(((1R,5S)-6-(6-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00898] 590.21 408 1-((1R,5S)-6-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00899] 568.30 409 1-((1R,5S)-6-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00900] 598.23 410 1-((1R,5S)-6-(6-fluoro-7-(8-chloro-7-fluoronaphthalen- 1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00901] 616.21 411 1-(((1R,5S)-6-(6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy]]- 7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00902] 586.29 412 1-(((1R,5S)-6-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00903] 616.22 413 1-(((1R,5S)-6-(6-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00904] 634.21 414 1-((1R,5S)-6-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00905] 560.28 415 1-((1R,5S)-6-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00906] 590.21 416 1-(((1R,5S)-6-(6-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00907] 608.2 417 1-((S)-4-(6-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en- 1-one [00908] 544.3 418 1-((S)-4-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00909] 574.23 419 1-((S)-4-(6-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00910] 591.22 420 (S)-1-(4-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2- en-1-one [00911] 570.32 421 (S)-1-(4-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00912] 580.25 422 (S)-1-(4-(6-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00913] 618.24 423 1-((3S)-4-(6-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00914] 588.31 424 1-((3S)-4-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00915] 618.24 425 1-((3S)-4-(6-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H))-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00916] 636.23 426 1-((S)-4-(6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00917] 56229 427 1-((S)-4-(6-fluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00918] 592.22 428 1-((S)-4-(6-fluoro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00919] 610.21 429 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00920] 587.29 430 2-((S)-1-acryloyl-4-(6,8-difluoro-7-(8- chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00921] 617.22 431 2-((S)-1-acryloyl-4-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00922] 635.21 432 2-((S)-1-acryloyl-4-(6,8-difluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2- ylacetonitrile [00923] 605.28 433 2-((S)-1-acryloyl-4-(6,8-difluoro-7-(8- chloronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-(yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00924] 635.21 434 2-((S)-1-acryloyl-4-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- ylpiperazin-2-yl)acetonitrile [00925] 653.2 435 (S)-2-(1-acryloyl-4-(6,8-difluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00926] 612.3 436 1-((1R,5S)-6-(6,8-difluoro-7-(8-chloronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00927] 643.23 437 1-((1R,5S)-6-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00928] 661.22 438 1-(((1R,5S)-6-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00929] 631.29 439 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00930] 661.22 440 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00931] 679.21 441 1-((1R,5S)-6-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00932] 560.28 442 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloronaphthalen-1- yl)-2-((((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00933] 590.21 443 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00934] 608.2 444 1-((1R,5S)-6-(6,8-difluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00935] 586.29 445 1-((1R,5S)-6-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00936] 616.22 446 1-((1R,5S)-6-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00937] 634.21 447 1-(((1R,5S)-6-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00938] 604.28 448 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00939] 634.21 449 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00940] 652.2 450 1-((1R,5S)-6-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00941] 578.27 451 1-((1R,5S)-6-(6,8-difluoro-7-(8-chloronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00942] 608.2 452 1-(((1R,5S)-6-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00943] 626.19 453 1-((S)-4-(6,8-difluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en- 1-one [00944] 562.29 454 1-((S)-4-(6,8-difluoro-7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-3-methylpiperazin-1-yl)prop-2-en-1-one [00945] 592.22 455 1-((S)-4-(6,8-difluoro-7-(8-chloro-7-fluoronaphthalen- 1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00946] 610.21 456 (S)-1-(4-(6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2- en-1-one [00947] 588.31 457 (S)-1-(4-(6,8-difluoro-7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00948] 618.24 458 (S)-1-(4-(6,8-difluoro-7-(8-chloro-7-fluoronaphthalen- 1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00949] 652.20 459 1-((3S)-4-(6,8-difluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00950] 606.3 460 1-((3S)-4-(6,8-difluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00951] 636.23 461 1-((3S)-4-(6,8-difluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H))- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00952] 655.22 462 1-((S)-4-(6,8-difluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00953] 580.28 463 1-((S)-4-(6,8-difluoro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00954] 610.21 464 1-((S)-4-(6,8-difluoro-7-(8-chloro-7-fluoronaphthalen- 1-yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00955] 628.2 465 2-((S)-1-acryloyl-4-(6-chloro-7-(8-chloronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00956] 615.20 466 2-((S)-1-acryloyl-4-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00957] 633.19 467 2-((S)-1-acryloyl-4-(6-chloro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2- ylacetonitrile [00958] 603.26 468 2-((S)-1-acryloyl-4-(6-chloro-7-(8-chloronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- (yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00959] 633.19 469 2-((S)-1-acryloyl-4-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- ylpiperazin-2-yl)acetonitrile [00960] 651.18 470 (S)-2-(1-acryloyl-4-(6-chloro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00961] 611.28 471 1-((1R,5S)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00962] 614.20 472 1-((1R,5S)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00963] 632.19 473 1-(((1R,5S)-6-(6-chloro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00964] 602.26 474 1-(((1R,5S)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00965] 632.19 475 1-(((1R,5S)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00966] 650.18 476 1-((1R,5S)-6-(6-chloro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00967] 576.25 477 1-(((1R,5S)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00968] 632.19 478 1-(((1R,5S)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00969] 650.18 479 1-((1R,5S)-6-(6-chloro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-2,6-diazabicyclo[3.2.0]hept-2- yl)prop-2-en-1-one [00970] 575.25 480 1-((1R,5S)-6-(6-chloro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00971] 616.22 481 1-((1R,5S)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00972] 632.20 482 1-(((1R,5S)-6-(6-chloro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00973] 602.26 483 1-(((1R,5S)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00974] 632.19 484 1-(((1R,5S)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00975] 650.18 485 1-((1R,5S)-6-(6-chloro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00976] 576.25 486 1-((1R,5S)-6-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00977] 606.18 487 1-(((1R,5S)-6-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00978] 624.17 488 1-((S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en- 1-one [00979] 560.27 489 1-((S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00980] 590.20 490 1-((S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00981] 608.19 491 (S)-1-(4-(6-chloro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen- 1-yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2- en-1-one [00982] 586.29 492 (S)-1-(4-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00983] 616.22 493 (S)-1-(4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00984] 634.21 494 1-((3S)-4-(6-chloro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00985] 604.28 495 1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00986] 634.21 496 1-((3S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H))-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00987] 652.20 497 1-((S)-4-(6-chloro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [00988] 578.26 498 1-((S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00989] 608.19 499 1-((S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [00990] 626.18 500 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2- ylacetonitrile [00991] 603.26 501 2-((S)-1-acryloyl-4-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00992] 633.19 502 2-((S)-1-acryloyl-4-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl))methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [00993] 651.18 503 2-((S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2- ylacetonitrile [00994] 621.25 504 2-((S)-1-acryloyl-4-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-(yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [00995] 651.18 505 2-((S)-1-acryloyl-4-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- ylpiperazin-2-yl)acetonitrile [00996] 669.17 506 (S)-2-(1-acryloyl-4-(6-chloro-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-ylpiperazin-2- yl)acetonitrile [00997] 628.27 507 1-((1R,5S)-6-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00998] 659.20 508 1-((1R,5S)-6-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [00999] 677.19 509 1-(((1R,5S)-6-(6-chloro-8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01000] 647.26 510 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01001] 677.19 511 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01002] 695.18 512 1-((1R,5S)-6-(6-chloro-8-fluoro-2-((((2S,4R)-4-fluoro- 1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01003] 576.25 513 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01004] 606.18 514 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01005] 624.17 515 1-((1R,5S)-6-(6-chloro-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01006] 602.26 516 1-((1R,5S)-6-(6-chloro-8-fluoro-2-((((2S,4R)-4-fluoro- 1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01007] 632.19 517 1-((1R,5S)-6-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01008] 650.18 518 1-(((1R,5S)-6-(6-chloro-8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-5-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01009] 620.25 519 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01010] 650.18 520 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)- 2,6-diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01011] 668.17 521 1-((1R,5S)-6-(6-chloro-8-fluoro-2-((((2S,4R)-4-fluoro- 1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01012] 594.24 522 1-((1R,5S)-6-(6-chloro-8-fluoro-7-(8- chloronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01013] 624.17 523 1-(((1R,5S)-6-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6- diazabicyclo[3.2.0]hept-2-yl)prop-2-en-1-one [01014] 642.16 524 1-((S)-4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en- 1-one [01015] 578.26 525 1-((S)-4-(6-chloro-8-fluoro-7-(8-chloronaphthalen-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [01016] 608.19 526 1-((S)-4-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [01017] 626.18 527 (S)-1-(4-(6-chloro-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [01018] 604.28 528 (S)-1-(4-(6-chloro-8-fluoro-7-(8-chloronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [01019] 634.21 529 (S)-1-(4-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [01020] 652.20 530 1-((3S)-4-(6-chloro-8-fluoro-2-((((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [01021] 622.27 531 1-((3S)-4-(6-chloro-8-fluoro-7-(8-chloronaphthalen-1- yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [01022] 652.20 532 1-((3S)-4-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H))- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [01023] 670.19 533 1-((S)-4-(6-chloro-8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [01024] 596.25 534 1-((S)-4-(6-chloro-8-fluoro-7-(8-chloronaphthalen-1- yl)-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1- yl)prop-2-en-1-one [01025] 626.18 535 1-((S)-4-(6-chloro-8-fluoro-7-(8-chloro-7- fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one [01026] 643.17 536 2-((2S)-1-acryloyl-4-(2-((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01027] 549.3 537 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01028] 567.3 538 2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(thiochroman-8-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01029] 569.3 539 2-((S)-1-acryloyl-4-(7-(benzothien-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01030] 553.2 540 2-((S)-4-(7-(benzo[b]thien-7-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01031] 571.2 541 2-((S)-1-acryloyl-4-(7-(benzothien-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01032] 553.2 542 2-((S)-4-(7-(benzo[b]thien-4-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01033] 571.2 543 2-((2S)-1-acryloyl-4-(2-(((2R)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01034] 593.3 544 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01035] 611.3 545 2-((2S)-1-acryloyl-4-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01036] 575.3 546 2-((2S)-1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01037] 593.3 547 2-((S)-1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01038] 593.3 548 2-((S)-1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-((1aR,6aR)- 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01039] 593.3 549 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- ((1aS,6aS)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01040] 611.3 550 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- ((1aR,6aR)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-2- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01041] 611.3 551 2-((2S)-4-(7-(benzo[b]thien-7-yl)-2-((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01042] 615.2 552 (S)-2-(4-(7-(benzothien-7-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01043] 597.2 553 2-((2S)-4-(7-(benzo[b]thien-4-yl)-2-((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01044] 615.2 554 (S)-2-(4-(7-(benzothien-4-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01045] 597.2 555 2-((2S)-1-acryloyl-4-(6-chloro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01046] 583.3 556 2-((S)-1-acryloyl-4-(6-chloro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiocyano- 8)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01047] 603.2 557 2-((S)-1-acryloyl-4-(7-(benzothien-7-yl)-6-chloro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01048] 587.2 558 2-((S)-4-(7-(benzothien-4-yl)-6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01049] 605.2 559 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01050] 601.2 560 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01051] 621.2 561 2-((2S)-1-acryloyl-4-(7-(benzothien-7-yl)-6-chloro-8- fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01052] 605.2 562 2-((2S)-4-(7-(benzothien-4-yl)-6-chloro-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01053] 623.2 563 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01054] 585.3 564 2-((2S)-1-acryloyl-4-(6,8-difluoro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiocyano- 8)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01055] 605.2 565 2-((2S)-1-acryloyl-4-(7-(benzothien-7-yl)-6,8-difluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01056] 589.2 566 2-((2S)-4-(7-(benzothien-4-yl)-6,8-difluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01057] 607.2 567 2-((2S)-1-acryloyl-4-(6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01058] 567.3 568 2-((2S)-4-(6-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01059] 585.3 569 2-((S)-1-acryloyl-4-(6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01060] 587.3 570 2-((S)-1-acryloyl-4-(7-(benzothien-7-yl)-6-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01061] 571.2 571 2-((S)-4-(7-(benzothien-7-yl)-6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01062] 589.2 572 2-((S)-1-acryloyl-4-(7-(benzothien-4-yl)-6-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01063] 571.2 573 2-((S)-4-(7-(benzothien-4-yl)-6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01064] 589.2 574 2-(((2S)-1-acryloyl-4-(6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]indan-2- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01065] 611.3 575 2-((2S)-4-(6-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]indan-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01066] 629.7 576 2-((2S)-1-acryloyl-4-(6-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01067] 593.3 577 2-((2S)-4-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01068] 611.3 578 2-((S)-4-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01069] 611.3 579 2-((S)-4-(6-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-((1aR,6aR)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01070] 611.3 580 2-((S)-4-(6-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)-7-((1aS,6aS)- 1,1a,6,6a-tetrahydrocyclopropa[a]indan-2- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01071] 629.3 581 2-((S)-4-(6-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)-7-((1aR,6aR)- 1,1a,6,6a-tetrahydrocyclopropa[a]indan-2- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01072] 629.3 582 (S)-2-(4-(7-(benzothien-4-yl)-6-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01073] 615.2 583 2-((2S)-4-(7-(benzo[b]thien-4-yl)-6-fluoro-2-(((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01074] 633.2 584 2-((2S)-1-acryloyl-4-(8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01075] 567.3 585 2-((2S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01076] 585.3 586 2-((S)-1-acryloyl-4-(8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiocyano- 8)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01077] 587.3 587 2-((S)-1-acryloyl-4-(7-(benzothien-7-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01078] 571.2 588 2-((S)-4-(7-(benzothien-7-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01079] 589.2 589 2-((S)-1-acryloyl-4-(7-(benzothien-4-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01080] 571.2 590 2-((S)-4-(7-(benzo[b]thien-4-yl)-8-fluoro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01081] 589.2 591 2-((2S)-1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01082] 593.3 592 2-((2S)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01083] 611.3 593 2-(((2S)-1-acryloyl-4-(8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]indan-2- yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01084] 611.3 594 2-((2S)-4-(8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]indan-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01085] 629.3 595 2-((S)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-((1aS,6aS)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01086] 611.3 596 2-((S)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-((1aR,6aR)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01087] 611.3 597 2-((S)-4-(8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-((1aS,6aS)- 1,1a,6,6a-tetrahydrocyclopropa[a]indan-2- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01088] 629.3 598 2-((S)-4-(8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)-7-((1aR,6aR)- 1,1a,6,6a-tetrahydrocyclopropa[a]indan-2- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01089] 629.3 599 2-((2S)-4-(7-(benzo[b]thien-7-yl)-8-fluoro-2-((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01090] 633.2 600 (S)-2-(4-(7-(benzothien-7-yl)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01091] 615.2 601 2-((2S)-4-(7-(benzothien-4-yl)-8-fluoro-2-((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01092] 633.2 602 (S)-2-(4-(7-(benzothien-4-yl)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01093] 615.2 603 2-((2S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01094] 550.3 604 2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(thiochroman-8-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01095] 570.3 605 2-((S)-1-acryloyl-4-(7-(benzo[b]thien-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01096] 554.2 606 2-((S)-4-(7-(benzo[b]thien-4-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01097] 572.2 607 2-((2S)-1-acryloyl-4-(6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01098] 584.3 608 2-((S)-1-acryloyl-4-(6-chloro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8- yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [01099] 604.2 609 2-((S)-1-acryloyl-4-(7-(benzo[b]thien-7-yl)-6-chloro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01100] 588.2 610 2-((S)-4-(7-(benzothien-4-yl)-6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01101] 606.2 611 2-((2S)-1-acryloyl-4-(6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01102] 568.3 612 2-((S)-1-acryloyl-4-(6-fluoro-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8- yl)pyridino[2,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [01103] 588.3 613 2-((S)-1-acryloyl-4-(7-(benzo[b]thien-7-yl)-6-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01104] 572.2 614 2-((S)-4-(7-(benzothien-4-yl)-6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[2,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01105] 590.2

