WO2022170947A1 - Tetrahydronaphthyridine derivatives as kras mutant g12c inhibitors, preparation method therefor, and application thereof - Google Patents

Abstract

The present invention relates to the technical field of KRAS mutant G12C inhibitors, and specifically relates to tetrahydronaphthyridine derivatives as KRAS mutant G12C inhibitors, a preparation method therefor, and an application thereof. Specifically, the structure of each tetrahydronaphthyridine derivative is as shown in formula (I). Further provided is a novel tetrahydronaphthyridine derivative, having significant effects of inhabiting KRAS G12C activity and treating a cancer, wherein the cancer is preferably a lung cancer, a colorectal cancer, or a pancreatic cancer.

Description

A class of tetrahydronaphthyridine derivatives as KRAS mutant G12C inhibitors, preparation method and application thereof technical field

The invention belongs to the technical field of KRAS mutant G12C inhibitors, in particular to a tetrahydronaphthyridine derivative as a KRAS mutant G12C inhibitor, a preparation method and application thereof.

Background technique

The RAS gene is the first discovered human tumor gene. The RAS protein it encodes is a globular monomeric GTP-binding protein (MW=21kDa) distributed on the cytoplasmic side of the plasma membrane. inactive state. RAS proteins are activated by binding to GTP under the catalysis of guanine nucleotide exchange factor (GEF), while GTPase activating proteins (GAPs) catalyze the hydrolysis of RAS-bound GTP into a GDP-terminating active state to inhibit RAS activity. By cycling between active (GTP-bound) and inactive (GDP-bound) states, RAS proteins transduce upstream signals received from a variety of tyrosine kinases to downstream effectors to regulate cell proliferation, survival, migration, and processes such as apoptosis. Because RAS proteins are central to the axis of many important cellular signaling networks, and these signals are associated with multiple tumor markers, overactive RAS signaling may ultimately lead to tumorigenesis.

Among RAS family members, oncogenic mutations are most common in KRAS (85%), while NRAS (12%) and HRAS (3%) are less common, and KRAS mutations are common in pancreatic cancer, colorectal cancer, lung cancer, gallbladder cancer, And thyroid cancer, etc., the abnormal expression of KRAS accounts for up to 20% of all cancers, and 80% of KRAS mutations are missense mutations of a single amino acid substitution at codon 12. Among them, KRAS G12C mutation accounts for 12% of all KRAS mutations, but it has a higher proportion in lung cancer, especially non-small cell lung cancer (14%). Mutations in oncogenes, such as EGFR, ALK, and BRAF, are mutually exclusive, suggesting that KRAS mutations are unique in lung cancer and that they may serve as an important indicator of tumor prognosis.

Due to the protein structure of KRAS without obvious binding sites, after more than 30 years of research efforts by scientists, there is still no KRAS inhibitor with sufficient safety and efficacy in clinical practice. In recent years, breakthroughs in the study of covalent inhibitors of KRAS mutants have made it possible to target KRAS mutants through allosteric sites. In the KRAS G12C mutant, the small molecule covalently bound to the cysteine replaced by the missense mutation is more likely to bind to the GDP-binding KRAS protein to reduce the affinity of GTP to KRAS, while preventing GEF from catalyzing the replacement of GDP by GTP, Locking the KRAS G12C mutant in an inactive state. Using this strategy, AMG510 and MRTX-849 are currently in clinical studies ^1-2 . At the same time, various drug research and development companies continued to publish a number of patents, such as WO2019150305, WO2020106640, WO2020146613, WO2019215203, WO2020081282, and WO2020085493. Therefore, continuing to develop novel KRAS G12C inhibitors that can demonstrate efficacy, stability and safety in the treatment of KRAS G12C-mediated tumors is urgently needed and of great significance in the field of KRAS mutation-induced tumors.

references:

1. Lanman et al. Discovery of a Covalent Inhibitor of KRAS ^G12C (AMG510) for the Treatment of Solid Tumors. J. Med. Chem. 63, 52-65 (2020).

2. Fell et al.Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS ^G12C Inhibitor for the Treatment of Cancer.J.Med.Chem.63,6679-6693(2020).

SUMMARY OF THE INVENTION

In order to solve the above problems of the prior art, the object of the present invention is to provide a tetrahydronaphthyridine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof as a KRAS mutant G12C inhibitor isomers in order to screen out compounds with excellent properties in terms of efficacy, safety and selectivity as KRAS mutant G12C inhibitors.

Another object of the present invention is to provide a method for the preparation of the derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers.

In order to achieve this object of the invention, the present invention adopts the following technical solutions:

In a first aspect, the present invention provides a tetrahydronaphthyridine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, wherein the structure of the tetrahydronaphthyridine derivative is as follows Formula (I) shows:

in:

R ¹ is selected from H or F;

R ² is selected from 6-12-membered aryl or 5-12-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1-4 R ^c ;

R ^c is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl or 3-8 membered heterocycle group, wherein said alkyl, alkenyl, cycloalkyl, R ^a , R ^b or heterocyclyl is optionally substituted with 1-3 R ^c1 ;

R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;

R ^c1 is selected from halogen, hydroxy, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy.

L ¹ is selected from bond, O, S, NH or NCH ₃ ;

R ³ is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8-membered heterocyclic group, 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group cyclic group, 5-10-membered spiro heterocyclic group, 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl group, alkenyl group, cycloalkyl group, heterocyclic group, fused heterocyclic group Cyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl or heteroaryl may be optionally substituted with 1-4 R ^c2 .

R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ;

L ² is selected from C3-C8 cycloalkyl, C5-C10 spirocycloalkyl, C4-C10 fused cycloalkyl, C5-C10 bridged cycloalkyl, 3-8-membered heterocyclyl, 5-10-membered Condensed heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, 6-12-membered aryl group, 5-12-membered heteroaryl group, wherein the cycloalkyl, spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl, heteroaryl optionally surrounded by 1-4 R ^c replaced;

R ⁴ is selected from -C(O)R ^d or -S(O) ₂ R ^d ;

R ^d is selected from C2-C4 alkenyl or C2-C4 alkynyl, wherein the alkenyl and alkynyl can be optionally further substituted by 1-3 R ^d1 ;

R ^d1 is selected from halogen, cyano, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl is optionally replaced by 1- 3 R ^c substitutions;

The heteroatoms in the heterocyclic group and the heteroaryl group in the formula (I) are 1-4 and are selected from one or more of oxygen, nitrogen and sulfur.

Preferably, the structure of the tetrahydronaphthyridine derivatives is shown in formula (II):

wherein, R ¹ , R ² , R ³ , R ^c and L ¹ have the same defined ranges as above; n=0-4 (eg n=0, n=1, n=2, n=3, n=4 );

R ^e1 , R ^e2 or R ^e3 are independently selected from H, halogen, cyano, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclic group, and the above-mentioned alkyl, ring Alkyl or heterocyclyl is optionally substituted with 1-3 halogens, C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, hydroxy or amino;

The heteroatoms in the heterocyclic group are 1-3 one or more selected from oxygen, nitrogen and sulfur;

And/or, R ² is selected from 6-12-membered aryl or 5-12-membered heteroaryl, wherein said aryl or ^heteroaryl is optionally substituted by 1-4 R; wherein, R ^c is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl or 3-8 membered heterocycle group, wherein said alkyl, alkenyl, cycloalkyl, R ^a , R ^b or heterocyclyl is optionally substituted with 1-3 R ^c1 ;

R ^c1 is selected from halogen, hydroxyl, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy;

And/or, R ³ is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused heterocyclyl, 5-10 membered heterocyclyl Bridged heterocyclyl with 5-10 members, spiro heterocyclyl with 5-10 members, aryl with 6-12 members or heteroaryl with 5-12 members, wherein the alkyl, alkenyl, cycloalkyl, heterocycle base, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl or heteroaryl may be optionally substituted with 1-4 R ^c2 ;

R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ;

R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c 2 , when the R ^c 2 is 2-4, the R ^c 2 are the same or different;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ³ is a 4-8 membered heterocyclic group optionally substituted by 1-4 R ^c2 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different.

