BENZOTHIAZOLYL BIARYL COMPOUND, AND PREPARATION METHOD AND USE

Abstract

A benzothiazolyl biaryl compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, a preparation method therefor, and a use thereof as a KRAS.sup.G12C inhibitor.

##STR00001##

Claims

1-15. (canceled)

16. A benzothiazolyl biaryl compound having formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, ##STR00139## Wherein, M is N or CR5; When M is N, R is independently halogen, cyano, hydroxyl, nitro, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered cycloalkyl—O—, 3-12-membered cycloalkyl—NR′R″—, 3-12-membered heterocycloalkyl—O—, 3-12-membered heterocycloalkyl—NR′R″—, Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″—Q3—, 5-12-membered aryl or 5-12-membered heteroaryl; When M is CR5, R is independently hydrogen, halogen, cyano, hydroxyl, nitro, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered cycloalkyl—O—, 3-12-membered cycloalkyl—NR′R″—, 3-12-membered heterocycloalkyl—O—, 3-12-membered heterocycloalkyl—NR′R″—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″—Q6—, 5-12 membered aryl or 5-12 membered heteroaryl; Q1, Q2, Q3, Q4, Q5 and Q6 are independently 3-7-membered heterocycloalkyl or 3-7-membered heterocycloalkyl substituted by one or more Rq; when there are multiple substituents, they are the same or different; Rq is independently halogen, cyano, hydroxyl, amino, or C.sub.1-C.sub.4alkyl; R5 is independently hydrogen, halogen, cyano, hydroxyl, nitro, amino, C1-C6alkyl, C1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered cycloalkyl—O—, 3-12-membered cycloalkyl—NR′R″—, 3-12-membered heterocycloalkyl—O—, 3-12-membered heterocycloalkyl—NR′R″—, 5-12-membered aryl or 5-12-membered heteroaryl; R′ and R″ are independently hydrogen, C.sub.1-C.sub.6alkyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered aryl or heteroaryl; R1 is independently hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO—, or C.sub.1-C.sub.6haloalkyl; R2, R3 are independently hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO—, N(R.sub.2a)(R.sub.2b)—(CH.sub.2)x—; R.sub.2a and R.sub.2b are each independently hydrogen or C.sub.1-C.sub.6alkyl, x is selected from any integer inbetween 0-5; the above alkyl can be further substituted by deuterium, halogen, substituted or unsubstituted amino/cyclic amine group; or, R.sub.2a and R.sub.2b together form a 5-10 membered nitrogen-containing heterocycloalkyl substituted by C.sub.1-C.sub.6alkyl; R4 is independently hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6haloalkyl, or C.sub.1-C.sub.6alkyl—O—; m is an integer independently selected from0-4; W,W1,W2 are independently CR6 or N; R6 is independently H, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkyl—O—, hydroxyl substituted C.sub.1-C.sub.6alkyl, cyano substituted C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, 3-8 membered cycloalkyl or 3-8-membered heterocycloalkyl; Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh are independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6haloalkyl, cyano substituted C.sub.1-C.sub.6alkyl; or Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a saturated or partially unsaturated 3-8-membered ring system between the two; or either Rg orRh can form Cy together with M and the attached moiety; Cy is a saturated or partially unsaturated or unsaturated 3-10-membered ring system or a saturated or partially unsaturated or unsaturated 3-10-membered ring system substituted by one or more Rp; when there are multiple substituents, the substituents are the same or different; Rp is independently halogen, cyano, hydroxyl, amino, C.sub.1-C.sub.4alkyl; or, when two Rp are located on the same C-atom, they jointly form = O; one or more hydrogen atoms on any of the abovementioned groups can be substituted by Rr substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino or cycloamino, cyano, nitro, sulfone or sulfoxide, C.sub.1-C.sub.8alkyl, 3-8-membered cycloalkyl or heterocycloalkyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkylamino, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5~8-membered aryl or heteroaryl; or when two Rr are located on the same C-atom, they jointly form = O; the heteroaryl comprises 1-3 heteroatoms selected from the group consisting of: N, O, P and S; the heterocycloalkyl comprises 1-3 heteroatoms selected from the group consisting of: N, O, P and S; the ring system comprises saturated or partially unsaturated ring system such as a spiro ring, a bridged ring, a fused-ringand a fused ring.

17. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein, when M is N, R is halogen, cyano, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkylamino, NR′R″-(Ci-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″—Q3—; for example, halogen, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q3—; and/or, when M is CR5, R is hydrogen, halogen, cyano, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C6alkylamino, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″—Q6—; for example, hydrogen, halogen, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q6—; and/or, Q1, Q2, Q3, Q4, Q5, and Q6 are independently 3-7-membered heterocycloalkyl substituted by one or more Rq; and/or, Rq is independently halogen, hydroxyl, or C.sub.1-C.sub.4alkyl; and/or, R5 is independently cyano; and/or, R′, R″ are independently hydrogen, or C.sub.1-C.sub.6alkyl; and/or, R1 is hydrogen, halogen, cyano, or C.sub.1-C.sub.6alkyl; for example, hydrogen, or halogen; and/or, R2, R3 are independently hydrogen, C.sub.1-C.sub.6alkyl, or halogen; For example, hydrogen; and/or, R4 is halogen; e.g. fluorine; and/or, m is 0,1 or 2; for example 1; and/or, W is independently CR6; for example, R6 is halogen; and/or, W1 is independently CR6; for example, R6 is hydrogen; and/or, W2 is independently CR6; for example, R6 is halogen; and/or, R6 is hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, hydroxyl substituted C.sub.1-C.sub.6alkyl, cyano substituted C.sub.1-C.sub.6alkyl, 3-8-membered cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl, or C.sub.1-C.sub.6haloalkyl—O—; for example, hydrogen, halogen, C.sub.1-C.sub.4alkyl, or C.sub.1-C.sub.4haloalkyl—O—; and/or, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh are independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, cyano substituted C.sub.1-C.sub.6alkyl, hydroxyl substituted C.sub.1-C.sub.6alkyl;for example, hydrogen, C.sub.1-C.sub.6alkyl, or cyano substituted C.sub.1-C.sub.6alkyl; and/or, Cy is a 3-10-membered partially unsaturated ring system or a 3-10-membered partially unsaturated ring system substituted by one or more Rp; for example, a 5-6-membered partially unsaturated ring system substituted by one or more Rp; and/or, Rp is independently C.sub.1-C.sub.4alkyl; or, when two Rp are located on the same C, they jointly form = O.

18. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein, when R is halogen, or C.sub.1-C.sub.6haloalkyl, the halogen andthe halogen inC.sub.1-C.sub.6haloalkyl is independently fluorine, chlorine, or bromine; for example, fluorine or chlorine. and/or, when R is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, the C.sub.1-C.sub.6alkyl in C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O— andC.sub.1-C.sub.6alkyl—NR′R″— are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example, methyl; and/or, when R is Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, the C.sub.1-C.sub.4alkylene in Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′— are independently—CH.sub.2—,—CH.sub.2CH.sub.2—,—CH(CH.sub.3)—, —CH(CH.sub.3)CH.sub.2—, —C(CH.sub.3).sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2—; for example, methylene; and/or,when Q1, Q2, Q3, Q4, Q5 and Q6 are independently 3-7-membered heterocycloalkyl or 3-7-membered heterocycloalkyl substituted by one or more Rq, the 3-7-membered heterocycloalkyl in the 3-7-membered heterocycloalkyl and3-7-membered heterocycloalkyl substituted by one or more Rq is a 4-6-membered heterocycloalkyl, the heteroatom is selected fromN, O and S, and the number of heteroatoms is 1, 2 or 3; for example, in a4-5-membered heterocycloalkyl, the heteroatom is selected from N, and the number of heteroatoms is 1; for example, ##STR00140## ##STR00141## also for example, ##STR00142## ##STR00143## and/or, when Rq is independently halogen, the halogen is independently fluorine, chlorine or bromine; for example fluorine, or chlorine; and/or,when Rq is independently C.sub.1-C.sub.4alkyl, the C.sub.1-C.sub.4alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl; also for example, methyl; and/or, when R′, R″ areindependently C.sub.1-C.sub.6alkyl, the C.sub.1—C alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl; for example, methyl; and/or, when R1, R2, R3, R4 and R5 are independently halogen, the halogen is independently fluorine, chlorine or bromine; for example,fluorine, chlorine; and/or, when R1, R2, R3, R4 and R5 are independently C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO—, the C.sub.1-C.sub.6alkyl in the C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl-SO.sub.2-and C.sub.1-C.sub.6alkyl—SO— are independently C.sub.1-C.sub.4alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isobutyl, sec-butyl or t-butyl; also for example, methyl; and/or, when R6 is independently C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, hydroxyl substituted C.sub.1-C.sub.6alkyl, cyano substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkyl—O—, the C.sub.1-C.sub.6alkyl in the C.sub.1-C.sub.6alkyl, C.sub.1-Calkyl.sub.6—O—, hydroxyl substituted C.sub.1-C.sub.6alkyl, cyano substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkyl—O— are independently C.sub.1-C.sub.4alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; also for example, methyl; and/or,when R6 is independently halogen, C.sub.1-C.sub.6haloalkyl, or C.sub.1-C.sub.6haloalkyl—O—, the halogen and the halogen inC.sub.1-C.sub.6haloalkyl and C.sub.1-C.sub.6haloalkyl—O— are independently fluorine, chlorine or bromine; for example, fluorine or chlorine; and/or, when Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are independently halogen or C.sub.1-C.sub.6haloalkyl group, the halogen and the halogen inC.sub.1-C.sub.6haloalkyl are independently fluorine, chlorine or bromine; for example, fluorine or chlorine; when Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are independently C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6haloalkyl or cyano substituted C.sub.1-C.sub.6alkyl, the C.sub.1-C.sub.6alkyl in the C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6haloalkyl and cyano substituted C.sub.1-C.sub.6alkyl are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example, methyl; and/or, when Cy is a3-8-membered saturated or partially unsaturated or unsaturated ring system or a 3-10-membered saturated or partially unsaturated or unsaturated ring system substituted by one or more Rp, the 3-10-membered saturated or partially unsaturated or unsaturated ring system in the 3-10-membered saturated or partially unsaturated or unsaturated ring system or 3-10-membered saturated orpartially unsaturated or unsaturated ring system substituted by one or more Rp of Cy is a 5-10-membered saturated or partially unsaturated or unsaturated heterocyclyl, the heteroatom is selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; for example, ##STR00144## .

19. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein, ##STR00145## ##STR00146## such as ##STR00147## ##STR00148## and/or, ##STR00149## ##STR00150## such as ##STR00151## and/or, ##STR00152## ##STR00153## such as ##STR00154## and/or, ##STR00155## ##STR00156## ##STR00157## such as ##STR00158## ##STR00159## ##STR00160## ##STR00161## and/or, R is hydrogen, chlorine, ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## and/or, Cy is selected from the ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## for example, ##STR00176## .

20. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein, in the formula: when M is N, R is independently selected from the group consisting of halogen, cyano, hydroxyl, nitro, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered cycloalkyl—O—, 3-12-membered cycloalkyl—NR′R″—, 3-12-membered heterocycloalkyl—O—, 3-12-membered heterocycloalkyl—NR′R″—, 5-12-membered aryl and 5-12-membered heteroaryl; when M is CR5, R is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, nitro, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered cycloalkyl—O—, 3-12-membered cycloalkyl—NR′R″—, 3-12-membered heterocycloalkyl—O—, 3-12-membered heterocycloalkyl—NR′R″—, 5-12-membered aryl and 5-12-membered heteroaryl; R5 is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, nitro, amino, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—S—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkyl—O—, C.sub.1-C.sub.6alkyl—NR′R″—, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered cycloalkyl—O—, 3-12-membered cycloalkyl—NR′R″—, 3-12-membered heterocycloalkyl—O—, 3-12-membered heterocycloalkyl—NR′R″—, 5-12-membered aryl and5-12-membered heteroaryl; R′, R″ are independently selected from hydrogen, C.sub.1-C.sub.6alkyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, and 5-12-membered aryl and heteroaryl; R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO—, andC.sub.1-C.sub.6haloalkyl; R2 and R3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO— and N(R.sub.2a)(R.sub.2b)—(CH.sub.2)x—; or R.sub.9 and R.sub.10together form a 5-10-membered nitrogen-containing heterocycloalkyl substituted by C.sub.1-C6alkyl; wherein, R.sub.2aand R.sub.2b are independently selected from hydrogen and C.sub.1-C.sub.6alkyl, and x is selected from any integer of 0-5; R4 is independently selected from hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl—SO.sub.2—, C.sub.1-C.sub.6alkyl—SO—, C.sub.1-C.sub.6haloalkyl and C.sub.1-C.sub.6alkoxy, etc., m is an integer independently selected from the integer of 0-4; W, W1 and W2 are independently selected from CR6 or N, R6 is independently selected from H, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, haloalkyl,haloalkoxy, alkenyl, alkynyl, 3-8-membered cycloalkyl and heterocycloalkyl, etc; Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are independently selected from hydrogen, halogen, C1-C6 alkyl, alkoxy and haloalkyl, etc., respectively, orany two of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a saturated or partially unsaturated 3-8-membered ring system; or eitherRg or Rh can form a saturated or partially unsaturated or unsaturated 3-8-membered ring system together with M; one or more hydrogen atoms on any of the abovementioned groups can be substituted by a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxyl, amino or cycloamino, cyano, nitro, sulfone or sulfoxide, C.sub.1-C.sub.8alkyl, 3-8-membered cycloalkyl or heterocycloalkyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-8 membered aryl or heteroaryl; wherein the heteroaryl comprises 1-3 heteroatoms selected from the group consisting of N, O, P and S, the heterocycloalkyl group comprises 1-3 heteroatoms selected from the group consisting of N, O, P and S, the ring system comprises saturated or partially unsaturated ring system such as a spiro ring, a bridged ring, a fused-ring and a fused ring.

21. The benzothiazolyl biaryl compound of formula I according to claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, a tautomer, a torsional isomer, a solvate, a polymorph or a prodrug thereof, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, is the compound of formula IIA, IIB or IIC, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof: ##STR00177## ##STR00178## ##STR00179## wherein, Cy, R, R1, R2, R3, R4, m, Ra, Rb, Rc, Rd, Re, Rf, Rg, W, Wland W2 are as defined in claim 16.

22. The benzothiazolyl biaryl compound of formula I of claim 21, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein, R1 is preferably selected from hydrogen, fluorine, methyl and cyano, etc.; R2 and R3 are independently preferably selected from hydrogen, methyl and fluorine, etc.; R4 is preferably selected from one or more fluorine; m is preferably selected from 0, 1 and 2; Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are independently preferably selected from hydrogen, fluorine, methyl, hydroxymethyl, hydroxyethyl and cyano methyl, etc; W is preferably selected from N, C—F, C—Cl, C—Me, C—OMe, C—OCH2CHF2, C—OCH2CF3, etc.; W2 is independently preferably selected from N, CH, C— F, C—Cl, C—Me and C—OMe, etc; W1 is independently selected from —CH, —C—halogen, —C—cyano, —C—cyclopropyl, —C—C1-C4alkyl, —C—C1-C4alkoxy, —C—C2-C4alkenyl, —C—C2-C4alkynyl, —C—C1-C4alkoxy, —C—C1-C4haloalkyland —C—C1-C4haloalkoxy, etc; R is preferably selected from halogen, cyano, amino, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkylaminoalkylene ether group, C1-C6alkylaminoalkylene amino group, 3-10membered cycloalkylalkylene ether group and 3-10 membered heterocycloalkylalkylene ether group, etc.

23. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein the benzothiazolyl biaryl compound of formula I is as the following scheme 1, scheme 2, scheme 3 or scheme 4; Scheme 1, when M is N, R is halogen, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q3—; when M is CR5, R is hydrogen, halogen, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q6—; Q1, Q2, Q3, Q4, Q5 and Q6 are independently 3-7-membered heterocycloalkyl or 3-7-membered heterocycloalkyl substituted by one or more Rq; when there are multiple substituents, they are the same or different; Rq is independently halogen, hydroxyl or C.sub.1-C.sub.4alkyl; R5 is independently cyano; R′ and R″ are independently hydrogen or C.sub.1-C.sub.6alkyl; R1 is hydrogen or halogen; R2 and R3 are independently hydrogen; R4 is halogen; m is 0,1 or 2; W is independently C (halogen); W1 is independently C (halogen); W2 is CH; any one of Ra, Rb, Re and Rf is hydrogen, C.sub.1-C.sub.6alkyl or cyano-substituted C1-C6alkyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; or, any one of Rc, Rd, Rg and Rh is hydrogen or methyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; or either Rg orRh may form Cy together with M and the attached group; Cy is a saturated or partially unsaturated or unsaturated 3-10-membered ring system or a saturated or partially unsaturated or unsaturated 3-10-membered ring system substituted by one or more Rp; Rp is independently C.sub.1-C.sub.4alkyl; or, when two Rp are located on the same C-atom, they jointly form = O; Scheme 2, when M is N, R is halogen, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q3—; when M is CR5, R is hydrogen, halogen, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q6—; Q1, Q2, Q3, Q4, Q5 and Q6 are independently 3-7-membered heterocycloalkyl or 3-7-membered heterocycloalkyl substituted by one or more Rq; when there are multiple substituents, they are the same or different; Rq is independently halogen, hydroxyl or C.sub.1-C.sub.4alkyl; R5 is independently cyano; R′ and R″ are independently hydrogen or C.sub.1-C.sub.6alkyl; R1 is hydrogen or halogen; R2 and R3 are independently hydrogen; R4 is halogen; m is 0,1 or 2; W is independently C (halogen); W1 is independently C (halogen); W2 is CH; when M is N, any one of Ra, Rb, Re and Rf is hydrogen, C1-C6alkyl or cyano-substituted C1-C6alkyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; or, any one of Rc, Rd, Rg and Rh is hydrogen or methyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; when M is CR5, any one of Ra, Rb, Re and Rf is hydrogen or C.sub.1-C.sub.6alkyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; or any one of Rc, Rd, Rg and Rh is hydrogen or methyl, the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; or either Rg or Rh may form Cy together with M and the attached group; Cy is a saturated or partially unsaturated or unsaturated 3-10-membered ring system or a saturated or partially unsaturated or unsaturated 3-10-membered ring system substituted by one or more Rp; Rp is independently C.sub.1-C.sub.4alkyl; or, when two Rp are located on the same C-atom, they jointly form = O; Scheme 3, when M is N, R is NR′R″-(C.sub.1-C.sub.4alkylene)—O—, Q1-(C.sub.1-C.sub.4alkylene)—O— or NR′R″—Q3—; when M is CR5, R is NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, or NR′R″—Q6—; Q1, Q3, Q4, Q5 and Q6 are independently 3-7-membered heterocycloalkyl or 3-7-membered heterocycloalkyl substituted by one or more Rq; when there are multiple substituents, they are the same or different; Rq is independently halogen, hydroxyl or C.sub.1-C.sub.4alkyl; R5 is independently cyano; R′ and R″ are independently hydrogen or C.sub.1-C.sub.6alkyl; When M is N, R1 is hydrogen, when M is CR5, R1 is hydrogen or halogen; R2 and R3 are independently hydrogen; R4 is halogen; m is 0,1 or 2; W is independently C (halogen); W1 is independently C (halogen); W2 is CH; when M is N, any one of Rc, Rd, Rg and Rh is hydrogen, or methyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; when M is CR5, any one of Ra, Rb, Re and Rf is hydrogen or C.sub.1-C.sub.6alkyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; or any one of Rc, Rd, Rg and Rh is hydrogen or methyl, the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; Scheme 4, when M is N, R is NR′R″-(C.sub.1-C.sub.4alkylene)—O—, Q1-(C.sub.1-C.sub.4alkylene)—O—, Q2-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″—Q3—; when M is CR5, R is hydrogen, Q4-(C.sub.1-C.sub.4alkylene)—O—, Q5-(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″—CO—(C.sub.1-C.sub.4alkylene)—NR′—, NR′R″-(C.sub.1-C.sub.4alkylene)—O—, NR′R″—Q6—; Q1, Q2, Q3, Q4, Q5 and Q6 are independently 3-7-membered heterocycloalkyl or 3-7-membered heterocycloalkyl substituted by one or more Rq; when there are multiple substituents, they are the same or different; Rq is independently halogen, hydroxyl or C.sub.1-C.sub.4alkyl; R5 is independently cyano; R′ and R″ are independently hydrogen or C.sub.1-C.sub.6alkyl; R1 is hydrogen; R2 and R3 are independently hydrogen; R4 is halogen; for example, F; m is 0,1 or 2; for example, 1; W is independently C (halogen); For example, C(F); W1 is independently C (halogen); For example, C(C1); W2 is CH; when M is N, any one of Rc, Rd, Rg and Rh is hydrogen, or methyl, and the rest of Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen; When M is CR5, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are hydrogen.

24. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein the compound has the following structure: ##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## .

25. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein the compound is the following compound: the retention time of the compound ##STR00214## is 8.476 min under the following conditions: preparative chromatographic resolution, chromatographic column:Sunfire C18 4.6*150mm, 5uM, elution gradient time: 13 min, mobile phase: A:0.1% formic acid/water; B:0.1% formic acid/acetonitrile; flow rate:40 mL/min; wavelength:254nm; theretention time of the compound ##STR00215## is 8.469 min under the following conditions: preparative chromatographic resolution, chromatographic column:Sunfire C18 4.6*150mm, 5uM, elution gradient time: 13 min, mobile phase: A:0.1% formic acid/water; B:0.1% formic acid/acetonitrile; flow rate:40 mL/min; wavelength:254nm.

26. The benzothiazolyl biaryl compound of formula I of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof, wherein the compound is a compound of formula A, B or C, ##STR00216## ##STR00217## ##STR00218## wherein, R, R4, m, Ra, Rb, Rc, Rd, Re, Rf, Rg, W, W1, W2 and M are as defined in claim 16; for example, the compound of formula A, B and C are selected from the following compound; ##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226## .

27. A pharmaceutical composition comprising an effective amount of the benzothiazolyl biaryl compound of formula I according to claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, a tautomer, a torsional isomer, a solvate, a polymorph or a prodrug thereof, and pharmaceutically acceptable carriers.

28. A method for the prevention and/or treatment of diseases or tumors related to the activity or expression of Ras mutant protein, which comprises administering to a patient a therapeutically effective amountof thebenzothiazolyl biaryl compound of formula I according to claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof; the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, and pancreatic cancer.