Example 615: Synthesis of (S)-1-(4-(6-chloro-8-fluoro-7-(6 fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0214] ##STR01106##

Step 1: Synthesis of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid

[0215] 2-amino-4-bromo-3-fluorobenzoic acid (2.30 g, 10 mmol) and NCS (1.60 g, 12 mmol) were dissolved in 30 ml of DMF, and the reaction system was stirred overnight at 70? C. After the reaction was complete, 300 ml of water was added to the reaction system, and a large amount of solid was precipitated. Suction filtration, drying and weighing were carried out to obtain a light yellow solid. (1.34 g, yield: 50%). .sup.1H NMR (400 MHz, DMSO) ? 13.11 (s, 1H), 7.63 (s, 1H), 6.62 (s, 2H).

Step 2: Synthesis of 7-bromo-6-chloro-8-fluoroquinazolin-2,4-diol

[0216] 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.34 g, 5 mmol) and urea (1.5 g, 25 mmol) were placed in a 50 ml one-mouth flask, and the reaction system was heated to 180? C. under nitrogen protection; and after three hours of reaction, 30 ml of 1 N/mol NaOH solution was added to the reaction system, the reaction system was stirred, whereby a large amount of insoluble solid precipitated out, and suction filtration was carried out to obtain a light yellow solid. (514 mg, 35%). .sup.1H NMR (400 MHz, DMSO) ? 11.40 (s, 1H), 11.34 (s, 1H), 7.70 (s, 1H).

Step 3: Synthesis of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0217] The compound 7-bromo-6-chloro-8-fluoroquinazolin-2,4-diol (500 mg, 1.73 mmol) was dissolved in 10 ml of phosphorus oxychloride, 1 ml of DMF was added, and the reaction system was heated to 110? C. and stirred overnight. After the reaction was complete, phosphorus oxychloride was removed under reduced pressure to obtain a black pasty liquid. Under ice-water bath condition, ice water was added and stirred, whereby a large amount of solid precipitated out, and after suction filtration and drying, a yellow solid was obtained (300 mg, 54%). .sup.1H NMR (400 MHz, DMSO) ? 7.70 (s, 1H).

Step 4: Synthesis of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0218] The compound tert-butyl 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 0.9 mmol) and piperazine-1-carboxylate (167.4 mg, 0.9 mmol) was dissolved in 4 ml of 1,4-dioxane, and after DIEA (0.5 ml, 2.25 mmol) was added, the reaction system was heated at 55? C. for three hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain a crude product. After the crude product was dissolved in DCM, the organic phase was washed with 0.5 mol/L HCl three times. After extraction and separation, the organic phase was dried and then subjected to removal under reduced pressure to obtain a yellow solid. (414 mg, yield: 96%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.70 (s, 1H), 3.73 (m, 4H), 3.32 (m, 4H), 1.44 (s, 9H).

Step 5: Synthesis of tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0219] The compound tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (414 mg, 0.86 mmol) and K.sub.2CO.sub.3 (240 mg, 1.72 mmol) were dissolved in 30 ml of ultradry acetonitrile, and (S)-(1-methylpyrrolidin-2-yl)methanol (96 mg, 0.86 mmol) was added. The reaction system was heated to 90? C. under nitrogen protection and stirred for 6 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain a crude product, which was separated by column chromatography (DCM:MeOH=10:1) to obtain a brown solid. (170 mg, 35%)

Step 6: Synthesis of tert-butyl (S)-4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-(((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid

[0220] The compound tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (38 mg, 0.05 mmol), 6-fluoro-1,2,3,4-tetrahydroquinoline (26 mg, 0.18 mmol), t-BuONa (34 mg, 0.34 mmol), and RuPhos (38 mg, 0.08 mmol) were dissolved in 6 ml of toluene. After displacement with nitrogen, Pd2(dba)3 (38 mg, 0.04 mmol) was added, and after continued displacement with nitrogen, the reaction was carried out at 100? C. overnight. After the reaction was complete, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain a light yellow target product. (70 mg, 65%).

Step 7: Synthesis of (S)-6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline

[0221] The compound tert-butyl (S)-4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-(((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid (62 mg, 0.1 mmol) was dissolved in a hybrid solvent of DCM and CF3COOH (3 ml/1 ml) and stirred at room temperature for 1 h; and after the reaction was complete, the organic solvent was removed from the reaction system under reduced pressure, dichloromethane was added for dissolution, the system was then spin-dried again, and the same operation was repeated again. The resulting crude product was directly used for the next step of reaction. (53 mg, yield: 100%)

Step 8: Synthesis of (S)-1-(4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0222] The compound (S)-6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline (53 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL), DIEA (80 mg, 0.60 mmol) was added under ice-water bath cooling condition, acryloyl chloride (18 mg, 0.13 mmol) was then added, and the mixture was reacted under stirring and ice-water bath conditions for 10 min. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by PLC (dichloromethane/methanol=15/1) to obtain an off-white solid. (30 mg, yield: 50%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.47 (d, J=9.1 Hz, 1H), 7.31-7.23 (m, 1H), 6.93-6.80 (m, 1H), 6.71 (s, 1H), 6.54 (dd, J=16.7, 10.5 Hz, 1H), 6.30 (d, J=16.7 Hz, 1H), 5.71 (d, J=11.9 Hz, 1H), 5.12 (s, 1H), 4.67 (d, J=10.9 Hz, 1H), 4.10 (t, J=8.1 Hz, 2H), 3.80 (s, 7H), 3.13 (t, J=8.2 Hz, 2H), 2.95 (s, 3H), 2.77 (s, 1H), 2.37-1.86 (m, 5H), 1.61 (s, 4H). MS m/z: 583.23 [M+H]+

[0223] The compounds of Examples 616-619 were prepared by preparation by the method for Examples 615

TABLE-US-00004 m/z: Example Compound name Structural formula ES.sup.+[M + H] 616 2-((S)-1-acryloyl-4-(7-(3,4-dihydroquinoline- 1(2H)-yl)-8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01107] 588.28 617 (S)-1-(4-(8-fluoro-7-(indol-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one [01108] 535.26 618 2-((S)-1-acryloyl-4-(7-(8-chloro-3,4- dihydroquinoline-1(2H)-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01109] 586 619 2-((S)-4-(7-(8-chloro-3,4-dihydroquinoline- 1(2H)-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01110] 604

Example 620: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile

[0224] ##STR01111## ##STR01112##

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

[0225] The compound methyl 2-amino-4-bromobenzoate (10 g, 43.47 mmol) and cyanoacetic acid (4.44 g, 52.16 mmol) were dissolved in dichloromethane (100 mL), EDCI (12.5 g, 65.10 mmol) was added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 1 h. After the reaction was complete, the reaction liquid was diluted by adding water and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain a target compound. (12.9 g, yield: 100%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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: 7-bromo-2,4-dihydroxyquinoline-3-acetonitrile

[0226] The compound methyl 4-bromo-2-(2-cyanoacetamido)benzoate (12.9 g, 43.42 mmol) was dissolved in anhydrous methanol (100 mL), 30% sodium methoxide solution (11.73 g, 65.13 mmol) was added dropwise under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 30 min. After the reaction was complete, the reaction product was adjusted to pH 2-3 with 10% hydrochloric acid aqueous solution, the reaction liquid was diluted by adding 100 mL of water, whereby a solid precipitated out, and after filtration, the solid was dried in vacuo to obtain an off-white solid. (11.18 g, yield: 97%). .sup.1H NMR (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-acetonitrile

[0227] The compound 7-bromo-2,4-dihydroxyquinoline-3-acetonitrile (11.0 g, 41.50 mmol) was dissolved in acetonitrile (10 mL) and POCl.sub.3 (40 mL), and the mixture was heated to 90? C. and reacted under stirring for 16 h. After the reaction was complete, the reaction product was cooled to room temperature and concentrated to obtain a light yellow solid, which was directly used for the next step. (12.53 g, yield: 100%).

Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2-chloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0228] The compound 7-bromo-2,4-dichloroquinoline-3-acetonitrile (5.00 g, 16.56 mmol) was dissolved in anhydrous DMF (50 mL), DIEA (12.84 g, 16.42 mL, 99.36 mmol) was added under ice-water bath cooling condition, (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (3.6 g, 18.22 mmol) was then added, the mixture was reacted under stirring and ice-water bath cooling conditions for 10 min; and di-tert butyl dicarbonate (7.25 g, 33.12 mmol) was then added, and the mixture was reacted at room temperature under stirring for 16 h. After the reaction was complete, the reaction liquid was diluted by adding 100 mL of cold water under stirring, whereby a solid precipitated out, and after filtration, the solid was washed with water and dried in vacuo to obtain a light yellow solid, which was directly used for the next step. (7.2 g, yield: 88.59%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.20 (d, J=1.8 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 1.8 Hz, 1H), 4.76 (s, 1H), 4.20 (s, 1H), 4.07 (dd, J=12.5, 3.5 Hz, 1H), 3.76 (d, J=13.0 Hz, 1H), 3.67 (d, J=11.7 Hz, 1H), 3.56 (s, 1H), 3.44 (s, 1H), 2.83 (s, 2H).

Step 5: Synthesis of tert-butyl (S)-4-(7-bromo-3-cyano-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0229] The compound (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (44 mg, 0.31 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), 60% NaH (13 mg, 0.31 mmol) was added under ice-water bath cooling condition, the mixture was reacted under stirring and ice-water bath cooling conditions for 20 min, tert-butyl (S)-4-(7-bromo-2-chloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.20 mmol) was then added to the reaction liquid, and the mixture was reacted at room temperature under stirring for 4 h. After the reaction was complete, the reaction was quenched with cold water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain a beige solid. (100 mg, yield: 82.7%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.05-7.99 (m, 1H), 7.77-7.68 (m, 1H), 7.57-7.48 (m, 1H), 4.81-4.62 (m, 3H), 4.18 (s, 1H), 4.00 (dd, J=12.4, 3.5 Hz, 1H), 3.82 (d, J=42.0 Hz, 2H), 3.66 (dd, J=29.7, 12.2 Hz, 2H), 3.49 (s, 1H), 3.35 (t, J=11.2 Hz, 1H), 3.06-2.72 (m, 4H), 2.29 (d, J=20.6 Hz, 4H), 2.11 (d, J=5.8 Hz, 2H), 1.98 (s, 2H), 1.53 (s, 9H).

Step 6: Synthesis of tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-3-cyano-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0230] The compound tert-butyl (S)-4-(7-bromo-3-cyano-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (35 mg, 0.06 mmol) and 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (22 mg, 0.07 mmol) was dissolved in dioxane/water=5/1 (3 mL), cesium carbonate (58 mg, 0.18 mmol) and Pd(PPh.sub.3).sub.4 (34 mg, 0.03 mmol) were then added, and after displacement with nitrogen, the mixture was heated to 90? C. and reacted under stirring for 1 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 TLC to obtain a beige solid. (22 mg, yield: 53%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.93 (d, J=8.2 Hz, 1H), 7.87 (dd, J=9.4, 3.7 Hz, 1H), 7.83 (s, 1H), 7.57-7.50 (m, 2H), 7.48-7.36 (m, 4H), 4.93 (dd, J=20.0, 11.4 Hz, 1H), 4.84-4.65 (m, 2H), 4.20 (s, 1H), 4.11-3.97 (m, 3H), 3.91-3.65 (m, 2H), 3.46 (d, J=39.4 Hz, 3H), 3.00 (s, 3H), 2.93-2.70 (m, 1H), 2.58-2.28 (m, 4H), 2.22-1.95 (m, 4H), 1.54 (s, 9H).