Preferably, the structure of the tetrahydronaphthyridine derivatives is shown in formula (III):

Wherein, R ¹ , R ³ , R ^e1 , R ^e2 , R ^e3 and L ¹ have the same limited range as above;

Preferably, for compounds of formula (III), wherein ^R is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused Heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered spiro heterocyclyl, 6-12-membered aryl or 5-12-membered heteroaryl, wherein the alkyl, alkenyl , cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl can be optionally replaced by 1-4 R replaced by ^c2 ;

R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ;

R ^c1 is selected from halogen, hydroxyl, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy;

R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c 2 , when the R ^c 2 is 2-4, the R ^c 2 are the same or different;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ³ is a 4-8 membered heterocyclic group optionally substituted by 1-4 R ^c2 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different.

Preferably, the structure of the tetrahydronaphthyridine derivatives is shown in formula (IV):

Wherein, R ³ , R ^e1 , R ^e2 , R ^e3 and L ¹ have the same limited range as above;

Preferably, for compounds of formula (IV), wherein ^R is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused Heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered spiro heterocyclyl, 6-12-membered aryl or 5-12-membered heteroaryl, wherein the alkyl, alkenyl , cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl can be optionally replaced by 1-4 R replaced by ^c2 ;

R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ;

R ^c1 is selected from halogen, hydroxyl, NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy;

R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c 2 , when the R ^c 2 is 2-4, the R ^c 2 are the same or different;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ³ is a 4-8 membered heterocyclic group optionally substituted by 1-4 R ^c2 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different.

Further preferably, the tetrahydronaphthyridine derivatives are selected from any one of the following structures:

In the second aspect, the present invention provides a preparation method of the tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as described in the first aspect, which are selected from From the following schemes:

The preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt, comprises the following steps:

Key intermediate (I-A) preparation method, method one:

In the first step, the compound of general formula (I-1) is reacted with ammonia methanol to obtain the compound of general formula (I-2);

In the second step, the compound of the general formula (I-2) and the compound of the general formula (I-3) are subjected to condensation reaction in the presence of a basic reagent and a condensing agent to obtain the compound of the general formula (I-4);

In the third step, under basic conditions, the compound of general formula (I-4) is ring-closed to obtain the compound of general formula (I-5);

The fourth step, the compound of general formula (I-5) under basic conditions, the 3-hydroxyl group is halogenated to obtain the compound of general formula (I-6);

In the fifth step, the compound of general formula (I-6) and the compound of general formula (I-7) are subjected to Mitsunobu reaction to obtain the compound of general formula (I-8);

In the sixth step, the compound of the general formula (I-8) is reacted with the compound of the general formula (I-9) to obtain the compound of the general formula (I-A).

Wherein, PG is Boc or Cbz; X is halogen, preferably bromine; R ¹ , R ³ , L ¹ , L ² have the same limited ranges as above; R ¹ is preferably cyano; L ¹ is preferably O.

Key intermediate (I-A) preparation method, method two:

In the first step, the compound of general formula (I-10) and monoethyl malonate are reacted under basic conditions to obtain the compound of general formula (I-11);

In the second step, under basic conditions of the compound of the general formula (I-11), the ring is closed to obtain the compound of the general formula (I-12);

In the third step, the compound of the general formula (I-12) is de-esterified to obtain the compound of the general formula (I-13) under acidic conditions;

In the fourth step, the compound of the general formula (I-13) is halogenated at the 2-position under basic conditions to obtain the compound of the general formula (I-14);

In the fifth step, the hydroxyl group of the compound of the general formula (I-14) is halogenated to obtain the compound of the general formula (I-15);

The 6th step, under the acid condition of the compound of general formula (I-15), obtains the compound of general formula (I-16);

In the seventh step, the compound of the general formula (I-16) and the compound of the general formula (I-7) are subjected to Mitsunobu reaction to obtain the compound of the general formula (I-17);

In the eighth step, the compound of the general formula (I-17) and the compound of the general formula (I-9) are subjected to Buchwald reaction under basic conditions, in the presence of a metal catalyst and a ligand, to obtain the compound of the general formula (I-18) ;

In the ninth step, the compound of the general formula (I-18) is subjected to a reduction reaction to obtain the compound of the general formula (I-A).

Wherein, X is halogen, preferably bromine; R ¹ , R ³ , L ¹ , L ² have the same limited ranges as above; R ¹ is preferably fluorine; L ¹ is preferably O.

Key intermediate (I-A) preparation method, method three:

In the first step, the compound of the general formula (I-2) is protected by a protective group under acid conditions to obtain the compound of the general formula (I-19);

In the second step, the compound of the general formula (I-19) is reacted with methyl malonate under basic conditions to obtain the compound of the general formula (I-20);

In the third step, under acidic conditions, the compound of general formula (I-20) is closed to obtain the compound of general formula (I-21);

The fourth step, the compound of general formula (I-21) is reacted with 4-methylbenzenesulfonyl chloride to obtain the compound of general formula (I-22) under basic conditions;

The fifth step, the compound of the general formula (I-22) and the compound of the general formula (I-9) obtain the compound of the general formula (I-23) under basic conditions;

In the sixth step, the compound of the general formula (I-23) is de-esterified and the protecting group is obtained to obtain the compound of the general formula (I-24);

The seventh step, the compound of general formula (I-24) is deprotected to obtain the compound of general formula (I-25);

In the eighth step, the compound of general formula (I-25) and the compound of general formula (I-7) are subjected to Mitsunobu reaction to obtain the compound of general formula (I-A).

Wherein, PG and PG ¹ are protecting groups; PG is preferably Boc or Cbz; PG ¹ is preferably PMB; X is halogen or OTs, preferably bromine; R ¹ , R ³ and L ¹ , L ² have the same definitions as above range; R ¹ is preferably hydrogen; L ¹ is preferably O.

General formula (I) preparation method:

In the first step, the compound of the general formula (I-A) and the compound of the general formula (I-B) are subjected to Buchwald reaction under basic conditions, in the presence of a metal catalyst and a ligand, to obtain the compound of the general formula (I-C);

In the second step, the compound of general formula (I-C) and the compound of general formula (I-D) are reacted under basic conditions to obtain the compound of general formula (I);

Wherein, R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² have the same limited range as the general formula (I); X is halogen or OTs, preferably bromine.

For the above preparation method, the reagent for providing alkaline conditions is selected from organic bases or inorganic bases, and the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine One or more of lithium amide, bis-trimethylsilyl amide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, One or more of potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;

The reagent for providing acidic conditions is one or more of hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrogen chloride solution in methanol, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid kind;

The metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl ₂ ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphonium palladium dichloride (Pd(PPh) ₃ ) one or more of Cl ₂ ) and tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ );

The ligands are 2-dicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1, One or more of 1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1 '-Binaphthalene-2,2'-bisdiphenylphosphine (BINAP);

The reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum tetrahydrogen;

The oxidant is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;

The above reaction is preferably carried out in a solvent, and the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.

