CN116332948A - A nitrogen-containing tetracyclic compound and its preparation method and medicinal use - Google Patents

Abstract

The invention discloses a nitrogen-containing tetracyclic compound and its preparation method and medicinal use, specifically a compound of formula (I) which can be used as a KRAS mutation inhibitor, its preparation method, a pharmaceutical composition containing the compound and Medicinal use for the treatment of a KRAS-mediated disease or condition.

Description

A nitrogen-containing tetracyclic compound and its preparation method and medicinal use

Technical Field

The present invention belongs to the field of medicine, and relates to a nitrogen-containing tetracyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound, and medical uses thereof.

Background Art

Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas acts as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states, converting upstream cellular signals received from a variety of tyrosine kinases into downstream effectors to regulate a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

The role of activated KRas in malignancies was observed more than 30 years ago. Abnormal expression of KRas accounts for 20% of all cancers and oncogenic KRas mutations, and in 25-30% of lung adenocarcinomas these mutations stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942). In lung adenocarcinoma, single nucleotide substitutions leading to missense mutations in codons 12 and 13 of the KRas primary amino acid sequence account for approximately 40% of these KRas driver mutations. KRAS G12D mutations are present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal cancer patients, 10.1% of all rectal cancer patients, 4.1% of all non-small cell lung cancer patients, and 1.7% of all small cell lung cancer patients (e.g., see AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8): 818-831. Dataset version 4).

The well-known role of KRas in malignancies, and the frequent KRas mutations found in various tumor types, make KRas an attractive cancer therapeutic target for the pharmaceutical industry. Despite three decades of extensive research efforts to develop KRas inhibitors for the treatment of cancer, as disclosed in patent WO2021/041671, KRas inhibitors have not yet been demonstrated to be sufficiently safe and/or effective to obtain regulatory approval.

Compounds that inhibit KRas activity remain in great demand and are under investigation, including those that interfere with effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143) and recent advances in covalent targeting of the KRas G12C allosteric pocket (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. Inc. 9:1230-1234). Clearly, there is continued interest and effort in developing KRas inhibitors, especially inhibitors of activating KRas mutants, particularly inhibitors of KRas G12D. Therefore, there is a need to develop new KRas G12D inhibitors that show sufficient efficacy for treating KRas G12D-mediated cancers.

Summary of the invention

The invention disclosed in this document provides a novel tetracyclic scaffold that selectively inhibits KRAS G12D. These compounds have the advantage of a unique chemical type and have the potential to provide KRAS G12D inhibitors with improved physicochemical properties.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, including tautomers, cis or trans isomers, meso-isomers, racemates, enantiomers, diastereomers and mixtures thereof:

in:

Ring A is aryl or heteroaryl;

M is N or CR ₃ ;

_M1 is N or _CR6 ;

R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

_R1 and _R2 together with the carbon atom to which they are attached form a spirocycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, a spiroheterocyclyl, a fused heterocyclyl or a bridged heterocyclyl, further optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, -( _{CRaRb ) n} -cycloalkyl--( _NRcRd ) _r , alkyl-( _NRcRd ) _r , heterocyclylalkyl, cyano-alkyl and haloalkyl-C( _O )- _;

Alternatively, _R1 and R+ together with the carbon atoms to which they are attached form a spirocycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, a spiroheterocyclyl, a fused heterocyclyl or a bridged heterocyclyl;

L is a bond, -( _{CRaRb ) nO} ( _{CRcRd ) r-} , -(CRaRb _{)nS ( CRcRd} ) _r- and -( _CRaRb ) _nNRe ( _CRcRd ) _r- ; Ra, _Rb , _Rc and Rd are independently selected from hydrogen, _deuterium , halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and _{hydroxyalkyl ;}

R is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; _R is hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, heterocyclyl, or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, halogen, hydroxy, alkoxy, haloalkyl, hydroxyalkyl, - _{( NRcRd} ) _r , alkyl-OC(=O)N( _R9 ) ₂ , heterocyclylalkyl, cyanoalkyl, and haloalkyl-C(O)-;

m is 0, 1, 2 or 3;

n is 0, 1, or 2; and

r is 0, 1, 2 or 3.

In one embodiment, Ring A is C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl.

In a preferred embodiment, Ring A is phenyl or naphthyl.

In one embodiment, M ₁ is N; R ₁ and R ₂ together with the C atom to which they are attached form a 9-14 membered spirocyclic heterocyclyl, a 9-14 membered fused heterocyclyl, or a 9-14 membered bridged heterocyclyl.

In one embodiment, M ₁ is CR ₆ ; R ₁ and R ₂ together with the C atom to which they are attached form a 9-14 membered spiroheterocyclyl, a 9-14 membered fused heterocyclyl or a 9-14 membered bridged heterocyclyl;

Alternatively, _R1 and _R2 together with the C atom to which they are attached form a 9-14 membered spirocycloalkyl or heterocyclyl, a 9-14 membered fused cycloalkyl or heterocyclyl, or a 9-14 membered bridged cycloalkyl or heterocyclyl.

In a more preferred embodiment, the 9-14 membered fused heterocyclyl is bicyclic or tricyclic, and the third ring is fused or bridged to the second ring.

In more specific embodiments, R ₁ forms a ring with R ₂ or R ₆ via a nitrogen atom as the first connecting atom.

In a more preferred embodiment, the 9-14 membered fused heterocyclic group is

in:

_M2 is O, S, NRa or CRaRb;

_M3 is independently selected from NRa, C(O) or CRaRb;

_X1 is C, CH or N;

_X2 is CRaRb or NRa;

_X3 is C, CH or N;

R ₈ is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl;

Alternatively, two of _R8 together with the atoms to which they are attached form a _C6 - _C8 cycloalkyl or a 5-8 membered heterocyclyl; Ra, Rb, Rc and Rd are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl and _C1 - _C6 hydroxyalkyl;

p is 0, 1, or 2;

q is 0, 1, 2, or 3;

s is 0, 1 or 2;

s1 is 0, 1, or 2; and

t is 0, 1, 2, or 3.

In one embodiment, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C 2 -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkyl and C _{1 -C 6} hydroxyalkyl.

In a preferred embodiment, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl.

In a preferred embodiment, R2, R3, R4 and R6 are independently selected from hydrogen, fluorine, chlorine and bromine.

In a more preferred embodiment, R3 and R4 are fluoro or chloro.

In a more preferred embodiment, R2 and R6 are hydrogen.

In a preferred embodiment, R5 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, methoxy and methylthio. In a preferred embodiment, R5 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, methoxy, methylthio and ethynyl.

In _one embodiment, L is a bond, -O( _CRcRd ) _r- , _-S ( _CRcRd ) _{r- and -NRe} ( _CRcRd ) _r- .

In preferred embodiments, L is a bond, -O( _CRcRd ) _- , _-S ( _{CRcRd )} - and _-NRe ( _CRcRd )-.

In more preferred embodiments, L is a bond, -OCH2-, -SCH2-, and -NHCH2-.

In one embodiment, Ra, Rb, Rc, Rd and Re are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl.

In a preferred embodiment, Re is selected from hydrogen and C1-C3 alkyl.

In a preferred embodiment, Rc and Rd are independently selected from hydrogen and C1-C3 alkyl.

In one embodiment, R7 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1 _{- C6} alkyl, _C1 - _C6 alkoxy _, C1 _{- C6 alkylthio, C1-C6 haloalkyl} , C1- _C6 hydroxyalkyl and _{C1 - C6} haloalkenyl;.

In a preferred embodiment, R7 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1 _{- C3} alkyl, C1- _C3 alkoxy, _{C1 - C3} alkylthio, C1- _C3 haloalkyl and C1 _{- C3 hydroxyalkyl} .

In one embodiment, R7 is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, C1 _{- C6} haloalkyl and _C1 - _C6 hydroxyalkyl.

在一个实施方案中，式(I)化合物可以是式(II-a)-(II-d)化合物，或互变异构体、顺式或反式异构体、内消旋体、外消旋体、对映体、非对映体或其混合物，或其药学上可接受的盐、溶剂化物或前药：In a preferred embodiment, R7 is H

In one embodiment, the compound of formula (I) can be a compound of formula (II-a)-(II-d), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

in

Ring A is phenyl, naphthyl or pyridyl.

是单键还是双键

Is it a single bond or a double bond?

_M2 is O, S, NRa or CRaRb;

_M3 is independently selected from CH2 or C(O);

Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C 1 -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C _{1 -C 3} hydroxyalkyl;

R8 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Alternatively, two of R8 together with the atoms to which they are attached form a cycloalkyl or heterocyclyl group;

m is 1 or 2;

p is 1 or 2;

q is 0, 1, 2, or 3;

s is 0, 1, or 2; and

t is 0, 1, or 2.

In one embodiment, M2 is O, S, NH, NCH3, CH2 or CHCH3.

In one embodiment, R8 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C _{1 -C 6} hydroxyalkyl;

Alternatively, two R8 together with the atoms to which they are attached form a C3-C8 cycloalkyl or a 5-7 membered heterocyclyl.

In one embodiment, the compound of formula (I) can be a compound of formula (III-a)-(III-1), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

in

M2 is O, S, NRa or CHRa;

M3 is independently selected from CH2 or C(O);

Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl;

R8 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl;

Alternatively, two of R8 together with the atoms to which they are attached form a C6-C8 cycloalkyl or a 5-8 membered heterocyclyl; t is 0, 1 or 2.

在一个实施方案中，式(I)化合物可以是式(IV-a)-(IV-l)化合物，或互变异构体、顺式或反式异构体、内消旋体、外消旋体、对映体、非对映体或其混合物，或其药学上可接受的盐、溶剂化物或前药：In a preferred embodiment, L is -OCH2-, R7 is

In one embodiment, the compound of formula (I) can be a compound of formula (IV-a)-(IV-1), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

In one embodiment, the compound of formula (I) may be a compound of formula (V-a) or (V-b), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

Ring A is phenyl, naphthyl or pyridyl;

是单键还是双键

Is it a single bond or a double bond?

M2 is O, S, NRa or CRaRb;

M3 is C(O) or CRaRb;

Each of X1 or X3 is C, CH or N;

X2 is CRaRb or NRa;

Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C 1 -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C _{1 -C 3} hydroxyalkyl;

R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl;

R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C 2 -C ₃ alkenyl, C ₂ -C ₃ alkynyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, C ₁ -C ₃ haloalkyl and C _{1 -C 3} hydroxyalkyl;

L is a bond, -OCH2-, -SCH2-, and -NHCH2-;

R7 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C _{1 -C 6 alkoxy, C 1 -C 6 alkylthio} , C ₁ -C ₆ haloalkyl and C _{1 -C 6} hydroxyalkyl;

Alternatively, R7 is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl;

R8 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Alternatively, two of R8 together with the atoms to which they are attached form a cycloalkyl or heterocyclyl group;

m is 1, 2, 3 or 4;

p is 0, 1, or 2;

q is 0, 1, 2, or 3;

s is 0, 1, or 2; and

t is 0, 1, 2, or 3.

In a preferred embodiment, for compounds of formula (V), X1 is N.

In a preferred embodiment, for compounds of formula (V), R8 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl;

Alternatively, two R8 together with the atoms to which they are attached form a C3-C8 cycloalkyl or a 5-7 membered heterocyclyl.

In a preferred embodiment, for compounds of formula (V), M2 is NH, CH2, O or S.

In a preferred embodiment, for compounds of formula (V), R3 and R4 are hydrogen or halogen.

In a preferred embodiment, for compounds of formula (V), R5 is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, methyl, methoxy, methylthio and ethynyl.

或L是键，R7是H。In a preferred embodiment, for compounds of formula (V), L is -OCH2-, R7 is

Or L is a bond and R7 is H.

In a preferred embodiment, the compound of formula (V-a) or (V-b) can be a compound of formula (V-a-1), (V-a-2), (V-a-3), (V-1), V-b-2 or (V-b-3), or a tautomer, cis or trans isomer, intermediate isomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

M is N or CH;

X4 is NRa or CRaRb;

Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1-C3 alkyl, C1-C4 alkoxy, C1-C5 haloalkyl and C1-C3 hydroxyalkyl;

v is 1, 2, or 3.

In another aspect, the present invention also provides a compound of formula (VI), (VII) or (VIII):

or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

In one embodiment, Ring A is aryl, heteroaryl, cycloalkyl or heterocyclyl;

M is N or CR3;

M1 is N or CR6;

R3, R4, R5 and R6 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, cyanoalkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylheteroaryl and oxo;

R1 and R2 together with the atoms to which they are attached form a spirocycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, a spiroheterocyclyl, a fused heterocyclyl or a bridged heterocyclyl, optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, -(CRaRb)n-cycloalkyl-(NRcRd)r, heterocycloalkyl and cyanoalkyl, haloalkyl-C(O)- and -CO2alkyl;

L is a bond, -( _{CRaRb ) nO} ( _{CRcRd ) r-} , -( _{CRaRb )nS ( CRcRd} ) _r- , and -( _CRaRb ) _nNRe ( _CRcRd ) _{r- ;} Ra, _Rb , _Rc , and Rd are independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl _;

or Rc and Rd together with the atoms to which they are attached form a cycloalkyl group;

R is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; R is hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, heterocyclyl or heteroaryl, optionally substituted by one or more selected from hydrogen, deuterium, halogen, amino, cyano,

hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, ( _NRcRd ) _r , alkyl-OC(=O)N( _R9 ) ₂ and haloalkenyl _;

R9 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; m is 0, 1, 2 or 3;

n is 0, 1, or 2;

i is 0, 1, or 2; and

r is 0, 1, 2 or 3.

In some embodiments, Ring A is C6-C10 aryl or 5-10 membered heteroaryl, 5-10 membered heterocyclyl.

In some embodiments, M1 is N; R1 and R2, together with the atoms to which they are attached, form a 9-14 membered spirocyclic heterocyclyl, a 9-14 membered fused heterocyclyl, a 9-14 membered bridged heterocyclyl, or a 6-8 membered heterocyclyl, optionally substituted with one or more substituents selected from -( _CH2 ) _n- ( _C3 - _C6 ) _cycloalkyl ( _NRcRd ) _r , -( _{C1 - C6} )alkyl-( _NRcRd ) _r , _-CO2 -alkyl.

In some embodiments, the 9-14 membered fused heterocyclyl is bicyclic or tricyclic, and the third ring is fused or bridged to the second ring.

In some embodiments, the 6-8 membered heterocyclyl comprises at least two substituents selected from N, O; optionally substituted with one or more substituents selected from -( _CH2 ) _n- ( _C3 - _C6 )cycloalkyl-N( _CH3 ) ₂ , -( _C1 - _C6 )alkyl-N( _CH3 ) ₂ , _-CO2 - _C1 - _C6 -alkyl.

In some embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C6 cyanoalkyl, C1- _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, C1 _{- C6} alkylthio, _C1 - _C6 haloalkyl and C1 _{- C6} hydroxyalkyl, _C3 - _C6 heterocyclyl _{, C3} - _C6 cycloalkyl, _C5 - _C10 heteroaryl, _C1 - _C6 alkyl- _C5 - _C10 heteroaryl and oxo.

In some embodiments, R4 and R6 are independently selected from hydrogen, fluorine, chlorine, and bromine.

In some embodiments, R3, R5 are selected from hydrogen, hydroxy, fluoro, chloro, bromo _, methyl, methoxy, methylthio, _ethynyl , _amino , _cyano , _ethyl , _cyclopropane , -CH2CN _, -CH2CH2CN, _{-CF3 , -CHF2} , _{-CH2CH2CH2CHF2} , _{-CH2CH2CH2CF3} , _CH2 - _thienyl .

In some embodiments, L is a bond _, -O( _CRcRd ) _r- , _-S ( _CRcRd ) _r- , _{and -NRe} ( _CRcRd ) _r- .

In some embodiments, _L is a bond, -O( _CRcRd ) _- , -S( _CRcRd )-, _{and -NRe} ( _CRcRd )-.

In some embodiments, L is a bond, -OCH2-, -SCH2-, and -NHCH2-.

In some embodiments, Ra, Rb, Rc, Rd and Re are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl, -CO ₂ -C ₁ -C ₆ alkyl.

In some embodiments, R7 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C 1 -C ₆ haloalkyl, and C ₁ -C 6 hydroxyalkyl;

Alternatively, R7 is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl, -N(RcRd) and C ₁ -C ₆ alkylOC(＝O)N(R9) ₂ , and C2-C6 haloalkenyl; and R9 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl.