Step 7: Synthesis of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile

[0231] The compound tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-3-cyano-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (22 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated to remove excess trifluoroacetic acid, then dissolved in dichloromethane, washed with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain an off-white solid, which was directly used for the next step. (19 mg, yield: 100%).

Step 8: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile

[0232] The compound (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile (18 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (7 mg, 0.05 mmol) and acryloyl chloride (3.2 mg, 0.04 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath conditions for 10 min. After the reaction was complete, the reaction was quenched with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (18 mg, yield: 91.7%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.94-7.84 (m, 4H), 7.55-7.38 (m, 4H), 6.67-6.64 (m, 1H), 6.42 (d, J=16.7 Hz, 1H), 5.85 (d, J=10.3 Hz, 1H), 4.92 (dd, J=20.6, 11.8 Hz, 1H), 4.71 (d, J=11.6 Hz, 1H), 4.16-3.75 (m, 6H), 3.49 (s, 1H), 3.01 (s, 4H), 2.58-2.25 (m, 4H), 2.15-2.12 (m, 2H), 2.09-1.94 (m, 2H). MS m/z: 649.67 [M+H].sup.+

Example 621: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile

[0233] ##STR01113## ##STR01114##

Step 1: Synthesis of methyl 4-bromo-2-(2-cyanoacetamido)-5-fluorobenzoate

[0234] The compound methyl 2-amino-4-bromo-5-fluorobenzoate (1.2 g, 4.84 mmol) and cyanoacetic acid (0.49 g, 5.81 mmol) were dissolved in dichloromethane (15 mL), EDCI (1.39 g, 7.26 mmol) was added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 1 h. After the reaction was complete, the reaction liquid was diluted by adding water and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain a target compound. (1.5 g, yield: 98%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 11.58 (s, 1H), 8.97 (d, J=6.4 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.60 (s, 2H).

Step 2: Synthesis of 7-bromo-6-fluoro-2,4-dihydroxyquinoline-3-acetonitrile

[0235] The compound methyl 4-bromo-2-(2-cyanoacetamido)-5-fluorobenzoate (1.5 g, 4.76 mmol) was dissolved in anhydrous methanol (10 mL), 30% sodium methoxide solution (1.29 g, 7.14 mmol) was added dropwise under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 30 min. After the reaction was complete, the reaction product was adjusted to pH 2-3 with 10% hydrochloric acid aqueous solution, the reaction liquid was diluted by adding 50 mL of water, whereby a solid precipitated out, and after filtration, the solid was dried in vacuo to obtain an off-white solid. (1.35 g, yield: 100%). .sup.1H NMR (400 MHz, DMSO) ? 11.47 (s, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.53 (d, J=5.9 Hz, 1H).

Step 3: Synthesis of 7-bromo-2,4-dichloro-6-fluoroquinoline-3-acetonitrile

[0236] The compound 7-bromo-6-fluoro-2,4-dihydroxyquinoline-3-acetonitrile (0.24 g, 0.85 mmol) was dissolved in acetonitrile (1 mL) and POCl.sub.3 (4 mL), and the mixture was heated to 90? C. and reacted under stirring for 16 h. After the reaction was complete, the reaction product was cooled to room temperature and concentrated to obtain a light yellow solid, which was directly used for the next step. (271 mg, yield: 100%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.38 (d, J=6.3 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H).

Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0237] The compound 7-bromo-2,4-dichloro-6-fluoroquinoline-3-acetonitrile (271 mg, 0.85 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (659 mg, 5.09 mmol) was added under ice-water bath cooling condition, (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (185 mg, 0.93 mmol) was then added, the mixture was reacted under stirring and ice-water bath cooling conditions for 10 min; and di-tert butyl dicarbonate (372 mg, 1.70 mmol) was then added, and the mixture was reacted at room temperature under stirring for 16 h. After the reaction was complete, the reaction liquid was diluted by adding 30 mL of cold water under stirring, whereby a solid precipitated out, and after filtration, the solid was washed with water and dried in vacuo to obtain a light yellow solid, which was directly used for the next step. (400 mg, yield: 93%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.31 (d, J=6.6 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 4.76 (s, 1H), 4.21 (s, 1H), 4.08 (dd, J=12.4, 3.6 Hz, 1H), 3.78-3.33 (m, 4H), 2.83 (qd, J=16.9, 7.6 Hz, 2H), 1.53 (s, 9H).

Step 5: Synthesis of tert-butyl (S)-4-(7-bromo-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0238] The compound (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (44 mg, 0.31 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), 60% NaH (13 mg, 0.31 mmol) was added under ice-water bath cooling condition, the mixture was reacted under stirring and ice-water bath cooling conditions for 20 min, tert-butyl (S)-4-(7-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.20 mmol) was then added to the reaction liquid, and the mixture was heated to 60? C. and reacted under stirring for 2 h. After the reaction was complete, the reaction product was cooled to room temperature, the reaction was quenched with cold water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (100 mg, yield: 83%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10 (d, J=6.6 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 4.75 (s, 3H), 4.19 (s, 1H), 4.01 (dd, J=12.4, 3.5 Hz, 1H), 3.82 (d, J=42.0 Hz, 2H), 3.66 (dd, J=29.7, 12.2 Hz, 2H), 3.49 (s, 1H), 3.35 (t, J=11.2 Hz, 1H), 3.06-2.72 (m, 4H), 2.29 (d, J=20.6 Hz, 4H), 2.11 (d, J=5.8 Hz, 2H), 1.98 (s, 2H), 1.53 (s, 9H).

Step 6: Synthesis of tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0239] The compound tert-butyl (S)-4-(7-bromo-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (30 mg, 0.05 mmol) and 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (22 mg, 0.07 mmol) was dissolved in dioxane/water=5/1 (3 mL), cesium carbonate (58 mg, 0.18 mmol) and Pd(PPh.sub.3).sub.4 (34 mg, 0.03 mmol) were then added, and after displacement with nitrogen, the mixture was heated to 90? C. and reacted under stirring for 1 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 TLC to obtain a beige solid. (20 mg, yield: 57%). MS m/z: 714 [M+H].sup.+

Step 7: Synthesis of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile

[0240] The compound tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated to remove excess trifluoroacetic acid, then dissolved in dichloromethane, washed with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain an off-white solid, which was directly used for the next step. (17 mg, yield: 100%).

Step 8: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile

[0241] The compound (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile (17 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (7 mg, 0.05 mmol) and acryloyl chloride (3.2 mg, 0.04 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath conditions for 10 min. After the reaction was complete, the reaction was quenched with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (10 mg, yield: 54%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.93-7.84 (m, 4H), 7.55-7.38 (m, 3H), 6.67-6.63 (m, 1H), 6.41 (d, J=16.7 Hz, 1H), 5.84 (d, J=10.3 Hz, 1H), 4.93 (dd, J=20.6, 11.8 Hz, 1H), 4.72 (d, J=11.6 Hz, 1H), 4.17-3.75 (m, 6H), 3.49 (s, 1H), 3.01 (s, 4H), 2.58-2.25 (m, 4H), 2.15-2.12 (m, 2H), 2.09-1.94 (m, 2H). MS m/z: 667.6[M+H].sup.+

Example 622: Synthesis of 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinoline-3-carbonitrile

[0242] ##STR01115## ##STR01116##

Step 1: Synthesis of methyl 4-bromo-5-chloro-2-(2-cyanoacetamido)benzoate

[0243] The compound methyl 2-amino-4-bromo-5-chlorobenzoate (1.0 g, 3.78 mmol) and cyanoacetic acid (0.39 g, 4.53 mmol) were dissolved in dichloromethane (15 mL), EDCI (1.08 g, 5.67 mmol) was added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 1 h. After the reaction was complete, the reaction liquid was diluted by adding water and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain a target compound. (1.19 g, yield: 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 11.63 (s, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 3.99 (s, 3H), 3.61 (s, 2H).

Step 2: Synthesis of 7-bromo-6-chloro-2,4-dihydroxyquinoline-3-acetonitrile

[0244] The compound methyl 4-bromo-2-(2-cyanoacetamido)-5-chlorobenzoate (1.19 g, 3.59 mmol) was dissolved in anhydrous methanol (10 mL), 30% sodium methoxide solution (0.97 g, 5.39 mmol) was added dropwise under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 30 min. After the reaction was complete, the reaction product was adjusted to pH 2-3 with 10% hydrochloric acid aqueous solution, the reaction liquid was diluted by adding 50 mL of water, whereby a solid precipitated out, and after filtration, the solid was dried in vacuo to obtain an off-white solid. (1.07 g, yield: 100%). .sup.1H NMR (400 MHz, DMSO) ? 11.40 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H).

Step 3: Synthesis of 7-bromo-2,4,6-trichloroquinoline-3-acetonitrile

[0245] The compound 7-bromo-6-chloro-2,4-dihydroxyquinoline-3-acetonitrile (0.20 g, 0.67 mmol) was dissolved in acetonitrile (1 mL) and POCl.sub.3 (4 mL), and the mixture was heated to 90? C. and reacted under stirring for 16 h. After the reaction was complete, the reaction product was cooled to room temperature and concentrated to obtain a light yellow solid, which was directly used for the next step. (225 mg, yield: 100%).

Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2,6-dichloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0246] The compound 7-bromo-2,4,6-trichloroquinoline-3-acetonitrile (225 mg, 0.67 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (518 mg, 4.01 mmol) was added under ice-water bath cooling condition, (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (146 mg, 0.74 mmol) was then added, the mixture was reacted under stirring and ice-water bath cooling conditions for 10 min; and di-tert butyl dicarbonate (2922 mg, 1.34 mmol) was then added, and the mixture was reacted at room temperature under stirring for 4 h. After the reaction was complete, the reaction liquid was diluted by adding 30 mL of cold water under stirring, whereby a solid precipitated out, and after filtration, the solid was washed with water and dried in vacuo to obtain a light yellow solid, which was directly used for the next step. (230 mg, yield: 89%). .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.35 (s, 1H), 8.05 (s, 1H), 4.78 (s, 1H), 4.51 (s, 1H), 4.26 (d, J=22.4 Hz, 1H), 3.82-3.39 (m, 4H), 3.10 (d, J=13.7 Hz, 1H), 2.83 (qd, J=16.9, 7.6 Hz, 2H), 1.55 (s, 9H).

Step 5: Synthesis of tert-butyl (S)-4-(7-bromo-6-chloro-3-cyano-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0247] The compound (S)-(1-methylpyrrolidin-2-yl)methanol (40 mg, 0.34 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), 60% NaH (14 mg, 0.34 mmol) was added under ice-water bath cooling condition, the mixture was reacted under stirring and ice-water bath cooling conditions for 20 min, tert-butyl (S)-4-(7-bromo-2,6-dichloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was then added to the reaction liquid, and the mixture was heated to 60? C. and reacted under stirring for 2 h. After the reaction was complete, the reaction product was cooled to room temperature, the reaction was quenched with cold water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (50 mg, yield: 83%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.13 (s, 1H), 7.92 (s, 1H), 4.75 (s, 1H), 4.60 (s, 1H), 4.19 (s, 1H), 4.02 (dd, J=12.4, 3.6 Hz, 1H), 3.71-3.31 (m, 6H), 2.84 (s, 3H), 2.72 (s, 3H), 2.52 (s, 1H), 2.18 (s, 1H), 2.03 (s, 1H), 1.91 (s, 3H), 1.53 (s, 9H).

Step 6: Synthesis of tert-butyl (S)-4-(6-chloro-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0248] The compound tert-butyl (S)-4-(7-bromo-6-chloro-3-cyano-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (25 mg, 0.04 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3,2-dioxaborane (13 mg, 0.05 mmol) were dissolved in dioxane/water=5/1 (3 mL), cesium carbonate (40 mg, 0.12 mmol) and Pd(PPh.sub.3).sub.4 (24 mg, 0.02 mmol) were then added, and after displacement with nitrogen, the mixture was heated to 90? C. and reacted under stirring for 1 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 TLC to obtain a beige solid. (27 mg, yield: 100%). MS m/z: 655.7 [M+H].sup.+

Step 7: Synthesis of 6-chloro-4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile

[0249] The compound tert-butyl (S)-4-(6-chloro-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (27 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated to remove excess trifluoroacetic acid, then dissolved in dichloromethane, washed with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was washed with a saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated to obtain an off-white solid, which was directly used for the next step. (23 mg, yield: 100%).

Step 8: Synthesis of 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinoline-3-carbonitrile

[0250] Compound 6-chloro-4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile (23 mg, 0.04 mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (7 mg, 0.05 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath conditions for 10 min. After the reaction was complete, the reaction was quenched with a saturated sodium carbonate aqueous solution and extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by TLC to obtain an off-white solid. (8 mg, yield: 32%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.94 (d, J=2.5 Hz, 1H), 7.73 (t, J=10.6 Hz, 1H), 7.19 (t, J=5.1 Hz, 2H), 6.96 (dd, J=10.4, 6.6 Hz, 1H), 6.61 (d, J=10.6 Hz, 1H), 6.43 (d, J=15.8 Hz, 1H), 5.87 (d, J=10.9 Hz, 1H), 4.69 (s, 1H), 4.07 (d, J=12.9 Hz, 1H), 3.93-3.69 (m, 3H), 3.48 (s, 2H), 3.01 (d, J=8.4 Hz, 2H), 2.87-2.55 (m, 6H), 2.54-2.14 (m, 4H), 1.88-1.74 (m, 10H). MS m/z: 609.67 [M+H].sup.+.