In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof body;

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.

In the present invention, "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to animals or humans. The carrier can be liquid or solid.

In the present invention, the pharmaceutical composition contains a safe and effective amount (such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight) of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.

Or, the pharmaceutical composition of the present invention contains 0.001-99.9 wt %, more preferably 0.01-99 wt %, more preferably 0.1-90 wt % of the total weight of the compound represented by formula (I) or its pharmacy an acceptable salt; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100% by weight.

In another preferred example, the preferred ratio of the compound of formula (I) to a pharmaceutically acceptable carrier, excipient or sustained-release agent is that formula (I) as an active ingredient accounts for more than 65% of the total weight, and the rest accounts for The total weight ratio is 0.5-40%, or more preferably 1-20%, or more preferably 1-10%.

The various formulation forms of the pharmaceutical composition of the present invention, the unit dose of each dose comprises 0.05mg-500mg, preferably 0.5mg-200mg, more preferably 0.1mg-100mg of the compound of formula (I), enantiomer, external Racemates, pharmaceutically acceptable salts or mixtures thereof.

When the pharmaceutical composition contains additional active pharmaceutical ingredients for treating or preventing cancer, the amount of the active ingredients can generally be the conventional amount or lower in the prior art.

The pharmaceutical compositions of the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent middle. The pharmaceutical compositions of the present invention may also be stored in a suitable sterile device for injection or instillation. The pharmaceutical composition may also contain odorants, flavoring agents, and the like.

The compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) of the present invention can be clinically used in mammals (including humans) through oral, nasal, skin, lung or gastrointestinal routes of administration. The preferred route of administration is oral. The preferred daily dose is 0.5 mg to 200 mg/kg body weight, taken in one or divided doses. Regardless of the method of administration, the optimal dose for an individual should depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.

The effective dose of active ingredient employed may vary with the compound employed, the mode of administration, and the severity of the disease to be treated. Generally, however, satisfactory results are obtained when the compounds of the present invention are administered in doses of about 1-300 mg/kg of animal body weight per day, preferably in 1-3 divided doses per day, or in sustained release form Dosing. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg. Dosage forms suitable for oral administration contain about 1-200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced, as dictated by the exigencies of the therapeutic situation.

The compounds or pharmaceutically acceptable salts and compositions thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously. From the standpoint of ease of preparation and administration, the preferred pharmaceutical compositions are solid compositions, especially tablets and solid- or liquid-filled capsules. Oral administration of the pharmaceutical composition is preferred.

Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include: sterile water, polyethylene glycols, nonionic surfactants and edible oils (eg corn oil, peanut oil and sesame oil) as appropriate to the characteristics of the active ingredient and the particular mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, such as flavors, colors, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.

The active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as the free base or as a pharmaceutically acceptable salt) can also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, these forms must be sterile and must be fluid for easy syringe expelling. It must be stable under the conditions of manufacture and storage and must be resistant to the contaminating influence of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, alcohol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compound represented by formula (I) or its pharmaceutically acceptable salt and its composition can also be administered in combination with other active ingredients or drugs for treating or preventing chronic pain diseases. When two or more drugs are administered in combination, they generally have better effects than when the two drugs are administered separately.

In the fourth aspect, the present invention provides a tetrahydronaphthyridine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, or a tetrahydronaphthyridine derivative as described in the third aspect. Use of the pharmaceutical composition in the preparation of a medicament for the treatment of cancer;

The cancers described therein are, but are not limited to, astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, pancreatic cancer, Lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, kidney cancer and bile duct cancer; preferably lung cancer, pancreatic cancer or colorectal cancer.

In the fifth aspect, the present invention provides a tetrahydronaphthyridine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof or as described in the third aspect Application of the pharmaceutical composition in the preparation of KRAS mutant G12C inhibitor.

In a sixth aspect, the present invention provides a method for treating and/or preventing cancer, comprising administering to a human a therapeutically effective amount of the tetrahydronaphthyridine derivative as described in the first aspect, a pharmaceutically acceptable A salt, a tautomer or a stereoisomer thereof or a pharmaceutical composition as described in the third aspect.

Terminology Explanation

Unless stated to the contrary, some terms used in the specification and claims of the present invention are defined as follows:

"Alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted by one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, 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-di Methylbutyl etc. Alkyl groups can be optionally substituted or unsubstituted.

"Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is sp ² double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, specific examples of which include, but are not limited to, vinyl, allyl and alkene Butyl and so on. Alkenyl groups can be optionally substituted or unsubstituted.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups can be optionally substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:

"Fused cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

"Bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application, and are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic groups, wherein at least one ring atom atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl. The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl. Heterocyclyl groups can be optionally substituted or unsubstituted.

"Spiroheterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and single rings share one atom with each other, and the ring contains one or more double bonds, but no An aromatic system with fully conjugated pi electrons in one ring, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m heteroatoms, the remaining ring atoms are carbon, and m=1 or 2. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to:

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has complete Conjugated pi-electron aromatic systems in which one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m heteroatoms, the remaining ring atoms are carbon, and m=1 or 2. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to:

"Bridged heterocyclyl" refers to a 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron aromatic system, where one or more ring atoms are selected from nitrogen, oxygen, sulfur, or heteroatoms of S(O) _m , the remaining ring atoms are carbon, and m = 1 or 2. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. 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, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to:

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are _C6 - _C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups. Aryl groups can be substituted or unsubstituted. The "aryl" can be fused with a heteroaryl, a heterocyclyl or a cycloalkyl, wherein the parent structure is linked together by an aryl ring, non-limiting examples include but are not limited to:

"Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-diazolyl Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzo oxazolyl and benzisoxazolyl. Heteroaryl groups can be optionally substituted or unsubstituted. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

"Alkoxy" refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci _{- C6} alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

"Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

"Hydroxy" refers to the -OH group.

"Halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Benzyl" refers to _-CH2 -phenyl.

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

"Acetyl" refers to -C(O) _CH3 or Ac.

"Carboxylate" means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Optional" means that the event it describes can, but need not, occur. For example, the description "AR is optionally substituted with 1 to more ^Rc " includes instances where the AR group may be substituted with 1 to more ^Rc or not ^.

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

"Substituted" or "substituted" in this specification, unless otherwise specified, means that the group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R ^b , -OC(O)R ^b , -NR ^b R ^b , -C(O)NR ^b R ^b , -NR ^b C(O)R ^b , -S(O)NR ^b R ^b or -S(O) ₂ NR ^b R ^b , wherein R ^b is defined as in the general formula as described in (I).

The definitions and conventions of stereochemistry used in the present invention are generally referred to the following documents:

S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-HillBook Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York , 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part. Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation on the basis of their physicochemical differences. Enantiomers can be separated by converting a chiral mixture into a diastereomeric mixture by reaction with an appropriate optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride , the diastereomers are separated, and the individual diastereomers are converted to the corresponding pure enantiomers. The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. The atoms or groups of atoms of these stereoisomers are connected to each other in the same order, but their steric structures are different. A specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

"Tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions by migration of protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include interconversions that recombine bond electrons. Unless otherwise indicated, the structural formulas described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): such as R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are within the scope of the present invention.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention which are safe and effective when used in humans or animals. The salts of the compounds can be obtained by using a sufficient amount of base or acid in neat solution or in a suitable inert solution to obtain the corresponding addition salts. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc. Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, rice butenedioic acid, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, among others (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).