任选被一个或多个选自氢、氘、卤素、氨基、氰基、羟基、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆卤代烷基和C₁-C₆羟烷基的取代基取代。In some embodiments, R7 is H,

Optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C _{1 -C 6} hydroxyalkyl.

In some embodiments, the 9-14 membered fused heterocyclyl is

in:

M2 is O, S, NRa or CRaRb;

M3 is independently selected from NRa, C(O) or CRaRb;

M4 is C, CH, N

X1 is CH or N;

X2 is CRaRb or NRa;

X3 is CH or N;

R8 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl;

Alternatively, two R8 together with the atoms to which they are attached form a C6-C8 cycloalkyl or a 5-8 membered heterocyclyl; Ra, Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C5 haloalkyl and C1-C6 hydroxyalkyl;

p is 0, 1, or 2;

q is 0, 1, 2, or 3;

s is 0, 1, or 2; and

t is 0, 1, 2, or 3.

In some embodiments, the 6-8 membered heterocyclyl is

M2 is O, S, NRa or CRaRb;

M3 is independently selected from NRa, C(O) or CRaRb;

M4 is C, CH, N

X1 is CH or N;

R10 and R11 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _{1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl} , C1 -C2 alkyl-(C3 -C6)cycloalkyl-N(CH ₃ ) ₂ , C1 -C4 alkyl-N(CH ₃ ) ₂ ;

s is 0, 1, or 2.

Ra, Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C _{1 -C 6 alkoxy, C 1 -C 6 haloalkyl} and C ₁ -C ₆ hydroxyalkyl.

In a preferred embodiment, the compound of formula (VI)-(VIII) can be a compound of formula (V-c-1), (V-c-2), (V-d-1), (V-d-2), (V-e-1) or (V-e-2), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

in

Ring A is

M is N or CR3;

M1 is N or CH;

M2 is O, S, NRa or CRaRb;

M3 is CRaRb;

X1 is CH or N;

Each of X2 or X4 is CRaRb or NRa;

Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ haloalkyl-C(O)-, -CO ₂ -C ₁ -C ₆ alkyl, wherein the C ₁ -C ₃ alkyl is optionally substituted by cyano, halogen and a C3-C6 heterocyclic group containing one or two heteroatoms selected from O, N, S;

R4 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C _{1 -C 3 alkoxy, C 1 -C 3} alkylthio, C ₁ -C ₃ haloalkyl and C _{1 -C 3} hydroxyalkyl;

R3 and R5 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C4 cyanoalkyl, _C1 - _C4 alkyl, C2- _C4 alkenyl, C2 _{- C4} alkynyl, C1 _- C4 alkoxy, _{C1 - C4} alkylthio, _C1 - _C4 haloalkyl and C1- _C4 hydroxyalkyl, C3 _{- C64} cycloalkyl, _C1 - _C3 alkyl-C5-C8 heteroaryl containing one or two heteroatoms selected from O, N, S and oxo.

L is a bond, -OCH2-, -SCH2-, and -NHCH2-;

R7 is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, -N(CH 3 ) 2 and C ₁ -C ₃ alkoxy OC(═O)N(R ₉ ) ₂ ;

R9 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl;.

m is 1, 2, 3 or 4;

i is 0, 1, or 2;

s is 0, 1 or 2;

t is 0, 1, 2, or 3; and

v is 1, 2, or 3;

时，R₃为Cl，X₂为NRa，NRa不是

If ring A is

When R ₃ is Cl, X ₂ is NRa, and NRa is not

时，R₃既不是F也不是Cl；If ring A is

When R ₃ is neither F nor Cl;

不是

在一些实施方案中,L是-OCH2-，R₇是

任选被一个或多个选自氢、羟基、氟、氯、溴、-CH＝CHF的取代基取代。

no

In some embodiments, L is -OCH2-, _R7 is

Optionally substituted with one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, -CH=CHF.

In some embodiments, L is -OCH2-, R7 is

In some embodiments, Ring A is

In some embodiments, R5 is selected from hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, _ethyl , cyclopropyl, cyclobutyl _, -CH2CN, -CH2CH2CN, _{-CF3 ,} -CHF2 _{, -CH2F} , _-CCl3 , _-CHCl2 , _-CH2Cl , _-CBr3 , _-CHBr2 , _-CH2Br , -CH2CHCH2CHF2, _-CH2CHCH2CF3 , _{CH3 - thienyl} , _{-S - CH3 ;}

m is 0, 1, 2, or 3.

In some embodiments, R ₃ is hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropyl, cyclobutyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF ₂ , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CBr ₃ , -CHBr ₂ , -CH ₂ Br, -CH ₂ CHCHCHF, -CH ₂ CHCHCHF ₂ , -CH ₂ CHCHCF ₃ .

In some embodiments,

X ₄ is CRaRb;

Ra is hydrogen;

Rb is hydrogen; and

v is 2.

In some embodiments,

_X2 is NRa;

和CF₃-C(O)-；t is 1。Ra is selected from hydrogen, deuterium, methyl, ethyl, methoxy _, ethynyl _{, -CH2CN} , _{-CH2CH2CN , -CF3} , _{-CHF2 , -CH2F , -CCl3} , _{-CHCl2 , -CH2Cl} , _{-CBr3 , -CHBr2 , -CH2Br , -CH2CH2CH2CH2F ,} -CH2CH2CH2CHF2 _{, -CH2CH2CH2CF3 , -CH2CH2CH2CN ,}

and CF ₃ —C(O)—; t is 1.

In some embodiments,

M ₃ is -C(CH ₃ ) ₂ - or -C(CH ₂ )-;

s is 1.

In a preferred embodiment, compound (V) is a compound of formula (V-c-3):

or a tautomer, a cis or trans isomer, a meso racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a preferred embodiment, compound (V) is a compound of formula (V-f), (V-g):

or a tautomer, a cis or trans isomer, a meso racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

in

Ring A and Ring B are independently selected from C ₆ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ heterocyclyl, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ heteroaryl;

_M1 is N or CH;

_M2 is O, S, NRa or CRaRb;

M ₃ is CRaRb;

_M4 is CH, _CH2 or N;

_M5 is _CH2 or oxo (C=O);

_X1 is CH or N;

Each of _X2 or _X4 is CRaRb or NRa;

R ₁₂ and R ₁₃ together with the carbon atoms to which they are attached form a C ₆ -C ₁₀ cycloalkyl group, a C 6 -C ₁₀ heterocyclyl group, a C ₁ -C ₃ haloalkyl group and a C ₁ -C ₃ hydroxyalkyl group containing one or more heteroatoms selected from N, O, and S; Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C _{1 -C 3} alkylthio, C ₁ -C ₃ haloalkyl group, -CO ₂ -C ₁ -C ₆ alkyl group and C ₁ -C ₃ hydroxyalkyl group;

_R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C4 cyanoalkyl, _C1 - _C4 alkyl, C2- _C4 alkenyl, C2 _- C4 alkynyl, C1-C4 alkoxy, _{C1 - C4} alkylthio, _{C1 - C4} haloalkyl, C1 _{-C4 hydroxyalkyl, C3-C6 cycloalkyl, C1-C3 alkyl - C5 - C8 heteroaryl or oxo .}

L is a bond, -OCH ₂ -, -SCH ₂ -, and -NHCH ₂ -;

R ₇ is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, -N(CH ₃ ) 2, C ₁ -C ₃ alkylOC(═O)N(R ₉ ) ₂ , -CH═CHF;

R ₉ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl;

m is 1, 2, 3 or 4;

i is 0, 1, or 2;

s is 0, 1 or 2;

t is 0, 1, 2, or 3; and

v is 1, 2, or 3.

In a preferred embodiment, compound (V) is of formula (V-f-1), (V-g-1),

or a tautomer, a cis or trans isomer, a meso racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

in

Ring A is

In a preferred embodiment, Ring B is

In a preferred embodiment, R12 and R13 together with the carbon atom to which they are attached form a

In some embodiments, compound (V) is a compound of formula (V-h), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

in

Ring A is

M is N or CR3;

M1 is N or CH;

M2 is O, S, NRa or CRaRb;

M3 is CRaRb;

X1 is CH or N;

Each of X2 or X4 is CRaRb or NRa;

Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ haloalkyl-C(O)-, -CO ₂ -C ₁ -C ₆ alkyl, wherein the C ₁ -C ₃ alkyl is substituted with cyano, halogen and a C ₃ -C ₆ heterocyclyl containing one or two heteroatoms selected from O, N, S;

R4 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C _{1 -C 3 alkoxy, C 1 -C 3} alkylthio, C ₁ -C ₃ haloalkyl and C _{1 -C 3} hydroxyalkyl;

_R3 and _R5 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C4 cyanoalkyl, _C1 -C4 alkyl, C2- _C4 alkenyl, C2 _- C4 alkynyl, _C1 - _C4 alkoxy, _{C1 - C4} alkylthio, _C1 - _C4 haloalkyl, _C1 - _C4 hydroxyalkyl, _C3 - _C6 cycloalkyl, _C1 - _C3 alkyl- _C5 - _C8 heteroaryl containing one or _two heteroatoms selected from O, N, _S , oxo, -COOH and -CONH2;

L is a bond, -OCH2-, -SCH2-, and -NHCH2-;

R ₇ is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, -N(CH ₃ ) ₂ , C ₁ -C ₃ alkyl-OC(═O)N(R ₉ ) ₂ , C 1 -C 3 haloalkenyl;

R ₉ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl;

R ₁₄ is selected from deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl;

m is 1, 2, 3 or 4;

i is 0, 1, or 2;

s is 0, 1 or 2;

t is 0, 1, 2, or 3;

w is 1, 2, or 3

v is 1, 2, or 3.

In a preferred embodiment, formula (v-h) is a compound of formula (v-h-1):

进一步任选地被一个或多个选自氢、羟基、氟、氯、，溴，-CH＝CHF的取代基取代。In a preferred embodiment, L is -OCH2-, R7 is

It is further optionally substituted with one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, and -CH=CHF.

In a preferred embodiment, L is _-OCH2- ; R7 is

In a preferred embodiment, R5 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl _, cyclopropyl, cyclobutyl, -CH2CN _, -CH2CH2CN, _-CF3 , -CHF2, _-CH2F , _-CCl3 , _-CHCl2 , _-CH2Cl , _{-CBr3 , -CHBr2} , _-CH2Br , _{-CH2CHCHCHF2-} , _CH2CHCHCF3 , _{CH3 -} thienyl, -S _{- CH3} ;

In a preferred embodiment, m is 0, 1, 2, or 3.

In preferred embodiments, R ₃ is hydrogen, hydroxy, fluoro, chloro, bromo, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropyl, cyclobutyl, -CH ₂ CN, -CH ₂ CHCN, -CF ₃ , -CHF ₂ , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CBr ₃ , -CHBr 2 , -CH ₂ Br, -CH ₂ Br, -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH _{2 CH 2 CHF 2 , -CH 2 CH 2 CH 2 CF 3 ;}

In a preferred embodiment,

X4 is CRaRb;

Ra is hydrogen;

Rb is hydrogen;

X2 is NRa;

and CF₃-C(O)-,-CO₂tBu,-CO₂Me；Ra is selected from hydrogen, deuterium, methyl, ethyl, methoxy, ethynyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF ₂ , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CBr ₃ , -CHBr ₂ , -CH ₂ Br, -CH ₂ CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ CN,

and CF ₃ -C(O)-,-CO ₂ tBu,-CO ₂ Me;

M ₃ is -C(CH ₃ ) ₂ - or -C(CH ₂ )-;

t is 1;

v is 2; and

s is 1.

In a preferred embodiment, the compound may be a compound:

or a tautomer, a cis or trans isomer, a meso racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The present invention also provides a prodrug of the above-mentioned compound, or a tautomer, a cis or trans isomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the prodrug is:

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any compound of formula (I)-(III-1), (VI)-(VIII) or tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. On the other hand, the present invention relates to a method for treating a disease mediated by a KRAS mutation, comprising administering to a subject in need thereof an effective amount of any compound of formula (I)-(III-1), or tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt solvate, or a prodrug thereof or a pharmaceutical composition comprising the same.

In one embodiment, the KRAS mutation comprises a KRAS G12D, KRAS G12V, or KRAS G13D mutation.

On the other hand, the present invention relates to a method for treating cancer, which comprises administering to a subject in need of cancer treatment an effective amount of a compound of formula (I)-(III-1), (VI)-(VIII) or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutical composition containing the same.

In one embodiment, the cancer is associated with a KRAS G12D, KRAS G12V or KRAS G13D mutation. In a preferred embodiment, the cancer is selected from the group consisting of cardiac sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, ovarian cancer, ovarian cancer and ovarian cancer, rhabdomyomas, fibromas, lipomas and teratomas; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, unclassified large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, vascular =Tumors, lipomas, neurofibromas, fibromas), colorectal (adenocarcinomas, tubular adenomas, villous adenomas, hamartomas, leiomyomas); genital tract: kidneys (adenocarcinomas, Wilms' tumors, lymphomas, leukemias), bladder and urethra (squamous cell carcinomas, transitional cell carcinomas, adenocarcinomas), prostate (adenocarcinomas and sarcomas), testicles (seminomas, teratomas, embryonal carcinomas, teratocarcinomas, choriocarcinomas, sarcomas, stromal cell carcinomas, fibromas, fibroadenomas, adenomatoid tumors, lipomas); liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcomas, hepatocellular adenomas, hemangiomas; bile duct: gallbladder cancer, ampullary carcinoma, bile duct cancer; bone: osteogenic sarcomas (osteosarcomas), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, Ewing's sarcomas, malignant lymphomas (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrotic exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, deforming osteitis), meninges (meningiomas, meningiomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme (oligodendroglioma, schwannoma, retinoblastoma), congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenoma, unclassified carcinoma), granulosa cell tumor, S =Hermatovenous: Hematology: Blood (Myeloid Leukemias (Acute and Chronic), Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Myeloproliferative Disorders, Multiple Myeloma, Myelodysplastic Syndrome), Hodgkin's Disease, Non-Hodgkin's Lymphoma (Malignant Lymphoma), Skin: Malignant Melanoma, Basal Cell Carcinoma, Squamous Cell Carcinoma, Kaposi's Sarcoma, Nevus, Dysplastic Nevus, Lipoma, Hemangioma, Dermatofibroma, Keloid, Psoriasis, Adrenal: Neuroblastoma.

In some embodiments, the prodrug used in the pharmaceutical composition is

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Mean plasma concentration-time curves after single IV and PO administration of Example Compound 268 in male C57BL/6 mice

Figure 2: Average plasma concentration-time curves of Example Compound 268CO ₂ tBu and metabolized Example Compound 268 administered IV at 1 mg/kg, and average plasma concentration-time curves of Example Compound 268CO ₂ tBu administered PO at 5 mg/kg in male C57BL/6 mice

Figure 3: Average plasma concentration-time curves of Example Compound 268CO ₂ Me and metabolized Example Compound 268 administered IV at 1 mg/kg and average plasma concentration-time curves of Example Compound 268CO ₂ Me administered PO at 5 mg/kg in male C57BL/6 mice

Detailed description of the invention

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to _-CH2- , "ethylene" refers to -( _CH2 ) _2- , "propylene" refers to -( _CH2 ) _3- , "butylene" refers to -( _CH2 ) _4- , etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan/6 yuan, 3 yuan/5 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

等；

wait;

It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

等。

wait.

The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

等。

wait.

The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclyl, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclyl, nitrogen-containing spiro heterocyclyl or nitrogen-containing fused heterocyclyl.

Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide, and the like, preferably oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide. The polycyclic heterocyclic group includes spirocyclic, condensed and bridged heterocyclic groups; the spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/5-yuan or 5-yuan/6-yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

等。

wait.

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

等。

wait.

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

等。

wait.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

等。

wait.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

等。

wait.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridazinyl, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, furyl, thienyl, pyridazinyl, pyrazinyl or thiazolyl; more preferably pyridyl, furyl, thienyl, pyrimidinyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrazinyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

等。

wait.

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carbonyl" refers to -C(O)-.