[0251] The compounds of Examples 623-839 were prepared by preparation method 3.

TABLE-US-00005 m/z: Ex. Compound name Structural formula ES.sup.+ [M + H] 623 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloro-7-fluoronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01117] 625 624 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- (((S-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01118] 643 625 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloro-7-fluoronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01119] 643 626 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((((4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01120] 661 627 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01121] 669 628 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloro-7-fluoronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01122] 669 629 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01123] 687 630 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01124] 596 631 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-6yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline-3- acetonitrile [01125] 614 632 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)quinoline-3- acetonitrile [01126] 614 633 7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((1R,5R)-2- (2-fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6- yl)quinoline-3-acetonitrile [01127] 632 634 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01128] 622 635 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01129] 640 636 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01130] 640 637 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-6yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01131] 658 638 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01132] 607 639 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-2-((((S)-1- methylpyrrolidone)-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01133] 625 640 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-(yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01134] 625 641 7-(8-chloronaphthlalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-2-((((2S,4R)-4-fluoro- 1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01135] 643 642 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-2-(((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline-3- acetonitrile [01136] 633 643 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01137] 651 644 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01138] 651 645 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01139] 669 646 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-2-(((S-1-methylpyrrolidin- 2-(yl)methoxy)quinoline-3-acetonitrile [01140] 578 647 7-(8-chloronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01141] 596 648 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01142] 596 649 7-(8-chloronaphthalen-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6- yl)quinoline-3-acetonitrile [01143] 614 650 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01144] 604 651 7-(8-chloronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- (((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01145] 622 652 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01146] 622 653 7-(8-chloronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01147] 640 654 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-((((S)-1- methylpyrrolidon-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01148] 625 655 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-(((S-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01149] 643 656 4-((S)-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01150] 643 657 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-(((4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01151] 661 658 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01152] 651 659 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01153] 669 660 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01154] 669 661 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01155] 687 662 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01156] 596 663 7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01157] 614 664 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01158] 614 665 (8-chloronaphthalen-1-yl)-8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((1R,5R)-2- (2-fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6- yl)quinoline-3-acetonitrile [01159] 632 666 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01160] 622 667 7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01161] 640 668 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [01162] 640 669 7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-6yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [01163] 658 670 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)-4a,8a- dihydroquinoline-3-acetonitrile [01164] 595 671 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 7-(5,6,7,8-tetrahydronaphthalen-1-yl)-4a,8a- dihydroquinoline-3-acetonitrile [01165] 613 672 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01166] 613 673 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01167] 631 674 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01168] 621 675 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01169] 639 676 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl))methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)-4a,8a-dihydroquinoline-3-acetonitrile [01170] 639 677 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-4a,8a-dihydroquinoline- 3-acetonitrile [01171] 657 678 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)- 7-(5,6,7,8-tetrahydronaphthalen-1-yl)quinoline- 3-acetonitrile [01172] 566 679 8-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01173] 584 680 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 8-fluoro-2-(((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinoline-3-acetonitrile [01174] 584 681 8-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01175] 602 682 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinoline-3-acetonitrile [01176] 592 683 8-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01177] 610 684 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-8-fluoro-2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-carbonitrile [01178] 610 685 8-fluoro-4-(((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinoline- 3-acetonitrile [01179] 628 686 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7,8- chloronaphthalen-1-yl)-8-fluoro-2-((((S)-1- methylpyrrolidon-2-yl)methoxy)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01180] 626 687 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-(((S-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01181] 644 688 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01182] 644 689 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-(((4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydro- 1,6-naphthyridine-3-acetonitrile [01183] 662 690 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01184] 652 691 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydro-1,6-naphthyridine-3-acetonitrile [01185] 670 692 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)- 4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01186] 670 693 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)- 4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01187] 688 694 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine-3- acetonitrile [01188] 597 695 7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6- naphthyridine-3-acetonitrile [01189] 615 696 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- 6yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-1,6- naphthyridine-3-acetonitrile [01190] 615 697 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((1R,5R)-2- (2-fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-1,6- naphthyridine-3-acetonitrile [01191] 633 698 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridine- 3-acetonitrile [01192] 623 699 7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-6yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6- naphthyridine-3-acetonitrile [01193] 641 700 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6- naphthyridine-3-acetonitrile [01194] 641 701 7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-6yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,6-naphthyridine-3-acetonitrile [01195] 659 702 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronapthalen-1-yl)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01196] 596 703 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 7-(5,6,7,8-tetrahydronaphthalen-1-yl)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01197] 614 704 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01198] 614 705 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01199] 632 706 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01200] 622 707 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01201] 640 708 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl))methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)-4a,8a-dihydro-1,6-naphthyridine-3-acetonitrile [01202] 640 709 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-4a,8a-dihydro-1,6- naphthyridine-3-acetonitrile [01203] 658 710 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)-1,6-naphthyridine- 3-acetonitrile [01204] 567 711 8-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-1,6-naphthyridine-3- acetonitrile [01205] 585 712 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,6- naphthyridine-3-acetonitrile [01206] 585 713 8-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-1,6-naphthyridine-3- acetonitrile [01207] 603 714 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,6- naphthyridine-3-acetonitrile [01208] 593 715 8-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-1,6-naphthyridine-3- acetonitrile [01209] 611 716 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-8-fluoro-2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-1,6-naphthyridine-3- acetonitrile [01210] 611 717 8-fluoro-4-(((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)-1,6-naphthyridine-3- acetonitrile [01211] 629 718 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01212] 659 719 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01213] 677 720 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01214] 677 721 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01215] 695 722 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01216] 685 723 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01217] 703 724 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01218] 703 725 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01219] 721 726 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((S)- 1-methylpyrrolidin-2-yl)methoxy)quinoline-3- acetonitrile [01220] 630 727 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4- ((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01221] 648 728 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinoline-3-acetonitrile [01222] 648 729 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)quinoline-3-acetonitrile [01223] 666 730 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01224] 656 731 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4- ((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01225] 674 732 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-2- (((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01226] 674 733 6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-4- ((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01227] 692 734 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloronaphthalen-1-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01228] 641 735 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- (((S-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01229] 659 736 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloronaphthalen-1-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01230] 659 737 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((((4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01231] 677 738 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01232] 667 739 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01233] 685 740 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-7-(8-chloronaphthalen-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01234] 685 741 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01235] 703 742 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01236] 612 743 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01237] 630 744 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01238] 630 745 6-chloro-7-(8-chloronaphthalen-1-yl)-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((1R,5R)-2- (2-fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6- yl)quinoline-3-acetonitrile [01239] 648 746 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01240] 638 747 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01241] 656 748 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01242] 656 749 6-chloro-7-(8-chloronaphthalen-1-yl)-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01243] 674 750 6-chloro-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((((S-1--1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-4a,8a-dihydroquinoline- 3-acetonitrile [01244] 629 751 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01245] 629 752 6-chloro-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-4a,8a-dihydroquinoline- 3-acetonitrile [01246] 647 753 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronapthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01247] 637 754 6-chloro-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-4a,8a-dihydroquinoline- 3-acetonitrile [01248] 655 755 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)-4a,8a-dihydroquinoline-3-acetonitrile [01249] 655 756 6-chloro-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)-4a,8a- dihydroquinoline-3-acetonitrile [01250] 673 757 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinoline- 3-acetonitrile [01251] 582 758 6-chloro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01252] 600 759 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-6-chloro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinoline-3-acetonitrile [01253] 600 760 6-chloro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01254] 618 761 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-chloro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinoline-3-acetonitrile [01255] 608 762 6-chloro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01256] 626 763 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-6-chloro-2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01257] 626 764 6-chloro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinoline- 3-acetonitrile [01258] 644 765 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01259] 643 766 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-6- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-4a,8a- dihydroquinoline-3-acetonitrile [01260] 661 767 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7,8- chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2-((((4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01261] 661 768 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-6- fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01262] 679 769 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-6- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4a,8a-dihydroquinoline-3-acetonitrile [01263] 687 770 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01264] 687 771 7-(8-chloro-7-fluoronaphthalen-1-yl)-4-((S)-3- (cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-6- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01265] 705 772 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2-((((S)- 1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01266] 614 773 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-4- ((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01267] 632 774 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)quinoline-3-acetonitrile [01268] 632 775 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2- ((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)quinoline-3-acetonitrile [01269] 650 776 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01270] 640 777 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-4- ((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01271] 658 778 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-carbonitrile [01272] 658 779 7-(8-chloro-7-fluoronaphthalen-1-yl)-6-fluoro-4- ((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-(((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01273] 676 780 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01274] 625 781 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01275] 643 782 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-6-fluoro-2-((((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01276] 643 783 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-6-fluoro-2-((((4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01277] 661 784 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-6-fluoro-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01278] 651 785 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4a,8a- dihydroquinoline-3-acetonitrile [01279] 669 786 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01280] 669 787 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-6-fluoro-2-((((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4a,8a-dihydroquinoline-3-acetonitrile [01281] 687 788 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01282] 596 789 7-(8-chloronaphthalen-1-yl)-6-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline-3- acetonitrile [01283] 614 790 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-6-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)quinoline- 3-acetonitrile [01284] 614 791 7-(8-chloronaphthalen-1-yl)-6-fluoro-2-((((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((1R,5R)-2- (2-fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6- yl)quinoline-3-acetonitrile [01285] 632 792 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-6-fluoro-2-(((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinoline- 3-acetonitrile [01286] 622 793 7-(8-chloronaphthalen-1-yl)-6-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01287] 640 794 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(8-chloronaphthalen-1-yl)-6-fluoro-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01288] 640 795 7-(8-chloronaphthalen-1-yl)-6-fluoro-4-((1R,5R)-2-(2- fluoroacryloyl)-2,6-diazabicyclo[3.2.0]hept-6-yl)-2- ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinoline-3-acetonitrile [01289] 658 796 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)-4a,8a- dihydroquinoline-3-acetonitrile [01290] 595 797 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 7-(5,6,7,8-tetrahydronaphthalen-1-yl)-4a,8a- dihydroquinoline-3-acetonitrile [01291] 613 798 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01292] 613 799 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-6-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrol-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01293] 631 800 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-(((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01294] 621 801 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01295] 639 802 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin- 7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)-4a,8a-dihydroquinoline-3-acetonitrile [01296] 639 803 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-6-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)-4a,8a-dihydroquinoline- 3-acetonitrile [01297] 657 804 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinoline- 3-acetonitrile [01298] 566 805 6-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01299] 584 806 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-6-fluoro-2-(((((2S,4R)-4-fluoro-1-methylpyrrolidin- 2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinoline-3-acetonitrile [01300] 584 807 6-fluoro-2-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01301] 602 808 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)quinoline-3-acetonitrile [01302] 592 809 6-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-yl)-2-((tetrahydro-1H- pyrrolidon-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01303] 610 810 4-(((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6- yl)-6-fluoro-2-(((((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)quinoline-3-acetonitrile [01304] 610 811 6-fluoro-4-((1R,5R)-2-(2-fluoroacryloyl)-2,6- diazabicyclo[3.2.0]hept-6-6yl)-2-((((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5,6,7,8-tetrahydronaphthalen-1-yl)quinoline- 3-acetonitrile [01305] 628 812 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4- yl)quinoline-3-acetonitrile [01306] 593 813 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)quinoline- 3-acetonitrile [01307] 567 814 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-(((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5,6,7,8-tetrahydroisoquinolin-4-yl)- 4a,8a-dihydroquinoline-3-acetonitrile [01308] 622 815 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (5,6,7,8-tetrahydroisoquinolin-4-yl)-4a,8a- dihydroquinoline-3-acetonitrile [01309] 596 816 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(5-chloroisoquinolin-4-yl)-6-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinoline-3-acetonitrile [01310] 623 817 4-((1R,5R)-2-acryloyl-2,6-diazabicyclo[3.2.0]hept-6-yl)- 7-(5-chloroisoquinolin-4-yl)-6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01311] 597 818 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(5- chloroisoquinolin-4-yl)-6-fluoro-2-(((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01312] 652 819 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(5- chloroisoquinolin-4-yl)-6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-4a,8a-dihydroquinoline- 3-acetonitrile [01313] 626 820 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)quinoline-3- acetonitrile [01314] 573.3 821 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (thiochroman-8-yl)quinoline-3-acetonitrile [01315] 593.3 822 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7- (benzothien-7-yl)-2-((((S)-1-methylpyrrolidin-2- yl)methoxy)quinoline-3-acetonitrile [01316] 577.2 823 7-(benzothien-4-yl)-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01317] 595.2 824 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)quinoline- 3-acetonitrile [01318] 607.3 825 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (thiochroman-8-yl)quinoline-3-acetonitrile [01319] 627.2 826 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7- (benzo[b]thien-7-yl)-6-chloro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01320] 611.2 827 7-(benzothien-4-yl)-6-chloro-4-((S)-3-(cyanomethyl)-4- (2-fluoroacryloyl)piperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01321] 629.2 828 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl) quinoline-3-acetonitrile [01322] 591.3 829 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (thiochroman-8-yl)quinoline-3-carbonitrile [01323] 611.3 830 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7- (benzo[b]thien-7-yl)-8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile [01324] 595.2 831 7-(benzothien-4-yl)-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile [01325] 613.2 832 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)quinoline- 3-carbonitrile [01326] 591.3 833 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6- fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (thiochroman-8-yl)quinoline-3-acetonitrile [01327] 611.3 834 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7- (benzo[b]thien-7-yl)-6-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01328] 595.2 835 7-(benzothien-4-yl)-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-6-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)quinoline-3-acetonitrile [01329] 613.2 836 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)-1,6- naphthyridine-3-acetonitrile [01330] 592.3 837 4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1- yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 7-(thiochroman-8-yl)-1,6-naphthyridine-3-acetonitrile [01331] 630.2 838 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7- (benzo[b]thien-7-yl)-8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine- 3-acetonitrile [01332] 596.2 839 7-(benzothien-4-yl)-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-8-fluoro-2-((((S)-1- methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine- 3-acetonitrile [01333] 614.2

Example 840: 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0252] ##STR01334##

Step 1: Synthesis of 7-bromo-2,4-dichloropyridino[3,2-d]pyrimidine

[0253] N,N-diethylaniline (1.41 g, 9.45 mmol) was added to a mixture of 7-bromopyridino[3,2-d]pyrimidine-2,4-diphenol (1.04 g, 4.3 mmol) and phosphorus oxychloride (10 mL) at room temperature. The resulting light yellow suspension was stirred for 5 min, and then heated and stirred in a 110? C. oil bath for 16 h. After cooling to room temperature, concentration under reduced pressure was performed. The residue was mixed with toluene (20 mL?2) and subjected to concentration under reduced pressure. The resulting light brown solid was directly used for the next step of reaction.