The invention provides a KRAS mutant G12C inhibitor with a new structure, and the test results show that the tetrahydronaphthyridine derivative exhibits excellent KRAS mutant G12C inhibitory activity, and at the same time exhibits excellent safety and selectivity, It can be used to prepare medicines for treating cancer, especially lung cancer, colorectal cancer or pancreatic cancer.

Description of drawings

Fig. 1 is a graph showing the effect of the compounds of the present invention on the KRAS/ERK1/2 signal transduction pathway of KRAS G12C mutant MIAPaCa-2 pancreatic cells.

Figure 2 is a graph showing the in vivo antitumor effect of the compounds of the present invention on KRAS G12C mutant MIAPaCa-2 pancreatic xenograft tumor nude mice model.

Figure 3 is a graph showing the effect of the compounds of the present invention on the body weight of mice in a nude mouse model of KRAS G12C mutant MIAPaCa-2 pancreatic xenograft tumor.

Detailed ways

The method of the present invention will be described below through specific examples, so as to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. In the following examples, the ¹ H NMR spectrum was measured with a Bruker instrument (400 MHz), and the chemical shifts were expressed in ppm. A tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, dd=doublet of doublet, dt=triplet of double peaks. When coupling constants are provided, they are in Hz.

The mass spectrum was measured by LC/MS, and the ionization mode was ESI.

HPLC model: Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5μm); Mobile phase: A: ACN, B: Water (0.1% H ₃ PO ₄ ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column oven: 35°C.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and various starting materials and reagents were obtained from commercially available or synthesized according to known methods without further purification. For direct use, unless otherwise specified, commercially available manufacturers include but are not limited to Sinopharm Group, Bailingwei Technology Co., Ltd., Tixiai (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd. and Shanghai Merrill Chemical Technology Co., Ltd. Wait.

CD ₃ OD: Deuterated methanol

CDCl ₃ : deuterated chloroform

DMSO-d ₆ : deuterated dimethyl sulfoxide

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

XantPhos: 4,5-Bisdiphenylphosphine-9,9-dimethylxanthene

XPhos: 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl

HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate

TLC: Thin Layer Chromatography

HPLC: High Performance Liquid Chromatography

purity: purity

&:and

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

There is no special description in the examples, and the solution in the reaction refers to an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C-30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound or the developing solvent system of the thin layer chromatography method includes: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added Adjustments such as acetic acid or triethylamine, etc.

Preparation of intermediates

Intermediate 1

1-Benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate IN-1

The first step 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate IN-1b

(R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate IN-1a (35 g, 0.16 mol) was dissolved in ethyl acetate (300 mL), water (300 mL) and hydrogen carbonate were added at room temperature Sodium (40.8 g, 0.49 mol) was cooled to 0 °C, benzyl chloroformate (41.4 g, 0.24 mol) was added, and the reaction was raised to room temperature overnight. TLC showed that the reaction was complete. The reaction solution was extracted and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound IN-1b (57 g, yield 100%).

LC-MS: m/z=251.2[M-Boc+H] ⁺

The second step 1-benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate IN-1c

Compound IN-1b (57 g, 0.16 mol) was dissolved in dichloromethane (400 mL), triethylamine (24.6 g, 0.24 mol) was added at room temperature, cooled to 0 °C, and methylsulfonyl chloride (22.4 g, 0.2 mol) was added. ), the reaction was raised to room temperature for 1 hour after the addition, and TLC showed that the reaction was complete. The reaction solution was added with water (200 mL), extracted and separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-1c (70 g, crude product), which was directly used in the next step.

The third step 1-benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate IN-1

Compound IN-1c (70 g, crude product) was dissolved in N,N-dimethylformamide (350 mL), potassium carbonate (45 g, 0.33 mol) and trimethylsilyl cyanide (32.3 g, 0.33 mol) were added at room temperature, The temperature was raised to 80°C for 5 hours, and TLC showed that the reaction was complete. The reaction solution was added with water (500 mL), extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound IN-1 (29.3 g, yield 50% for two steps).

LC-MS: m/z=304.2[M-tBu+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.42-7.31(m,5H), 5.17(s,2H), 4.55(br,1H), 4.20-3.88(m,3H), 3.20-3.09(m,2H) ), 2.86(br, 1H), 2.72-2.54(m, 2H), 1.48(s, 9H).

Intermediate 2

4-Bromo-3-fluoro-1,7-naphthyridin-2-ol IN-2

The first step 3-(3-ethoxy-3-oxopropionamido) isonicotinic acid methyl ester IN-2b

Methyl 3-amino-4-pyridinecarboxylate IN-2a (1.0 g, 6.57 mmol), monoethyl malonate (1.0 g, 7.88 mmol) and pyridine (1.6 g, 19.71 mmol) were dissolved in ethyl acetate ( 20 mL), 1-propyl phosphoric anhydride (6.4 g, 10.06 mmol, 50% N,N-dimethylformamide solution) was added, and the reaction was carried out at room temperature overnight, with a small amount of raw material remaining. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-2b (1.3 g, yield 74%).

The second step 2,4-dihydroxyquinoline-3-carboxylic acid ethyl ester IN-2c

Compound IN-2b (300 mg, 1.13 mmol) was dissolved in methanol (4 mL), sodium methoxide (122 mg, 2.25 mmol) was added at room temperature, and the temperature was raised to 70 °C for 3 hours. , 2.25 mmol), continued the reaction at 70°C overnight, and TLC showed that the reaction of the starting materials was complete. The reaction solution was concentrated, dissolved in water, and diluted hydrochloric acid (0.5 mL) was added dropwise to adjust the pH to 4-5. The solid was precipitated, filtered, and the filter cake was washed and dried to obtain the title compound IN-2c (180 mg, crude product), which was directly used in the next step.

The third step 1,7-naphthyridine-2,4-diol IN-2d

Compound IN-2c (2.0 g, crude product) was dissolved in hydrochloric acid (10 mL, 6N), and the reaction was heated under reflux overnight. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, and saturated aqueous sodium bicarbonate solution was added to adjust the pH of the system to 7, filtered, and the filter cake was washed and dried to obtain the title compound IN-2d (1.3 g, crude product), which was directly used in the next step.

LC-MS: m/z=163.1[M+H] ⁺

The fourth step 3-fluoro-1,7-naphthyridine-2,4-diol IN-2e

Compound IN-2d (50 mg, crude product) was dispersed in acetonitrile (3 mL), and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroboron) was added at room temperature acid salt) (330 mg, 0.93 mmol), the temperature was raised to 60° C. to react overnight, and TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-2e (25 mg, crude product), which was directly used in the next step.

The fifth step 2,4-dibromo-3-fluoro-1,7-naphthyridine IN-2f

Compound IN-2e (600 mg, crude product) was dispersed in phosphorus oxybromide (5 mL), and the temperature was raised to 120° C. to react overnight. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, ice water and sodium hydroxide solution (15%) were added, the pH of the system was adjusted to 8, filtered, and the filter cake was washed and dried to obtain the title compound IN-2f (800 mg, crude product), which was directly used in the next step.