"Carboxy" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

"EtOAc" means ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetylene.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

DETAILED DESCRIPTION

The following examples are used to illustrate the present invention, but these examples should not be considered to limit the scope of the present invention. If the specific conditions of the experimental methods are not specified in the examples of the present invention, they are generally in accordance with the conventional conditions or recommended conditions of the raw materials and product manufacturers. Reagents that do not specify a specific source are commercially available conventional reagents.

The structure of each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). Nuclear magnetic resonance chemical shifts () are in 10-6 (ppm). NMR was measured by Varian Mercury 300MHz Bruker Avance III 400MHz machine. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD).

High performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18

150mm×4.6mm chromatography column). Liquid chromatography-mass spectrometry (LCMS) was measured on Agilent 1200 high pressure liquid chromatograph and mass spectrometer (Sunfire C18 4.6*50mm 3.5μm chromatography column) and Agilent 19091S-433HP-5 high pressure liquid chromatograph and mass spectrometer (XBridge C18 4.6x50mm 3.5um chromatography column).

Chiral High Performance Liquid Chromatography (HPLC) was performed on SFC Thar 80 & 150 & 200 (water). The average rate and IC50 values of ATPase inhibition were determined by Victor Nivo multimode plate reader (PerkinElmer, USA).

The thin layer silica gel plate used for thin layer chromatography is Yantai Xinnuo silica gel plate. The size of the plate used for TLC is 0.15mm to 0.2mm, and the size of the plate used in the thin layer chromatography for product purification is 0.4mm to 0.5mm.

Column chromatography usually uses Qingdao Ocean 200 to 300 mesh silica gel as the carrier.

The starting materials known in the present invention can be prepared by conventional synthesis methods in the prior art, or purchased from companies such as ABCR MBH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari Chemical Corporation.

Unless otherwise stated in the examples, the following reactions were placed under an argon or nitrogen atmosphere.

The term "argon atmosphere" or "nitrogen atmosphere" means that the reaction flask is equipped with a balloon containing 1 L of argon or nitrogen. The term "hydrogen atmosphere" means that the reaction flask is equipped with a balloon containing 1 L of hydrogen.

MS is mass spectroscopy, where (+) refers to the positive mode which usually gives M+1 (or M+H) absorption, where M = molecular mass.

Preparation steps

Synthesis of key intermediate A

3-Bromo-4-chloro-2-fluoroaniline (Int A-1): 1-Chloropyrrolidine-2.5-dione (7.38 g, 55.3 mmol, 1.05 eq.) was added proportionally to a solution of 3-bromo-2-fluoroamine (CAS: 58534-95-5, 10.0 g, 52.6 mmol, 1.0 eq.) in DMF (50 mL) and the resulting mixture was stirred at room temperature for 3 h. The mixture was poured into ice water (300 mL) and then extracted with ethyl acetate (200 mL), then the organic phase was washed with water (2 x 200 mL) and brine (200 mL). The organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel with a gradient of 0-5% EtOAc in heptane to give 3-bromo-4-chloro-2-fluoroaniline (5.69 g, 48%) as a brown oil which solidified on standing.

1H NMR (400MHz, DMSO-d6) 5.58 (2H, s), 6.73-6.82 (1H, m), 7.12 (1H, dd).

LCMS [ESI, M+1]: 224.

7-Bromo-6-chloro-8-fluoroquinolin-4(1H)-one (Int A-3): 2,2-Dimethyl-1,3-dioxane-4,6-dione (4.94 g, 34.3 mmol, 1.10 equiv) was added to trimethoxymethane (17.06 mL, 155.93 mmol, 5.00 equiv) and heated at 110 °C (reflux) under nitrogen for 10 min. The resulting solution was stirred at 85 °C under nitrogen for 1.5 h. 3-Bromo-4-chloro-2-fluoroaniline (7.00 g, 31.2 mmol, 1.00 equiv) was added and the solution was stirred at 85 °C for another 60 min. The mixture was cooled to room temperature and the solid formed in the mixture was collected by filtration and washed with isopropanol (2 x 1 mL) and diethyl ether (2 x 2 mL) to give a light orange solid. The solid was added to stirred DOWTHERM (200 mL) at 210°C: gas was released vigorously. The orange solution was stirred at 210°C for another 40 minutes, then cooled to room temperature and stirred for 10 minutes. Heptane (200 mL) was added to the mixture, the mixture was filtered, and the collected solid was washed on the filter with heptane, then with ether, and dried on the filter to give 7-bromo-6-chloro-8-fluoroquinolin-4(1H)-one (5.6 g, 20.3 mmol, 65%) as a tan solid.

1H NMR (400MHz, DMSO-d6, 30°C) 6.15 (1H, d), 7.90 (1H, d), 8.01 (1H), 12.11 (1H, s). LCMS[ESI,M+1]:276.

7-Bromo-6-chloro-8-fluoro-3-nitroquinolin-4(1H)-one (Int A-4): 7-Bromo-6-fluoro-8-fluoroquinolin-4(3H)-(5.6 g, 20.3 mmol, 1.00 equiv) was added to stirring propionic acid (45 mL, 602.03 mmol, 29.9 equiv) and the mixture was heated with stirring at 125 °C. Nitric acid (fuming) (1.697 mL, 40.51 mmol, 2.00 equiv) was added dropwise and the solution was stirred at 125 °C for 2 hours and then cooled to room temperature. Water (50 mL) was added and the mixture was filtered. The collected solid was washed with water (2×20 mL) and ether (20 mL) and then dried to give 7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4(1H)-one (4.81 g, 74%) as a light solid without further purification.

1H NMR (400MHz, DMSO-d6, 30°C) 8.15 (1H, d), 8.96 (1H, s), 13.32 (1H).

LCMS [ESI, M+1]: 321.

[0136] 6-Chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4(1H)-one (IntA-5): A stirred suspension of 7-bromo-6-chloro-8-chloro-3-nitroquinolin-4-(1H)-one (2480 mg, 7.7 mmol, 1.00 equiv), 2-(2-fluoro-6-((4-methylbenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (Int D, 5.47 g, 15.3 mmol, 2.00 equiv), a solution of potassium carbonate (3.2 g, 23.2 mmol, 3.00 equiv) in dioxane/water (40 mL, 3:1) was degassed with nitrogen for 10 min. RuPhos Pd G3 (404 mg, 0.5 mmol, 0.1 eq.) and RuPhos (225 mg, 0.5 mol, 0.1 eq.) were added. After 1.5 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The solution was washed with water (100 ml), and the aqueous portion was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow residue. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-5% to give 6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4(1H)-one (3.1 g, 6.6 mmol, 85% yield).

LCMS [ESI, M+1]: 473.

MS(0.4g)在二氯甲烷(20mL)中的溶液中(0.63mL，3.8mmol，1.50当量)。在该温度下搅拌混合物30分钟。在-40℃下用水(20mL)稀释反应混合物。水层用二氯甲烷(3×15mL)萃取。洗涤合并的有机层用盐水(2×15mL)，用硫酸钠干燥并减压浓缩。残余物通过硅胶快速色谱(0至100％乙酸乙酯在石油醚中)纯化，得到6-氯-8-氟-7-(2-氟-6-((4-甲氧基苄基)氧基)苯基)-3-硝基喹啉-4-基三氟甲磺酸酯(708mg，1.17mmol，45％产率)。6-Chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl trifluoromethanesulfonate (Int A): TEA (1.07 mL, 7.7 mmol, 3.00 equiv) and trifluoromethanesulfonic anhydride were added to 6-chloro-8-fluoro-7-(2-chloro-6-(((4-methylbenzyl)oxy)phenyl)-3-nitroquinolin-4(1H)-one (1.23 g, 2.6 mmol, 1.00 equiv) and

MS (0.4 g) in a solution of dichloromethane (20 mL) (0.63 mL, 3.8 mmol, 1.50 equiv). The mixture was stirred at this temperature for 30 minutes. The reaction mixture was diluted with water (20 mL) at -40 ° C. The aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0 to 100% ethyl acetate in petroleum ether) to give 6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinoline-4-yl trifluoromethanesulfonate (708 mg, 1.17 mmol, 45% yield).

LCMS [ESI, M+1]: 605.

Synthesis of key intermediate C

1-Fluoro-3-((4-methoxybenzyl)oxy)-2-nitrobenzene (C-1): A mixture of 3-fluoro-2-nitrophenol (CAS: 385-01-3, 5.0 g, 31.8 mmol, 1.00 equiv), K2CO3 (13.0 g, 95.5 mmol, 3.00 equiv) and 1-(bromomethyl)-4-methoxybenzene (7.32 g, 36.6 mmol, 1.10 equiv) in acetone (100 mL) was refluxed for 8 h and then allowed to cool to room temperature. The reaction was filtered and the residue was washed with acetone. The combined filtrate and washings were concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:EtOAc=5:1) to give 1-fluoro-3-((4-methoxybenzyl)oxy)-2-nitrobenzene (7.5 g, 27.0 mmol, 85% yield).

LCMS [ESI, M+1]:278.

(3-((4-methoxybenzyl)oxy)-2-nitrophenyl)(methyl)sulfonamide (C-2): Stir at 100° C. for 4 hours. Then, 1 M NaOH solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are washed with 1 M hydrochloric acid and dried (sodium sulfate). Removal of the solvent gives 1.30 g of (3-((4-methoxybenzyl)oxy)-2-nitrophenyl)(methyl)sulfonamide (100% of theory).

LCMS [ESI, M+1]: 306.

2-((4-Methoxybenzyl)oxy)-6-(methylthio)aniline (C-3): Iron powder (0.65 g, 11.6 mmol, 3.00 equiv) and concentrated HCl (0.2 mL) were added to a solution of (3-((4-ethoxybenzyloxy)-2-nitrophenyl)(methyl)sulfonamide (1.3 g, 4.25 mmol, 1.00 equiv) in EtOH/AcOH/water 2:2:1 (25 mL). The reaction mixture was refluxed for 15 min, then stirred at room temperature for 40 min, filtered, and extracted with EtOAc (3×50 mL). The organic layer was washed with saturated NaHCO3 (3×30 mL) and saturated NaCl (40 mL), dried over Na2SO4, and then washed with petroleum ether/EtOAc Purification by flash chromatography using 10:1 as eluent gave the product 2-((4-methoxybenzyl)oxy)-6-(methylthio)aniline (1.07 g, 3.88 mmol, 91% yield) as an oil.

LCMS [ESI, M+1]:276.

(2-Bromo-3-((4-methoxybenzyl)oxy)phenyl)(methyl)sulfonamide (C-4): To a stirred solution of 2-((4-methylbenzyl)oxy)-6-(methylthio)aniline (800 mg, 2.9 mmol, 1.00 equiv) in HBr (1.5 mL, 48%) was added water (5 mL) and the mixture was cooled to 0°C. A cold solution of sodium nitrite (2.10 g, 30.5 mmol, 10.5 equiv) in water (5 mL) was added dropwise over 30 min and the mixture was stirred for an additional 45 min. After the diazotization was complete, freshly prepared CuBr powder (168 mg, 1.17 mmol, 0.40 equiv) was added and the suspension was heated at 70°C for 1 h until a solid product separated. The reaction mixture was cooled and extracted with ether (2 x 30 mL). The combined organic extracts were washed with brine, dried and evaporated to dryness. The residue was crystallized from ethanol to give (2-bromo-3-((4-methoxybenzyl)oxy)phenyl)(methyl)sulfonamide (864 mg, 2.55 mmol, 88%).

LCMS [ESI, M+1]:339.

2-(2-((4-methoxybenzyl)oxy)-6-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int C): A mixture of (2-bromo-3-((4-ethoxybenzyloxy)benzene)(methyl)sulfonamide (864 mg, 2.55 mmol, 1.00 equiv), KOAc (744 mg, 7.58 mmol, 3.00 equiv) and bis(hydroxy)diborane (767 mg, 3.05 mmol, 1.20 equiv) in dioxane (25 mL) was degassed under nitrogen for 5 min. Pd(dppf)Cl2DCM (120 mg, 0.14 mmol, 0.055 equiv) was added and the mixture was heated to 40°C. The mixture was stirred for 16 hours. The dark mixture was cooled to room temperature and filtered through diatomaceous earth, and the diatomaceous earth pad was washed with toluene (100 mL). The filtrate was concentrated under reduced pressure to give a dark brown oil, which was adsorbed onto silica gel using DCM. The column was eluted with heptane (100 mL) and 5% EtOAc/heptane (250 mL). The product fractions were concentrated under reduced pressure to give 809 mg (82%) of 2-(2-((4-methoxybenzyl)oxy)-6-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborohexane.

LCMS [ESI, M+1]: 387.

Synthesis of key intermediate F

8-(tert-Butyl)2-ethyl 3-oxo-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (F-1): A solution of diethyl carbonate (5.3 g, 44.9 mmol, 2.00 equiv) in anhydrous toluene (20 mL) was added dropwise over 30 min to a suspension of sodium hydride (3.2 g, 82.1 mmol, 3.70 equiv, 60% dispersion in mineral oil) in anhydrous toluene (60 mL) under nitrogen at room temperature, and the mixture was then heated to 80° C. Anhydrous methanol (0.5 mL) was added, followed by a solution of commercially available (+/-)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS: 185099-67-6, 5.0 g, 22.2 mmol, 1.00 equiv) in anhydrous toluene (20 mL) over 30 min. Stirring was continued at 80°C for 12 h, then the mixture was cooled to room temperature, slowly diluted with water (5 mL), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate to give 8-(tert-butyl) 2-ethyl-3-oxo-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (5.4 g, 18.2 mmol, 82%) as a pale yellow oil.

LCMS (ESI, M+H) 298.

8-(tert-Butyl) 2-ethyl-3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate (Int F): Trifluoromethanesulfonic anhydride (3.3 mL, 20 mmol, 1.10 equiv) was added portionwise to a mixture of (tert-butyl) 2-ethyl 3-oxo-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (5.00 g, 18.2 mmol, 1.00 equiv) and N,N-diisopropylethylamine (4.8 mL, 28 mmol, 1.53 equiv) in anhydrous toluene (92 mL) at 0° C. under nitrogen at a rate to keep the internal reaction temperature below 40° C. The mixture was stirred at 0° C. for 2 hours, then it was allowed to warm to room temperature and the solids were removed by filtration. The filtrate solvent was removed under reduced pressure to afford crude 2 as brown oil, which was used in the next step without purification (7.4 g, 18.0 mmol, 99%).

LCMS (ESI, M+H):430.