Step 2: Synthesis of (S)-2-(4-(7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0254] N,N-diisopropylethylamine (4.27 mL, 25.8 mmol) was added to a mixture of 7-bromo-2,4-dichloropyridino[3,2-d]pyrimidine and tetrahydrofuran (30 mL) in one portion in an ice-water bath. After 2 minutes of stirring, (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (0.85 g, 4.3 mmol) was added. The reaction liquid was gradually warmed to room temperature and stirred for 5 h. The reaction liquid was directly used for the next step of reaction without treatment.

Step 3: Synthesis of tert-butyl (S)-4-(7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0255] At room temperature, triethylamine (0.6 mL, 4.3 mmol) and di-tert-butyl dicarbonate (1.31 g, 6 mmol) were added to the reaction liquid from the previous step. The reaction liquid was stirred at room temperature for 17 h. Ethyl acetate (100 mL) and water (100 mL) were added for extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a dark brown viscous material. Purification by column chromatography (silica gel, ethyl acetate:petroleum ether=1:20 to ethyl acetate:petroleum ether=1:5) gave a yellow solid. (210 mg, 0.449 mmol, overall yield over three steps: 10%). MS m/z: 467.4 [M+H].sup.+.

Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0256] dissolved in (S)-(1-methylpyrrolidin-2-yl)methanol (77 mg, 0.67 mmol) tetrahydrofuran (2 mL), sodium hydride (16 mg, 0.67 mmol) was added at 0? C., and the mixture was reacted at room temperature for 0.5 h. A solution of the compound tert-butyl (S)-4-(7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.22 mmol) in tetrahydrofuran (2 mL) was then added and the reaction continued at room temperature for 1 h. The mixed reaction liquid was concentrated under reduced pressure and purified by PLC to obtain the compound tert-butyl (S)-4-(7-bromo-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (82 mg, 67%). MS m/z: [M+H].sup.+=546.6.

Step 5: Synthesis of tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino [3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0257] The compound tert-butyl (S)-4-(7-bromo-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (50 mg, 0.091 mmol) and 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (56.1 mg, 0.18 mmol) were dissolved in 1,4-dioxane (2.0 mL). Pd(PPh.sub.3).sub.4 (31.7 mg, 0.027 mmol), cesium carbonate (89.4 mg, 0.27 mmol) and water (0.1 mL) were added in order in a nitrogen atmosphere, and the mixture was then heated to 100? C. and reacted at this temperature under stirring for 5 h. The mixed reaction liquid was concentrated under reduced pressure and purified by PLC to obtain the compound tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (35.5 mg, 60%). MS m/z: [M+H].sup.+=646.7.

Step 6: Synthesis of 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridinyl[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0258] The compound tert-butyl (S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (34 mg, 0.053 mmol) was dissolved in CH.sub.2Cl.sub.2 (1.5 mL), and TFA (0.5 mL) was added dropwise. The reaction liquid was stirred at room temperature until the reaction was complete. Subsequently, the reaction liquid was adjusted to pH=10 with 10% NaOH aqueous solution, separated, extracted with CH.sub.2Cl.sub.2, washed with a saturated aqueous NaCl solution, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to obtain the compound 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridinyl[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (24.3 mg, 84%). MS m/z: [M+H].sup.+=546.6.

Step 7: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0259] The compound 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (23 mg, 0.042 mmol) and triethylamine (13 mg, 0.13 mmol) were dissolved in CH.sub.2Cl.sub.2 (1.0 mL), acryloyl chloride (7.6 mg, 0.08 mmol) was then added dropwise to the solution, and the mixture was stirred at room temperature for 1 h. The reaction liquid was concentrated under pressurized condition and purified by PLC to obtain the compound 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (24 mg, 94%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.59 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91 (dd, J=8.9, 5.5 Hz, 2H), 7.56 (dd, J=15.5, 7.4 Hz, 1H), 7.50-7.38 (m, 2H), 7.05-6.81 (m, 1H), 6.45-6.30 (m, 1H), 5.81 (dd, J=21.5, 10.7 Hz, 1H), 4.76-4.68 (m, 1H), 4.43 (s, 1H), 4.25-3.28 (m, 5H), 3.05-2.91 (m, 4H), 2.49-1.87 (m, 10H). MS m/z: [M+H].sup.+=600.6

[0260] The compounds of Examples 841-853 were prepared by the preparation method for Example 840

TABLE-US-00006 m/z: Ex. Compound name Structural formula ES.sup.+[M + H] 841 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01335] 618.2 842 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2- ((S)-1-methylpyrrolidin-2-yl)methoxy)pyridino[3,2- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01336] 582.2 843 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyridino[3,2- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01337] 600.2 844 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1- yl)pyridino[3,2-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile [01338] 552.3 845 2-((S)-1-(2-fluoroacryloyl)-4-(2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8- tetrahydronaphthalen-1-yl)pyridino[3,2-d]pyrimidin- 4-yl)piperazin-2-yl)acetonitrile [01339] 570.3 846 2-((2S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[3,2- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01340] 550.3 847 2-((2S)-1-(2-fluoroacryloyl)-4-(2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[3,2- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01341] 568.3 848 2-((2S)-1-acryloyl-4-(2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[3,2- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01342] 576.3 849 2-((2S)-1-(2-fluoroacryloyl)-4-(2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl)pyridino[3,2- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [01343] 594.3 850 (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen- 1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[3,2-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [01344] 626.2 851 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01345] 644.2 852 2-((2S)-4-(7-(benzo[b]thien-4-yl)-2-((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01346] 616.2 853 2-((2S)-4-(7-(benzo[b]thien-7-yl)-2-((2R)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01347] 616.2

Example 854: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0261] ##STR01348##

Step 1: Synthesis of (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol

[0262] The compound (1-(aminomethyl)cyclopropyl)methanol (500 mg, 4.94 mmol) and 1,4-dibromobutane (1.12 g, 5.19 mmol) were dissolved in acetonitrile (20 mL), potassium carbonate (1.78 g, 12.85 mmol) was then added, and the mixture was reacted at room temperature under stirring for 12 h. After the reaction was complete, filtration was carried out to remove a solid. The organic phase was concentrated and separated by column chromatography (DCM/7M NH3 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).

Step 2: Synthesis of tert-butyl (S)-4-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0263] The compound tert-butyl (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyridino[4,3-d]pyrimidin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.21 mmol) and (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (37 mg, 0.23 mmol) were dissolved in anhydrous toluene (3 mL), sodium tert-butoxide (25 mg, 0.25 mmol) was added under ice-water bath cooling condition, and the mixture was reacted under stirring for 30 min. After the reaction liquid was complete, the reaction was quenched with cold water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, separated and purified by prep-TLC to obtain an off-white solid. (50 mg, yield: 42%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.78 (s, 1H), 4.62 (s, 1H), 4.42 (q, J=10.9 Hz, 3H), 4.29 (d, J=12.8 Hz, 1H), 4.08 (s, 1H), 3.88 (s, 1H), 3.66 (s, 1H), 3.46 (s, 1H), 2.87-2.77 (m, 1H), 2.73 (d, J=5.7 Hz, 1H), 2.53 (s, 6H), 1.74 (s, 4H), 1.51 (s, 9H), 0.68 (s, 2H), 0.51 (s, 2H).

Step 3: Synthesis of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0264] The compound tert-butyl (S)-4-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (50 mg, 0.09 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (34 mg, 0.12 mmol) and cesium carbonate (87 mg, 0.27 mmol) were dissolved in 1,4-dioxane/water=5/1 (3 mL), Pd(PPh.sub.3).sub.4 (52 mg, 0.04 mmol) was then added, and after displacement with nitrogen three times, the mixture was heated to 100? C. and reacted under stirring for 2 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, separated and purified by prep-TLC to obtain an off-white solid. (20 mg, yield: 33%).

Step 4: Synthesis of (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0265] The compound tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 30 min. After the reaction was complete, the reaction liquid was concentrated to obtain a crude product, which was directly used for the next step.

Step 5: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0266] The compound (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (17 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), DIEA (5 mg, 0.03 mmol) and acryloyl chloride (3 mg, 0.03 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 5 min. After the reaction was complete, the reaction was quenched 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 prep-TLC to obtain an off-white solid. (10 mg, yield: 50%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.05 (s, 1H), 8.01 (dd, J=7.9, 1.5 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.66-7.50 (m, 3H), 7.42 (td, J=7.8, 2.4 Hz, 1H), 6.59 (s, 1H), 6.42 (d, J=16.8 Hz, 1H), 5.85 (d, J=10.8 Hz, 1H), 5.08 (s, 1H), 4.46 (d, J=10.5 Hz, 4H), 3.90 (d, J=103.6 Hz, 5H), 3.06 (s, 1H), 2.82 (d, J=17.1 Hz, 2H), 2.55 (s, 4H), 1.78 (s, 4H), 0.73 (s, 2H), 0.57 (s, 2H). MS m/z: [M+H].sup.+=640.59

Example 855: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0267] ##STR01349##

Step 1: Synthesis of tert-butyl (S)-4-(7-bromo-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate

[0268] The compound (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (84 mg, 0.54 mmol) was dissolved in anhydrous THF (5 mL), 60% NaH (20 mg, 0.50 mmol) was added under ice-water bath cooling condition, the mixture was reacted under stirring and ice-water bath cooling conditions for 20 min, the compound tert-butyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.41 mmol) was added, and the mixture was then reacted at room temperature under stirring for 8 h. After the reaction was complete, the reaction was quenched with cold water and extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a light yellow solid. (150 mg, yield: 61%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.46 (d, J=9.1 Hz, 1H), 7.38 (dd, J=9.0, 6.0 Hz, 1H), 4.65 (s, 1H), 4.42 (s, 2H), 4.24 (d, J=12.2 Hz, 1H), 4.16 (d, J=10.8 Hz, 2H), 3.54 (dd, J=13.8, 3.6 Hz, 1H), 3.32 (d, J=10.4 Hz, 2H), 2.87-2.69 (m, 2H), 2.50 (s, 6H), 1.71 (s, 4H), 1.52 (s, 11H), 0.67 (s, 2H), 0.48 (s, 2H).

Step 2: Synthesis of tert-butyl (S)-4-(7-(8-chloronaphthalene)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0269] The compound tert-butyl (S)-4-(7-bromo-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl-2-(cyanomethyl)piperazine-1-carboxylate (130 mg, 0.22 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (93 mg, 0.0.32 mmol) and potassium carbonate (60 mg, 0.43 mmol) were dissolved in 1,4-dioxane/water=5/1 (3 mL), Pd(dppf)Cl.sub.2 (31 mg, 0.04 mmol) was then added, and after displacement with nitrogen three times, the mixture was heated to 100? C. and reacted under stirring for 2 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, separated and purified by prep-TLC to obtain an off-white solid. (80 mg, yield: 54.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.97 (d, J=8.1 Hz, 1H), 7.88 (d, J=7.4 Hz, 1H), 7.54 (dd, J=14.2, 4.9 Hz, 3H), 7.45-7.38 (m, 2H), 7.23 (d, J=6.6 Hz, 1H), 4.70 (s, 1H), 4.36 (dd, J=30.7, 19.9 Hz, 4H), 4.14 (s, 1H), 3.55 (d, J=11.7 Hz, 1H), 3.36 (s, 2H), 2.87 (s, 2H), 2.51 (s, 4H), 1.71 (s, 4H), 1.53 (s, 9H), 0.67 (s, 2H), 0.47 (s, 2H).

Step 3: Synthesis of (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0270] The compound tert-butyl (S)-4-(7-(8-chloronaphthalene)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (80 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was then added, and the mixture was reacted at room temperature under stirring for 1 h. After the reaction was complete, the reaction liquid was concentrated to obtain a crude product, which was directly used for the next step.