The sixth step 4-bromo-3-fluoro-1,7 naphthyridin-2-ol IN-2

Compound IN-2f (800 mg, crude product) was dispersed in water (4.5 mL), 1,4-dioxane (3 mL) and hydrobromic acid (4.5 mL, 48%), and the temperature was raised to 80 °C for overnight reaction. TLC showed The reaction is complete. The reaction solution was cooled to room temperature, the pH of the system was adjusted to 7 with aqueous sodium hydroxide solution (15%), extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound IN-2 (580 mg , five-step yield 21%).

LC-MS: m/z=245.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ12.45(br,1H),8.70(s,1H),8.49(d,J=5.2Hz,2H),7.73(d,J=5.2Hz,1H)

Intermediate 3

7-Benzyl-1-(4-methoxybenzyl)-2-oxo-4-(toluenesulfonyloxy)-1,2,5,6,7,8-hexahydro-1,7 -Methyl naphthyridine-3-carboxylate IN-3

The first step 1-benzyl-5-((4-methoxybenzyl)amino)-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester IN-3b

Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate IN-3a (15.0 g, 57.40 mmol) was dissolved in methanol (150 mL), acetic acid (1.5 g, 24.98 mmol) and 4-methoxyl were added at room temperature Benzylamine (6.9 g, 50.30 mmol) was heated to 50° C. and reacted overnight. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3b (16.0 g, yield 73%).

LC-MS: m/z=381.3 [M+H] ⁺

The second step 1-benzyl-5-(3-methoxy-N-(4-methoxybenzyl)-3-oxopropionamido)-1,2,3,6-tetrahydropyridine- Ethyl 4-formate IN-3c

Compound IN-3b (8.0 g, 21.03 mmol) was dissolved in acetonitrile (80 mL), potassium carbonate (5.8 g, 41.97 mmol) and malonyl chloride methyl ester (4.3 g, 31.49 mmol) were added at room temperature, and the temperature was raised to 50 ° C The reaction was carried out overnight, and TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, the filter cake was washed, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3c (9.7 g, yield 96%).

LC-MS: m/z=481.3 [M+H] ⁺

The third step 7-benzyl-4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine -Methyl 3-carboxylate IN-3d

Compound IN-3c (10.0 g, 20.81 mmol) was dissolved in methanol (50 mL), sodium methoxide (2.2 g, 40.73 mmol) was added, and the reaction was carried out at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, diluted hydrochloric acid (2N) was added to adjust the pH of the system to 6, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether to obtain the title compound IN-3d (9.0 g, crude product), used directly in the next step.

LC-MS: m/z=435.2[M+H] ⁺

The fourth step 7-benzyl-1-(4-methoxybenzyl)-2-oxo-4-(toluenesulfonyloxy)-1,2,5,6,7,8-hexahydro- 1,7-Naphthyridine-3-carboxylic acid methyl ester IN-3

Compound IN-3d (2.0 g, 4.60 mmol) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (1.2 g, 9.29 mmol) and 4-methylbenzenesulfonyl chloride (1.05 g) were added , 5.51 mmol), reacted at room temperature for 2 hours, TLC showed that the reaction was complete. A small amount of water was added to the reaction solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3 (2.1 g, 75% yield in two steps).

¹ H NMR (400MHz, DMSO-d ₆ )δ7.85(d, J=8.4Hz, 2H), 7.55(d, J=8.0Hz, 2H), 7.31-7.26(m, 3H), 7.23-7.19( m, 2H), 6.97(d, J=8.8Hz, 2H), 6.82(d, J=8.8Hz, 2H), 5.08(s, 2H), 3.73(s, 3H), 3.57(s, 2H), 3.52(s, 5H), 2.51-2.49(m, 2H), 2.45(s, 3H), 2.38-2.28(m, 2H).

Intermediate 4

((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) )-based) methanol mixture IN-4

The first step 2-(2-(chloromethyl)allyl)-5-oxopyrrolidine-2-carboxylic acid ethyl ester IN-4b

(S)-ethyl 5-oxopyrrolidine-2-carboxylate IN-4a (300.0 g, 1.91 mol) and 3-chloro-2-chloromethylpropene (716.0 g, 5.73 mol) were added to tetrahydrofuran (2.0 L), cool down to -40°C, under nitrogen protection, slowly add lithium bis-trimethylsilyl amide (3.82L, 3.82mol, 1N) dropwise, complete the dropwise addition, continue stirring for 1.0 hours at -40°C, The reaction of the starting material was complete as monitored by TLC. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (1.0 L), extracted with ethyl acetate (1.5 L), the organic phases were combined, washed with saturated brine (1.0 L), dried over anhydrous sodium sulfate, concentrated, and the crude product was filtered through a silica gel column Analysis and purification gave the title compound IN-4b (303.0 g, 65% yield) as a yellow solid.

LC-MS: m/z=246.1 [M+H] ⁺ .

The second step 2-methylene-5-oxotetrahydro-1H-pyrroleazine-7a(5H)-ethyl formate IN-4c

Under nitrogen protection, sodium hydride (74.0 g, 1.85 mol, 60%) was added in batches to tetrahydrofuran (18 L) cooled to 0 °C, and then compound IN-4b (303.0 g, 1.23 mol) in tetrahydrofuran (3 L) was added dropwise After the dropwise addition of the mixed solution was completed, the temperature was raised to reflux for 6.0 hours, and the reaction of the raw materials was monitored by LCMS. The reaction solution was concentrated to (4.0 L), quenched by adding saturated aqueous ammonium chloride solution (3 L), extracted with ethyl acetate (2.0 L), the organic phases were combined, washed with saturated brine (3 L), and concentrated to obtain the title compound IN- 4c (140.0 g, 54% yield).

LC-MS: m/z=210.2[M+H] ⁺ .

The third step 2,5-Dioxytetrahydro-1H-pyrroleazine-7a(5H)-ethyl formate IN-4d

Compound IN-4c (140.0 g, 0.67 mol) was dissolved in a mixture of acetone/water (v/v=2/1; 4.0 L), and an aqueous solution of potassium osmate dihydrate (1.2 g, 3.25 mmol) was added at room temperature, Continue stirring for 30 minutes, cool to 0° C., add potassium periodate (572.0 g, 2.67 mol) in batches, complete the addition, slowly rise to room temperature and continue stirring for 1 hour, TLC monitoring the reaction of the raw materials is complete. The reaction solution was filtered, water (2.5L) and dichloromethane (2.5L) were added to the filtrate, the layers were separated, the aqueous phase was extracted with dichloromethane (2.0L), the organic phases were combined, washed with saturated brine (2.5L), and anhydrous sulfuric acid It was dried over sodium, concentrated, and the crude product was purified by silica gel column chromatography to give the title compound IN-4d (68.6 g, 49% yield) as a brown oil.

LC-MS: m/z=212.1[M+H] ⁺ .

The fourth step (2R,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrroleazine-7a(5H)-ethyl formate and (2S,7aS)-2-hydroxy-5-oxotetrahydro -1H-Pyrrozine-7a(5H)-ethyl formate mixture IN-4e

Compound IN-4d (68.6 g, 0.32 mol) was dissolved in methanol (1.0 L), cooled to 0 °C in an ice-water bath, sodium borohydride (3.08 g, 81.19 mmol) was added in batches, and the reaction was continued at 0 °C for 1.0 hour. The reaction of the starting material was complete as monitored by TLC. Water (20 mL) was added and stirred for 1.0 h, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain yellow oily trans-configuration impurities and yellow oily title compound IN-4e (32.8 g, yield 47%).

LC-MS: m/z=214.1[M+H] ⁺ .