29. A medicament for the prevention and/or treatment of diseases or tumors associated with the activity or expression of Ras mutant protein, comprising the benzothiazolyl biaryl compound of formula I according to claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorph, or a prodrug thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0283] After long-term and in-depth research, the inventor prepared a class of benzothiazolyl biaryl compound with novel structure shown in Formula I, and found that they have better inhibitory activity against KRas.sup.G12C protein, and the compound has a specific inhibitory effect on KRas.sup.G12Cprotein at a very low concentration (as low as less than 100 nM), moreover, it has excellent inhibitory activity on cell proliferation related to KRas.sup.G12C and downstream signal pERK, so it can be used to treat related diseases caused by mutation or abnormal expression of KRas.sup.G12C, such as tumors.The present invention has been completed on this basis.

[0284] Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited to the scope of the described examples.In the following examples, the test methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the commodity instructions.In the following examples, the test methods without specific conditions are usually in accordance with conventional conditions or the conditions recommended by the manufacturer.Unless otherwise specified, percentages or parts are percentages by weight or parts by weight.

Preparation Method I of Intermediate: Synthesis of Quinoline/Quinazoline Compounds

[0285] With reference to the synthetic routes and methods of patented WO2019110751A1, WO2019014402A1 and WO201367597A1, the quinoline/quinazoline intermediate compound 1A-1D isprepared.

TABLE-US-00001 No. Structure LC-MS No. Structure LC-MS 1A 329.1/331.1 1B 353.1/355.1 1C [00098] 295.2/297.2 1D [00099] 319.1/321.1

[0286] General Preparation Method III of Example

##STR00100##

##STR00101##

[0287] Step 1: A quinoline intermediate (1 eq.) was dissolved in tetrahydrofuran, followed by the addition of DIPEA(1.6 eq.) and piperazine intermediate (1.5 eq.), then heated to 60 degrees under nitrogen protection and stirred for 12 hours.The reaction was monitored completely by TLC, cooled to room temperature, concentrated under reduced pressure, the residue was added into water and dichloromethane to separate the phase, the aqueous phase was extracted three times with dichloromethane, the extract was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target product, and the structure is confirmed by NMR and mass spectrometry.

[0288] Step 2: The product of the step 1 above (1 eq.) was dissolved in an appropriate solvent, under the nitrogen protection, raw materials such as alcohol and amine were added, and heated and stirred for 12 hours.The reaction was monitored completely by TLC, cooled to room temperature, poured into saturated aqueous ammonium chloride solution andsolid precipitated. After filtraion, the filter cake was vacuum dried to obtain the target product, and the structure was confirmed by NMR and mass spectrometry.

[0289] Step 3: The product of the above step 2 (1 eq.) was dissolved in a mixture of anhydrous dioxane/water (4/1), followed by the addition ofbenzothiazolylboronic acid or boronic acid pinacol ester (2 eq.), anhydrous potassium carbonate powder (2.5 eq.) and Pd(dppf)Cl.sub.2 (0.1 eq.), then heated to reflux for 2 h under nitrogen protection. The reaction was monitored completely by TLC, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with dichloromethane, washed with saturated ammonium chloride solution and saturated salt water in turn, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target product, and the structure was confirmed by NMR and mass spectrometry.

[0290] Step 4: The product of step 3 above (1 eq.) was dissolved in methanol, and 4 M HCl methanol solution (20 eq.) was added, and the Boc protecting group was removed by stirring for 3 h at room temperature; or the Cbz protecting group was removed by palladium-carbon catalysis under hydrogen atmosphere. The reaction was monitored completely by TLC, concentrated under reduced pressure, and the residue was used directly in the next reaction step.

[0291] Step 5: The residue of the previous step was dissolved in dichloromethane, followed by the addition of DIPEA (3 eq.) and acryloyl chloride (1 eq.) at 0 degrees. The reaction solution was stirred for 0.5 h, then washed with saturated ammonium chloride solution and saturated saline water, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target compound, and the structure was confirmed by NMR and mass spectrometry.

Example 1:1-(4-(7-(2-Amino -7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-8-Fluoro-2-(((S)-1-Methylpyrrolin-2-yl) Methoxy) Quinazolin-4-yl) Piperazin-1-Yl) Prop-2-En-1-One

[0292] ##STR00102##

[0293] Step 1: 7-Bromo- 8-fluoro-2 ,4 ,6-trichloroquinazoline (984 mg, 3 mmol), DIPEA (580 mg, 4.5 mmol), N—Boc—piperazine (558 mg, 3 mmol) were dissolved in N,N-dimethylformamide (DMF) (15 mL) and the reaction was carried out under Ar protection by heating to 60° C. for 20 hours.The complete reaction of the raw materials was monitored by TLC, and after the reaction solution was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (10 mL*2), the organic phases were combined, washed with saturated sodium chloride, the organic phases were concentrated and purified by column chromatography to give tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate ester (white solid, 836 mg), ESI-MSm/z:479.1/481.1[M+H]+..sup.1H-NMR (400 MHz, CDCl.sub.3) δ:7.76 (d, J= 1.8 Hz, 1H), 3.90-3.87 (m, 4H), 3.67-3.64 (m, 4H), 1.49 (s, 9H).sub.∘

[0294] Step 2: To a solution of compound tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate ester(316 mg ,0.62 mmol) in dimethyl sulfoxide (DMSO) (10 mL) at room temperature was added raw material (S)-(1-methylpyrrolidin-2-yl)methanol (163 mg ,1.24 mmol) and potassium fluoride (KF) (290 mg ,4.96 mmol). The reaction mixture was stirred at 120° C. under argon for 16 h. After completetion of the reaction, the mixture was poured into ice waterand extracted with ethyl acetate, then the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate (Na.sub.2SO.sub.4), concentrated under reduced pressure and purified by rapid column chromatography on silica gel to give tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carbox ylate ester(180 mg, white solid).ESI-MS m/z:558.1/560/1[M+H].sup.+..sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.09 (s, 1H), 3.93 (s, 4H), 3.56 (s, 4H), 1.43 (s, 9H).

[0295] Step 3: To a solution of tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carbox ylate ester(112 mg, 0.2 mmol) in 1 ,4-dioxane/water (12 mL/4 mL) at room temperature was added fluoro-substituted benzothiazolylboronic acid material(178 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (24 mg ,0.02 mmol) and sodium carbonate powder (Na.sub.2CO.sub.3) (108 mg ,1 mmol), and the reaction mixture was stirred at 100° C. under argon overnight. After the completion of the reaction, the mixture was extracted with ethyl acetate and the organic phase was washed with saturated saline, dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by rapid column chromatography on silica gel to give tert-butyl 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)qui nazolin-4-yl)piperazin-1-carboxylate (86 mg, yellow solid).ESI-MS m/z:646.2/648.2[M+H].sup.+ .

[0296] Step 4: To a stirred solution of tert-butyl 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)qui nazolin-4-yl)piperazine-1-carboxylate(83 mg ,0.13 mmol) in dichloromethane (DCM) (6 mL) under ice bath cooling was added trifluoroacetic acid (CF.sub.3COOH, TFA) (3 mL) and the reaction solution was warmed up to room temperature and stirred for 2 h.After completion of the reaction, the mixture wasconcentrated under reduced pressure and the residue wasused directly in the next step without further purification.

[0297] Step 5: To a stirred solution of 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-7-fluorob enzo[d]thiazol-2-amine (65 mg) in DCM (10 mL) was added triethylamine (Et.sub.3N) (66 mg, 0.66 mmol) and cooled to 0° C., then acryloyl chloride (18.1 mg, 0.144 mmol) was added. The reaction mixture was slowly warmed to room temperature and the reaction was monitored by LC-MS showing reactioncompleted, quenched with saturated sodium bicarbonate (NaHCO.sub.3) (10 mL), extracted with ethyl acetate, washed with water, dried over Na.sub.2SO.sub.4, concentrated and purified by reversed-phase preparative chromatography to give 1-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (13 mg, yellow powder), ESI-MS m/z:600.1/602.1[M+H].sup.+..sup.1H NMR (400 MHz, MeOD-d.sub.4): δ 7.95 (s, 1H), 7.31-7.16 (m, 1H), 6.99 (t, 1H), 6.82 (dd, 1H), 6.28 (d, 1H), 5.81 (d, 1H), 4.56-4.38 (m, 2H), 4.01-3.95 (m, 8H), 3.10 (s, 1H), 2.81 (s, 1H), 2.53 (s, 3H), 2.37 (d, 1H), 2.25-1.64 (m, 4H).

Example 2: 1-(4-(7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-8-Fluoro-2-((((S)-1-Methylpyrrolidin-2-yl)Methyl)Amino)Quinazolin-4-yl)Piperazin-1-yl)Prop-2-En-1-One

[0298] ##STR00103##

[0299] Example compound 2 (light yellow solid, 12 mg) was obtained by the same method as in Example 1 using (S)-1-methylpyrrolidinylmethylamine as the raw material.ESI-MS m/z:599.1/601.1 [M+H].sup.+.

Example 3:4-(4-Piperazinylacryloylpiperazin-1-yl)-7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-8-Fluoro-2-(((S)-1-Methylpyrrolidin-2-Yl)Methoxy)Quinoline-3-Cyano

[0300] ##STR00104##

[0301] Example 3 (white solid, 13 mg) was prepared by the same method as Example 1 using intermediate 1B as raw material.ESI-MS m/z:624.1/626.1[M+H].sup.+..sup.1H-NMR (400 MHz, MeOD-d.sub.4): δ 7.96 (s, 1H), 7.20-7.24 (m, 1H), 6.97-7.02 (m, 1H), 6.29 (dd, 1H), 5.82 (dd, 1H), 4.74-4.88 (m, 1H), 4.48-4.54 (m, 1H), 3.96-3.98 (m, 4H), 3.72-3.78 (m, 4H), 3.29-3.34 (m, 2H), 2.78 (s, 3H), 2.69-2.78 (m, 1H), 2.19-2.26 (m, 1H), 1.85-2.00 (m, 3H).

Example 4 4-(4-Piperazinylacryloylpiperazin-1-yl)-7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-Yl)-6-Chloro-8-Fluoro-2-((((S)-1-Methylpyrrolin-2-yl)Methyl)Amino)Quinoline-3-Cyano

[0302] ##STR00105##

[0303] Example compound 4 (light yellow solid, 5 mg) was prepared using the same method as Example 3.ESI-MS m/z:623.1/625.1[M+H]+.

Example 5:1-(4-(7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Dichloro-2-(2-(Dimethylamino)Ethoxy)-8-Fluoroquinolin-4-yl)Piperazin-1-yl)Prop-2-En-1-One

[0304] ##STR00106##

[0305] Example compound 4 (light yellow solid, 10 mg) was prepared using the same method as Example 3.ESI-MS m/z:574.2/576.1[M+H].sup.+..sup.1H-NMR (400 MHz,CD.sub.3OD): δ 8.05 (d, 1H), 7.27-7.23 (m, 1H), 7.05-7.01 (m, 1H), 6.81 (dd, 1H), 6.29 (dd, 1H), 5.82 (dd, 1H), 4.16-4.10 (m, 4H), 3.97-3.90 (m, 4H), 3.66-3.64 (m, 2H), 3.33-3.31 (m, 2H).

Example 6:1-(4-(7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl)-2,6-Dichloro-8-Fluoroquinazolin-4-yl) Piperazin-1-yl) Prop-2-Ene-1-One

[0306] ##STR00107##

[0307] Example compound 4 (light yellow solid, 23 mg) was prepared using the same method as Example 3.ESI-MS m/z:521.2/523.1[M+H].sup.+..sup.1H-NMR (400 MHz, DMSO-d6) δ 8.15(s, 1H), 7.94 (bs, 2H) , 7.23(dd, J=8.4, 5.6 Hz, 1H), 7.09(t, J=8.8 Hz, 1H), 6.71-6.83(m, 1H), 6.27(dd, J=16.8, 2.0 Hz, 1H), 5.73(dd, J=10.8, 2.0 Hz, 1H), 3.62-3.73(m, 4H), 3.31-3.48(m, 4H).