Step 4: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0271] The compound (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (68 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL), DIEA (18 mg, 0.14 mmol) and acryloyl chloride (12 mg, 0.13 mmol) were added under ice-water bath cooling condition, and the mixture was reacted under stirring and ice-water bath cooling conditions for 5 min. After the reaction was complete, the reaction was quenched 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 prep-TLC to obtain an off-white solid. (42 mg, yield: 56%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.97 (d, J=7.3 Hz, 1H), 7.88 (d, J=7.4 Hz, 1H), 7.68-7.60 (m, 1H), 7.55 (dd, J=9.7, 8.0 Hz, 2H), 7.43 (dd, J=7.8, 2.3 Hz, 2H), 7.26 (m, 1H), 6.61 (s, 1H), 6.42 (d, J=16.8 Hz, 1H), 5.84 (d, J=10.5 Hz, 1H), 5.16 (s, 1H), 4.54-4.26 (m, 4H), 4.02 (s, 1H), 3.53 (d, J=89.6 Hz, 4H), 3.01 (s, 1H), 2.89 (d, J=34.6 Hz, 1H), 2.51 (s, 6H), 1.72 (s, 4H), 0.69 (s, 2H), 0.48 (s, 2H). MS m/z: [M+H].sup.+=639.61.

[0272] The compounds of Examples 856-871 were prepared by the preparation method for Examples 854 and 855

TABLE-US-00007 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 856 (S)-2-(4-(7-(8-chloronaphthalen-1- yl)-8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)pyridino[4,3- d]pyrimidin-4-yl)-1- (2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01350] 658.2 857 (S)-2-(4-(7-(8-chloro-7- fluoronaphthalen-1-yl)-8- fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy) pyridino[4,3-d]pyrimidin-4- yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile [01351] 676.2 858 (S)-2-(1-acryloyl-4-(7-(8-chloro- 7-fluoronaphthalen-1-yl)-8- fluoro-2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl)methoxy) pyridino[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [01352] 658 859 (S)-2-(4-(7-(8- acetenylnaphthalen- 1-yl)-8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)c yclopropyl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2- yl)acetonitrile [01353] 648 860 (S)-2-(1-acryloyl-4-(7-(8- acetenylnaphthalen-1-yl)-8- fluoro-2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl)methoxy) pyridino[4,3-d]pyrimidin-4-yl) piperazin-2-yl)acetonitrile [01354] 630 861 (S)-2-(4-(7-(8-chloronaphthalen- 1-yl)-8-fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2-yl)acetonitrile [01355] 657 862 (S)-2-(4-(7-(8-chloro-7- fluoronaphthalen-1-yl)-8-fluoro- 2-((1-(pyrrolidin-1-ylmethyl) cyclopropyl)methoxy) quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2- yl)acetonitrile [01356] 675 863 (S)-2-(1-acryloyl-4-(7-(8- chloro-7-fluoronaphthalen-1- yl)-8-fluoro-2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl)methoxy) quinazolin-4-yl)piperazin-2- yl)acetonitrile [01357] 657 864 (S)-2-(4-(7-(8-acetenylnaphthalen- 1-yl)-8-fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2-yl)acetonitrile [01358] 647 865 (S)-2-(1-acryloyl-4-(7-(8- acetenylnaphthalen-1-yl)-8-fluoro-2- ((1-(pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01359] 629 866 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2- yl)pyridinyl[4,3-d]pyrimidin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2-yl)acetonitrile [01360] 626.5 867 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden- 2-yl)pyridinyl[4,3-d]pyrimidin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2-yl)acetonitrile, isomer 1 [01361] 626.5 868 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2- yl)pyridinyl[4,3-d]pyrimidin- 4-yl)-1-(2-fluoroacryloyl)piperazin- 2-yl)acetonitrile, isomer 2 [01362] 626.5 869 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2- yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl) acetonitrile [01363] 625.5 870 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden- 2-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl) acetonitrile, isomer 1 [01364] 625.5 871 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1-ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-2-yl) quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl) acetonitrile, isomer 2 [01365] 625.5

Example 872: Synthesis of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0273] ##STR01366##

Step 1: Synthesis of 5-bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene

[0274] A solution of diethyl zinc/n-hexane (1M, 423 mL) in anhydrous dichloromethane (200 mL) was cooled in an ice-water bath. A solution of trifluoroacetic acid (31 mL, 423 mmol) in anhydrous dichloromethane (200 mL) was added dropwise. After stirring at this temperature for 20 min, a solution of diiodomethane (34.3 mL, 423 mmol) in anhydrous dichloromethane (100 mL) was added. After continued stirring for 20 min, a solution of 7-bromo-1H-indene (22 g, 113 mmol) in anhydrous dichloromethane (100 mL) was slowly added dropwise. The ice-water bath was removed, and after stirring for 16 h, a white suspension was obtained. Dilute hydrochloric acid (0.1 M, 500 mL) was slowly added under stirring. The resulting mixture was extracted with petroleum ether (500 mL+200 mL). The organic phases were combined, washed with a saturated sodium bicarbonate solution (300 mL) and with a saturated aqueous NaCl solution (300 mL), dried with sodium sulfate and concentrated in vacuo to obtain a yellow oil. The product 5-bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene was obtained by column chromatography (silica gel, petroleum ether) as a light yellow oil (22 g, 105 mmol, yield 93%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.24-7.20 (m, 2H), 7.00-6.96 (m, 1H), 3.13 (dd, J=17.6, 6.7 Hz, 1H), 2.97 (d, J=17.6 Hz, 1H), 2.46-2.41 (m, 1H), 1.91-1.85 (m, 1H), 1.12-1.06 (m, 1H), 0.13-0.10 (m, 1H)

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

[0275] 5-bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene (30 g, 144 mmol), bis(pinacolato)diboron (72.9 g, 287 mmol), Pd(dppf)Cl.sub.2 (21 g, 28.7 mmol) and potassium acetate (42 g, 431 mmol) were added to a round-bottomed flask. After displacement with nitrogen, anhydrous 1,4-dioxane (400 mL) which had been deoxidized in advance was added. The resulting suspension was stirred at 100? C. for 16 h. After cooling to room temperature, the reaction mixture was extracted with water (500 mL) and methyl tert-butyl ether (500 mL). After layering, the aqueous phase was extracted with methyl tert-butyl ether (300 mL). The combined organic phases were washed with a saturated aqueous NaCl solution (300 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=1:40) to obtain a colorless oil, which was left to stand to slowly become a light yellow solid (26 g, 101 mmol, yield: 70%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.54 (dd, J=8.0, 2.0 Hz, 1H), 7.38 (dd, J=8.0, 0.2 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 3.29 (dd, J=17.6, 6.7 Hz, 1H), 3.20 (d, J=17.6 Hz, 1H), 2.36-2.31 (m, 1H), 1.88-1.81 (m, 1H), 1.55 (s, 12H), 1.05-1.00 (m, 1H), 0.06-0.01 (m, 1H)

Step 3: Synthesis of tert-butyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0276] Tert-butyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (300 mg, 0.53 mmol), 4,4,5,5-tetramethyl-2-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yl)-1,3,2-dioxolane (244 mg, 0.954 mmol), Pd(dppf)Cl.sub.2 (78 mg, 0.106 mmol) and potassium carbonate (146 mg, 1.06 mmol) were added to a round-bottomed flask. After displacement with nitrogen, 1,4-dioxane (5 mL) and water (1 mL) which had been deoxidized in advance was added. The reaction liquid was stirred at 100? C. for 4 h. Ethyl acetate (30 mL) and water (20 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with a saturated aqueous NaCl solution (20 mL), dried with sodium sulfate and spin-dried in vacuo. The remaining brown viscous material was purified by prep-TLC (silica gel, methanol:dichloromethane=1:9) to obtain a light yellow solid. (140 mg, 0.228 mmol, yield: 43%) MS m/z: 613.4 [M+H].sup.+.

Step 4: Synthesis of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0277] Trifluoroacetic acid (0.8 mL) was added dropwise to a solution of tert-butyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)piperazine-1-carboxylate (29 mg, 0.047 mmol) in dichloromethane (4 mL) at room temperature. The resulting solution was stirred at room temperature for 4 h. Dichloromethane (10 mL) was added and concentration in vacuo was performed. Dichloromethane (5 mL) was added to the resulting residue, concentration was performed again, and this process was repeated once. The resulting yellow solid was directly used for the next step.

Step 5: Synthesis of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0278] A solution of 2-fluoroacrylic acid (8.5 mg, 0.095 mmol) and HATU (27 mg, 0.071 mmol) in dichloromethane (3 mL) was cooled in an ice-water bath. Triethylamine (0.026 mL, 0.189 mmol) was added dropwise. The ice-water bath was removed and stirring was performed for 20 min. A solution of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile in dichloromethane (2 mL) was added in one portion. Stirring was performed at room temperature for 6 h. Dichloromethane (17 mL), water (15 mL) and a saturated sodium carbonate solution (5 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation under reduced pressure to obtain a yellow solid. Purification by prep-TLC (methanol:dichloromethane=1:8) gave 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (60 mg, 0.103 mmol, overall yield over two steps: 63%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.64 (d, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 5.46 (d, J=16 Hz, 1H), 5.27 (dd, J=16.4, 4.0 Hz, 1H), 4.99-4.94 (m, 1H), 4.64 (dd, J=8.0, 4.0 Hz, 1H), 4.44 (d, J=16 Hz, 1H), 4.34 (d, J=16 Hz, 1H), 3.73-3.40 (m, 6H), 3.16-3.05 (m, 2H), 2.86 (s, 3H), 2.77-2.73 (m, 1H), 2.45-2.41 (m, 1H), 2.30-2.25 (m, 1H), 2.30-2.25 (, 1H), 2.16-2.00 (, 3H), 1.88-1.83 (m, 1H), 1.11-1.06 (nm, 1H), 0.14-0.12 (i, 1H). MS m/z: [M+H].sup.+=5185.4.

[0279] The compounds of Examples 873-902 were prepared by the preparation method for Example 872

TABLE-US-00008 Ex. Compound name Structural formula m/z: ES.sup.+[M + H] 873 2-((2S)-1-acryloyl-4- (8-fluoro-2-((S)-1- methylpyrrolidin-2-yl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)pyridinyl [4,3-d]pyrimidin-4-yl) piperazin-2-yl)acetonitrile, 1st eluting isomer [01367] 568.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 874 2-((2S)-1-acryloyl-4- (8-fluoro-2-((S)-1- methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)pyridinyl[4,3- d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile, 2nd eluting isomer [01368] 568.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 875 2-((2S)-4-(8-fluoro-2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)pyridinyl[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile, 1st eluting isomer [01369] 586.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 876 2-((2S)-4-(8-fluoro-2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)pyridinyl[4,3- d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile, 2nd eluting isomer [01370] 586.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 877 2-((2S)-1-acryloyl-4-(8- fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile, 1st eluting isomer [01371] 612.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 878 2-((2S)-1-acryloyl-4-(8- fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)pyridino[4,3- d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile, 2nd eluting isomer [01372] 612.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 879 2-((2S)-4-(8-fluoro-2- ((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)pyridinyl [4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile, 1st eluting isomer [01373] 630.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 880 2-((2S)-4-(8-fluoro- 2-((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)pyridinyl [4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile, 2nd eluting isomer [01374] 630.4 SFC(Chiralpak AD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 3.4 mL/min, 1800 psi 881 2-((2S)-1-acryloyl-4- (8-fluoro-2-((S)-1- methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, 1st eluting isomer [01375] 567.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 882 2-((2S)-1-acryloyl-4- (8-fluoro-2-((S)-1- methylpyrrolidin-2-yl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, 2nd eluting isomer [01376] 567.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 883 2-((2S)-4-(8-fluoro-2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, 1st eluting isomer [01377] 585.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 884 2-((2S)-4-(8-fluoro-2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, 2nd eluting isomer [01378] 585.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 885 2-((2S)-1-acryloyl-4-(8- fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, 1st eluting isomer [01379] 611.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 886 2-((2S)-1-acryloyl-4-(8- fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, 2nd eluting isomer [01380] 611.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 887 2-((2S)-4-(8-fluoro-2- ((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, 1st eluting isomer [01381] 629.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 888 2-((2S)-4-(8-fluoro-2- ((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, 2nd eluting isomer [01382] 629.4 SFC(Chiralcel OD-3, 50 ? 4.6 mm I.D., 3 ?m, 50% EtOH (0.1% IPAm)/CO.sub.2, 4 mL/min, 1800 psi 889 2-((2S)-1-acryloyl-4-(8- fluoro-2-((S)-1- methylpyrrolidin-2-yl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-2-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 1 [01383] 567.4 890 2-((2S)-1-acryloyl-4-(8- fluoro-2-((S)-1- methylpyrrolidin-2-yl )methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-2-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 2 [01384] 567.4 891 2-((2S)-4-(8-fluoro-2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-2-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, isomer 1 [01385] 585.4 892 2-((2S)-4-(8-fluoro-2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-2-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, isomer 2 [01386] 585.4 893 2-((2S)-1-acryloyl-4-(8- fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-2-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 1 [01387] 611.4 894 2-((2S)-1-acryloyl-4-(8- fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-2-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 2 [01388] 611.4 895 2-((2S)-1-acryloyl-4- (2-((S)-1- methylpyrrolidin-2-yl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 1 [01389] 549.4 896 2-((2S)-1-acryloyl- 4-(2-((S)-1- methylpyrrolidin-2- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 2 [01390] 549.4 897 2-((2S)-1-(2- fluoroacryloyl)-4-(2- ((S)-1-methylpyrrolidin- 2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 1 [01391] 567.4 898 2-((2S)-1-(2-fluoroacryloyl)- 4-(2-((S)-1- methylpyrrolidin-2-yl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a] inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 2 [01392] 567.4 899 2-((2S)-1-acryloyl-4- (2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7- (1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 1 [01393] 593.4 900 2-((2S)-1-acryloyl-4- (2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 2 [01394] 593.4 901 2-((2S)-1-(2- fluoroacryloyl)-4- (2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 1 [01395] 611.4 902 2-((2S)-1-(2- fluoroacryloyl)-4- (2-(((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)piperazin-2-yl) acetonitrile, isomer 2 [01396] 611.4 903 2-((S)-4-(7-(8- chloronaphthalen-1- yl)-8-fluoro- 2-((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin- 4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile [01397] 617.3 904 2-((S)-4-(7-(8- chloronaphthalen-1- yl)-8-fluoro- 2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin- 7a(5H)-methoxy) quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile [01398] 661.3 905 2-((2S)-1-acryloyl-4- (8-fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)- 7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5- yl)pyridinyl[4,3-d] pyrimidin-4-yl)piperazin-2- yl)acetonitrile, isomer 1 [01399] 608.4 906 2-((2S)-1-acryloyl-4- (8-fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)- 7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5- yl)pyridinyl[4,3-d] pyrimidin-4-yl)piperazin-2- yl)acetonitrile, isomer 2 [01400] 608.4 907 2-((2S)-4-(8-fluoro-2- ((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)pyridinyl [4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin- 2-yl)acetonitrile, isomer 1 [01401] 626.4 908 2-((2S)-4-(8-fluoro-2-((1- (pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5- yl)pyridinyl[4,3-d] pyrimidin-4-yl)-1-(2- fluoroacryloyl) piperazin-2-yl)acetonitrile, isomer 2 [01402] 626.4 909 2-((2S)-1-acryloyl-4-(8- fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)- 7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5- yl)quinazolin-4-yl) piperazin-2-yl)acetonitrile, isomer 1 [01403] 607.4 910 2-((2S)-1-acryloyl-4- (8-fluoro-2-((1- (pyrrolidin-1-ylmethyl) cyclopropyl)methoxy)- 7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5- yl)quinazolin-4-yl) piperazin-2-yl)acetonitrile, isomer 2 [01404] 607.4 911 2-((2S)-4-(8-fluoro-2- ((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, isomer 1 [01405] 625.4 912 2-((2S)-4-(8-fluoro-2- ((1-(pyrrolidin-1- ylmethyl)cyclopropyl) methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa [a]inden-5-yl)quinazolin- 4-yl)-1-(2-fluoroacryloyl) piperazin-2- yl)acetonitrile, isomer 2 [01406] 625.4 913 2-((S)-4-(7-(8-chloro-7- fluoronaphthalen-1-yl)- 8-fluoro-2-((S)-1- methylpyrrolidin-2- yl)methoxy)quinazolin- 4-yl)-1-(2- fluoroacryloyl) piperazin-2-yl)acetonitrile [01407] 635.4 914 2-((S)-4-(7-(8-chloro-7- fluoronaphthalen-1-yl)- 8-fluoro-2-((2R,7aS)-2- fluorotetrahydro-1H- pyrrolizin-7a(5H)- ylmethoxy)quinazolin-4-yl)- 1-(2-fluoroacryloyl) piperazin-2-yl)acetonitrile [01408] 679.4