The fifth step (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-ethyl formate and (2S,7aR)-2-fluoro-5-oxotetrahydro -1H-Pyrrozine-7a(5H)-ethyl formate mixture IN-4f

Compound IN-4e (32.8 g, 0.15 mol) was dissolved in dichloromethane (800 mL), and under nitrogen protection, the temperature was lowered to -60 °C and diethylaminosulfur trifluoride (37.2 g, 0.23 mmol) was slowly added dropwise. Chloromethane (200 mL) solution was added dropwise and then warmed to room temperature and reacted overnight. TLC monitored the reaction of the raw materials, quenched by adding methanol (200 mL), concentrated, and the crude product was purified by silica gel column chromatography to give the title compound IN-4f (18.8 g, yield 57%).

LC-MS: m/z=216.1 [M+H] ⁺ .

The sixth step ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl)methanol mixture IN-4

Under nitrogen protection, lithium aluminum hydride (9.95g, 0.26mol) was added to tetrahydrofuran (200ml), cooled to 0°C in an ice-water bath, compound IN-4f (18.8g, 87.35mmol) was added dropwise and dissolved in tetrahydrofuran (30mL) solution, After dripping, the temperature was raised to reflux for 4.5 hours. The reaction of the raw materials was monitored by LCMS, cooled to 0°C, and water (10 mL), sodium hydroxide (15%, 10 mL), and water (30 mL) were slowly added dropwise successively, and stirred for 30 minutes. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-4f (6.8 g, yield 49%) as pale yellow oil.

¹ H NMR (400MHz, CDCl ₃ ) δ 5.29-5.24(m, 0.5H), 5.15-5.10(m, 0.5H), 3.27(s, 2H), 3.27-3.10(m, 1H), 3.09-2.97 (m,2H),2.96-2.88(m,1H),2.18-2.20(m,2H),1.96-1.82(m,2H),1.82-1.70(m,2H).

Example 1

2-((S)-1-Acryloyl-4-(7-(8-chloronaphthalen-1-yl)-3-fluoro-2-(((S)-1-methylpyrrolidin-2-yl )methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 1

The first step (S)-benzyl 2-(cyanomethyl)piperazine-1-carboxylate 1a

Intermediate IN-1 (10 g, 27.82 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (15 mL) was added, and the reaction was performed at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1a (6.5 g, crude product), which was directly used in the next step.

The second step (S)-4-bromo-3-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,7-naphthyridine 1b

Intermediate IN-2 (300mg, 1.24mmol), compound (S)-(1-methylpyrrolidin-2-yl)methanol (284mg, 2.47mmol) and triphenylphosphine (1.3g, 4.96mmol) were added successively In the three-necked flask, under nitrogen protection, tetrahydrofuran (8 mL) was added, cooled to 0° C., and diisopropyl azodicarboxylate (998 mg, 4.94 mmol) was added, and the reaction was raised to room temperature overnight after the addition, and TLC showed that the raw materials were consumed. The reaction solution was concentrated, and the crude product was purified by silica gel column to obtain the title compound 1b (220 mg, yield 52%).

The third step (S)-2-(cyanomethyl)-4-(3-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,7 -Naphthyridin-4-yl)piperazine-1-carboxylate benzyl ester 1c

Compound 1b (500 mg, 1.47 mmol), compound 1a (762 mg, 2.94 mmol), Pd ₂ (dba) ₃ (296 mg, 0.29 mmol), Xantphos (340 mg, 0.59 mmol) and cesium carbonate (1.2 g, 3.69 mmol) were added sequentially In the three-necked flask, under nitrogen protection, toluene (20 mL) was added, and the reaction was heated under reflux for 24 hours. The reaction solution was cooled to room temperature, concentrated to remove the solvent, and the crude product was purified by silica gel column to obtain the title compound 1c (150 mg, yield 20%).

LC-MS: m/z=519.3[M+H] ⁺

The fourth step (S)-2-(cyanomethyl)-4-(3-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6 ,7,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate benzyl ester 1d

Compound 1c (150 mg, 0.29 mmol) was dissolved in acetic acid (2 mL), sodium borohydride (150 mg, 3.95 mmol) was added, and the reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated, a small amount of sodium bicarbonate and dichloromethane were added to the crude product, stirred, filtered, the filtrate was concentrated, and the crude product was purified by silica gel column to obtain the title compound 1d (100 mg, yield 66%).

The fifth step (S)-4-(7-(8-chloronaphthalene-1-yl)-3-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) -5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester 1e

Compound 1d (100 mg, 0.19 mmol), compound 1-bromo-8-chloronaphthalene (94 mg, 0.38 mmol), Pd ₂ (dba) ₃ (35 mg, 0.04 mmol), Xantphos (44.3 mg, 0.08 mmol) and cesium carbonate ( 187 mg, 0.57 mmol) were successively added to the three-necked flask, and under nitrogen protection, toluene (6 mL) was added, and the reaction was heated under reflux for 4 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated to remove the solvent, and the crude product was purified by silica gel column to obtain the title compound 1e (60 mg, yield 46%).

The sixth step 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-3-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methane oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 1f

Compound 1e (60 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, boron tribromide (220 mg, 0.88 mmol) was added, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was filtered, the filter cake was washed with dichloromethane, and dried to obtain the title compound 1f (60 mg, crude product), which was directly used in the next step.

The seventh step 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-3-fluoro-2-(((S)-1-methylpyrrolidine- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 1

Compound 1f (30 mg, crude product) was dissolved in dichloromethane (2 mL), sodium bicarbonate (46 mg, 0.55 mmol) and water (2 mL) were added at room temperature, cooled to 0 °C, and acryloyl chloride (2.5 mg, 0.03 mmol) was added. , 0 °C for 30 minutes. The reaction solution was extracted and separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-HPLC to obtain the title compound 1 (4.5 mg, two-step yield 9%).

LC-MS: m/z=603.3[M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 (d, J=8.0 Hz, 1H), 7.69-7.64 (m, 1H), 7.53-7.46 (m, 2H), 7.39-7.31 (m, 2H) ,7.00-6.71(m,1H),6.28(d,J=16.8Hz,1H),5.82(d,J=10.0Hz,1H),5.14-5.11(m,0.5H),4.80-4.64(m, 2H), 4.59-4.38(m, 1H), 4.38-4.20(m, 1H), 4.15-3.98(m, 0.5H), 3.87-3.72(m, 2H), 3.70-3.51(m, 4H), 3.25 -3.12(m, 4H), 3.01(s, 3H), 2.81-2.72(m, 1H), 2.45-2.24(m, 1H), 2.23-1.70(m, 4H), 1.52-1.45(m, 1H) ,1.37-1.17(m,2H).(96.18%purity by HPLC)

Example 2

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-3-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) -5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 2

Compound 1f (30 mg, 0.056 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-fluoroacrylic acid (10 mg, 0.11 mmol), N,N-diisopropylethylamine ( 21 mg, 0.16 mmol) and HATU (31 mg, 0.08 mmol) were reacted at room temperature for 1.5 hours, and TLC showed that the reaction was complete. The reaction solution was quenched by adding a small amount of water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 2 (3.5 mg, yield 10%).