Synthesis of Int 1

Synthesis of compound Int 1a: Me3OBF4 (221 g, 1.49 mol) was added to a solution of methyl (S)-5-oxopyrrolidine-2-carboxylate (CAS: 4931-66-2-192 g, 1.34 mol) in dichloromethane (2.02 L) in batches. The resulting mixture was stirred at room temperature overnight. TLC (dichloromethane/MeOH=10:1) showed that the reaction was complete. The mixture was cooled to 0°C and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution (1.44 L). The aqueous layer was extracted with dichloromethane (2.7 L*2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to give (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester Int 1a (201 g, 1.28 mol, 95% yield) as a light yellow liquid. LCMS [ESI, M+1]+: 158.0 Synthesis of compound Int 1b: A mixture of (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester Int 1a (201 g, 1.28 mol) and ethyl 2-nitroacetate (SM2) (511 g, 3.84 mol) was stirred at 60° C. under N2 atmosphere for 16 hours. TLC (petroleum ether/ethyl acetate=3:1) showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column (petroleum ether/ethyl acetate=10:1-3:1) to give a light yellow liquid (S, Z)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylic acid methyl ester Int1b (118 g, 0.46 mol, 35% yield). LCMS [ESI, M+1]+: 258.9

Synthesis of compound Int 1c: A mixture of (S, Z)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylic acid methyl ester Int 1b (14 g, 54.2 mmol) and 10% Pd/C (14 g) in EtOH (1.4 L) was stirred at room temperature under H2 (0.35-0.40 MPa) atmosphere for 72 hours. TLC (dichloromethane/MeOH=20:1) showed that the reaction was complete. The reaction solution was filtered and concentrated under vacuum to provide crude (1R, 5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester Int 1c (10.8 g, 54.5 mmol) in the form of a light yellow liquid. LCMS [ESI, M+1]+: 199.1

Synthesis of compound Int 1d: A solution of (1R, 5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester Int 1c (34.9 g, 176 mmol), Boc2O (38.4 g, 176 mmol), triethylamine (35.3 g, 348 mmol) in dichloromethane (350 ml) was stirred at room temperature overnight, when TLC (petroleum ether/ethyl acetate = 1:1) showed that the reaction was complete. The reaction mixture was concentrated under vacuum and the resin was purified with a silica gel column (petroleum ether/ethyl acetate = 10:1 to 1:1 gradient) to provide 8-(tert-butyl) 2-ethyl (1R, 5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate Int 1d (17.9 g, 60.0 mmol, 34% yield) in the form of a light yellow solid. LCMS [ESI, M+1]+: 243.1

Synthesis of compound Int 1e: BH3.DMS (2M, 137 mL, 274 mmol) was added to a solution of 8-(tert-butyl) 2-ethyl (1R, 5S) -4-oxo-3,8-diazabicyclo [3.2.1] octane-2,8-dicarboxylic acid Int 1d (15.8 g, 53.0 mmol) in THF (18 mL). The resulting mixture was stirred at room temperature overnight, then cooled to 0 ° C, and quenched with 60 mL MeOH at 0 ° C. The resulting mixture was stirred at 50 ° C overnight, when LCMS showed the consumption of starting material. The reaction mixture was concentrated to provide 8-(tert-butyl) 2-ethyl (1R, 5S) -3,8-diazabicyclo [3.2.1] octane-2,8-dicarboxylic acid Int 1e (15.8 g, 55.6 mmol) in the form of a light yellow liquid. LCMS [ESI, M+1]+: 285.0 Synthesis of Compound Int 1f: To a solution of crude 8-(tert-butyl) 2-ethyl (1R, 5S) -3,8-diazabicyclo [3.2.1] octane-2,8-dicarboxylic acid Int 1e (15.8 g, 55.6 mmol) in THF (200 mL) was added LiBH4 (dropwise, 2M in THF, 51 mL, 102 mmol). The mixture was then heated to 40°C and stirred for 3 h. TLC (petroleum ether/ethyl acetate = 1:1) showed that the reaction was complete, and the mixture was cooled to 0°C and treated with 250 mL H2O and 500 mL dichloromethane. The organic layer was washed with brine (220 mL twice) and dried with Na2SO4. After concentration, the residue was purified by silica gel column (petroleum ether/ethyl acetate=5:1 to 1:1) to give colorless liquid (1R, 5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 1f (3.80 g, 15.7 mmol, 28% yield). LCMS [ESI, M+1]+: 243.2 Synthesis of compound Int 1: A solution of tert-butyl (1R, 5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 1f (3.80 g, 15.7 mmmol), imidazole (2.30 g, 34.6 mmol), TBDPSCl (10.8 g, 39.3 mmol) in DMF (130 mL) was stirred at room temperature overnight. TLC (petroleum ether/ethyl acetate=5:1) and LCMS show that the reaction is complete, and 680mL H is used O and 550mL ethyl acetate are processed and reacted. Use Na SO Dry organic layer. After concentration, use silica gel column (petroleum ether/ethyl acetate=10:1 to 5:1) purification residue to obtain tert-butyl (1R, 5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate Int 1 isomer 1 (5.10g, 10.6mmol, 67% yield) as white solid. LCMS [ESI, M+1]+: 481.0 and tert-butyl (1R, 5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 1 Isomer 2 (1.28 g, 2.65 mmol, 17% yield) as a white solid. LCMS [ESI, M+1]+: 481.0 and tert-butyl (1R, 5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 1 Isomer 2 (1.28 g, 2.65 mmol, 17% yield) as a white solid. LCMS [ESI, M+1]+: 481.0

The compounds in the following table were synthesized using (R)-5-oxopyrrolidine-2-carboxylic acid methyl ester and referring to the route for synthesizing Int 1 isomers 1 and 2:

Int 2: Synthesis of 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid

To a solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (CAS: 1698535-33-9 8.00 g, 31.7 mmol) in H2SO4 (80 mL) was added N-chlorosuccinimide (8.47 g, 63.4 mmol) at 25°C. The mixture was stirred at 80°C for 12 hours. Cooled, poured onto ice, filtered, and the filter cake was collected to give 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid Int 2 (6.00 g, 66% yield) as a brown solid. MS: m/z = 285.7287.8 (m+1, ESI+).

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

Step 1: 2,6-dichloro-3-fluoropyridin-4-amine To a solution of 2,6-dichloropyridin-4-amine (5.00 g, 30.67 mmol) in MeOH (50 mL) and H2O (10 mL) was added selectfluor (11.96 g, 33.74 mmol). The reaction mixture was stirred at 45 °C for 16 h. The reaction was concentrated, diluted with H2O (30 mL) and extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column eluting with PE and EA (10:1) to give Int 3a (2.70 g, yield: 48.6%) as a white solid. MS: m/z = 180.9 (m+1, ESI+).

Step 2: tert-Butyl (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate To a solution of Int 3a (2.70 g, 14.9 mmol) in THF (30 mL) was added (Boc)2O (8.14 g, 37.3 mmol) and DMAP (91 mg, 0.75 mmol). The reaction mixture was stirred at 60 °C for 4 h. The mixture was concentrated. The residue was triturated with MeOH to give Int 3b (3.60 g, crude) as a white solid. H NMR (400 MHz, DMSO) δ 8.03 (d, J = 4.5 Hz, 1 H), 1.41 (s, 18 H).

Step 3: tert-Butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate To a solution of Int3b (3.60 g, 9.44 mmol) in THF (50 mL) at -78 °C was added LDA (2M in THF, 13.2 mL, 26.4 mmol). The reaction mixture was stirred at -78 °C for 1 hour, quenched with acetic acid (3 mL), diluted with H2O (30 mL), extracted with ethyl acetate (3x50 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column eluting with PE and EA (5:1) to give Int 3c (2.70 g, 75.7% yield) as a yellow solid. HNMR (400MHz, DMSO) δ10.08 (s, 1H), 1.54 (s, 9H), 1.46 (s, 9H).

Step 4: 4-Amino-2,6-dichloro-5-fluoronicotinic acid

Int 3c (2.70 g, 7.08 mmol) was added to a solution of HCl (g) / dioxane (40 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give Int 3d (1.40 g, crude), which was used directly in the next step without purification. MS: m/z = 224.8 (m+1, ESI+).

Step 5: 5,7-Dichloro-8-fluoro-2-mercaptopyrimido[4,3d]pyrimidin-4(3H)-one was added to a solution of Int 3d (1.40 g, 7.08 mmol) in SOCl2 (35 mL). The reaction mixture was stirred at 50°C for 3 hours, then cooled and concentrated. The residue was dissolved in acetone (8 mL). The solution was added dropwise to a solution of ammonium thiocyanate (1.42 g, 18.7 mmol) in acetone (35 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and diluted with H2O. Filtering and washing the filter cake with H2O and drying gave Int 3e (1.0 g, impure). MS: m/z=265.9 (m+1, ESI+).

Step 6: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one To a solution of Int 3e (1.0 g, 3.8 mmol, crude) in MeOH (75 mL) was added NaOH (0.1 M H2O solution, 75 mL, 7.5 mmol) and CH3I (1.07 g, 7.52 mmol). The mixture was stirred at room temperature for 2 h, then poured into H2O (100 mL) and acidified to pH~6 with 1 M HCl. Filtered, the filter cake was washed with H2O and dried to give the crude product, which was triturated with MeCN to give Int 3f (530 mg, impure). MS: m/z=279.9 (m+1, ESI+).

Step 7: 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3d]pyrimidine To a solution of Int 3f (530 mg, 1.89 mmol) in CH3CN (10 mL) was added POCl3 (348 mg, 2.27 mmol) and DIPEA (367 mg, 2.84 mmol). The mixture was stirred at 80°C for 1 hour, diluted with H2O (10 mL), extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column eluting with PE and EA (10:1) to give Int 3 (350 mg, 62.1% yield) as a yellow solid. MS: m/z = 297.7299.7 (m+1, ESI+).

Synthesis of Example 1

1-(tert-Butyl)3-ethyl-3-ethyl-4-(6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (1-1): 6-chloro-8-fluoro-7-(2-chloro-6-(((4-ethoxyphenyl)phenyl)-phenyl)-3-nitroquinolin-4-yl trifluoromethanesulfonate (Int a, 605 mg, 1.00 mmol, 1.00 equiv) was added to a vial of 1-(tert-butyl) 3-ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate. (CAS: 1194488-90-8, 381 mg, 1.00 mmol, 1.00 equiv) sodium carbonate monohydrate (330 mg, 2.66 mmol, 2.66 equiv) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol, 0.03 equiv). The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL). The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate in hexanes to give 1-(tert-butyl)3-ethyl-4-(6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (497 mg, 0.7 mmol, 70% yield).

LCMS [ESI, M+1]:710.

Tert-butyl 4-(6-chloro-8-fluoro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (1-2): To a solution of lithium aluminum hydride (1.4 mmol, 2.00 equiv) in tetrahydrofuran (5 mL) was added 1-(tert-butyl)-3-methyl-4-(6-chloro-4-(6-fluoro-8-chloro-7-(4-methylbenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (497 mg, 0.7 mmol, 1.00 equiv) and tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was cooled to 0 [UNK], and water (1 mL), 15% NaOH aqueous solution (1 ml) and finally water (1 mL) were carefully added. The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate in hexane to give 4-(6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (374 mg, 0.56 mmol, 80% yield). LCMS [ESI, M+1]: 668.

11-Chloro-9-fluoro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrido[4',3':4,3':4,5':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylic acid tert-butyl ester (1-3): At room temperature, tert-butyl 4-(6-chloro-8-fluoro-7-(2-chloro-6-((-4-methoxybenzyl)oxyphenyl)-3-nitroquinoline-4-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (267 mg, 0.4 mmol, 1.00 equiv) solution) and N were added. N-dimethylformamide (3 mL) was added under nitrogen atmosphere to obtain tert-butyl 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrido[4',3':4,3':4,5':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylate. To the chloroform of 11- (2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrido [4', 3': 4,5] pyrans [2,3-c] quinoline -3 (4H) -carboxylic acid tert-butyl ester (199mg, 0.32mmol, 81% yield).

LCMS [ESI, M+1]: 621.

2-(11-Chloro-9-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4',3':4,5]pyrano[2,3-c]quinolin-10-yl)-3-fluorophenol (Example 1): To a solution of tert-butyl 11-chloro-7-fluoro-10-(2-fluoro-6-((4-methoxybenzobenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrano[4',3':4,3':4,5]pyrano[3,3-c]quinoxaline-3(4H)-carboxylate (62.1 mg, 0.1 mmol, 1.00 equiv) in a mixture of acetonitrile and water (3:1 v/v, 1.6 mL) was added solid ACN (220 mg, 0.40 mmol, 4.00 equiv) and the mixture was stirred at 0 [UNK] for 30 minutes. Upon completion, the reaction mixture was diluted with ethyl acetate (4 mL) and saturated NaHCO 3 (4 ml) was added. The resulting suspension was stirred at room temperature for 30 minutes and then vacuum filtered through a pad of celite.

After separation of the two layers, the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in hydrogen chloride (4M in 1,4-dioxane, 2.00 mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and washed with 1N sodium hydroxide solution (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 2-(11-chloro-9-fluoro-1,3,4,5-tetrahydro-2H-pyridine [4', 3': 4,5] pyrano [2,3-c] quinoline-10-yl) -3-fluorophenol (24.0 mg, 0.06 mmol, 60% yield for two steps).

LCMS [ESI, M+1]: 401.

Synthesis of Example 2

2-(11-chloro-9-fluoro-1,3,4,4a,5,12c-hexahydro-2H-pyrido [4', 3': 4,5] pyranos [2,3-c] quinoline-10-yl)-3-fluorophenol (Example 2): Pd/c (10 wt% Pd, 53mg, 0.05mmol) was added to a flask with a stirring bar. Then a solution of 2-(11-chloro-9-fluoro-1,3,4,5-tetrahydro-2H-pyrido [4', 3': 4,5] pyranos [2,3-c] quinoline-10-yl)-3-fluorophenol (40.1mg, 0.10mmol, 1.00 equivalent) in ethyl acetate was added. The flask was closed with a septum and purged with nitrogen three times, then stirred at room temperature under a hydrogen balloon for 15 hours. After completion, the flask was flashed with nitrogen for 10 minutes. The mixture was filtered through diatomaceous earth and further washed with dichloromethane/methanol (2:1, 20 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 2-(11-chloro-9-fluoro-1,3,4,4a,5,12c-hexahydro-2H-pyrido[4',3':4,5]pyrano[2,3-c]quinoline-10-yl)-3-fluorophenol (36.3 mg, 0.09 mmol, 90% yield).

LCMS [ESI, M+1]: 403.

The compounds were synthesized using routes similar to those in Examples 1 and 2.

Table 1

Synthesis of Example 9

Tert-butyl 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-5-oxo-1,4,5,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-3(2H)-carboxylate (9-1): To a solution of 1-(tert-butyl)3-ethyl-4-(6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (440 mg, 0.62 mmol, 1.00 equiv) in acetic acid (6 mL) was added iron powder (139 mg, 2.5 mmol, 4.00 equiv) at room temperature. The mixture was stirred at 80[UNK] for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure to give a brown solid. The solid was suspended in dichloromethane (30 mL) and saturated aqueous sodium bicarbonate solution was added until the solution pH was 8. The mixture was filtered through diatomaceous earth (washed with dichloromethane). The phases were separated and the aqueous solution was washed with dichloromethane (30 mL). The combined organic extracts were washed with brine (30 mL) and concentrated to give 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-5-oxo-1,4,5,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthypyridine-3(2H)-carboxylic acid tert-butyl ester (345 mg, crude product) through a hydrophobic glass frit. LCMS[ESI, M+1]: 634.

11-Chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-6-methyl-5-oxo-1,4,5,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-3(2H)-carboxylate (9-2): 11-Chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-5-oxo-5-oxo-1,4,5 A stirred suspension of tert-butyl 6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-3(2H)-carboxylate (345 mg, 0.56 mmol, 1.00 equiv) and potassium carbonate (154 mg, 1.12 mmol, 2.00 equiv) and acetone (5 mL) was stirred at room temperature in a stirred suspension of tert-butyl 11-chloro-9-fluoro-9-fluoro-10(10-)tert-butyl. Iodomethane (0.35 mL, 5.6 mmol, 10.0 equiv) was added and the resulting mixture was stirred at 40 °C overnight. The reaction mixture was cooled to room temperature and evaporated to dryness. The crude residue was dissolved in DCM (20 mL), extracted with water (10 mL) and washed with brine (10 ml). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography with a gradient of 0-100% ethyl acetate in heptane to afford tert-butyl 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-6-methyl-5-methyl-5-oxo-1,4,5,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-3(2H)-carboxylate (281 mg, 0.43 mmol, 70% yield over two steps)

LCMS [ESI, M+1]: 648.

tert-Butyl 11-chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-5-oxo-1,4,4a,5,6,12c-hexahydrobenzo[f]pyrido[3,4-c][1,7]naphthopyridine-3(2H)-carboxylate (9-3): Pd/C (10 wt% Pd, 200 mg, 0.20 mmol) was added to a flask with a stir bar. Then a solution of tert-butyl 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-6-methyl-5-oxo-1,4,5,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthopyridine-3(2H)-carboxylate (259 mg, 0.4 mmol, 1.00 equiv) was added. The flask was closed with a septum, purged with nitrogen three times, and then stirred at room temperature under a hydrogen balloon for 15 hours. After completion, the mixture was filtered through diatomaceous earth and the diatomaceous earth was further washed with dichloromethane/methanol (2:1, 20 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 11-chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-5-oxo-1,4,4a,5,6,12c-hexahydrobenzo[f]pyrido[3,4-c][1,7]naphthypyridine-3(2H)-carboxylic acid tert-butyl ester (165 mg, 0,31 mmol, 78% yield).

LCMS [ESI, M+1]:530.