Example 7

[0308] 4-piperazinylacrylpiperazin-1-yl)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-2,6-dichloro-8-fluoroquinolin -3-cyano

##STR00108##

[0309] Example compound 4 (light yellow solid, 8 mg) was prepared using the same method as Example 3.ESI-MS m/z:545.2/547.1[M+H].sup.+..sup.1H-NMR (400 MHz, DMSO-d6) δ 8.16(s, 1H), 7.93 (bs, 2H) , 7.22(dd, J=8.4, 5.6 Hz, 1H), 7.10(t, J=8.8 Hz, 1H), 6.76-6.83(m, 1H), 6.25(dd, J=16.8, 2.0 Hz, 1H), 5.78(dd, J=10.8, 2.0 Hz, 1H), 3.52-3.64(m, 4H), 3.33(t, J=5.4 Hz, 4H).

Example 8

[0310] 4-acryloylpiperazin-1-yl)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoroquinolin-3-cyano

##STR00109##

[0311] Step 1: A quinoline material (209 mg, 0.65 mmol) was dissolved in DMF (5 mL), followed by the addition of N—Boc piperazine (133.6 mg, 0.72 mmol) and DIPEA (252.7 mg, 1.96 mmol), stirred for 16 h, poured into 100 mL of water and extracted with ethyl acetate (50 mL*3), washed with saturated saline, dried, and concentrated by column chromatography to give tert-butyl 4-(7-bromo-6-chloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate (yellow solid, 249 mg).LC-MS[M H]: m/z 471.0/473.0

[0312] ..sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 8.86 (s, 1H), 8.09 (s, 1H), 3.67 (d, 4H), 3.62 (d, 4H), 1.45 (s, 9H).

[0313] Step 2: The intermediate (50 mg, 0.11 mmol) obtained from the previous step and boronic acid ester (54.8 mg, 0.14 mmol) were dissolved in dioxane/water (1.5 mL/0.45 mL), under the nitrogen protection, 1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (7 mg, 0.011 mmol) and potassium phosphate (K.sub.3PO.sub.4) (34 mg, 0.16 mmol) were added, reacted at 90° C. for 2 h, poured into 100 mL of water and extracted with ethyl acetate (50 mL*3), washed with saturated salt water and dried to give a reddish-brown solid crude product (45 mg), which was directly used in the next step.LC-MS[M H]: m/z 657.2/659.2.

[0314] Step 3: The crude product (45 mg) from the previous step was dissolved in dichloromethane (5 mL), followed by the addition of TFA (1 mL) and stirred at room temperature for 3 h. After concentration, TFA was removed to obtain a yellow solid (35 mg), which was used directly in the next step.LC-MS[M H]: m/z 457.0/459.0.

[0315] Step 4: The yellow crude compound (35 mg, 0.077 mmol) from the previous step was dissolved in THF/H.sub.2O (4 mL/2 mL), followed by the addition of K.sub.3PO.sub.4 (654 mg, 0.154 mmol), cooled to 0 degree, added acryloyl chloride (6.95 mg, 0.077 mmol) dropwise, stirred for 1 h, poured into 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated salt water, dried, concentrated, and purified by liquid phase preparative chromatography to give Example 8 (white solid, 21 mg).LC-MS[M H]: m/z 511.1/513.1..sup.1H NMR (400 MHz, MeOD-d.sub.4): δ 8.79 (s, 1H), 8.11 (d, 1H), 7.28 (dd, 1H), 7.12-6.92 (m, 1H), 6.87 (dd, 1H), 6.30 (dd, 1H), 5.83 (dd, 1H), 4.09-3.92 (m, 4H), 3.86 (s, 4H).

Example 9:7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-8-Fluoro-4-(4-(2-Fluoroacryloyl) Piperazin-1-yl) Quinolin-3-Cyano

[0316] ##STR00110##

[0317] The compound 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinolin-3-cyano (17.3 mg, 0.038 mmol) was dissolved in DMF (2 mL), followed by the addition of fluoroacrylic acid (3.4 mg, 0.038 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N′ N′-tetramethyluronium hexafluorophosphate (HATU) (18.8 mg, 0.049 mmol), N,N-diisopropylethylamine (DIEA) (24.51 mg, 0.19 mmol), stirred for 1 h at room temperature, poured into 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated salt water, dried, concentrated and conducted preparative separation to give Example 9 compound (gray solid, 2.8 mg).LC-MS[M H]: m/z 529.0/531.0..sup.1H-NMR (400 MHz, MeOD-d.sub.4): δ 8.79 (s, 1H), 8.11 (d, 1H), 7.27 (dd, 1H), 7.03 (t, 1H), 5.38-5.26 (m, 2H), 3.97 (d, 4H), 3.86 (d, 4H).

Example 10:4-((S)-4-Acryloyl-2-Methylpiperazin-1-yl)-7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-8-Fluoroquinolin-3-Cyano

[0318] ##STR00111##

[0319] Step 1: 7-bromo-4,6-dichloro-8-fluoroquinolin-3-cyano (100 mg, 0.3 mmol) was dissolved in DMF (20 mL), tert-butyl (S)-3-methylpiperazine-1-carboxylate (66.0 mg, 0.33 mmol) and DIEA (116.1 mg, 0.9 mmol) were added and the reaction was carried out overnight at room temperature. The reaction was detected to be finished and spun dry DMF, then dissolved with ethyl acetate (30 mL) and separated by column chromatography (PE/EA=10/1, petroleum ether/ethyl acetate volume ratio) to give tert-butyl (S)-4-(7-bromo-6-chloro-3-cyano-8-fluoroquinolin-4-yl)-3-methylpiperazin-1-carboxylate ester (white solid, 100 mg).LC-MS[M H]: m/z 484.8.

[0320] Step 2: The compound (50.0 mg, 0.1 mmol) from the previous step, benzothiazole borate (54.0 mg, 0.13 mmol) were dissolved in dioxane/H.sub.2O (30 mL /10 mL), and potassium phosphate (32.1 mg, 0.15 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (Pd( dtbpf)Cl.sub.2) (7.0 mg, 0.01 mmol) were added, reacted at 90° C. for 4 h under nitrogen protection, cooled down, mixed directly and separated by column chromatography (PE/EA=3/1) to give tert-butyl (3S)-4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-3-cyano-8-fluoroquinolin-4-yl) -3-methylpiperazin-1-carboxylate (white solid, 40.0 mg).LC-MS[M H]: m/z 670.9.

[0321] Step 3: The compound (40.0 mg, 0.06 mmol) from the previous step was dissolved in DCM (5 mL), TFA (1 mL) was added, and stirred at room temperature overnight. The reaction was detected completely by LCMS and spun dry to obtain a yellow crude solid (40.0 mg).LC-MS[M H]: 471.1 m/z .

[0322] Step 4: The yellow crude product (40 mg, 0.09 mmol) from the previous step was dissolved in THF/water (6 mL / 2 mL), followed by the addition ofK.sub.3PO.sub.4 (38.0 mg, 0.18 mmol)andacryloyl chloride (10.0 mg, 0.099 mmol), then stirred at room temperature for 1 hour. 10 mL of water was added, extracted with EA, dried over MgSO4, filtered, spun dry, and conducted preparative separation to give the compound of Example 10 (yellow solid, 10.0 mg).LC-MS[M H]: m/z. 525.2/527.2..sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.90 (s, 1H), 8.10 (s, 1H), 7.96 (s, 2H), 7.27-7.29 (m, 1H), 7.07-7.12 (m, 1H), 6.85-6.89 (m, 1H), 6.16-6.21 (m, 1H), 5.73-5.77 (m, 1H), 4.02-4.06 (m, 4H), 3.81-3.99 (m, 3H), 1.26 (d, 3H).

Example 11:1-((2R)-4-(7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-8-Fluoro-2-(((S)-1-Methylpyrrolidin-2-yl) Methoxy) Quinazolin-4-yl)-2-Methylpiperazin-1-yl) Prop -2-En-1-One

[0323] ##STR00112##

##STR00113##

[0324] Example 11 (white solid, 6.5 mg) was prepared with reference to the synthesis method of Example 3. LC-MS[M+H].sup.+: m/z 614.1/616.1..sup.1H NMR (400 MHz, MeOD-d4): δ 8.04 (s, 1H), 7.22-7.26 (m, 1H), 6.99-7.04 (m, 1H), 6.76-6.83 (m, 1H), 6.28 (d, 1H), 5.80 (d, 1H), 4.89-4.94 (m, 1H), 4.46-4.67 (m, 2.5H), 4.01-4.4 (m, 2H), 3.81-3.98 (m, 2.5H), 3.64-3.75 (m, 3H), 3.24-3.31 (m, 1H), 3.08 (s, 3H), 2.36-2.41 (m, 1H), 2.05-2.22 (m, 3H), 1.34 (d, 3H).

Example 12: 2-(1-acryloyl -4-(7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-8-Fluoro-2-(((S)-1-Methylpyrrolidin-2-yl) Methoxy) Quinazolin-4-yl) Piperazin-2-yl) Acetonitrile

[0325] ##STR00114##

##STR00115##

[0326] Step 1: Dichloroquinazoline raw material (200 mg, 0.61 mmol), 2-piperazine acetonitrile (76 mg, 0.61 mmol), DIEA (236 mg, 1.83 mmol) were dissolved in DMF (3 mL).The reaction was carried out overnight at room temperature under nitrogen protection. Then Boc.sub.2O (266 mg, 1.22 mmol) was added dropwise and reacted at room temperature for 3 h.The mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated salt water, dried, concentrated and separated by column chromatography (PE:EA=3:1) to give a green oilysubstance(208 mg).

[0327] Step 2: The oily substance (430 mg, 0.83 mmol) from the previous step, (S)-(1-methylpyrrolin-2-yl)methanol (287 mg, 2.50 mmol), DIEA (645 mg, 5.00 mmol) were dissolved in N-methylpyrrolidone (NMP) (5 mL) and reacted at 50° C. for 3 days under nitrogen protection.The mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated saline, dried, concentrated and separated by column chromatography (DCM:MeOH=10:1) to give a pale yellow oily substance (101 mg).LC-MS[MH]: m/z 597.1.

[0328] Step 3: The oily substance (95 mg, 0.16 mmol) from the previous step and benzothiazole borate (63 mg, 0.20 mmol) were dissolved in dioxane/water (3 mL/1 mL), under nitrogen protection, followed by the addition of 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (13 mg, 0.02 mmol) and K.sub.3PO.sub.4 (50 mg, 0.24 mmol), reacted at 90° C. for 3 h, poured into 100 mL of water and extracted with ethyl acetate (50 mL*3), washed with saturated saline, dried, concentrated and separated by column chromatograph (DCM:MeOH=10:1) to give a yellow oil (50 mg).LC-MS[M H]: m/z 785.2.

[0329] Step 4: The oil (50 mg) from the previous step was dissolved in dichloromethane (5 mL), and TFA (1.5 mL) was added, stirred at room temperature for 1 h.Afterconcentration, TFA was removed to give a yellow solid (37 mg), which was directly used in the next step.LC-MS[M H]: m/z 585.1.