LC-MS: m/z=621.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.74-7.70 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.36 (m, 2H), 7.29-7.21 (m, 2H), 5.31- 5.08(m, 4H), 4.59-4.51(m, 4H), 4.39-4.25(m, 1H), 4.19(d, J=16.4Hz, 1H), 3.73-3.62(m, 1H), 3.57-3.49( m, 3H), 3.14-2.82 (m, 6H), 2.79 (s, 3H), 2.11-2.07 (m, 2H), 1.95-1.90 (m, 4H). (96.78% purity by HPLC)

Example 3

2-((S)-1-Acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )-5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 3

The first step (S)-7-benzyl-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-1-(4-methoxy Benzyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxylic acid methyl ester 3a

Intermediate IN-3 (200 mg, 0.33 mmol) was dissolved in acetonitrile (3 mL), N,N-diisopropylethylamine (132 mg, 1.02 mmol) and compound 1a (176 mg, 0.68 mmol) were added at room temperature, and the temperature was increased to The reaction was carried out at 80°C overnight, and LCMS indicated that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3a (137 mg, yield 60%).

LC-MS: m/z=676.3 [M+H] ⁺

The second step (S)-4-(7-benzyl-2-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl) tert-Butyl piperazine-1-carboxylate 3b

Compound 3a (400 mg, 0.59 mmol) was dissolved in methanol (2 mL), hydrochloric acid (6 mL, 4N) was added at room temperature, the temperature was raised to 100° C. and reacted for 20 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, dichloromethane (10 mL) was added to dissolve, triethylamine (1 mL) and di-tert-butyl dicarbonate (1 mL) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3b (105 mg, yield 38%).

LC-MS: m/z=464.3[M+H] ⁺

The third step (S)-2-(cyanomethyl)-4-(2-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 3c

Compound 3b (100 mg, 0.22 mmol) was dispersed in methanol (10 mL), ammonium formate (82 mg, 1.30 mmol) and palladium/carbon (35 mg, 10%) were added at room temperature, and the temperature was raised to 60 °C for 5 hours. TLC showed that the reaction was complete. . The reaction solution was filtered through a pad of celite, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3c (55 mg, yield 68%).

The fourth step (S)-4-(4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-hydroxy-5,8-dihydro-1,7- Naphthyridine-7(6H)-benzylcarboxylate 3d

Compound 3c (55 mg, 0.15 mmol) was dispersed in dichloromethane (2 mL), triethylamine (30 mg, 0.30 mmol) and benzyl chloroformate (25.1 mg, 0.15 mmol) were added, and the reaction was carried out at room temperature for 3 hours. TLC showed that the reaction was complete. . A small amount of water was added to the reaction solution, extracted and separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3d (48 mg, yield 64%).

The fifth step 4-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidine- 2-yl)methoxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate benzyl ester 3e

Compound 3d (48mg, 0.09mmol), compound (S)-(1-methylpyrrolidin-2-yl)methanol (32.7mg, 0.28mmol) and triphenylphosphine (99.3mg, 0.38mmol) were added to the there-necked flask successively Under nitrogen protection, tetrahydrofuran (5 mL) was added, cooled to 0°C, diisopropyl azodicarboxylate (76.6 mg, 0.38 mmol) was added, and the reaction was raised to room temperature overnight. TLC showed that the starting material was consumed. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3e (50 mg, yield 87%).

LC-MS: m/z=605.4[M+H] ⁺

The sixth step (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8 -Tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate tert-butyl ester 3f

Compound 3e (50 mg, 0.08 mmol) was dissolved in methanol (5 mL), palladium/carbon (45 mg, 10%) was added, and the reaction was carried out at room temperature for 3 hours under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound 3f (25 mg, crude product), which was directly used in the next step.

The seventh step (S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6 ,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester 3g

Compound 3f (25 mg, crude), 1-bromo-8-chloronaphthol (26 mg, 0.11 mmol), Pd ₂ (dba) ₃ (10 mg, 0.11 mmol), Xantphos (12.3 mg, 0.02 mmol) and cesium carbonate (52 mg , 0.16mmol) was added into the three-necked flask in turn, under nitrogen protection, toluene (6mL) was added, the reaction was refluxed for 4 hours, and TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, and the crude product was purified by silica gel column chromatography to obtain 3 g of the title compound (15 mg, 29% yield in two steps).

LC-MS: m/z=631.3[M+H] ⁺

The eighth step 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 3h

Compound 3 g (15 mg, 0.02 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 3h (10 mg, crude product), which was directly used in the next step.

The ninth step 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) Methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 3

Compound 3h (10 mg, crude product) was dissolved in dichloromethane (3 mL), water (3 mL), sodium bicarbonate (24 mg, 0.28 mmol) and acryloyl chloride (1.5 mg, 0.02 mmol) were sequentially added at room temperature, and stirred at room temperature for 10 minutes , TLC showed that the reaction was complete. The reaction solution was extracted and separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-HPLC to obtain the formate salt of the title compound 3 (5 mg, two-step yield 24%).

LC-MS: m/z=585.3 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.90 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.62-7.49 (m, 2H), 7.46-7.42 ( m,1H),7.40-7.30(m,1H),6.98-6.72(m,1H),6.29-6.10(m,2H),5.78(dd,J=2.0,10.4Hz,1H),5.11-4.65( m,1H),4.54-4.35(m,1H),4.28-4.14(m,2H),4.09-3.97(m,1H),3.80(dd,J=4.4,15.6Hz,1H),3.60-3.48( m, 4H), 3.18-2.89(m, 7H), 2.83-2.65(m, 2H), 2.32(s, 3H), 2.20-2.11(m, 1H), 1.95-1.85(m, 1H), 1.74- 1.49(m,3H).(86.78%purity by HPLC)

Example 4

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6 ,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 4

Compound 3h (35 mg, 0.066 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-fluoroacrylic acid (10 mg, 0.11 mmol), N,N-diisopropylethylamine (21 mg) were added successively at room temperature , 0.16 mmol) and HATU (38 mg, 0.10 mmol), reacted at room temperature for 1.5 hours, TLC showed that the reaction was complete. The reaction solution was quenched by adding a small amount of water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 4 (4.0 mg, yield 10%) .

LC-MS: m/z=603.3[M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 7.85-7.78 (m, 1H), 7.66 (dd, J=2.4, 8.0 Hz, 1H), 7.53-7.45 (m, 2H), 7.40-7.30 (m, 2H), 6.40(d, J＝16.8Hz, 1H), 5.42-5.19(m, 2H), 4.65-4.51(m, 2H), 4.46-4.33(m, 2H), 3.83-3.75(m, 1H) ,3.70-3.43(m,6H),3.30-3.11(m,4H),3.10-2.97(m,2H),2.94-2.63(m,6H),2.33-2.23(m,1H),2.15-2.04( m,1H),2.04-1.88(m,2H).(91.98%purity by HPLC)

Example 5

(S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6 ,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 5

The first step 1-(tert-butyl)2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylic acid 2-methyl ester 5b

Boc-proline methyl ester 5a (5.0 g, 21.81 mmol) was dissolved in dry tetrahydrofuran (20 mL), and under nitrogen protection, the temperature was lowered to -65 °C, and bistrimethylsilylamine was slowly added to a constant pressure dropping funnel Lithium (32 mL, 32 mmol, 1M tetrahydrofuran solution), after adding -65 ° C for 1 hour, slowly adding 1-bromo-3-chloropropane (17 g, 109.2 mmol), slowly warming to room temperature after the addition and reacting for 2 hours, TLC Shows that the reaction is complete. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5b (5.1 g, yield 80%) as a yellow liquid.