2-(11-Chloro-9-fluoro-6-fluoro-6-methyl-1,2,3,4,4,4a, 5,5,6,12c-octahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridin-10-yl)-3-fluorophenol (Example 9): To a solution of lithium aluminum hydride (1.4 mmol, 4.50 equiv) in tetrahydrofuran (5 mL) under nitrogen atmosphere was added a tert-butyl solution of 11-chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-5-oxo-1,4,4a, 5,6,12c-hexahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-3(2H)-carboxylate (165 mg, 0.31 mmol, 1.00 equiv) and tetrahydrofuran (5 mL) at 0% dropwise addition. The mixture was stirred at room temperature for 3 hrs. The mixture was cooled to 0°C, and water (1 mL), 15% aqueous NaOH (1 mL), and finally water (1 mL) were carefully added. The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in hydrogen chloride (4 M in 1,4-dioxane, 2.00 mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) , and washed with 1N sodium hydroxide solution (5mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography with a gradient of 0-100% ethyl acetate in heptane to give 2-(11-chloro-9-fluoro-6-methyl-1,2,3,4,4a,5,6,12c-octahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-10-yl)-3-fluorophenol (83.6 mg, 0.2 mmol, 65% yield).

LCMS [ESI, M+1]: 415.

Synthesis of Example 10

tert-Butyl 4-(6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5-(mercaptomethyl)-3,6-dihydropyridine-1(2H)-carboxylate (10-1): Added to a solution of sec-butyl 4-(6-fluoro-8-fluoro-8-fluoro-7-(2-fluoro-6-(4-methylbenzyloxy)benzene)-3-nitroquinoxalin-4-yl)-5-(hydroxymethyl)-3,8-dihydroquinoline-1(2H)-carboxylate (667 mg, 1,00 mmol, 1,00 equiv). ) in dichloromethane (5 mL) was added 0% triphenylphosphine (314 mg, 1.2 mmol, 1.2 equiv) and carbon tetrabromide (397 mg, 1.2 mol, 1.2 equiv). The mixture was stirred at room temperature for 1 hour. After completion, water (5 mL) was added to quench the reaction. The phases were separated and the aqueous solution was washed with dichloromethane (30 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and concentrated.

The residue was dissolved in N, N-dimethylformamide (5 mL). Disodium sulfide (85.8 mg, 1.1 mmol, 1.1 equivalents) was added to the solution. The mixture was stirred at room temperature for 12 hours. After completion, water (15 mL) was added to terminate the reaction. The mixture was extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 4-(6-chloro-8-fluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-3-nitroquinolin-4-yl)-5-(mercaptomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (479 mg, 0.70 mmol, 70% yield in two steps).

LCMS [ESI, M+1]: 684.

Tert-butyl 11-chloro-9-fluoro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrido[4',3':4,3':4,5]thiopyrano[2,3-c]quinoline-3(4H)-carboxylate (10-2): At room temperature, tert-butyl 4-(6-chloro-8-fluoro-7-(2-chloro-6-(((4-ethoxybenzyloxy)phenyl)phenyl)-3-nitroquinolin-4-yl)-5-(mercaptomethyl)-3,6-dihydropyridine-1(2H)-carboxylate (266 mg, 0.39 mmol, 1.0 0 equivalent) and N, N-dimethylformamide (3mL) sodium hydride (60% purity mineral oil, 48mg, 1.2mmol, 3.00 equivalent) were added under a nitrogen atmosphere. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted in dichloromethane (5mL). The organic layer was washed with brine, dried, filtered and evaporated. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrido [4', 3': 4,5]thiopyrano [2,3-c]quinoline-3 (4H)-carboxylic acid tert-butyl ester (208mg, 0.33mmol, 84% yield).

LCMS [ESI, M+1]: 637.

2-(11-chloro-9-fluoro-1,3,4,4a,5,12c-hexahydro-2H-pyrido[4',3':4,5]thiopyrano[2,3-c]quinoline-10-yl)-3-fluorophenol (Example 10): Pd/c (10 wt% Pd, 100 mg, 0.10 mmol) was added to a flask with a stirring bar. A solution of 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-6-methyl-5-oxo-1,4,5,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-3(2H)-carboxylic acid tert-butyl ester (127 mg, 0.2 mmol, 1.00 equiv) was then added. The flask was closed with a septum, purged with nitrogen three times, and then stirred at room temperature under a hydrogen balloon for 15 hours. After completion, the flask was flashed with nitrogen for 10 minutes. The mixture was filtered through celite and the celite was further washed with dichloromethane/methanol (2:1, 20 mL). The combined filtrates were concentrated under reduced pressure.

The residue was dissolved in hydrogen chloride (4M in 1,4-dioxane, 2.00mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10mL) and washed with 1N sodium hydroxide solution (5mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 2-(11-chloro-9-fluoro-1,3,4,4a,5,12c-hexahydro-2H-pyrido [4', 3':4,5] thiopyrano [2,3-c] quinoline-10-yl)-3-fluorophenol (54.3mg, 0.13mmol, 65% yield).

LCMS [ESI, M+1]:419.

Synthesis of Example 11

LCMS[ESI,M+1]:403.

Synthesis of Example 12

LCMS [ESI, M+1]: 416.

Synthesis of Example 13

11-Chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-7-iodo-1,5-dihydro-2H-pyrido[4',3':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylic acid tert-butyl ester (13-1): Under nitrogen atmosphere, -78[UNK], to lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene, 0.55 mL, 1.1 mmol, 1.1 equiv) in tetrahydrofuran (4 mL) was added dropwise a solution of 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,5-dihydro-2H-pyrido[4',3':3':4,5,5]pyrano[2,3-c]quinoline-3(444H)-carboxylic acid tert-butyl ester (620 mg, 1.00 mmol, 1.00 equiv) and tetrahydrofuran (2 mL). The mixture was stirred at -78[UNK] for 30 minutes. A solution of iodine (279 mg, 1.1 mmol, 1.1 equiv) and tetrahydrofuran (1 mL). Upon completion, the reaction was quenched with water (10 mL) and warmed to room temperature. The mixture was extracted with ethyl acetate (3×20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography, elution gradient 0-100% ethyl acetate in heptane to give tert-butyl 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-7-iodo-1,5-dihydro-2H-pyrido[4',3':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylate (671 mg, 0.90 mmol, 90%). LCMS [ESI, M+1]: 747.

MS(0.15g)和N，将N-二异丙基丙基乙胺(0.164g，0.22mL，1.26mmol，2.00当量)在2-甲基四氢呋喃(3mL)中的溶液添加到11-氯-9-氟-9-氟-10-(2-氟-6-((4-甲氧基苄基)氧苄基)氧基)苯基)-7-碘-1.5-二氢-2H-二氢-2H吡啶并[4'，3':4,5]吡喃并[2,3-c]喹啉-3(4H)-羧酸叔丁酯(470mg，0.0.63mmol，1.00当量)和2-甲基四氢呋喃(2mL)中，浓度为0至5[UNK]。将混合物在0-25[UNK]下搅拌2小时。完成后，过滤混合物并用乙酸乙酯(4mL)洗涤，用饱和氯化铵水溶液(300mL)洗涤滤液，过滤有机层并用无水硫酸钠干燥，过滤并在真空下在40[UNK]下浓缩至干。粗产物通过快速硅胶色谱法纯化，在庚烷中的洗脱梯度为0-100％乙酸乙酯，得到11-氯-9-氟-9-氟-10-(2-氟-6-((4-甲氧基苄基)氧基)苯基)-7-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,5-二氢-2H-吡啶并[4'，3':4,3'：4,5]吡喃并[2,3-c]喹啉-3(4H)-羧酸叔丁酯(345mg，0.45mmol，72％)。11-Chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-7-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,5-dihydro-2H-pyrido[4',3':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylic acid tert-butyl ester (13-2): (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (179 mg, 1.26 mmol, 2.00 equiv),

MS (0.15 g) and N, N-diisopropylethylamine (0.164 g, 0.22 mL, 1.26 mmol, 2.00 equiv) in 2-methyltetrahydrofuran (3 mL) was added to 11-chloro-9-fluoro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxybenzyl)oxy)phenyl)-7-iodo-1.5-dihydro-2H-dihydro-2Hpyrido[4',3':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylic acid tert-butyl ester (470 mg, 0.0.63 mmol, 1.00 equiv) and 2-methyltetrahydrofuran (2 mL) at a concentration of 0 to 5 [UNK]. The mixture was stirred at 0-25 [UNK] for 2 hours. After completion, the mixture was filtered and washed with ethyl acetate (4 mL), the filtrate was washed with saturated aqueous ammonium chloride solution (300 mL), the organic layer was filtered and dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum at 40 [UNK]. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 11-chloro-9-fluoro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-7-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-1,5-dihydro-2H-pyrido[4',3':4,3':4,5]pyrano[2,3-c]quinoline-3(4H)-carboxylic acid tert-butyl ester (345 mg, 0.45 mmol, 72%).

LCMS [ESI, M+1]:760.

2-(11-Chloro-9-fluoro-7-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,4,4a,5,12c-hexahydro-2H-pyrido[4',3':4,5]pyrano[2,3-c]quinolin-10-yl)-3-fluorophenol (Example 13): Pd/c (10 wt % Pd, 100 mg, 0.10 mmol) was added to a flask with a stirring bar. Then, by 11-chloro-9-fluoro-10-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-7-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-1,5-dihydro-2H-pyrido[4',3':4,5]pyrans[2,3-c]quinoline-3(4H)-carboxylic acid tert-butyl ester (152mg, 0.2mmol, 1.00 equivalent) solution is added in flask, flask is closed with septum, purged with nitrogen three times, then stirred at room temperature under hydrogen balloon for 15 hours. After completion, flask is flashed with nitrogen for 10 minutes. The mixture is filtered through diatomite, and diatomite is further washed with dichloromethane/methanol (2:1,20mL). The combined filtrate is concentrated under reduced pressure.

The residue was dissolved in hydrogen chloride (4M in 1,4-dioxane, 2.00mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10mL) and washed with 1N sodium hydroxide solution (5mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetic acid in heptane to give 2-(11-chloro-9-fluoro-7-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-1,3,4,4a,5,12c-hexahydro-2H-pyrido[4',3':4,5]pyranos[2,3-c]quinoline-10-yl)-3-fluorophenol (73.6mg, 0.136mmol, 68% yield).

LCMS [ESI, M+1]: 542.

Synthesis of Example 14

11-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-2,3,4,6-tetrahydrobenzo[p]pyrido[3,4-c][1,7]naphthyridin-5(1H)-one (Example 14): 11-chloro-7-fluoro-10-(2-fluoro-6-((4-methoxybenzo[p]pyrido[3,4-c][1,7]naphthyridin-5(1H)-one) was added. ,4-c][1,7]naphthyridine-3(2H)-carboxylic acid tert-butyl ester (64.7mg, 0.1mmol, 1.00equiv) was added to a mixture of acetonitrile and water (3:1v/v, 1.6mL) at 0[UNK] in one portion to solid CAN (220mg, 0.40mmol, 4.00equiv). The mixture was stirred at 0[UNK] for 30 minutes. Upon completion, the reaction mixture was diluted with ethyl acetate (4mL) and saturated NaHCO3 (4ml) was added. The resulting suspension was stirred at room temperature for 30 minutes and then vacuum filtered through a diatomaceous earth pad. After separation of the two layers, the aqueous layer was extracted with ethyl acetate (3×5mL). The combined organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in hydrogen chloride (4M in 1,4-dioxane, 2.00mL). The mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10mL) and 1N hydrogen The mixture was washed with sodium hydroxide solution (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 11-chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl-2,3,4,6-tetrahydrobenzo[f]pyrido[3,4-c][1,7]naphthyridine-5(1H)-one (27.8 mg, 0.065 mmol, 65% yield over two steps).

LCMS [ESI, M+1]: 428.

Synthesis of Example 15

Example 15 was synthesized using the starting materials of Example 14 in a similar route to Example 2.

LCMS [ESI, M+1]: 430.

The compounds in Table 2 were synthesized using routes similar to those of Examples 14 and 15.

Table 2

Synthesis of Example 23

Example 23 was synthesized using the starting material of compound 12-4 in a similar route to Example 2. LCMS [ESI, M+1]: 430.

Synthesis of Example 24

1-(tert-butyl)3-ethyl-3-ethyl-4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)quinazoline-quinazolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (24-1): 6-chloro-5,5,8-difluoro-7-difluoro(2-fluoro-6-((4-ethoxybenzyloxy)phenyl)quinazoline-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (IntB, Int To a vial (579 mg, 1.00 mmol, 1.00 equiv) was added 1-(tert-butyl) 3-ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (CAS: 1194488-90-8381 mg, 1,00 mmol, 1,00 equiv) sodium carbonate monohydrate (330 mg, 2,66 mmol, 2,66 equiv) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0,03 mmol, 0,02 equiv). The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL), then flushed with nitrogen, the vial was sealed and heated to 85 [UNK] for 5.5 hours. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to give 1-(tert-butyl)3-ethyl-4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)quinazolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (547 mg, 0.8 mmol, 80% yield).

LCMS [ESI, M+1]: 684.

Tert-butyl 4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzobenzyl)phenyl)quinazoline-4-quinazolinyl-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (24-2): A solution of 3-ethyl-4-(6-chloro-5,8-difluoro-7-(2-fluorobenzobenzyl)-5,6-dihydroxypyridine-1,3(2H)-dicarboxylic acid (273 mg, 0.40 mmol, 1.00 equiv) and anhydrous tetrahydrofuran (5 mL) was added dropwise to a stirred solution of LiAlH4 (30.0 mg, 0.80 mmol, 2.00 equiv) in anhydrous THF (5 mL). The mixture was stirred for 2 h. The mixture was stirred at reflux for 2 hours. After completion, the mixture was cooled to room temperature, and water (1mL), 15% NaOH aqueous solution (1ml) were carefully added, and finally water (1mL) was added. The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with a gradient of 0-100% ethyl acetate in hexane to obtain 4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)quinazoline-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (226mg, 0.35mmol, 88% yield).

LCMS [ESI, M+1]: 642.

6-Chloro-4-fluoro-4-fluoro-5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-11,12-dihydro-8H-pyrido[4′,3′:5,3′:5,6]oxapyridine[4,3,2-de]quinazoline-10(9H)-carboxylic acid tert-butyl ester (24-3): At room temperature, 4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methylbenzyl)oxy)phenyl)quinazolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid (226 mg, 0.35 mmol, 1.0 equiv) and N, N-dimethylformamide (3 mL) and sodium hydride (60% purity in mineral oil, 48 mg, 1.2 mmol, 3.00 equiv) were added. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted in dichloromethane (5mL). The organic layer was washed with brine, dried, filtered and evaporated. The crude product was purified by flash silica gel chromatography, and the elution gradient was 0-100% ethyl acetate in heptane to obtain 6-chloro-4-fluoro-5-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-11,12-dihydro-8H-pyrido[4',3':5,6]oxapino[4,3,2-on]quinazoline-10(9H)-carboxylic acid tert-butyl ester (152mg, 0.25mmol, 70% yield).

LCMS [ESI, M+1]: 622.

2-(6-Chloro-4-fluoro-9,10,11,12-tetrahydro-8H-pyrido[4′,3′:5,6]oxapyrido[4,3,2-yl]quinazolin-5-yl)-3-fluorophenol (Example 24): To 6-chloro-4-chloro-5-(2-fluoro-6-((4-methoxybenzobenzobenzyl)oxy)phenyl)-11,12-dihydro-8H-pyrimido[4′,3′:5,6]oxapyrido[4,3,3,2-yl]quinazoline-10(9H)-carboxylic acid tert-butyl ester (62.2 mg, 0.1 mmol, 1.00 equiv) in acetonitrile and water (3:1 v/v, 1.6 mL) was added solid CAN (220 mg, 0.41 mmol, 4.00 equiv), one portion, and 0.05 mL. After the stirring mixture was completed, the reaction mixture was diluted with ethyl acetate (4mL) and saturated NaHCO3 (4ml) was added. The resulting suspension was stirred at room temperature for 30 minutes and then vacuum filtered through a diatomaceous earth pad. After separation of the two layers, the aqueous layer was extracted with ethyl acetate (3×5mL). The combined organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in hydrogen chloride (4M in 1,4-dioxane, 2.00mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10mL) and washed with 1N sodium hydroxide solution (5mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography with a gradient of elution from 0-100% ethyl acetate in heptane to afford 2-(6-chloro-4-fluoro-9,10,11,12-tetrahydro-8H-pyrido[4′,3′:5,6]oxacyclo[4,3,2-hydroxy]quinazolin-5-yl)-3-fluorophenol (30.1 mg, 0.075 mmol, 75% yield over two steps).

LCMS [ESI, M+1]: 402.