Example 915: Synthesis of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-ylmethoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0280] ##STR01409##

Step 1: Synthesis of tert-butyl (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0281] N,N-diisopropylethylamine (4.27 mL, 25.8 mmol) was added to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.5 g, 7.58 mmol) and N,N-dimethylformamide (30 mL) in an ice-water bath. After 2 minutes of stirring, (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (1.50 g, 7.60 mmol) was added. The reaction was carried out in an ice-water bath at room temperature and stirred for 1 h.

[0282] N,N-diisopropylethylamine (1.42 mL, 8.6 mmol) and di-tert butyl dicarbonate (1.96 g, 9 mmol) were added to the above reaction liquid at room temperature. The reaction liquid was stirred at room temperature for 4 h. Ethyl acetate (200 mL) and water (200 mL) were added for exaction and separation. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with water (50 mL?3) and with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a dark brown viscous material. Purification by column chromatography (silica gel, ethyl acetate:petroleum ether=1:10 to ethyl acetate:petroleum ether=1:5) gave a yellow solid. (3.8 g, 7.32 mmol, yield: 96%). MS m/z: 518.2 [M+H].sup.+.

Step 2: Synthesis of tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0283] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.4 g, 8.78 mmol) in tetrahydrofuran (30 mL) was cooled in an ice-water bath. Sodium hydride (0.32 g, 8.05 mmol) was added, and a reaction was carried out at room temperature for 0.5 h. A solution of tert-butyl (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (3.8 g, 7.32 mmol) in tetrahydrofuran (15 mL) was added, and the reaction continued at room temperature for 1 h. Ethyl acetate (100 mL) and a diluted sodium carbonate aqueous solution (100 mL) were added for extraction, and the aqueous phase was extracted by ethyl acetate (50 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a light brown solid. Purification by column chromatography (silica gel, methanol:dichloromethane=1:40) gave tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2.1 g, 3.21 mmol, yield: 44%). MS m/z: [M+H].sup.+=641.3.

Step 3: Synthesis of tert-butyl (S)-4-(7-bromo-6-chloro-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0284] Tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.9 g, 2.96 mmol) and cyclopropanol (0.34 g, 6.0 mmol) were dissolved in tetrahydrofuran (20 mL). Sodium hydrogen (0.14 g, 3.5 mmol) was added in a nitrogen atmosphere, and the mixture was heated to 60? C. and reacted for 2 h. Ethyl acetate (100 mL) and water (100 mL) were added for extraction. The organic phase was washed with a saturated aqueous NaCl solution (30 mL), dried with sodium sulfate and then concentrated under reduced pressure. The remaining viscous material was purified by column chromatography (silica gel, methanol:dichloromethane=1:40) to obtain tert-butyl (S)-4-(7-bromo-6-chloro-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (0.8 g, 1.18 mmol, yield: 40%). MS m/z: [M+H].sup.+=679.4.

Step 4: Synthesis of tert-butyl (2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0285] Tert-butyl (S)-4-(7-bromo-6-chloro-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.294 mmol), 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (144 mg, 0.47 mmol), Pd(dppf)Cl.sub.2 (22 mg, 0.0294 mmol) and potassium carbonate (81 mg, 0.59 mmol) were added to an eggplant-shaped flask. Displacement with nitrogen was carried out three times. A mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) which had been deoxidized in advance was added. Displacement with nitrogen was carried out three times. Then, after heating to 100? C., a reaction was carried out under stirring for 4 h. After cooling to room temperature, ethyl acetate (50 mL) and a diluted sodium carbonate aqueous solution (50 mL) were added for extraction. The organic phase was washed with a saturated aqueous NaCl solution (20 mL), dried with sodium sulfate and then concentrated under reduced pressure. The resulting brown viscous material was subjected to column chromatography (silica gel, triethylamine:methanol:dichloromethane=0.04:1:40) to obtain the compound tert-butyl (2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (41 mg, 0.0525 mmol, yield: 18%). MS m/z: [M+H]+=779.5.

Step 5: Synthesis of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0286] The compound tert-butyl (2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (40 mg, 0.0513 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The reaction liquid was stirred at room temperature for 4 h. Dichloromethane (30 mL) and a saturated sodium carbonate aqueous solution (20 mL) were added for extraction. The aqueous phase was extracted with dichloromethane (10 mL?2). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile. The product was directly used for the next step of reaction without further purification. MS m/z: [M+H]+=679.4.

Step 6: Synthesis of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0287] A solution of 2-fluoroacrylic acid (8.5 mg, 0.095 mmol) and HATU (27 mg, 0.071 mmol) in dichloromethane (3 mL) was cooled in an ice-water bath. Triethylamine (0.026 mL, 0.189 mmol) was added dropwise. The ice-water bath was removed and stirring was performed for 20 min. A solution of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile in dichloromethane (2 mL) was added in one portion. Stirring was performed at room temperature for 6 h. Dichloromethane (17 mL), water (15 mL) and a saturated sodium carbonate solution (5 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation under reduced pressure to obtain a yellow solid. Purification by prep-TLC (methanol:dichloromethane=1:10) gave 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (19 mg, 0.0253 mmol, overall yield over two steps: 48%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.96 (d, J=7.8 Hz, 1H), 7.88-7.86 (m, 1H), 7.65-7.63 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.33 (s, 1H), 7.27-7.24 (m, 1H), 5.45 (d, J=48 Hz, 1H), 5.46 (d, J=16 Hz, 1H), 5.27 (dd, J=16.4, 4.0 Hz, 1H), 4.89 (brs, 1H), 4.45-4.24 (m, 4H), 3.67-3.64 (m, 2H), 3.48-3.44 (m, 2H), 3.33-3.31 (m, 3H), 3.24-3.19 (m, 2H), 3.10-2.88 (m, 3H), 2.29-2.16 (m, 2H), 1.96-1.92 (m, 3H), 0.30-0.10 (m, 4H). MS m/z: [M+H].sup.+=751.4

[0288] The compounds of Examples 916-938 were prepared by the preparation method for Example 915

TABLE-US-00009 Ex. Compound name Structural formula m/z: ES.sup.+ [M + H] 916 2-((2S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8- cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01410] 733.4 917 2-((2S)-4-(6-chloro-8-cyclopropoxy-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01411] 701.5 918 2-((2S)-4-(6-chloro-8-cyclopropoxy-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile, isomer 1 [01412] 701.5 919 2-((2S)-4-(6-chloro-8-cyclopropoxy-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile, isomer 2 [01413] 701.5 920 2-((2S)-1-acryloyl-4-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01414] 733.4 921 2-((2S)-1-acryloyl-4-(6-chloro-7-(8-chloronaphthalen- 1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-ylmethoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01415] 715.4 922 2-((2S)-1-acryloyl-4-(6-chloro-8-cyclopropoxy-2- ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile, isomer 1 [01416] 683.5 923 2-((2S)-1-acryloyl-4-(6-chloro-8-cyclopropoxy-2- ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile, isomer 2 [01417] 683.5 924 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthalen-1- yl)-8-cyclopropoxy-2-((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01418] 707.4 925 2-((2S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8- cyclopropoxy-2-((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01419] 689.4 926 2-((2S)-4-(6-chloro-8-cyclopropoxy-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile, isomer 1 [01420] 657.5 927 2-((2S)-4-(6-chloro-8-cyclopropoxy-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile, isomer 2 [01421] 657.5 928 2-((2S)-1-acryloyl-4-(6-chloro-7-(8-chloro-7- fluoronaphthalen-1-yl)-8-cyclopropoxy-2-((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)piperazin-2-yl)acetonitrile [01422] 689.4 929 2-((2S)-1-acryloyl-4-(6-chloro-7-(8-chloronaphthalen- 1-yl)-8-cyclopropoxy-2-((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [01423] 671.4 930 2-((2S)-1-acryloyl-4-(6-chloro-8-cyclopropoxy-2-((S)- 1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile, isomer 1 [01424] 639.3 931 2-((2S)-1-acryloyl-4-(6-chloro-8-cyclopropoxy-2-((S)- 1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4- yl)piperazin-2-yl)acetonitrile, isomer 2 [01425] 639.3 932 2-((2S)-4-(6-chloro-8-cyclopropoxy-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7- (5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01426] 703.5 933 2-((2S)-1-acryloyl-4-(6-chloro-8-cyclopropoxy-2- ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin- 4-yl)piperazin-2-yl)acetonitrile [01427] 685.5 934 2-((2S)-4-(8-cyclopropoxy-2-((2R,7aS)-2- fluorotetahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(5-methyl-1H-indazol-4-yl)pyridinyl[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01428] 670.5 935 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8- cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyridinyl[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01429] 700.5 936 2-((S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8- cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyridino[4,3- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile [01430] 718.4 937 2-((2S)-4-(8-cyclopropoxy-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)pyridinyl[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile, isomer 1 [01431] 668.5 938 2-((2S)-4-(8-cyclopropoxy-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)pyridinyl[4,3-d]pyrimidin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile, isomer 2 [01432] 668.5

Example 939: Synthesis of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0289] ##STR01433##

Step 1: Synthesis of tert-butyl (S)-4-(7-bromo-2-chloro-8-fluoro-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0290] N,N-diisopropylethylamine (6.6 mL, 40 mmol) was added to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-methoxyquinazoline (4.0 g, 12.3 mmol) in N,N-dimethylformamide (40 mL) in one portion in an ice-water bath. After one minute of stirring, (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (2.55 g, 12.9 mmol) was added. The reaction was carried out in an ice-water bath at room temperature and stirred for 1 h.

[0291] N,N-diisopropylethylamine (2.2 mL, 13.3 mmol) and di-tert butyl dicarbonate (3.27 g, 15 mmol) were added to the above reaction liquid at room temperature. The reaction liquid was stirred at room temperature for 4 h. Ethyl acetate (200 mL) and water (200 mL) were added for exaction and separation. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with water (60 mL?3) and with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a dark brown viscous material. Purification by column chromatography (silica gel, ethyl acetate:petroleum ether=1:10 to ethyl acetate:petroleum ether=1:5) gave a yellow solid. (5.4 g, 10.5 mmol, yield: 85%). MS m/z: 514.2 [M+H]+.

Step 2: Synthesis of tert-butyl (S)-4-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0292] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.9 g, 12 mmol) in tetrahydrofuran (40 mL) was cooled in an ice-water bath. Sodium hydride (0.44 g, 11 mmol) was added, and a reaction was carried out at room temperature for 0.5 h. Tert-butyl (S)-4-(7-bromo-2-chloro-8-fluoro-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (5.4 g, 10.5 mmol) was added in one portion, and the reaction continued at room temperature for 1 h. Ethyl acetate (100 mL) and a diluted sodium carbonate aqueous solution (100 mL) were added for extraction, and the aqueous phase was extracted by ethyl acetate (50 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (50 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a light brown solid. Purification by column chromatography (silica gel, methanol:dichloromethane=1:40) gave tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (4.0 g, 6.27 mmol, yield: 60%). MS m/z: [M+H].sup.+=637.4.