[0330] Step 5: The yellow solid (37 mg, 0.06 mmol) from the previous step was dissolved in THF/H.sub.2O (4 mL/2 mL), followed by the addition of K.sub.3PO.sub.4 (50 mg, 0.24 mmol) , cooled to 0 degree, and acryloyl chloride (4 mg, 0.05 mmol) was added dropwise, stirred for 1 h, poured into 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated salt water, dried, concentrated, and prepared by reversed-phase column to give Example 12 (pale yellow solid, 3.3 mg).LC-MS[M H]:m/z 639.1/641.1..sup.1H NMR (400 MHz,CD.sub.3OD): δ 8.05 (s, 1H), 7.24-7.21 (m, 1H), 7.03-6.99 (m, 1H), 6.80-6.79 (m, 1H), 6.33-6.29 (m, 1H), 5.85-5.82 (m, 1H), 5.18-5.06 (m, 1H), 4.80-4.48 (m, 5H), 4.35-3.69 (m, 6H), 3.16-2.98 (m, 5H), 2.43-2.37 (m, 1H), 2.22-2.03 (m, 3H).

Example 13:1-((3S)-4-(7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-8-Fluoro-2-(((S)-1-Methylpyrrolidin-2-yl) Methoxy) Quinazolin-4-yl)-3-Methylpiperazin-1-yl) Prop -2-En-1-One

[0331] ##STR00116##

[0332] 4-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-7-flu orobenzo[d]thiazol-2-amine (24 mg, 0.045 mmol) was dissolved in DMF (1.5 mL), followed by the addition of fluoroacrylic acid (6.1 mg, 0.067 mmol), HATU (26 mg, 0.067 mmol), and DIEA (17 mg, 0.14 mmol) in sequence, stirred at room temperature for 1 h, poured into 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated saline, dried, concentrated and conducted preparative separation (acid method) to give Example 13 (white solid, 11.6 mg).LC-MS[M H]:m/z 618.1/620.2..sup.1H-NMR (400 MHz, MeOD-d.sub.4): δ 8.02 (s, 1H), 7.21-7.25 (m, 1H), 7.02 (dd, 1H), 5.36 (dd, 1H), 5.28 (dd, 1H), 4.91-4.92 (m, 1H), 4.62-4.67 (m, 1H), 4.06-4.11 (m, 4H), 3.89-3.94 (m, 5H), 3.71-3.75 (m, 1H), 3.08 (s, 3H), 2.36-2.41 (m, 1H), 2.05-2.22 (m, 3H).

Example 14

[0333] 7-amino-7-fluoro-fluorophenyl[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(4-fluoroacryloyl) piperazin-1-yl)-2-(((S)-1-methylpyrroline-2-yl) methoxy) quinolin-3-cyano

##STR00117##

[0334] 7-amino-7-fluoro fluorophenyl[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolin-2-yl)methoxy)-4-(piperazin-1-yl)qu inolin-3-cyano (26 mg, 0.045 mmol) was dissolved in DMF (1.5 mL), followed by the addition of fluoroacrylic acid (6.1 mg, 0.067 mmol ), HATU (26 mg, 0.067 mmol), and DIEA (17 mg, 0.14 mmol) in sequence, stirred at room temperature for 1 h, poured into 20 mL of water and extracted with ethyl acetate (20 mL*3), washed with saturated salt water, dried, concentrated and conducted preparative separation (acid method) to give Example 14 (white solid, 12.1 mg).LC-MS[M H]: m/z 642.1/644.1..sup.1H-NMR (400 MHz, MeOD-d.sub.4): δ 8.09 (s, 1H), 7.98 (s, 2H), 7.23-7.28 (m, 1H), 7.05-7.11 (m, 1H), 5.36 (dd, 1H), 5.28 (dd, 1H), 4.91-4.92 (m, 1H), 4.62-4.67 (m, 1H), 4.06-4.11 (m, 4H), 3.89-3.94 (m, 5H), 3.71-3.75 (m, 1H), 3.08 (s, 3H), 2.36-2.41 (m, 1H), 2.05-2.22 (m, 3H).

Example 15: 4-(4-Acryloyl -3-(Cyanomethyl) Piperazin-1-yl)-7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl)-6-Chloro-8-Fluoroquinolin-3-Cyano

[0335] ##STR00118##

[0336] , the example compound 4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoroqu inolin-3-cyano (yellow solid, 14.0 mg) was prepared by the same synthetic method as in Example 10 using cyanomethyl piperazine compound as raw material.LC-MS[M H]: m/z 550.0/552.0..sup.1H-NMR (400 MHz, MeOD-d.sub.4): δ8.83 (s, 1H), 8.16 (s, 1H), 7.29-7.31(m, 1H), 7.25 (dd, 1H), 6.89-6.95 (m, 1H), 6.31-6.35 (m, 1H), 5.85-5.89 (m, 1H), 5.23-5.32 (m, 0.5H), 4.08-4.91 (m, 0.5H), 3.90-4.31 (m, 4H), 3.47-3.51(m, 2H), 3.22-3.29 (m, 1H), 3.13-3.18 (m, 1H).

Example 16: 4-((R)-4-Acryloyl -3-Methylpiperazin-1-yl)-7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl)-6-Chloro-8-Fluoroquinolin-3 -Cyano

[0337] ##STR00119##

[0338] Step 1: Chloroquinoline (100.0 mg, 0.3 mmol) was dissolved in anhydrous DMF (20 mL), piperazine (66.0 mg, 0.33 mmol) and DIEA (116.1 mg, 0.9 mmol) were added, reacted overnight at room temperature. After the completion of the reaction was detected, spun dry DMF, and separated by column chromatography (PE/EA=10/1) to give tert-butyl (R ) -4-(7-bromo-6-chloro-3-cyano-8-fluoroquinolin-4-yl)-2-methylpiperazine-1-carboxylate (white solid, 96.0 mg).LC-MS[M H]: m/z 485.0.

[0339] Step 2: The white solid (50.0 mg, 0.1 mmol) from the previous step, and benzothiazole borate (54.0 mg, 0.13 mmol) were dissolved in dioxane/H.sub.2O (30 mL /10 mL),followed by the addition of potassium phosphate (32.1 mg, 0.15 mmol) and Pd(tbdpf)Cl.sub.2 (7.0 mg, 0.01 mmol) in turn. The reaction was carried out at 90° C. for 4 h under nitrogen protection, cooled to room temperature, mixed directly and separated by column chromatography (PE/EA=3/1) to give tert-butyl (2R)-4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-3-cyano-8-fluoroquinolin -4-yl)-2-methylpiperazin-1-carboxylate (white solid, 50.0 mg ).LC-MS[M H]: m/z 671.1.

[0340] Step 3: The compound (50.0 mg, 0.07 mmol) from the previous step was dissolved in DCM (5 mL), followed by th addition of TFA(1 mL), and stirred at room temperature overnight. The reaction was detected completely by LCMS and spun dry to give a yellow crude solid (40.0 mg), which was directly used in the next step.LC-MS[M + H]+: m/z 471.0.

[0341] Step 4: The crude compound (50 mg, 0.1 mmol) from the previous step was dissolved in THF/water (6 mL / 2 mL), followed by the addition of K.sub.3PO.sub.4 (43.0 mg, 0.2 mmol) and acryloyl chloride (10.0 mg, 0.11 mmol), then stirred for 1 h at room temperature. 10 mL of water was added, extracted with EA, dried over MgSO4, filtered and spun dry, and conducted preparativeseparation to afford4-((R)-4-acryloyl-3-methylpiperazine-1-methyl)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoroquinolin-3-cyano(yellow solid, 17.0 mg).LC-MS[M H]: m/z. 525.0/527.0..sup.1H-NMR (400 MHz, MeOD-d4): δ8.87 (s, 1H), 8.19 (d, 1H), 7.27-7.31(m, 1H), 7.05 (dd, 1H), 6.35-6.90 (m, 1H), 6.05-6.29 (m, 1H), 5.82-5.89 (m, 1H), 3.73-4.30 (m, 7H), 1.20 (s, 3H).

Example 17: (2R,4aR)-3-Acryloyl -10-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -11-Chloro-9-Fluor-2, 6-Dimethyl-2, 3,4, 4a-Tetrahydro-1h-Pyrazine [1′,2′:4,5] Pyrazin [2,3-c] Quinolin -5(6H)-one

[0342] ##STR00120##

[0343] Step 1: tert-Butyl (2R,4aR)-10-bromo-11-chloro-9-fluoro-2,6-dimethyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1′,2′:4,5]py razino[2,3-c]quinoline-3-carboxylate (35 mg, 0.068 mmol) and benzothiazolylboronic acid (32 mg, 0.10 mmol) were dissolved in dioxane/water (3 mL/1 mL), followed by the addition of K.sub.3PO.sub.4 (22 mg, 0.10 mmol), and Pd(dtbpf)Cl.sub.2 (4.5 mg, 0.0068 mmol) under nitrogen protection, then heated to 90° C. and reacted overnight, spun dry and directly through the reversed-phase column to obtain the yellow crude product (36 mg).LC-MS[M + H]+: m/z 701.6.

[0344] Step 2: The crude product (36 mg, 0.051 mmol) from the previous step was dissolved in DCM (1.5 mL), and TFA (0.5 mL) was added and stirred for 2 h at room temperature under nitrogen protection, and spun dry to obtain the yellow crude product (26 mg).LC-MS[M H]: 501.6 m/z .

[0345] Step 3: The crude product (26 mg, 0.051 mmol) from the previous step was dissolved in THF/water (3/3 mL), followed by the addition of K.sub.3PO.sub.4 (33 mg, 0.15 mmol) and acryloyl chloride (5.6 mg, 0.062 mmol), then stirred for 2 h at room temperature under nitrogen protection. 10 mL of water was added andextracted with EA, dried over magnesium sulfate (MgSO.sub.4), filtered and spun dry. Preparative separation was conducted to give Example 17-1 (yellow solid, 8.8 mg) and Example 17-2 (yellow solid, 9.7 mg).

[0346] Example 17-1:LC-MS[M + H]+: m/z. 555.1/557.1,RT:8.476 min (Column:Sunfire C18 4.6*150 mm, 5uM,13 min,0.1% formic acid/water)..sup.1H-NMR (400 MHz, MeOD-d4): δ8.84 (s, 1H), 8.15 (s, 1H), 7.26-7.33 (m, 1H), 7.02-7.14 (m, 2H), 6.24-6.26 (m, 1H), 5.78-5.80 (m, 1H), 4.80-4.83 (m, 1H), 4.05-4.11 (m, 1H), 3.903.98 (m, 2H), 3.62 (s, 3H), 3.41-3.48 (m, 1H), 1.59 (d, 3H).

[0347] Example 17-2: LC-MS[M + H]+: m/z. 555.1/557.1,RT:8.469 min (Column:Sunfire C18 4.6*150mm, 5uM,13 min,0.1% formic acid/water)..sup.1H-NMR (400 MHz, MeOD-d4): δ8.84 (s, 1H), 8.15 (s, 1H), 7.26-7.33 (m, 1H), 7.02-7.14 (m, 2H), 6.24-6.26 (m, 1H), 5.79-5.83 (m, 1H), 4.80-4.83 (m, 2H), 4.06-4.11(m, 2H), 3.92-3.96 (m, 1H), 3.62 (s, 3H), 3.41-3.48 (m, 1H), 1.59 (d, 3H).