Synthesis of Example 25

Example 25 was synthesized using the starting materials of Example 24 in a similar route to Example 2.

LCMS [ESI, M+1]: 404.

The compounds in Table 3 were synthesized using routes similar to those of Examples 24 and 25.

Table 3

Synthesis of Example 32

LCMS[ESI,M+1]:402.

Synthesis of Example 33

LCMS[ESI,M+1]:403.

The compounds in Table 4 were synthesized using routes similar to those of Examples 34 and 35.

Table 4

Synthesis of Example 38

2-Amino-4-bromo-5-chloro-3,6-difluorobenzoic acid ethyl ester (38-1): To a solution of 2-amino-4-bromo-5-chloro-3,4-difluorophenylcarboxylic acid (28.5 g, 100 mmol, 1.00 equiv) in ethanol (150 mL) was added concentrated hydrochloric acid. Sulfuric acid (2 mL, 37.5 mmol, 0.38 equiv). The mixture was stirred at reflux for 10 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid ethyl ester (26.0 g, 83 mmol, 83%).

LCMS [ESI, M+1]: 313.9.

4-Bromo-3-chloro-2,5-difluoro-6-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid ethyl ester (38-2): To a solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid ethyl ester in tetrahydrofuran (60 mL) was added 2,2,2-dichloroacetyl isocyanate (20.7 g, 110 mmol, 1.50 equiv) at 25 [UNK]. The mixture was stirred at 25 [UNK] for 10 minutes. Upon completion, the mixture was concentrated under vacuum. The crude product was triturated with methyl tert-butyl ether (200 mL) at 25 [UNK] for 5 minutes. Ethyl 4-bromo-3-chloro-2,5-difluoro-6-(3-(2,2,2-trichloroacetyl)ureido)benzoate (33.8 g, 67.7 mmol, 92% yield) was obtained as a grey solid and used in the next step without further purification.

LCMS [ESI, M+1]: 500.8.

7-Bromo-6-chloro-5,8-difluorodiazoline-2,4-diol (38-3): To a solution of ethyl 4-bromo-3-chloro-2,5-difluoro-6-(3-(2,2,2-trichloroacetyl)ureido)benzoate (31.5 g, 63.1 mmol, 1.0 equiv) in methanol (290 mL) was added 25 [UNK] of NH3 MeOH (29 mL, 20% purity). The mixture was stirred at 25 [UNK] for 1 hour. After completion, the mixture was concentrated under vacuum. The crude product was ground with methyl tert-butyl ether (200 mL) at 25 [UNK] for 10 minutes. 7-Bromo-6-chloro-5,8-difluoroquinazoline-2,4-diol (18 g, crude) was obtained as a brown solid and used in the next step without further purification.

LCMS [ESI, M+1]: 310.9.

7-Bromo-2,4,6-trichloro-2,4,6-trichloro-5,8-difluoroquinazoline (38-4): To a solution of 7-bromo-6-chloro-5,8-difluoroquinoline-2,4-diol (28.8 g, 92.8 mmol, 1.00 equiv) in toluene (100 ml) was added phosphorus oxychloride (42.7 g, 278 mmol, 3.00 equiv) and N,N-diisopropylethylamine (36.0 g, 48.5 ml, 278 mmol, 4.00 equiv) at 0°C. The mixture was stirred at 110 [UNK] for 3 hours. Upon completion, the mixture was concentrated to dryness at 40 [UNK] under vacuum to give 7-bromo-2,4,6-trichloro-5,8-difluoroquinazoline (25.7 g, crude) as a black oil.

LCMS [ESI, M+1]: 346.8.

4-(Benzyloxy)-7-bromo-2,6-dichloro-5,8-difluoroquinazoline (36-5): MS (3A, 6.2 g), 1,4-dioxane (300 mL), benzyl alcohol (10.8 g, 11.6 mL, 100 mmol, 1.20 equiv.) and DIPEA (32.1 g, 48.3 mL, 48.3 mL, and DIPEA) (32.1 g, 48.3 mmol, 48.3 mL, and DIPE 249 mmol, 3.00 equiv.) were added. The mixture was stirred at 60 [UNK] under nitrogen for 7 hours. The mixture was concentrated to dryness and diluted with ethyl acetate. The resulting mixture was filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by flash column chromatography eluting with 0-100% ethyl acetate/hexanes to afford 4-(benzyloxy)-7-bromo-2,6-dichloro-5,8-difluoroquinazoline (15.8 g, 37.7 mmol, 45% yield).

LCMS [ESI, M+1]: 418.9.

MS(15克)和N，在0至5[UNK]下加入N-二异丙基乙胺(16.4克，22.0毫升，126毫摩尔，2.00当量)和2-甲基四氢呋喃(200毫升)4-(苄氧基)-7-溴-2,6-二氯-5,8-二氟喹唑啉(26.5克，63.3毫摩尔，1.00当量)和-2-甲基四氢呋喃(100毫升)。将混合物在0-25[UNK]下搅拌2小时。完成后，将混合物过滤并用乙酸乙酯(100mL)洗涤，用饱和氯化铵水溶液(300mL)猝灭滤液，对有机层进行分级并用无水硫酸钠干燥，过滤并在真空下在40[UNK]下浓缩至干。将粗产物用乙腈(20mL)在25[UNK]下研制15分钟。过滤混合物并在40[UNK]下减压浓缩滤液至干，得到浅黄色固体形式的4-(苄氧基)-7-溴-6-氯-5,8-二氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉(23.2g，44.3mmol，70％产率)。4-(Benzyloxy)-7-bromo-6-chloro-5,8-difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline (36-6): (tetrahydro-2H-pyrrolizin-7a(5H)-yl)methanol (17.9 g, 126 mmol, 2.00 eq.) was added.

MS (15 g) and N, N-diisopropylethylamine (16.4 g, 22.0 ml, 126 mmol, 2.00 eq) and 2-methyltetrahydrofuran (200 ml) 4-(benzyloxy)-7-bromo-2,6-dichloro-5,8-difluoroquinazoline (26.5 g, 63.3 mmol, 1.00 eq) and -2-methyltetrahydrofuran (100 ml) were added at 0 to 5 [UNK]. The mixture was stirred for 2 hours at 0-25 [UNK]. After completion, the mixture was filtered and washed with ethyl acetate (100 mL), the filtrate was quenched with saturated aqueous ammonium chloride solution (300 mL), the organic layer was graded and dried with anhydrous sodium sulfate, filtered and concentrated to dryness at 40 [UNK] under vacuum. The crude product was triturated with acetonitrile (20 mL) at 25 [UNK] for 15 minutes. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure at 40 [UNK] to give 4-(benzyloxy)-7-bromo-6-chloro-5,8-difluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline (23.2 g, 44.3 mmol, 70% yield) as a light yellow solid.

LCMS [ESI, M+1]: 524.

4-(Benzyloxy)-6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline Quinazoline (36-7): A solution of 4-(benzyloxy)-7-bromo-6-chloro-5-8-difluoro-2-(((tetrahydroxy-1H-pyrrolizin-7a(5H)-)yl)methyl)quinoline (2.51 g 4.8 mmol, 1.00 equiv), (2-fluoro-6-((4-methylbenzyl)oxy)phenyl)boronic acid (1.82 g, 9.7 mmol, 2.00 equiv),) and potassium carbonate (2.0 g, 14.5 mmol, 3.00 equiv) in dioxane/water (40 mL, 3:1) was degassed with nitrogen for 10 min. RuPhos PdG3 (404 mg, 0.5 mmol, 0.1 eq.) and RuPhos (225 mg, 0.5 mol, 0.1 eq.) were added. After 1.5 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The solution was washed with water (100 ml), and the aqueous portion was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow residue. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 4-(benzyloxy)-6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline (2.77 g, 4.1 mmol, 86% yield).

LCMS [ESI, M+1]: 676.

[0136] 6-Chloro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-ol (36-8): To a flask with a stir bar was added Pd/C (10 wt% Pd, 1.0 g, 1.0 mmol). Then a solution of 4-(benzyloxy)-6-chloro-5,8-difluoro-7-(2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline (2.77 g, 4.0 mmol, 1.00 equiv) in ethyl acetate (40 mL) was added. The flask was closed with a septum, purged with nitrogen three times, and then stirred at room temperature under a hydrogen balloon for 15 hours. Upon completion, the flask was flashed with nitrogen for 10 minutes. The mixture was filtered through diatomaceous earth and the diatomaceous earth was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0-100% ethyl acetate in heptane to give 6-chloro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)quinazoline-4-ol (1.58 g, 3.3 mmol, 83% yield).

LCMS [ESI, M+1]: 466.

MS(0.4g)在二氯甲烷(20mL)中的溶液中加入TEA(1.07mL，7.7mmol，3.00当量)和三氟甲磺酸酐(0.63mL，3.8mmol，1.50当量)。在该温度下搅拌混合物30分钟。在-40℃下用水(20mL)稀释反应混合物。水层用二氯甲烷(3×15mL)萃取。合并的有机层用盐水(2×15mL)洗涤，用硫酸钠干燥并减压浓缩。残余物通过硅胶快速色谱法(0至100％乙酸乙酯在石油醚中)纯化，得到6-氯-5,8-二氟-7-(2-氟-6-羟基苯基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基三氟甲磺酸酯(855mg，1.43mmol，55％产率)。6-Chloro-5,8-difluoro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ylquinazolin-4-yl trifluoromethanesulfonate (36-9): 6-Chloro-5,5,8-difluoro-7-(difluoro-6-hydroxyphenyl)-2-(tetrahydro-2H-pyrrolidin-7a(5H)-ylmethoxy)quinolin-4-ol (1.21 g, 2.2.6 mmol, 1.00 equiv) and

To a solution of MS (0.4 g) in dichloromethane (20 mL) was added TEA (1.07 mL, 7.7 mmol, 3.00 equiv) and trifluoromethanesulfonic anhydride (0.63 mL, 3.8 mmol, 1.50 equiv). The mixture was stirred at this temperature for 30 minutes. The reaction mixture was diluted with water (20 mL) at -40 ° C. The aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0 to 100% ethyl acetate in petroleum ether) to give 6-chloro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)quinazolin-4-yl trifluoromethanesulfonate (855 mg, 1.43 mmol, 55% yield).

LCMS [ESI, M+1]:598.

1-(tert-butyl)3-ethyl-3-ethyl-4-(6-chloro-5,8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolizine-7a(5H)-5H)-methoxymethoxy)quinazolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (36-10): to contain 6-chloro-5,6-fluoro-5,8-difluoro-7-difluoro(2-fluoro-6-hydroxyphenyl)-2-(tetrahydro-2H-pyrrolidine: to contain 6-chloro- To the mixture was added 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (CAS: 1194488-90-8, 381 mg, 1.00 mmol, 1.00 mmol), sodium carbonate monohydrate (330 mg, 2.66 mmol, 2.66 mmol, 2.66 mmol), and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol, 0.03 equiv). Laughter) The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL), then flushed with nitrogen, the vial was sealed and heated to 85 [UNK] for 5.5 hours. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate in hexanes to give 1-(tert-butyl) 3-ethyl-4-(6-chloro-5,8-difluoro-5,8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (541 mg, 0.77 mmol, 77% yield). LCMS [ESI, M+1]: 703.

Tert-butyl 4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (36-11): 1-(tert-butyl)-3-ethyl-3-ethyl-4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-phenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate A solution of ((tetrahydro-1H-pyrrolizin-7a(5H)-5H)-yl)methoxy)quinazolin-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (281 mg, 0.40 mmol, 1.00 equiv) and anhydrous tetrahydrofuran (5 mL) was added dropwise to LiAlH4 (LiAlH44 (5 mL, 30.0 mg, 0.80 mmol, 2.00 equivalents) and water THF (5mL) in a stirred solution. The mixture was stirred at reflux for 2 hours. After completion, the mixture was cooled to room temperature, and water (1mL), 15% NaOH aqueous solution (1ml) and finally water (1mL) were carefully added. The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0-100% ethyl acetate in hexanes to give 4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxyquinazolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (231mg, 0.35mmol, 87% yield)

LCMS [ESI, M+1]: 661.

6-Chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11,12-dihydro-8H-pyrido[4',3':5,6]oxapino[4,3,2-d]quinazoline-10(9H)-carboxylic acid tert-butyl ester (36-12): At room temperature, under a nitrogen atmosphere, 4-(6-chloro-5,8-difluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11,12-dihydro-8H-pyrido[4',3':5,6]oxapino[4,3,2-d]quinazoline-10(9H)-carboxylic acid tert-butyl ester (36-12) was added to the mixture. To a solution of tert-butyl 2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)-methoxy)quinazolin-4-yl)-5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (231 mg, 0.35 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% purity in mineral oil, 42 mg, 1.2 mmol, 3.00 equiv). Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted in dichloromethane (5 mL). The organic layer was washed with brine, dried, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to give tert-butyl 6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-11,12-dihydro-8H-pyrido[4',3':5,6,6]oxapino[4,3,3,2-dio]quinazoline-10(9H)-carboxylate (146 mg, 0.23 mmol, 65% yield)

LCMS [ESI, M+1]: 641.

2-(6-chloro-4-fluoro-2-((tetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-8a,9,10,11,12,12a-hexahydro-8H-pyrido[4',3':5,6]oxabino[4,3,2-de]quinazoline-5-yl)-3-fluorophenol (Example 36): Pd/C (10 wt % Pd, 100 mg, 0.10 mmol) was added to a flask with a stirring bar. The flask was closed with a septum and purged with nitrogen three times, then stirred at room temperature under a hydrogen balloon for 15 hours. Upon completion, the flask was flashed with nitrogen for 10 minutes. The mixture was filtered through diatomaceous earth and the diatomaceous earth was further washed with dichloromethane/methanol (2:1, 20 mL). The combined filtrate was concentrated under reduced pressure.

The residue was dissolved in hydrogen chloride (4M in 1,4-dioxane, 2,00 mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and washed with 1N sodium hydroxide solution (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in heptane to afford 2-(6-chloro-4-fluoro-4-fluoro-2-((tetrahydro-1H-pyrrolazine-7a(5H)-7a-pyrrolazine-1H-pyrroline-7a(5H)-methoxy)-8a,9,10,11,11,12,12,12a-hexahydro-8H-pyrido[4',3',3':5,6]oxapino[4,3,2-de]quinazolin-5-yl)-3-fluorophenol (65.0 mg, 0.12 mmol, 60% yield).

LCMS [ESI, M+1]: 542.

Example 39: (8aR, 9R, 12S)-5-(8-ethynyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9, 10, 11, 12, 13-hexahydro-8H-9, 12-pyrimidine [2', 1': 3, 4] [1, 4] oxazino [5, 6, 7] quinazoline

Synthesis of 1

To a solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (CAS: 1698535-33-9, 7.00 g, 27.80 mmol) in MeOH (60 mL) was added SOCl2 (60 mL) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 85:15–60:40) to give methyl 2-amino-4-bromo-3,6-difluorobenzoate 1 (5.00 g, 67.7%) as a yellow oil. MS: m/z = 266.0, 267.9 (m+1, ESI+).

Synthesis of 3

At room temperature, 2-amino-4-bromo-3,6-difluorobenzoic acid methyl ester 1 (2.00g, 1.14mmol) was added to a solution of THF (20mL) with 2,2,2-trichloroacetyl isocyanate (2.00g, 10.7mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, the residue was dissolved in MeOH (20mL), NH3 (7N, 7mL) was added to MeOH, and then the mixture was stirred at room temperature for 16 hours. The mixture was filtered to obtain 4-bromo-3,6-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid methyl ester 3 (1.00g, 50.5% yield) in the form of a yellow solid. MS: m/z=277.0, 279.0 (m+1, ESI+).