Step 3: Synthesis of tert-butyl (2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0293] Tert-butyl (S)-4-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (300 mg, 0.47 mmol), 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (230 mg, 0.75 mmol), Pd(dppf)Cl.sub.2 (34 mg, 0.047 mmol), and potassium carbonate (127 mg, 0.94 mmol) were added to an eggplant-shaped flask. Displacement with nitrogen was carried out three times. A mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) which had been deoxidized in advance was added. Displacement with nitrogen was carried out three times. Then, after heating to 100? C., a reaction was carried out under stirring for 4 h. After cooling to room temperature, ethyl acetate (50 mL) and a diluted sodium carbonate aqueous solution (50 mL) were added for extraction. The organic phase was washed with a saturated aqueous NaCl solution (20 mL), dried with sodium sulfate and then concentrated under reduced pressure. The resulting brown viscous material was subjected to column chromatography (silica gel, triethylamine:methanol:dichloromethane=0.04:1:50) to obtain the compound tert-butyl (2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (71 mg, 0.096 mmol, yield: 20%). MS m/z: [M+H].sup.+=737.5.

Step 4: Synthesis of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)piperazin-2-yl)acetonitrile

[0294] The compound tert-butyl (2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (70 mg, 0.096 mmol) was dissolved in dichloromethane (6 mL), the mixture was cooled in an ice-water bath, and a solution of boron tribromide (0.057 mL, 0.77 mmol) in dichloromethane (3 mL) was added dropwise. The reaction was carried out in an ice-water bath for 1. Dichloromethane (30 mL) was added and methanol (10 mL) was slowly added dropwise. Rotary evaporation under reduced pressure was carried out, and dichloromethane (20 mL) and a saturated sodium carbonate aqueous solution (20 mL) was added to the residue for extraction. The aqueous phase was extracted with dichloromethane (10 mL?2). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and concentrated under reduced pressure to obtain a yellow viscous material. Purification by prep-TLC (methanol:dichloromethane=1:7) gave 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.024 mmol, yield: 25%). MS m/z: [M+H]+=623.4.

Step 5: Synthesis of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0295] A solution of 2-fluoroacrylic acid (4.3 mg, 0.048 mmol) and HATU (11 mg, 0.03 mmol) in dichloromethane (3 mL) was cooled in an ice-water bath. Triethylamine (0.014 mL, 0.1 mmol) was added dropwise. The ice-water bath was removed and stirring was performed for 20 min. A solution of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.024 mmol) in dichloromethane (2 mL) was added in one portion. Stirring was performed at room temperature for 2 h. Dichloromethane (17 mL), water (15 mL) and a saturated sodium carbonate solution (5 mL) were added, and after shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, washed with a saturated aqueous NaCl solution (10 mL), dried with sodium sulfate and subjected to rotary evaporation under reduced pressure to obtain a yellow solid. Purification by prep-TLC (methanol:dichloromethane=1:10) gave 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (5 mg, 0.0072 mmol, yield: 30%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.88 (d, J=7.8 Hz, 1H), 7.88-7.86 (m, 1H), 7.65-7.63 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.27-7.24 (m, 1H), 7.01 (s, 1H), 5.45 (d, J=48 Hz, 1H), 5.46 (d, J=16 Hz, 1H), 5.27 (dd, J=16.4, 4.0 Hz, 1H), 4.90 (brs, 1H), 4.45-4.29 (m, 4H), 3.68-3.64 (m, 2H), 3.46-3.44 (m, 2H), 3.33-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.10-2.88 (m, 3H), 2.29-2.16 (m, 2H), 1.96-1.92 (m, 3H). MS m/z: [M+H].sup.+=695.4

[0296] The compounds of Examples 940-945 were prepared by the preparation method for Example 939

TABLE-US-00010 Ex. Compound name Structural formula ES.sup.+[M + H] 940 2-((2S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2- ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-hydroxyquinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01434] 677.4 941 2-((2S)-4-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-6-hydroxy-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile, isomer 1 [01435] 645.3 942 2-((2S)-4-(8-fluoro-2-((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-6-hydroxy-7- (1,1a,6,6a-tetrahydrocyclopropa[a]inden-5- yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)acetonitrile, isomer 2 [01436] 645.3 943 2-((2S)-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-8- fluoro-6-hydroxy-2-((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01437] 651.4 944 2-((2S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-6- hydroxy-2-((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-1-(2- fluoroacryloyl)piperazin-2-yl)acetonitrile [01438] 633.4 945 2-((2S)-4-(8-fluoro-6-hydroxy-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a- tetrahydrocyclopropa[a]inden-5-yl)quinazolin-4-yl)-1- (2-fluoroacryloyl)piperazin-2-yl)acetonitrile [01439] 601.5

Example: Cell Activity Experiment

[0297] 1. Cells: H358 purchased from Shanghai EK-Bioscience Biotechnology Co., Ltd.

[0298] 2. Reagents: RPMI 1640 medium, Tryple, MTT (5 mg/mL), DMSO, and DPBS.

[0299] 3. Instruments: an incubator at 37? C. and 5% CO2, a UTRAO microplate reader, a biosafety cabinet, a cell counting plate, and an Optec optical microscope.

[0300] 4. Experimental consumables: 96-well plate Item No.: 3599, and 96-well round-bottomed dispensing plate.

[0301] Experimental Steps of Activity Test of H358 Cells:

[0302] 1. Plating: Cells in the logarithmic growth phase were digested with Tryple and terminated with a fresh medium, and the cells were counted; and the cell concentration was adjusted to 55555 cells/mL with a fresh medium, wherein 90 ?L was added to each well, and those on edges were filled with sterile DPBS.

[0303] 2. The plate was incubated in the incubator at 37? C. and 5% CO2 for 24 h, so that the cells cover the bottom of the well by about 50%.

[0304] 3. Drug preparation for experimental group: The drug was dissolved in DMSO to prepare a 20 mmol/L stock solution; the stock solution was further diluted with DMSO to 2 mmol/L, which was serially 3-fold diluted to form an 8-concentration gradient, resulting in a 200? serial compound solution; 10 ?L of the serial compound solution was taken and added to 190 ?L?L of RPMI1640 medium to obtain a 10? serial compound solution; and 10 ?L of the 10? compound solution was taken and added to 90 ?L 96-well cell culture plate, with three replicates per grade. The concentration gradient of the compound in the 96-well cell culture plate was 0.05080526 nM, 1.524158 nM, 4.572474 nM, 13.717420 nM, 41.152260 nM, 123.456800 nM, 370.370400 nM, 1111.111000 nM, 3333.333000 nM, and 10000.000000 nM, with 100 ?L per well, and the final concentration of DMSO was 0.5%.

[0305] The control group contained the same volume of solvent as the experimental group and was diluted with a complete medium, with 100 ?L per well.

[0306] 4. Incubation was carried out for 5 days in an incubator with 5% CO2 at 37? C.

[0307] 5. After 5 days, 10 ?L of an MTT solution (5 mg/mL) was added to each well, and the culture was continued for 4 h.

[0308] 6. The culture was terminated, and the culture solution was carefully sucked out of the well.

[0309] 7. 150 ?L of dimethyl sulfoxide (DMSO) was added to each of the null wells in the experimental group and the control group; and after shaking at a medium speed for 10 s, the crystal was fully dissolved, and the optical absorbance value thereof was measured at a wavelength of 492 nm.

[0310] The IC.sub.50 values of some compounds were as shown in Table 1

TABLE-US-00011 Ex No. H358 IC.sub.50 (nM) 1 15 2 1 3 3.5 4 70 5 20 6 90 7 0.07 8 0.64 9 10 10 60 11 26 12 80 13 5 14 30 15 3 16 5 17 30 18 100 19 35 20 120 21 7 22 20 23 3 24 15 25 10 26 40 27 15 28 80 29 10 30 60 31 8 32 35 33 25 34 80 35 15 36 120 37 15 38 36 39 8 40 30 41 15 42 35 43 16 44 64 45 10 46 30 47 6.5 48 20 49 57 50 140 51 148 52 0.22 53 180 54 70 55 160 56 2.2 57 150 58 0.81 59 140 60 70 61 0.71 62 8 63 2.2 64 10 65 3.2 66 9 67 0.07 68 0.33 69 1.8 70 7 71 0.2 72 8 73 15 74 25 75 86 76 160 77 55 78 60 79 20 80 65 81 5.5 82 12 83 3.2 84 10 85 6 93 6.5 94 15 95 8 96 25 97 0.49 98 8 99 0.34 100 6 101 5 109 287 110 35 111 140 112 38 113 150 114 20 115 45 116 15 117 30 126 18 127 72 128 20 129 50 130 8 131 16 132 3 133 8 142 20 143 80 144 25 145 102 146 10 147 18 148 5 149 10 158 4 159 18 160 5 161 20 162 2 163 5 164 1.5 165 4 254 30 258 15 259 31 260 10 261 24 286 355 358 3.4 359 3 360 10 361 5 362 4.6 363 5 364 2 365 2 366 3 367 1.5 368 0.11 369 20 370 10 371 6 372 5 394 158 395 61 429 15 430 140 431 148 432 2.4 465 70 466 65 467 80 468 75 469 70 470 50 471 45 472 40 473 35 474 30 475 25 510 130 536 30 537 150 615 1007 616 473 617 884 618 200 619 496 620 138 621 330 622 231 623 200 624 800 625 850 626 1500 627 120 628 60 629 120 840 809 854 4.4 855 5.1 867 5.9 868 6.6 870 7.2 871 9.0 872 8.4 873 12 874 429 877 9.5 878 236 879 4.0 880 433 881 3.4 882 550 883 10.6 884 1256 887 2.65 888 292 903 0.7 904 0.4 913 3.6 914 0.4 915 33 916 37 918 40 919 1679 920 31 924 49 932 0.4 933 0.3 945 155

[0311] KRAS G12C-GDP Exchange Test:

[0312] 1. Serially 4?-diluted compounds (10 concentration points in total) were separately premixed with KRAS G12C-GDP (ICE, Kras 20191018) in a reaction buffer (25 mM Hepes PH7.4, 125 mM NaCl, 5 mM MgCl2, 0.01% Tween20, and 0.1% BSA) in the reaction wells for 1 h.

[0313] 2. A mixture of SOS (Pharmaron, ZZY-20190823), cRAF (Pharmaron, ZZY-20190823), GTP (Sigma, A6885-100MG), MAb Anti 6HIS-d2/MAb Anti GST-Eu (Cisbio, 61HISDLB/61GSTKLB) was added for a catalyzed reaction for 2 h.

[0314] 3. The fluorescence signals of the emitted light at 615 nm and 665 nm under 320 nm excitation light were read by Biotek Microplate Reader (Synergy4).

[0315] 4. The IC50 (median inhibitory concentration) of the compound was obtained by the following non-linear fitting formula: Y=Bottom+(Top?Bottom)/(1+10{circumflex over ()}((Log IC50?X)*Hill Slope)), and the data were analyzed by Graphpad 6-0 software.

TABLE-US-00012 Ex. No. IC.sub.50 (nM) 1 20.31 2 10.59 3 13.85 10 8.0 17 1.65 73 1.34 254 8.90 286 9.91 358 2.40 394 1.44 395 1.32 465 2.23 840 4.52 854 0.59 873 0.79 877 0.71 879 0.59 881 0.71 883 0.49 887 1.02 895 1.29 903 0.89 904 0.93

Pharmacokinetic Experiment in SD Rats:

[0316] 1. SPF male rats were randomly divided into groups. The compounds to be tested were separately administered by intravenous injection and oral gavage, with 3 animals for each compound to be tested in each mode of administration. The administration solvent was 5% DMSO+10% Solutol+85% normal saline or 85% PBS, and the substances to be tested were dissolved in the solvent to obtain clear solutions. Administration concentration and volume: 1) a single intravenous injection of 0.6 mg/mL of the compound to be tested, with an administration volume of 5 mL/kg and an administration dosage of 3 mg/kg; and 2) a single oral gavage of 1 mg/mL of the compound to be tested, with an administration volume of 10 mL/kg and an administration dosage of 10 mg/kg. The rats were fasted overnight (10-14 h) before administration and fed 4 h after administration.

[0317] 2. Blood was collected via the jugular vein or by other appropriate methods at 200 ?L per time point and anticoagulated with K2-EDTA, and after collection, the blood was placed on ice and centrifuged for plasma within 1 h (centrifugation conditions: 6800 g, 6 min 2-8? C.). The points for blood sampling from the animals in the intravenous injection group were respectively: before administration, and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration; and the points for blood sampling from the animals in the oral administration group were respectively: before administration, and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

[0318] 3. The blood concentration was detected, and the pharmacokinetic parameter AUC(0-t) was calculated by Phoenix WinNonlin based on the blood concentration data at various time points. When the pharmacokinetic parameters were calculated, the BLQ before Cmax (including No peak) was calculated as 0: and BLQ after Cmax (including No peak) was not involved in the calculation. The formula of calculating the oral bioavailability was: F %=AUC0?t.sub.oral/AUC0?t.sub.IV*(10/3)*100%.

TABLE-US-00013 Ex. No. Oral bioavailability, F % 358 2.35% 367 11.57% 879 16.9% 887 25.85% 903 28.6% 904 30.28% 914 28.49% Example 229 of WO 2020/146613 A1 22.69%