Example 18: 1-(4-(7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-2-(3-(Dimethylamino) Azetin-1-yl)-8-Fluoroquinazolin-4-yl) Piperazin-1-yl) Prop-2-En-1-One

[0348] ##STR00121##

##STR00122##

[0349] Step 1: Tert-butyl-3-oxoazetidine-1-carboxylate (1.0 g, 5.8 mmol), dimethylamine hydrochloride (947 mg, 11.7 mmol), palladium/carbon (Pd/C) (0.4 g) were dissolved in glacial acetic acid/methanol (AcOH/MeOH) (1 mL/8 mL).The reaction proceeded overnight at room temperature under hydrogen atmosphere, filtered, concentrated, extracted with ethyl acetate (50 mL), washed sequentially with saturated NaHCO.sub.3 (30 mL) and saturated saline (30 mL), dried, and concentrated to give a yellow oil (1.1 g), which was used directly in the next step.LC-MS[M + H]+: m/z 201.5.

[0350] Step 2: The yellow oil (1.1 g, 5.5 mmol) from the previous step was dissolved in DCM (8 mL). TFA (2 mL) was added slowly dropwise and the reaction was carried out at room temperature for 1h.Concentration was conducted to obtain a yellow oil (610 mg), which was used directly in the next step.LC-MS[M + H]+: m/z 101.6.

[0351] Step 3: The oil (200 mg, 0.4 mmol) from the previous step, tert-butyl-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazin-1-carboxylate (82 mg, 0.8 mmol) and DIEA (325 mg, 2.5 mmol)were dissolved in DMF (3 mL) and then reacted for 1 day at room temperature under nitrogen protection. The reacting solution wasdiluted with water (30 mL) and extracted with ethyl acetate (30 mL*3), washed with saturated salt water, dried, concentrated, and seperated by column chromatography (EA) to obtain a dark green solid (102 mg).LC-MS[M + H]+: m/z 543.1.

[0352] Step 4: The solid (90 mg, 0.16 mmol) from the previous step and benzothiazole boronic acid compound (83 mg, 0.21 mmol) were dissolved in dioxane/water (6 mL/2 mL) under nitrogen protection, followed by the addition of 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (13 mg, 0.02 mmol) and K.sub.3PO.sub.4 (53 mg, 0.25 mmol). The reacting solution wasreacted at 90° C. for 3 h, poured into 100 mL of water and extracted with ethyl acetate (50 mL*3), washed with saturated saline, dried, concentrated and separeated by column chromatography (DCM:MeOH=10:1) to give a yellow oil (100 mg).LC-MS[M + H]+: m/z 731.1.

[0353] Step 5: The oil (100 mg) from the previous step was dissolved in dichloromethane (5 mL), followed by the addition of TFA (1.5 mL), stirred for 1 h at room temperature, concentrated, and the TFA was removed to give a yellow solid (72 mg), which was directly used in next step.LC-MS[M + H]+: m/z 531.1.

[0354] Step 6: The solid (72 mg, 0.14 mmol) from the previous step , acrylic acid (13 mg, 0.17 mmol), HATU (79 mg, 0.20 mmol) and DIEA (52 mg, 0.41 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 1 h,separated by preparative reverse phase column to give the target compound (yellow solid, 11 mg) LC-MS[M + H]+: m/z 585.0.1H NMR (400 MHz, CD3OD): δ 8.02 (s, 1H), 7.26-7.22 (m, 1H), 7.05-7.00 (m, 1H), 6.80 (dd, 1H), 6.30 (dd, 1H), 5.83 (dd, 1H), 4.70-4.65 (m, 2H), 4.60-4.54 (m, 2H), 4.31-4.24 (m, 1H), 4.22-4.13 (m, 4H), 3.95-3.88 (m, 4H), 2.96 (s, 6H).

Example 19:3-((4-(4-Acryloylpiperazin-1-yl)-7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl)-6-Chloro-8-Fluoroquinazolin-2-yl) Amino)-N,N-Dimethylpropanamide

[0355] ##STR00123##

##STR00124##

[0356] Step 1: The raw materials tert-butoxycarbonyl-aminopropionate (1.0 g, 5.3 mmol), dimethylamine hydrochloride (428 mg, 5.4 mmol), HATU (3.1 g, 7.9 mmol) and DIEA (2.1 g, 15.9 mmol) were dissolved in DMF (8 mL). The reaction proceeded at room temperature under nitrogen protection overnight, diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3), the organic phase was washed with water (30 mL) and saturated saline (30 mL) in turn, dried, concentrated and separated by column chromatography (PE:EA=1:2) to give a brown oil (1.0 g).LC-MS[M H]: m/z 217.5.

[0357] Step 2: The oil (1.0 g, 4.6 mmol) from the previous step was dissolved in DCM (8 mL).TFA(2 mL) was added slowly and reacted at room temperature for 1h

[0358] . Concentration was conductedto obtain a yellow oil (530 mg), which was used directly in the next step.LC-MS[M H]: m/z 117.6.

[0359] Step 3: The yellow oil (200 mg, 0.4 mmol) from the previous step, tert-butyl-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazin-1-carboxylate (98 mg, 0.8 mmol) and DIEA (325 mg, 2.5 mmol) were dissolved in DMF (3 mL) and reacted for 1 day at room temperature under the protection of nitrogen.The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3), washed with saturated salt water, dried, concentrated and separated by column chromatography (PE:EA=1:2) to obtain a pale yellow solid (180 mg).LC-MS[M H]: m/z 558.9.

[0360] Step 4: The solid (90 mg, 0.16 mmol) from the previous step and benzothiazole boronic acid (83 mg, 0.21 mmol) were dissolved in dioxane/water (6 mL/2 mL), under the nitrogen protection, followed by the addition of 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (13 mg, 0.02 mmol) and K.sub.3PO.sub.4 (53 mg, 0.25 mmol), reacted at 90° C.for 3 h, poured into 100 mL of water and extracted with ethyl acetate (50 mL*3), washed with saturated saline, dried, concentrated and separated by column chromatography (DCM:MeOH=10:1) to give a yellow oil (120 mg).LC-MS[M H]: m/z 747.1.

[0361] Step 5: The oil (120 mg) from the previous step was dissolved in dichloromethane (5 mL), followed by the addition of TFA (1.5 mL), stirred for 1 h at room temperature, concentrated, and the TFA was removed to give a yellow solid (88 mg), which was directly used in next step.LC-MS[M H]: m/z 547.0.

[0362] Step 6: The yellow solid (88 mg, 0.16 mmol) from the previous step, acrylic acid (15 mg, 0.21 mmol), HATU (93 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol) were dissolved in DMF (2 mL) and reacted for 1 h at room temperature, and then separated bypreparative reverse phase column to give the target compound (yellow solid, 7.6 mg).LC-MS[M H]: m/z 601.1..sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.06 (s, 1H), 7.27-7.23 (m, 1H), 7.04-7.00 (m, 1H), 6.80 (m, 1H), 6.31 (m, 1H), 5.83 (m, 1H), 4.38-4.28 (m, 4H), 4.02-3.84 (m, 6H), 3.05 (s, 3H), 2.96 (s, 3H), 2.80-2.77 (m, 2H).

Example 20: 4-(4-Acryloyl Piperazin-1-yl)-7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-2-(2-(Dimethylamino) Ethoxy)-8-Fluoroquinolin-3 -Cyano

[0363] ##STR00125##

the intermediate 1B was used as the raw material and synthesized by the method of Example 3 to obtain Example 20.LC-MS[M H]: m/z 598.2/600.2.

Example 21:4-(4-acryloyl Piperazin-1-yl)-7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl) -6-Chloro-2-(3 -(Dimethylamino) Azetidine-1 -yl)-8-Fluoroquinolin-3 -Cyano

[0364] ##STR00126##

[0365] the intermediate 1B was used as the raw material and synthesized by the method of Example 18 to obtain Example 20.LC-MS[M H]: m/z 609.2/611.2.

Example 22:3-((4-(4-Acryloylpiperazin-1-yl)-7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl)-6-Chloro-3-Cyano-8-Fluoroquinolin-2-yl) Amino)-N,N-Dimethylpropanamide

[0366] ##STR00127##

[0367] the intermediate 1B was used as the raw material and synthesized by the method of Example 19 to obtain Example 20.LC-MS[M H]: m/z 625.1/627.1.

Example 23: 1-((3S)-4-(7-(2-Amino-7-Fluorobenzo [d] thiazol-4-yl) -6-Chloro-8-Fluoro-2-(((S)-1-Methylpyrrolin-2-yl) Methoxy) Quinazolin-4-yl)-3-Methylpiperazin-1-yl) Prop-2-En-1-One

[0368] ##STR00128##

[0369] Example 23 was obtained by synthesis referring to the method of Example 11.LC-MS[M H]: m/z 614.1/616.1..sup.1H-NMR (400 MHz,CD.sub.3OD) δ 7.92 (d, 1H), 7.25-7.21 (m, 1H), 7.03-6.98 (m, 1H), 6.89-6.77 (m, 1H), 6.32-6.28 (m, 1H), 5.83 (d, 1H), 4.98-4.89 (m, 2H), 4.66-4.61 (m, 1H), 4.54-4.32 (m, 2H), 4.22-4.01 (m, 1H), 3.91-3.61 (m, 4H), 3.24-3.12 (m, 2H), 3.08 (s, 3H), 2.44-2.35 (m, 1H), 2.25-2.03 (m, 3H), 1.45-1.39 (m, 3H).

Example 24:1-(4-(7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-8-Fluoro-2-(((2S,4R)-4-Hydroxy-1-Methylpyrrolin-2-yl) Methoxy) Quinazolin-4-yl) Piperazin-1-yl) Prop-2-En-1-One

[0370] ##STR00129##

Example 24 (white solid, 12.1 mg) was obtained by synthesis referring to the method of Example 11.LC-MS[M H]: m/z 616.1..sup.1H NMR (400 MHz, MeOD-d.sub.4): δ 7.95 (s, 1H), 7.21 (dd, J=5.6, 8.0 Hz, 1H), 6.99 (t, J=8.4 Hz,1H), 6.78-6.86(m, 1H), 6.28 (dd, J=2.0, 16.8 Hz, 1H), 5.81 (dd, J=2.0, 10.8 Hz, 1H), 4.49-4.61(m, 2H), 4.35-4.39 (m, 1H), 3.92-4.00 (m, 8H), 3.39-3.43 (m, 1H), 3.17-3.22 (m, 1H), 2.59 (s, 3H), 2.37-2.42 (m, 1H), 2.00-2.04 (m, 1H).

Example 25

[0371] 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2S,4S)-4-fluoro-1-methylpyrrolin-2-y 1) methoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

##STR00130##

Example 25 (white solid, 13.5 mg) was obtained by synthesis referring to the method of Example 11.LC-MS[M H]: m/z 618.0..sup.1H NMR (400 MHz, MeOD-d.sub.4): δ 7.94 (s, 1H), 7.21 (dd, 1H), 6.99 (t, 1H), 6.81 (dd, 1H), 6.28 (dd, 1H), 5.81 (dd, 1H), 5.06-5.23 (m, 1H), 4.55-4.60 (m, 1H), 4.43-4.49 (m, 1H), 3.92-4.00 (m, 8H), 3.24-3.31 (m, 1H), 2.82-2.86 (m, 1H), 2.43-2.62 (m, 5H), 1.89-2.04 (m, 1H).

Example 26

[0372] 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)metho xy)-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

##STR00131##

Example 26 (white solid, 6.3 mg) was obtained by synthesis referring to the method of Example 11.LC-MS[M H]: m/z 636.0.