Synthesis of 4

To a solution of 4-bromo-3,6-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid methyl ester 2 (1.00 g, 3.61 mmol) in POCl3 (10 ml) was added diisopropylethylamine (2.33 g, 18.1 mmol) at room temperature. The mixture was washed to 110°C and stirred at 110°C for 3 hours. The mixture was then concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/dichloromethane = 5:1 to 1:1) to give 7-bromo-2,4-dichloro-5,8-difluoroquinazoline 4 (700 mg, 61.9%) as a yellow solid. MS: m/z = 312.8314.8316.8 (m+1, ESI+). Synthesis of 4.5 To a solution of 7-bromo-2,4-dichloro-5,8-difluoroquinazoline 4 (700 mg, 2.23 mmol) in acetone (10 mL) was added Int 1 isomer 1 (1.07 g, 2.23 mol) and Na2CO3 (863 mg, 6.69 mmol). The mixture was stirred at 60°C for 2 hours, quenched with water (20 mL), extracted with dichloromethane (20 mL*3), and washed with brine (30 mL+3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 99:1 to 9:1) to give tert-butyl (1R, 5S)-3-(7-bromo-2-chloro-5,8-difluoroquinazolin-4-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 5 (1.1 g, 65%) as a yellow solid. MS: m/z = 756.9, 758.9, 760.9 (m+1, ESI+).

Synthesis of 6

To a solution of (tetrahydro-1H-pyrrolidin-7a(5H)yl)methanol (CAS: 78449-72-6204 mg, 1.45 mmol) in dioxane (10 mL) was added sodium hydride (105 mg, 4.35 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes, and then tert-butyl (1R, 5S)-3-(7-bromo-2-chloro-5,8-difluoroquinazolin-4-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 5 (1.10 g, 1.45 mmol) was added to the mixture, and stirred at 40°C for 30 min, and washed with brine (30 mL*3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol=99:1 to 9:1) to give tert-butyl (1R,5S)-3-(7-bromo-5,8-difluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 6 (700 mg, yield 56%) as a yellow oil. MS: m/z=861.8, 863.7 (m+1, ESI+).

Synthesis of 7

To a solution of tert-butyl (1R,5S)-3-(7-bromo-5,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-([(tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 6 (100 mg, 0.11 mmol) in dioxane/H2O (4/1 = 5 mL) were added (7-fluoro-8-((((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (CAS: 2621932-37286 mg, 0.23 mmol), catalytic Cxium A Pd G3 (8 mg, 0.011 mmol) and Na2CO3 (36 mg, 0.34 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was then quenched with water (20 mL), extracted with ethyl acetate (20 mL*3), and washed with brine (30 mL*3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol = 99:1 to 9:1) to give tert-butyl ( 1R,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(5,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 7 (70 mg, 57.3%) as a yellow solid. MS: m/z = 1108.9 (m+1, ESI+).

Synthesis of 8

A solution of tert-butyl (1R, 5S)-2-((((tert-butyldiphenylsilyl)oxy)methyl)-3-(5,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 7 (70 mg, 0.063 mmol) in THF (5 mL) was stirred at room temperature for 1 hour. The mixture was then stirred at 60°C for 1 hour. Diluted with water (20 mL), extracted with dichloromethane (20 mL*3), washed with citric acid solution (1N) (30 mL*3), and washed with brine (30 mL*3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by Prep HPLC (column Gemini C1821x150mm, 5μm, CH3CN in water (0.1% FA), flow rate: 20ml/min; wavelength: 214nm. Sample injection DMSO (+optional formic acid and water), 11 minutes linear gradient from 50% to 60% CH3CN. ) tert-Butyl (9R, 12S)-5-(8-ethynyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10,11,12,13-hexahydro-8H-9,12-pyraminoazepin [2', 1': 3,4] [1,4] oxazine [5,6,7-de] quinazoline-15-carboxylate 8 (25mg, mixture, 57.2% yield) was obtained as a white solid. MS: m/z=694.0(m+1, ESI+).

Synthesis of Example 39

To a solution of tert-butyl (9R, 12S)-5-(8-ethynyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a, 9,10,11,12,13-hexahydro-8H-9,12-pyraminoazepin [2', 1': 3,4] [1,4] oxa[5,6,7-de] quinazoline-15-carboxylate 8 (20 mg, 0.029 mmol) in dichloromethane (4 mL) was added TMSOTf (1 mL) and pyridine (1 mL), and the mixture was stirred at 25 ° C for 1 hour. The mixture was quenched by adjusting the pH to 8-9 with a saturated sodium carbonate solution, extracted with dichloromethane (15 mL*3) and washed with brine (10 ml*3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by Prep HPLC (column Gemini C18 21x150mm, 5μm, CH3CN in water (0.1% FA), flow rate: 20mL/min; wavelength: 214nm. Samples were injected into DMSO (+optionally formic acid and water) with a linear gradient of 45% to 50% CH3CN over 11 minutes. ) gave tert-butyl (9R, 12S)-5-(8-ethynyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10,11,12,13-hexahydro-8H-9,12-pyraminoazepin[2',1':3,4][1,4]oxazino[5,6,7-hydroxy]quinazoline-15-carboxylate Example 39 (5.2mg).

MS: m/z=594.1(m+1, ESI+).

1H NMR (400 MHz, MeOD) δ 8.37 (s, 2H), 8.02-7.95 (m, 2H 3.58-3.48 (m, 2H), 3.40 (d, J = 29.9 Hz, 1H), 3.27-3.22 (m, 1H, 2.20-1.82 (m, 12H). The compounds in Table 5 were synthesized by a route similar to that of Example 39, using appropriate starting materials as described above: Table 5

Example 126: (8aR,9R,12S)-5-(8-ethynyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-pyrimidine [2',1':3,4] [1,4] oxazino [5,6,7] quinazoline

Synthesis of 1

To a solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (CAS: 1698535-33-9, 7.00 g, 27.80 mmol) in MeOH (60 mL) was added SOCl2 (60 mL) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 85:15–60:40) to give methyl 2-amino-4-bromo-3,6-difluorobenzoate 1 (5.00 g, 67.7%) as a yellow oil. MS: m/z = 266.0, 267.9 (m+1, ESI+).

Synthesis of 3

At room temperature, 2-amino-4-bromo-3,6-difluorobenzoic acid methyl ester 1 (2.00g, 1.14mmol) was added to a solution of THF (20mL) with 2,2,2-trichloroacetyl isocyanate (2.00g, 10.7mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, the residue was dissolved in MeOH (20mL), NH3 (7N, 7mL) was added to MeOH, and then the mixture was stirred at room temperature for 16 hours. The mixture was filtered to obtain 4-bromo-3,6-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid methyl ester 3 (1.00g, 50.5% yield) in the form of a yellow solid. MS: m/z=277.0, 279.0 (m+1, ESI+).

Synthesis of 4

To a solution of 4-bromo-3,6-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid methyl ester 2 (1.00 g, 3.61 mmol) in POCl3 (10 ml) was added diisopropylethylamine (2.33 g, 18.1 mmol) at room temperature. The mixture was washed to 110°C and stirred at 110°C for 3 hours. The mixture was then concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/dichloromethane = 5:1 to 1:1) to give 7-bromo-2,4-dichloro-5,8-difluoroquinazoline 4 (700 mg, 61.9%) as a yellow solid. MS: m/z = 312.8314.8316.8 (m+1, ESI+).

Synthesis of 5

To a solution of 7-bromo-2,4-dichloro-5,8-difluoroquinazoline 4 (700 mg, 2.23 mmol) in acetone (10 mL) was added 1-((((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)methyl)-N,N-dimethylcyclobutane-1-amine Int 1 (0.915 g, 2.23 mol) and Na2CO3 (863 mg, 6.69 mmol). The mixture was stirred at 60 ° C for 2 hours, quenched with water (20 mL), extracted with dichloromethane (20 mL*3), and washed with brine (30 mL+3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate = 99:1 to 9:1) to give 7-bromo-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloro-N-((1-(dimethylamino)cyclobutyl)methyl)-5,8-difluoroquinazoline-4-amine 5 (996 mg, 1.45 mmol, 65%) as a yellow solid. MS: m/z = 687.2 (m+1, ESI+).

Synthesis of 6

To a solution of (tetrahydro-1H-pyrrolidin-7a(5H)yl)methanol (CAS: 78449-72-6204 mg, 1.45 mmol) in dioxane (10 mL) was added sodium hydride (105 mg, 4.35 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes, then 7-bromo-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloro-N-((1-(dimethylamino)cyclobutyl)methyl)-5,8-difluoroquinazolin-4-amine 5 (0.996 g, 1.45 mmol) was added to the mixture, stirred at 40°C for 30 min, and washed with brine (30 mL*3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol = 99:1 to 9:1) to give 7-bromo-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-((1-(dimethylamino)cyclobutyl)methyl)-5,8-difluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-amine 6 (643 mg, 0.812 mmol, yield 56%), yellow oil MS: m/z = 792.3 (m+1, ESI+).

Synthesis of 7

To a solution of 7-bromo-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-((1-(dimethylamino)cyclobutyl)methyl)-5,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-amine 6 (87 mg, 0.11 mmol) in dioxane/H2O (4/1 = 5 mL) were added (7-fluoro-8-((((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (CAS: 2621932-37-2, 86 mg, 0.23 mmol), catalytic Cxium A Pd G3 (8 mg, 0.011 mmol) and Na2CO3 (36 mg, 0.34 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was then quenched with water (20 mL), extracted with ethyl acetate (20 mL*3), and washed with brine (30 mL*3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol = 99:1 to 9:1) to obtain N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-((1-(dimethylamino)cyclobutyl)methyl)-5,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-amine 7 (65 mg, 0.63 mmol, 57.3%) as a yellow solid. MS: m/z = 1038.6 (m+1, ESI+).

Synthesis of Example 126

N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-((1-(dimethylamino)cyclobutyl)methyl)-5,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-amine 7 (65 mg, extracted with dichloromethane (20 mL*3), washed with citric acid solution (1N) (30 mL*3), and washed with brine (30 mL+3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by Prep HPLC (column Gemini C18 21x150mm, 5μm, CH3CN in water (0.1% FA), flow rate: 20mL/min; wavelength: 214nm. Sample injection DMSO (+optional formic acid and water), 11 min linear gradient from 50% to 60% CH3CN. ) 1-((9-(8-ethynyl-7-fluoronaphthalen-1-yl)-10-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxapino[5,6,7-hydroxy]quinazolin-4-yl)methyl)-N,N-dimethylcyclobutane-1-amine Example 1 (22 mg, 0.036 mmol, 57.2% yield) was obtained as a white solid. MS: m/z=624.3 (m+1, ESI+).

The compounds in the following table were synthesized by a similar route as in Example 1, using appropriate starting materials as described above: Table 6

Example 268 Synthesis of Prodrug

A solution of Ex 268 (30 mg, 0.048 mmol), Boc2O (10.5 mg, 0.048 mmmol), triethylamine (10.1 mg, 0.10 mmol) in dichloromethane (0.10 mL) was stirred at room temperature overnight, when TLC (petroleum ether/ethyl acetate = 1: 1) showed that the reaction was complete. The reaction mixture was concentrated under vacuum, and the resin was purified with a silica gel column (petroleum ether/ethyl acetate = 10: 1 to 1: 1 gradient) to provide Ex 268CO2tBu (11.9 mg, 0.016 mmol, 34% yield) in the form of a light yellow solid. LCMS [ESI, M+1]+: 728.7. 1H NMR (400MHz, MeOD) δ6.79 (t, J=9.9Hz, 1H), 5.32 (brs, 0.5H), 5.18 (brs, 0.5H), 5.05–5.01 (M, 1H, 4.56–4.52 (M, 3H), 4.46–4.32 (M , 2H), 4.28–4.18(M, 3H), 4.09–4.07(M, 1H), 3.40–3.23(M, 2H), 3.19–2.93(M, 3H), 2.38–1.69(M, 10H), 1.42(s, 9H).

The examples in the table below were synthesized using the above route:

Table 7

Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

Experiment 1: Isothermal Titration Calorimetry (ITC) Binding Assay Procedure for KRas G12D or WT 1 L of ITC buffer (50 mM Hepes pH 7.4, 100 mM NaCl, 1 mM TCEP, 5 mM MgCl2, 0.05% Tween 20) was prepared and filtered using a 0.22 m bottle top filter. Purified KRas G12D or WT was concentrated to 1 mM using a centrifugal concentrator and dialyzed extensively against ITC buffer overnight at room temperature. After dialysis, 100 mL of ITC buffer was taken, degassed, and saved for compound dilutions, ITC baselines, and rinsing ITC cells. All ITC experiments were performed using a MicroCal PEAQ-ITC instrument (Malvern Panalytical) and the ITC buffer contained 4% dimethyl sulfoxide at 20°C.

All compounds were prepared as 10 mM stock solutions in DMSO and then diluted 100X in ITC buffer. 1 mM of KRas G12D or WT in a syringe was titrated into 50-100 uM of compound in the measuring cell. Typically, in a preliminary 0.4 L injection, 19 injections were made 2 times in a single titration with an interval of 150 seconds between each injection. The syringe was stirred at a constant speed of 750 rpm during equilibration and the experiment. MicroCal PEAQ-ITC Analysis Software V.1.40 was used to analyze the resulting thermograms. Binding isotherms were fitted to a standard set of site models.

Conclusion: The compounds of the present invention show strong binding affinity to human KRas G12D kinase protein.

Experiment 2 KRas surface plasmon resonance (SPR) binding assay

Materials and related reagents

1. Biotinylated recombinant human KRAS WT/G12D/G12C/G12V (a.a.1-164, C-terminal AVI tag, produced in-house)

2. PBS-P+ buffer 10X (Cytiva, CAT#28995084)

3. Biotin-derivatized linear polycarboxylate saline gel sensor chip (XanTec Bioanalysis GmbH, Germany, CAT#SCBS BD200M)

4. Switchavidin (BioMediTech, Center for Protein Dynamics and Biology, Tampere, Finland)

5.50% citric acid (Millipore Sigma, CAT#4808551000)

6. Sodium dodecyl sulfate solution (Sigma-Aldrich, CAT#45-05030-500ML)

7. Dimethyl sulfoxide (Millipore Sigma, CAT#34869-1L)

8. Greiner 96-well plates, polypropylene (Sigma Aldrich, CAT#M7310-100EA)

9. Microplate foil, 96 wells (Cytiva, CAT# 28975816)

10. Biacore 8k (Cytiva)

Experimental Procedure

All SPR experiments were performed on a BIAcore 8K instrument. Biotin sensor chips (BD200M) were washed with 2.5% citric acid and 0.25% sodium dodecyl sulfate (SDS) before use. 150 nM of sitaviridine was immobilized on the biotin sensor chip to Fc1 in all eight channels at 25°C. 300 nM biotinylated KRAS (WT/G12D/G12C/G12V) protein was pre-incubated with 150 nM switch guanosine before immobilization on Fc2 in all channels, resulting in similar coupling densities of 1000 RU ± 200 RU in Fc2-1 in all channels.

After a short stabilization period of 20 minutes, the compound was injected into the running buffer (20mM phosphate buffer, pH 7.4 containing 2.7mM KCl, 137mM NaCl, 0.05% (v/v) Tween-20 and 5mM MgCl2) in two-fold dilutions. The kinetic constants of the compounds were determined by single-cycle kinetics, and six consecutive injections were performed, and the compound concentration increased in the range of 6.25-200nM, 62.5-2000nM or 312.5-1000nM according to the potency. The flow rate was 30μl/min and the injection time was 60 seconds. After a 300-second dissociation period, the surface was excited for 60 seconds with a regeneration solution (2.5% citric acid, pH 2, 0.5% SDS) to achieve a new immobilization cycle. The resulting sensorgram was used as a reference and the blank was subtracted before fitting to the 1:1 binding model of the slow compound or the steady-state affinity equation of the fast-on and fast-off compound. The steady state affinity KD is shown in Table 1 below.

Table 1. KD (μM) of the compounds of the present invention for KRAS WT/G12D/G12C/G12V protein.

Conclusion: The compounds of the present invention selectively inhibit KRAS G12D.

Experiment 3. Pharmacokinetic study in mice

The example compounds were orally administered to female C57BL/6 mice. Mouse serum samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and stored at -80°C. The concentration of the test article was measured in plasma. Chromatographic separation was performed on a WatersBEH C18 column (2.1×50 mm, 1.7 μm) (MAC-MOD Analytical, Chadds Ford, PA) using a water and acetonitrile gradient elution method, both containing 0.025% formic acid-1 mM NH4OAc. Mass spectrometry measurements in positive electrospray ionization were designed to quantify mass transitions with [M+H]+ as precursor ions on an API6500 triple quadruple mass spectrometer (Sciex, Framingham, MA). Relevant pharmacokinetic parameters were estimated using a non-departmental approach using WinNonlin (Enterprise, Version 8.2). The concentration-time distribution results of Example 169 and the prodrug of Example 169 (Example 169CO2tBu) are shown in Figures 1, 2, and 3.