Example 27

[0373] 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2 -yl)methoxy)quinazolin-4-yl)piperazin-1-y1)prop-2-en-1-one

##STR00132##

Example 27 (white solid, 12.3 mg) was obtained by synthesis referring to the method of Example 11.LC-MS[M H]: m/z 618.1.

Example 28:(2R,4aR)-10-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-11-Chloro-9-Fluoro-3-(2-Fluoroacryloyl)-2, 6-Dimethyl-2, 3,4, 4a-Tetrahydro-1H-Pyrazin [1′,2′:4,5] Pyrazin [2,3-c] Quinolin -5(6H)-one

[0374] ##STR00133##

[0375] (2R,4aR)-10-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-11-chloro-9-fluoro-2,6-dimethyl-2,3,4,4a-tetrahyd ro-1H-pyrazin[1′,2′:4,5]pyrazin[2,3-c]quinolin-5(6H)-one and fluoroacrylic acid were synthesized by the same route as in Example 17 and separated by silica gel column chromatography to give Example 28 (white solid, 8.2 mg).LC-MS[M H]: m/z. 573.2/575.2..sup.1H-NMR (400 MHz, MeOD-d.sub.4): δ8.84 (s, 1H), 8.15 (s, 1H), 7.26-7.33 (m, 1H), 7.02-7.14 (m, 2H), 5.81-5.83 (m, 1H), 4.80-4.82 (m, 2H), 4.06-4.10(m, 2H), 3.92-3.95 (m, 1H), 3.62 (s, 3H), 3.41-3.48 (m, 1H), 1.59 (d, 3H).

Example 29:7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-8-Fluoro-4-((R)-4-(2-Fluoroacryloyl)-3-Methylpiperazi n-1-yl)-2-((1-Methylpyrroline-2-yl) Methoxy) Quinolin-3-Cyano

[0376] ##STR00134##

Example 29 (white solid, 10.0 mg) was obtained by synthesis referring to the method of Example 13.LC-MS[M H]: m/z 656.3.

Example 30:7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-2-((4,4-Difluoro-1-Methylpyrrolin-2-yl) methoxy) -8-Fluoro-4-(4-(2-Fluoroacryloyl) Piperazin-1-yl) Quinolin-3-Cyano

[0377] ##STR00135##

Example 30 (white solid, 6.3 mg) was obtained by synthesis referring to the method of Example 13.LC-MS[M H]: m/z 678.1.

Example 31:7-(2-Amino-7-Fluorobenzo [d] Thiazol-4-yl)-6-Chloro-2-(3-(Dimethylamino)Azetidine-1-yl) -8-Fluoro-4-(4-(2-Fluoroacryloyl)Piperazin-1-yl)Quinolin-3-Cyano

[0378] ##STR00136##

Example 31 (white solid, 9.7 mg) was obtained by synthesis referring to the method of Example 18.LC-MS[M H]: m/z 627.1.

Comparative Compound 1:1-(4-(7-(2-Amino-7-Fluorobenzo[d]Thiazol-4-yl)-6-Chloro-8-Fluoroquinazolin-4-yl) Piperazin-1-yl) Prop-2-en-1-One

[0379] ##STR00137##

Comparative compound 1 was synthesized by referring to the method of Example 1 in Patent Document WO2020081282.LC-MS[M H]: m/z 487.0/489.0..sup.1H-NMR (400 MHz, CD.sub.3OD) δ 8.74 (s, 1H), 8.24 (s, 1H), 7.27-7.30(m, 1H), 7.01-7.06 (m, 1H), 6.80 (dd, J=16.8 Hz, 2.8 Hz, 1H), 6.31 (dd, J=1.6 Hz, 16.8 Hz, 1H), 5.83 (dd, J=1.6 Hz, 10.8 Hz, 1H), 4.37-4.39(m, 4H), 3.95-3.99(m, 4H).

Comparative Compound 2 (2R,4aR)-3-Acryloyl-11-Chloro-9-Fluoro-10-(2-Fluoro-6-Hydroxyphenyl)-2,6-Dimethyl-2,3,4,4a-Tetrahydro-1 H-Pyrazin[1′,2′:4,5]Pyrazin[2,3-c]Quinolin-5(6H)-One

[0380] ##STR00138##

Comparative compound 2-1 and 2-2 was synthesized by referring to the method of Example 21 and 22 in patent document WO2019110751A1.Comparative compound 2-1:LC-MS[M + H]+: m/z. 499.1/501.1,RT:5.466 min (column: Sunfire C18 4.6*150mm, 5uM, elution gradient time: 13 min, mobile phase: A:0.1% formic acid/water; B:0.1% formic acid/acetonitrile), wavelength: 254 nM..sup.1H-NMR (400 MHz, MeOD-d4): δ 8.84 (s, 1H), 8.13 (s, 1H), 7.30-7.36 (m, 1H), 7.07-7.14 (m, 1H), 6.79 (d, 1H), 6.71-6.77 (m, 1H), 6.23 (d, 1H), 5.80 (d, 1H), 4.80-4.83 (m, 1H), 3.90-3.99 (m, 2H), 3.56 (s, 3H), 3.34-3.37 (m, 1H), 3.15-3.19 (m, 1H), 1.59 (d, 3H).

[0381] Comparative compound 2-2:LC-MS[M + H]+: m/z. 499.1/501.1,RT:5.851 min (column: Sunfire C18 4.6.sup.∗150mm, 5uM, elution gradient time: 13 min, mobile phase: A:0.1% formic acid/water; B:0.1% formic acid/acetonitrile), wavelength: 254 nM..sup.1H-NMR (400 MHz, MeOD-d4): d 8.84 (s, 1H), 8.12 (s, 1H), 7.30-7.36 (m, 1H), 7.07-7.14 (m, 1H), 6.78 (d, 1H), 6.71-6.76 (m, 1H), 6.23 (d, 1H), 5.80 (d, 1H), 4.80-4.85 (m, 1H), 3.90-3.97 (m, 2H), 3.56 (s, 3H), 3.34-3.37 (m, 1H), 3.10-3.14 (m, 1H), 1.59 (d, 3H).

Test Example 1 Kras.SUP.G12C Functional Analysis

[0382] CisBio’s KRAS.sup.G12C/SOS1 kit was used to test the efficacy of the compound on inhibiting the protein-protein interaction between SOS1 and KRAS.sup.G12Cby Binding assay.Results were expressed as IC.sub.50values.

[0383] Test methods: (1) the test compound was tested at a concentration of 1000 nM. Diluted to 3-fold diluted compound of a 200-fold final concentration of 100% DMSO solution in a 384-well plate at 10 concentrations. 50 nL of 200-fold final concentration of compound was transferred to the destination plate 384 well plate using a dispenser Echo 550.50 nL of 100% DMSO was added to the negative control wells and positive control wells; (2) 4-fold final concentration of Tag1 SOS1 solution was prepared using Diluent buffer; (3) 2.5 .Math.L of 4-fold final concentration of Tag1 SOS1 solution was added to the 384-well plate; (4) 4-fold final concentration of Tag2 KRAS.sup.G12C solution was prepared using Diluent buffer; (5) 2.5 .Math.L of 4-fold final concentration of Tag2 KRAS.sup.G12C solution was added to compound wells and positive control wells, respectively; 2.5 .Math.L of diluent buffer was added to negative control wells; (6) the 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken and mixed, and incubated at room temperature for 15 min; (7) 1-fold final concentration of Anti Tag1 TB3+ solution and 1-fold final concentration of Anti Tag2 XL665 solution were prepared with Detection buffer, and 5 .Math.L of the mixture was added to each well after mixing the two solutions; (8) the 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken and mixed, and incubated at room temperature for 120 minutes; (9) the Envision enzyme marker was used to read

[00001]$\text{Inhibition\%=}\frac{\text{Max signal}-\text{Compound signal}}{\text{Max signal}-\text{Min signal}}\times 100$

Em665/620; (10) data analysis, calculation formula ; where Min signal is the mean value of negative control wells, Max signal is the mean value of positive control wells.The log value of concentration was used as the X-axis and the percentage inhibition as the Y-axis to fit the quantitative efficacy curve using the log(inhibitor) vs. response Variable slope of the quantitative efficacy curve of the analytical software GraphPad Prism 5 to derive the IC.sub.50 value of each compound on the enzyme activity.The fitting formula was: Y=Bottom+(Top Bottom)/(1+10.sup.A((LogIC50X).sup.∗ HillSlope)).

[0384] RESULTS: Most of the compound of the present invention showed significant inhibition againstKRAS.sup.G12C/SOS1 interaction with an inhibitory activity IC.sub.50 less than 500 nM, and in some embodiments the IC.sub.50 was less than 100 nM or even less than 50 nM.The results are shown in table 1, A<50 nM, 50 nM ≤B<200 nM, 200 nM ≤C<1000 nM, D>1000 nM.

TABLE-US-00002 No. ICso/nM No. IC.sub.50/nM No. ICso/nM No. IC.sub.50/nM 1 A 2 A 3 A 4 A 5 A 6 B 7 B 8 A 9 B 10 B 11 B 12 B 13 B 14 B 15 C 16 B 17-1/17-2 B/B 18 A 19 B 20 A 21 A 22 B 23 A 24 A 25 A 26 A 27 A 28 B 29 B 30 B 31 B Comparative Compound 1 B Comparative Compound 2-1 B Comparative Compound 2-2 D

Test Example 2: Effect of the Compound of the Present Invention on the Proliferation and Downstream Signaling ERK Phosphorylation Ability of NCI-H358 and MiaPaca-2 Cells Assay

[0385] Test method 1 (2D):NCI-H358 (lung cancer) and MiaPaca-2 cells (pancreatic cancer) cells (100 .Math.L/well, 20,000 cells/mL) were inoculated in 96-well culture plates supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin sulfate, respectively.Using 0.5% dimethyl sulfoxide as a blank control, cells were treated with a solution of the compound to be tested at a starting concentration of 10 .Math.M, tripled diluted testing solution of the compound in eight gradients were used to treat cells, and then incubated in a 5% CO.sub.2 incubator for a certain period of time (5-7 days).At the end of incubation, 10 .Math.L of MTT stock solution (5 mg/mL) was added to each well.The culture plates were incubated at 37° C. for 4 h and then the medium was removed.Dimethyl sulfoxide (100 .Math.L) was added to each well and then shaken sufficiently. The absorbance of the product formazanwas measured at 570 nm on the Thermo Scientific Varioskan Flash multimode reader.IC.sub.50 values were obtained by fitting dose-response data into a three-parameter nonlinear regression model using GraphPad Prism 6.0 software.

[0386] Results: The example compound provided by the present invention showed proliferation inhibitory activity against NCI-H358 and MiaPaca-2 cells with IC.sub.50 values less than 5000 nM; some of the Example compounds such as Examples 1, 3, 5, 8, 10, 11, 13, 16, 18, 20, 21, 25, 29 and 31 showed significant proliferation inhibitory activity against NCI-H358 and MiaPaca-2 cells with IC.sub.50 values less than 100 nM, and the proliferation inhibitory activity of some examples was even less than 10 nM, showing excellent in vitro antitumor effects.As shown in Table (II), the data of proliferation inhibitory activity of the compound of examples of the present invention on MiaPaca-2 cells are listed.