Claims (43)

1. A compound represented by formula (VI), (VII) or (VIII):

or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Ring A is aryl, heteroaryl, cycloalkyl or heterocyclyl; M is N or CR ₃ ; M1 is N or CR ₆ ; R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, cyanoalkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylheteroaryl, oxoalkylthio, -COOH and -CONH ₂ ; _R1 and _R2 together with the atoms to which they are attached form a spirocycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, a spiroheterocyclyl, a fused heterocyclyl or a bridged heterocyclyl, optionally substituted by one or more selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, -(CRaRb)n-cycloalkyl-(NRcRd)r, heterocycloalkyl, cyanoalkyl, haloalkyl-C(O)- and _-CO2alkyl ; L is a bond, -(CRaRb)n-O-(CRcRd)r-, -(CRaRb)n-S-(CRcRd)r-, and -; R ₇ is hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, heterocyclyl, heteroaryl or -NRcRd, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, -(NRcRd)r, alkylOC(=O)N(R9) ₂ and haloalkenyl; Ra, Rb, Rc and Rd are independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; or Rc and Rd together with the atoms to which they are attached form a cycloalkyl group; Re is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; R ₉ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, or 2; i is 0, 1, or 2; and r is 0, 1, 2 or 3. 2. The compound according to claim 1, or a tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein ring A is a _C6 - _C10 aryl group or a 5-10 membered heteroaryl group and a 5-10 membered heterocyclic group. 3. The compound according to claim 1, or a tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: M ₁ is N; _R1 and _R2, together with the atoms to which they are attached, form a 9-14 membered spirocyclic heterocyclyl, a 9-14 membered fused heterocyclyl, a 9-14 membered bridged heterocyclyl or a 6-8 membered heterocyclyl, optionally substituted by one or more substituents selected from -(CRaRb) _nC3 - _{C6cycloalkyl-} (NRcRd)r, -( _C1 - _C6 )alkyl-(NRcRd)r, _-CO2alkyl . 4. The compound of claim 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the 9-14 membered fused heterocyclic group is a bicyclic or tricyclic ring, and the third ring is fused or bridged to the second ring. 5. The compound according to claim 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the 6-8 membered heterocyclic group comprises at least two heteroatoms selected from N, O, and is optionally substituted by one or more selected from -(CH ₂ ) n-(C ₃ -C ₆ ) cycloalkyl-N(CH ₃ ) ₂ , -(C ₁ -C ₆ ) alkyl-N(CH ₃ ) ₂ , -CO ₂ - The substituents are substituted with C ₁ -C ₆ -alkyl. 6. The compound according to claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ alkyl, C 1 -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C _{1 -C 6 alkoxy, C 1 -C 6} alkylthio, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₆ heterocyclyl, C ₃ -C ₈ cycloalkyl, C _{5 -C 10} heteroaryl, C ₅ -C ₁₀ aryl, C ₁ -C ₆ alkyl-C ₅ -C _{10 heteroaryloxo} , C ₁ -C ₈ alkylthio, -COOH and -CONH ₂ . 7. The compound according to claim 6, or a tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R ₄ and R ₆ are independently selected from hydrogen, fluorine, chlorine and bromine. 8. The compound according to claim 6, or a tautomer, a cis or trans isomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R ₃ , R ₅ is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropane, cyclobutane, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF ₂ , -CH ₂ CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CH ₂ CF ₃ , CH ₃ -thienyl, -S-CH ₃ . 9. The compound according to claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is a bond, -O( _{CRcRd ) r- , -S(CRcRd ) r-} and _NRe ( _CRcRd ) _r- . 10. The compound of claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is a bond, -O( _CRcRd ) _- , -S _{( CRcRd} )- and _NRe ( _{CRcRd )} -. 11. The compound according to claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is a bond, _-OCH2- , _-SCH2- and _-NHCH2- . 12. A compound according to any one of claims 1, 9, 10, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Ra, Rb, Rc, Rd and Re are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-C(O)-, -CO ₂ -C ₁ -C ₆ -alkyl; Or Rc and Rd together with the atoms to which they are attached form a C ₃ -C ₆ cycloalkyl group. 13. The compound according to claim 1, or a tautomer, a cis or trans isomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R ₇ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, _{C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -NR c R} d ; Rc and Rd are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkyl; Alternatively, R ₇ is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl, -N(RcRd), C ₁ -C ₆ alkylOC(＝O)N(R ₉ ) ₂ and C ₂ -C ₆ haloalkenyl; R ₉ is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl. 14. The compound according to claim 13, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R7 is H,

Optionally, one or more are selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl. 15. The compound according to claim 4, or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the 9-14 membered fused heterocyclic group is

in, _M2 is O, S, NRa or CRaRb; _M3 is independently selected from NRa, C(O) or CRaRb; _M4 is C, CH, N _X1 is CH or N; _X2 is CRaRb or NRa; _X3 is CH or N; R ₈ is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl; Alternatively, two R ₈ together with the atoms to which they are attached form a C ₆ -C ₈ cycloalkyl or a 5-8 membered heterocyclyl; Ra, Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C _{1 -C 6} hydroxyalkyl; p is 0, 1, or 2; q is 0, 1, 2, or 3; s is 0, 1, or 2; and t is 0, 1, 2, or 3. 16. The compound according to claim 5, or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the 6-8 membered heterocyclic group is

_M2 is O, S, NRa or CRaRb; _M3 is independently selected from NRa, C(O) or CRaRb; _M4 is C, CH, N _X1 is CH or N; R ₁₀ and R ₁₁ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ hydroxyalkyl, -(CRaRb)n-(C ₃ -C ₆ )cycloalkyl-n(CH ₃ ) ₂ , C ₁ -C ₄ alkyl-n(CH ₂ ) ₂ ; Preferably, R ₁₀ and R ₁₁ are independently selected from C ₃ -C ₆ cycloalkyl-N(CH ₃ ) ₂ , -CH ₂ -(C ₃ -C ₆ )cycloalkyl-N(CH ₃ ) ₂ , -(CH ₂ ) ₃ -(C ₃ -C ₄ )cycloalkyl-N-(CH ₃ ) ₂ , branched or linear C ₁ -C ₄ alkyl-N(CH ₃ ) ₂ ; More preferably, R10 and R11 are independently selected from

s is 0, 1 or 2; Ra, Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C _{1 -C 6} hydroxyalkyl; n is 0, 1 or 2. 17. A compound according to any one of claims 1 to 16, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is of formula (V-c-1), (V-d-1), (V-e-1), (V-c-2), (V-d-2), (V-e-2):

in, Ring A is

M is N or CR ₃ ; _M1 is N or CH; _M2 is O, S, NRa or CRaRb; M ₃ is CRaRb; _X1 is CH or N; Each of _X2 or _X4 is CRaRb or NRa; Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ haloalkyl-C(O)-, -CO ₂ -C ₁ -C ₆ alkyl, wherein the C ₁ -C ₃ alkyl is substituted with a substituent selected from cyano, halogen and a C ₃ -C ₆ heterocyclic group containing one or two heteroatoms selected from O, N and S; R ₄ is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl; _R3 and _R5 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _{C1 - C4} cyanoalkyl, C1 _{- C4} alkyl, C2- _C4 alkenyl, C2-C4 alkynyl, _C1 - _C4 alkoxy, _C1 - _C4 alkylthio, _{C1 - C4} haloalkyl and _C1 - _C4 hydroxyalkyl, _C3 - _C6 cycloalkyl, C1 _{- C3} alkyl- _C5 - _C8 heteroaryl containing one or _two heteroatoms selected from O, N, _S , oxo, -COOH and -CONH2; L is a bond, -OCH ₂ -, -SCH ₂ -, and -NHCH ₂ -; R ₇ is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, -N(CH ₃ ) ₂ , C ₁ -C ₃ alkyl-OC(═O)N(R ₉ ) ₂ , C ₁ -C ₃ haloalkenyl; R ₉ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl; m is 1, 2, 3 or 4; i is 0, 1, or 2; s is 0, 1 or 2; t is 0, 1, 2, or 3; and v is 1, 2, or 3; If ring A is

When R ₃ is Cl, X ₂ is NRa, and NRa is not

If ring A is

When R ₃ is neither F nor Cl;

no

18. The compound according to claim 17, or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is -OCH2-, _R7 is

Optionally, it is replaced by one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, -CH=CHF. 19. The compound according to claim 17, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is -OCH2-, R7 is

20. The compound according to claim 17, or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: Ring A is

21. The compound according to claim 17, or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein R ₅ is selected from hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropyl, cyclobutyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF ₂ , -CH ₂ F , -CCl ₃ , -CHCl ₂ , -CH ₂ Cl , -CBr ₃ , -CHBr ₂ , -CH ₂ Br, -CH ₂ CHCH ₂ CHF ₂ , -CH ₂ CHCH ₂ CF ₃ , CH ₃ -thienyl, -S-CH ₃ ; m is 0, 1, 2, or 3. 22. The compound according to claim 17, or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein R ₃ is hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropyl, cyclobutyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF ₂ ,-CH ₂ F,-CCl ₃ ,-CHCl ₂ ,-CH ₂ Cl,-CBr ₃ ,-CHBr ₂ ,-CH ₂ Br,-CH ₂ CHCHCHF, -CH ₂ CHCHCHF ₂ ,-CH ₂ CHCHCF ₃ .. 23. The compound according to claim 17, or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: X ₄ is CRaRb; Ra is hydrogen; Rb is hydrogen; and v is 2. 24. The compound according to claim 17, or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: _X2 is NRa; Ra is selected from hydrogen, deuterium, methyl, ethyl, methoxy _, ethynyl _{, -CH2CN} , _{-CH2CH2CN , -CF3} , _{-CHF2 , -CH2F , -CCl3} , _{-CHCl2 , -CH2Cl} , _{-CBr3 , -CHBr2 , -CH2Br , -CH2CH2CH2CH2F ,} -CH2CH2CH2CHF2 _{, -CH2CH2CH2CF3 , -CH2CH2CH2CN ,}

and CF ₃ —C(O)—; t is 1. 25. The compound according to claim 17, or its tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: M ₃ is -C(CH ₃ ) ₂ - or -C(CH ₂ )-; s is 1. 26. A compound according to any one of claims 17 to 26, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (V-c-3):

27. A compound according to any one of claims 1 to 26, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (V-f), (V-g):

in, Ring A and Ring B are independently selected from C ₆ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ heterocyclyl, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ heteroaryl; _M1 is N or CH; _M2 is O, S, NRa or CRaRb; M ₃ is CRaRb; _M4 is CH, _CH2 or N; _M5 is _CH2 or oxo (C=O); _X1 is CH or N; Each of _X2 or _X4 is CRaRb or NRa; R ₁₂ and R ₁₃ together with the carbon atoms to which they are attached form a C ₆ -C ₁₀ cycloalkyl group, a C 6 -C 10 heterocyclyl group, a C ₁ -C ₃ haloalkyl group and a C ₁ -C ₃ hydroxyalkyl group containing one or _more heteroatoms selected from N, _O and S; Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, C ₁ -C ₃ haloalkyl, -CO ₂ -C ₁ -C ₆ alkyl and C ₁ -C ₃ hydroxyalkyl; _R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C4 cyanoalkyl, _C1 - _C4 alkyl, C2- _C4 alkenyl, C2 _- C4 alkynyl, C1-C4 alkoxy, _{C1 - C4} alkylthio, _{C1 - C4} haloalkyl, C1 _{-C4 hydroxyalkyl, C3-C6 cycloalkyl, C1-C3 alkyl - C5 - C8 heteroaryl or oxo .} L is a bond, -OCH ₂ -, -SCH ₂ -, and -NHCH ₂ -; R ₇ is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, -N(CH ₃ ) 2, C ₁ -C ₃ alkylOC(═O)N(R ₉ ) ₂ , -CH═CHF; R ₉ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl; m is 1, 2, 3 or 4; i is 0, 1, or 2; s is 0, 1 or 2; t is 0, 1, 2, or 3; and v is 1, 2, or 3. 28. The compound according to claim 28, or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (V-f-1), (V-g-1):

29. A compound according to any one of claims 28 to 29, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Ring A is

30. A compound according to any one of claims 28-29, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Ring B is

31. A compound according to any one of claims 28-29, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R12 and R13 together with the carbon atom to which they are attached form a

32. A compound represented by formula (v-h), or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

in Ring A is

M is N or CR ₃ ; _M1 is N or CH; _M2 is O, S, NRa or CRaRb; M ₃ is CRaRb; _X1 is CH or N; Each of _X2 or _X4 is CRaRb or NRa; Ra and Rb are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ haloalkyl-C(O)-, -CO ₂ -C ₁ -C ₆ alkyl, wherein the C ₁ -C ₃ alkyl is substituted with cyano, halogen and a C ₃ -C ₆ heterocyclyl containing one or two heteroatoms selected from O, N, S; R ₄ is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl; _R3 and _R5 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, _C1 - _C4 cyanoalkyl, _C1 -C4 alkyl, C2- _C4 alkenyl, C2 _- C4 alkynyl, _C1 - _C4 alkoxy, _{C1 - C4} alkylthio, _C1 - _C4 haloalkyl, _C1 - _C4 hydroxyalkyl, _C3 - _C6 cycloalkyl, _C1 - _C3 alkyl- _C5 - _C8 heteroaryl containing one or _two heteroatoms selected from O, N, _S , oxo, -COOH and -CONH2; L is a bond, -OCH ₂ -, -SCH ₂ -, and -NHCH ₂ -; R ₇ is a 5-10 membered N-heterocyclyl or a 5-10 membered N-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ hydroxyalkyl, -N(CH ₃ ) ₂ , C ₁ -C ₃ alkyl-OC(═O)N(R ₉ ) ₂ , C 1 -C 3 haloalkenyl; R ₉ is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl; R ₁₄ is selected from deuterium, halogen, amino, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ hydroxyalkyl; m is 1, 2, 3 or 4; i is 0, 1, or 2; s is 0, 1 or 2; t is 0, 1, 2, or 3; w is 1, 2, or 3 v is 1, 2, or 3. 33. A compound according to claim 32, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (V-h-1):

34. A compound according to any one of claims 32-33, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is _-OCH2- ; _R7 is

It is further optionally substituted with one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, and -CH=CHF. 35. A compound according to any one of claims 32-33, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein L is _-OCH2- ; R7 is

36. A compound according to any one of claims 32-33, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R5 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropyl, cyclobutyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF 2 , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CBr ₃ , -CHBr ₂ , -CH ₂ Br _{, -CH 2 CHCHCHF 2} -, CH ₂ CHCHCF ₃ , CH ₃ -thienyl, -S-CH3; m is 0, 1, 2, or 3. R ₃ is hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, methoxy, methylthio, ethynyl, amino, cyano, ethyl, cyclopropyl, cyclobutyl, -CH ₂ CN, -CH ₂ CHCN, -CF ₃ , -CHF ₂ , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CBr ₃ , -CHBr ₂ , -CH ₂ Br, -CH ₂ Br, -CH ₂ CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CH ₂ CF ₃ ; X ₄ is CRaRb; Ra is hydrogen; Rb is hydrogen; _X2 is NRa; Ra is selected from hydrogen, deuterium, methyl, ethyl, methoxy, ethynyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CF ₃ , -CHF ₂ , -CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, -CBr ₃ , -CHBr ₂ , -CH ₂ Br, -CH ₂ CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ CN,

and CF ₃ -C(O)-,-CO ₂ tBu,-CO ₂ Me; M ₃ is -C(CH ₃ ) ₂ - or -C(CH ₂ )-; t is 1; v is 2; and s is 1. 37. The compound of claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is:

38. A prodrug of a compound according to claims 1-37, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the prodrug is:

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims 1 to 37, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier. 40. The pharmaceutical composition of claim 39, wherein the prodrug is as described in claim 38. 41. A method for treating a disease mediated by a KRAS mutation, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-38, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt solvate or prodrug thereof, or a pharmaceutical composition of claims 39-40. 42. The method of claim 42, wherein the KRAS mutation comprises a KRAS G12D, KRAS G12V, or KRASG13D mutation. 43. A method for treating cancer comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-38, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt solvate or prodrug thereof, or a pharmaceutical composition of claims 39-40.

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