TABLE-US-00003 Example No. IC.sub.50/nM Example No. IC.sub.50/nM Example No. IC.sub.50/nM 1 5.5 2 13.2 3 <0.3 4 1.1 5 2.3 6 35.0 7 23.1 8 13.8 9 362.0 10 57.2 11 31.0 12 19.3 13 12.1 14 0.90 15 390 16 22.3 17-1/17-2 24.8/23.1 18 0.67 19 28.0 20 1.3 21 0.89 22 0.93 Comparative Compound 1 2.6 Comparative Compound 2-½-2 96.4/>10000 23 1.2 24 <1.0 25 <1.0 26 <1.0 27 <1.0 28 63.2 29 <1.0 30 <1.0 31 <1.0

[0387] Test method 2 (3D): The tumor cells in the logarithmic growth phase were diluted with culture solution to a certain concentration and inoculated on the 96-well plate on the ultra-low attachment surface, and the culture medium was 80 .Math.L/well. Cells were incubated overnight at 37° C. in a humidity chamber. On the second day, a series of diluted test compounds (10 concentrations, 3 times dilution) were added to the plate, 20 .Math.L/well, incubated in an incubator for 96h.The plates are removed and placed at room temperature and incubated with an equal volume of Cell Titer Glo®3D reagent for 1 h. The signal is detected by the En Vision™ plate reader. The signal is converted to percentage inhibition using the following formula: % Inhibition = 100 - [(test compound signal - median minimum signal) / (median maximum signal - median minimum signal) x 100].The maximum signal is the signal value of the inhibitor-free well, and the minimum signal is the signal value of the wellcontaining a reference inhibitor sufficient to completely inhibit cell proliferation. A four-parameter nonlinear regression curve was fitted to the percent inhibition for each concentration of the compound and the IC.sub.50 was calculated.

[0388] Results: The example compound provided by the present invention showed proliferation inhibitory activity against NCI-H358 and MiaPaca-2 cells with IC.sub.50 values all less than 1000 nM; some Examples such as Examples 1, 2, 3, 5, 8, 10, 11, 13, 16, 18, 20, 29, 31, etc. had an IC.sub.50 less than 200 nM for cell proliferation inhibitory activity against NCI-H358 and MiaPaca-2, and some Examples such as Examples 1, 3, 13, 18 had an IC.sub.50 even less than 10 nM.

[0389] Test method 3 (ERK phosphorylation): Miapaca-2 or H358 cells were inoculated at certain concentrations in 96-well plates and incubated overnight at 37° C., 5% CO2 in a cell culture incubator, and serial dilutions of the test compound (5 concentrations, 3-fold dilution) were added to the plates the next day for 24 h (Miapaca-2) or 3 h (H358), then lysis solution containing protease and phosphatase inhibitor were added to lyse the cells to extract proteins and western blot method was used to detect the level of p-ERK.

[0390] RESULTS: The example compounds provided by the present invention such as Examples 1, 3, 5, 8, 10, 11, 13, 16, 18, 20, 21, 25, 29 and 31 etc. inhibited the phosphorylated ERK levels of NCI-H358 and MiaPaca-2 significantly, with IC.sub.50 less than 500 nM.

Test Example 3:ADMET Test ofExample Compounds

[0391] Metabolic stability assay: A warm incubation for metabolic stability was performed with a system of 150 .Math.L of liver microsomes (final concentration 0.5 mg/mL) containing NADPH (final concentration 1 mM), 1 .Math.M of the test compound and positive control midazolam or negative control atenolol, and the reaction was terminated with acetonitrile containing tinidazole at 0 min, 5 min, 10 min and 30 min, respectively. The reaction was vortexed for 10 min and centrifuged at 15000 rmp for 10 min, and 50 .Math.L of supernatant was taken into the 96-well plate for sampling. The metabolic stability of the compound was calculated by measuring the relative reduction of the drugs.

[0392] Results: the example compounds of the invention were stable to various genera (rat, mouse, monkey, human) of liver microsomes with half-lives greater than 30 min, such as Example compounds 1, 3, 8, 11, 13, 14, 17-1, 20, 21, 23, etc.

TABLE-US-00004 Example No. Liver microsomal stability (T.sub.½ /min) Rat Mouse monkey human 1 155 249 163 403 3 147 99 47 403 8 40 34 60 262 11 48 110 104 403 13 45 95 184 221 14 121 403 403 48 17-1 403 44 64 131 20 36 35 52 113 21 37 166 57 202 23 28 241 47 68 Comparative Compound 1 31 32 31 44 Comparative Compound 2-1 41 47 42 54

[0393] Direct inhibition test (DI test): direct inhibition warm incubation was performed with a system of 100 .Math.L of human liver microsomes (final concentration 0.2 mg/mL) containing NADPH (final concentration 1 mM), 10 .Math.M compound, positive inhibitor cocktail (ketoconazole 10 .Math.M, quinidine 10 .Math.M, sulfobenzyrazole 100 .Math.M, α-naphthoflavone 10 .Math.M, tranylcypromine 1000 .Math.M), a negative control (BPS with 0.1% DMSO) and a mixed probe substrate (midazolam 10 .Math.M, testosterone 100 .Math.M, dextromethorphan 10 .Math.M, diclofenac 20 .Math.M, phenacetin100 .Math.M, mephenytoin100 .Math.M), and the reaction was terminated after a warm incubation for 20 min.The relative enzyme activity was calculated by measuring the relative amount of metabolites produced.

[0394] Results: The example compounds of the present invention, such as 3, 8, 11, 17-1, 21,etc., did not significantly inhibit major metabolic enzyme isoforms (e.g., CYP1A2, 2C8, 2C19, 3A4) with IC.sub.50 greater than 10 .Math.M.

[0395] hERG inhibition test: 20 mM of compound stock solution was diluted with DMSO, 10 .Math.L of 20 mM compound stock solution was added to 20 .Math.L of DMSO solution, and 3-fold serial dilution was made to 6 DMSO concentrations; 4 .Math.L of each of the 6 DMSO concentrations were added to 396 .Math.L of extracellular solution and diluted 100-fold to 6 intermediate concentrations, then 80 .Math.L of each of the 6 intermediate concentrations were added to 320 .Math.L of extracellular solutions respectively and diluted 5-fold to the final concentration to be tested; the highest test concentration was 40 .Math.M, followed by 6 concentrations of 40, 13.3, 4.4, 1.48, 0.494, and 0.165 .Math.M, respectively; the DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel; compound preparation was done by Bravo apparatus throughout the dilution process; current and time course plots of compounds on hERG potassium channels were read, and curves were fitted to make the inhibition curves of compoundsagainst hERG.

[0396] Results: The example compounds of the present invention, such as 3, 8, 11, 17-1, 21, etc., had no significant inhibitory effect on hERG potassium channels with IC.sub.50 greater than 20 uM.

Test Example 4:In Vivo Pharmacokinetic Parameter Testing of Example Compounds in Mice

[0397] Six male SPF ICR mice (Shanghai Sipur-Bikai experimental animals) were divided into two groups, the test compounds were configured into a suitable solution or suspension; one group was administered intravenously and one group was administered orally.Blood was collected via jugular venous puncture at approximately 0.2 mL/time point for each sample, anticoagulated with sodium heparin,blood was collected at the following time points: before and 5, 15 and 30 min, 1, 2, 4, 6, 8 and 24 h after administration; blood samples were collected and placed on ice, plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 min, 2-8° C.) and collected plasma was stored at -80° C. before analysis.Plasma samples were analyzed by LC-MS/MS.The pharmacokinetic parameters of AUC.sub.0-t, AUC.sub.0-∞, MRT.sub.0-∞, C.sub.max, T.sub.max, T.sub.½ and V.sub.d of the subjects and their mean and standard deviation were calculated separately based on the blood concentration data of the drug using the pharmacokinetic calculation software WinNonlin 5.2 non-atrial chamber model.In addition, the bioavailability (F) will be calculated by the following formula.For samples with concentrations below the lower limit of quantification (BLQ), when performing pharmacokinetic parameter calculations, samples sampled before reaching C.sub.max should be calculated as zero values, and samples sampled at points after reaching C.sub.max should be calculated as not quantifiable (BLQ).

TABLE-US-00005 No. iv(1 mg/kg) Below the curve and AUC.sub.0-t (nM.h) Clearance rate Cl (mL/min/kg) Half-life T.sub.½ (h) 3 4095±373 6.35±0.67 6.5 8 2848±363 11.53±1.52 0.52 13 985±42 26.59±1.29 1.9 17-1 3315±187 9.04±0.50 1.1 21 1295±70 21.62±1.05 1.3 Comparative Compound 1 1620±188 21.16±2.36 0.6

[0398] Results: the pharmacokinetic properties of some Examples 3, 8, 13, 17-1, 21of the present invention in mice were significantly better than those of the comparative compound 1: for example, the AUC of Example 3, 8, 17-1 were significantly increased compared to the comparative compound 1; the clearance rate Cl of Examples 3, 8, 17-1 were significantly lower than that of the comparative compound 1; and the in vivo metabolic half-life of Example 3 was significantly longer than that of the comparative compound 1.

Test Example 5: Test of Example Compound for Growth Inhibition of the Transplanted Tumor of MiaPaca-2, NCI-H358 Tumor Cells in Nude Mice

[0399] The tumor tissues in the peak growth period were cut into 1.5 mm.sup.3 and inoculated into the right axillary subcutis of nude mice under aseptic conditions. The subcutaneous transplanted tumors of nude mice were measured by vernier calipers for the diameter of the transplanted tumors, and the animals were randomly grouped when the average volume of the tumors reached about 130 mm.sup.3.The example compound (injection water containing 1% Tween 80 was prepared to the desired concentration and then left to be used) was administered orally at the given dose daily for three weeks, and the solvent control group was given an equal amount of solvent. The transplanted tumor diameter was measured twice a week throughout the experiment, and the mice were weighed at the same time.The tumor volume (TV) was calculated by the formula: TV = ½×a×b.sup.2, where a and b are the length and width, respectively. The relative tumor volume (RTV) was calculated from the measured results by the formula: RTV = V.sub.t/V.sub.0.Where Vo is the tumor volume measured at the time of cagingand administration(i.e., d0), and V.sub.t is the tumor volume at each measurement.The evaluation indexes of antitumor activity are 1) relative tumor proliferation rate T/C (%), calculated as follows: T/C (%) = (TRTV/CRTV) × 100%, TRTV: RTV of the treatment group; CRTV: RTV of the negative control group; 2) tumor volume growth inhibition rate GI%, calculated as follows: GI% = [1-(TV.sub.t-TV.sub.0)/(CV.sub.t- CT.sub.0)]×100%, TV.sub.t is the tumor volume measured in each treatment group; TV.sub.0 is the tumor volume obtained when the treatment group was caged and administered; CV.sub.t is the tumor volume measured in each control group; CV.sub.0is tumor volume obtained when the control group was caged; 3) tumor weight inhibition rate, calculated as follows: tumor weight inhibition rate%=(W.sub.c-WT)/W.sub.c×100%, W.sub.c: tumor weight of the control group, WT. tumor weight of the treatment group.

[0400] Results: The example compounds of the present invention such as Examples 3, 8, 17-1 showed significant tumor growth inhibition at 10 mg/kg and 30 mg/kg doses administered orally once daily for 21 days, with tumor inhibition rates greater than 60%; Example 8 showed tumor inhibition rates greater than 90% at 10 mg/kg doses, and tumor regression was achieved after two weeks of administration.

[0401] All documents referred to in the present invention are incorporated by reference herein as if each document is individually incorporated by reference.Further, it should be understood that upon reading the above teaching of the present invention, various modifications or revisonsmay be made to the present invention by those skilled in the art, and those equivalents also fall within the scope defined by the appended claims of the present application.