LC-MS: m/z=250.1[M-tBu+H] ⁺

The second step 2-(3-chloropropyl) pyrrolidine-2-carboxylic acid methyl ester 5c

Compound 5b (4.1 g, 13.41 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (6 mL) was slowly added at room temperature, and the reaction was completed at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 5c (3.5 g, crude product) as a yellow viscous liquid, which was directly used in the next step.

The third step Tetrahydro-1H-pyrroleazine-7a(5H)-methyl formate 5d

Compound 5c (3.5 g, crude product) was dissolved in methanol (20 mL), potassium iodide (232 mg, 1.40 mmol) and potassium carbonate (5.7 g, 41.23 mmol) were added successively, and the reaction was carried out at room temperature for 2 hours, and the system gradually changed from a yellow transparent liquid to White cloudy liquid, TLC showed the reaction was complete. The reaction solution was concentrated, the residue was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5d (2.0 g, two step yield 88%).

LC-MS: m/z=170.2 [M+H] ⁺ .

The fourth step (tetrahydro-1H-pyrroleazine-7a(5H)-yl) methanol 5e

Compound 5d (2.0 g, 11.82 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0° C., slowly added aluminum lithium hydride (1.3 g, 34.26 mmol), and reacted at room temperature for 3 hours. TLC showed that the reaction was complete. The reaction solution was quenched by adding water (1.3 mL), stirred at room temperature for 0.5 hours, filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5e (1.3 g, yield 78%) as a yellow viscous liquid.

LC-MS: m/z=142.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ4.37(br,1H), 3.04(s,2H), 2.86-2.81(m,2H), 2.49-2.44(m,2H), 1.81-1.69( m,4H),1.65-1.57(m,2H),1.40-1.35(m,2H).

The fifth step (S)-4-(4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazine-1-yl)-2-((tetrahydro-1H-pyrroleazine-7a(5H )-yl)methoxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate benzyl ester 5f

Compound 3d (100 mg, 0.20 mmol), compound 5e (84 mg, 0.59 mmol) and triphenylphosphine (207 mg, 0.79 mmol) were successively added to the there-necked flask, under nitrogen protection, tetrahydrofuran (5 mL) was added, cooled to 0° C., added Diisopropyl azodicarboxylate (160 mg, 0.79 mmol) was added and warmed to room temperature overnight. TLC showed that the starting material was consumed. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5f (100 mg, yield 80%).

The sixth step (S)-2-(cyanomethyl)-4-(2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8 -Tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate 5g

Compound 5f (100 mg, 0.16 mmol) was dissolved in methanol (10 mL), palladium/carbon (60 mg, 10%) was added, and the reaction was carried out at room temperature for 3 hours under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound 5g (90 mg, crude product), which was directly used in the next step.

The seventh step (S)-4-(7-(8-chloronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6 ,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester 5h

Compound 5g (90mg, crude product), 1-bromo-8-chloronaphthol (133mg, 0.54mmol), Pd2(dba _{)3 (} 50mg, 0.05mmol), Xantphos (63mg, 0.11mmol) and cesium carbonate (236mg, 0.72 mmol) was successively added to the three-necked flask, under nitrogen protection, toluene (10 mL) was added, and the reaction was heated under reflux for 4 hours, and TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, and the crude product was purified by silica gel column chromatography to obtain the title compound 5h (100 mg, two-step yield 77%).

LC-MS: m/z=657.4[M+H] ⁺

The eighth step (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- 5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 5i

Compound 5h (100 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, the crude product was added with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5i (30 mg, yield 35%) .

LC-MS: m/z=557.3 [M+H] ⁺

The ninth step (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- 5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 5

Compound 5i (30mg, 0.05mmol) was dissolved in N,N-dimethylformamide (2mL), 2-fluoroacrylic acid (7.3mg, 0.08mmol), N,N-diisopropylethylamine were added at room temperature in sequence (21 mg, 0.16 mmol) and HATU (31 mg, 0.08 mmol) were reacted at room temperature for 1.5 hours, and TLC showed that the reaction was complete. A small amount of water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5 (9.0 mg, yield 27%).

LC-MS: m/z=629.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.93(d, J=8.0H _Z , 1H), 7.74(d, J=8.0H _Z , 1H), 7.62-7.50(m, 2H), 7.46 ( t,J=7.6H _Z ,1H),7.34(t,J=6.8H _Z ,1H),6.30(d,J=18.4H _Z ,1H),5.46-5.37(m,1H),5.37-5.20( m, 1H), 4.24(d, J＝17.2H _Z , 1H), 4.10(s, 2H), 3.91-3.65(m, 2H), 3.59-3.39(m, 4H), 3.25-2.94(m, 7H) ), 2.93-2.62 (m, 4H), 2.05-1.67 (m, 9H). (92.58% purity by HPLC)

Example 6

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-3-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidine- 3-yl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 6

The first step (3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-carboxylate tert-butyl ester 6b-1&(3S,4S)-3-hydroxy-4-methoxypyrrolidine-1- tert-Butyl formate 6b-2

3-N-tert-butoxycarbonyl-6-oxa-3-azabicyclo[3.1.0]hexane 6a (10.6 g, 57.2 mmol) was dissolved in methanol (50 mL), and sodium methoxide ( 3.71 g, 68.7 mmol), the temperature was raised to 60° C. for 5 hours, and the reaction of the raw materials was monitored by TLC for completeness. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 6b (8.0 g, yield) as a white solid. 65%). Compound 6b (6.0g) was subjected to chiral resolution (LC016-1, 21.2*250mm, 5um, 20mL/min, EtOH:Hexane=5:95) to obtain compound 6b-2 (peak 1, RT 10.62min) (1.8g , yield 77%) and compound 6b-1 (peak No. 2, RT 13.01 min) (2.3 g, yield 60%).

The second step (3R,4R)-4-methoxy-1-methylpyrrolidin-3-ol 6c-1

Lithium aluminum hydride (595 mg, 15.6 mmol) was dispersed in dry tetrahydrofuran (30 mL), cooled to 0 °C, and a solution of 6b-1 (1.7 g, 7.8 mmol) in tetrahydrofuran (15 mL) was added dropwise under nitrogen protection. After completion, the temperature was raised to 50° C. to react for 2 hours, and the reaction of the raw materials was monitored by TLC. The reaction solution was cooled to room temperature, quenched by adding water (0.6 mL), 15% sodium hydroxide solution (0.6 mL) and water (1.8 mL) successively, filtered, and the filtrate was concentrated to give the title compound 6c-1 (1.0 g, crude product), used directly in the next step.

¹ H NMR (400MHz, DMSO-d ₆ )δ5.02(s,1H), 3.93(s,1H), 3.55-3.52(m,1H), 3.22(s,3H), 2.71-2.64(m,2H) ), 2.34(dd, J=3.6, 9.6Hz, 1H), 2.21(dd, J=4.8, 9.6Hz, 1H), 2.16(s, 3H).

The third step 4-bromo-3-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-1,7-naphthyridine 6d

Intermediate IN-2 (500mg, 2.07mmol), compound 6c-1 (405mg, 3.09mmol) and triphenylphosphine (1.6g, 6.1mmol) were added to the there-necked flask successively, under nitrogen protection, tetrahydrofuran (15mL) was added, Cool to 0° C., add diisopropyl azodicarboxylate (1.2 g, 5.93 mmol), complete the addition and warm to room temperature to react overnight, and TLC shows that the reaction is complete. The reaction solution was concentrated, and the crude product was purified by silica gel column to obtain the title compound 6d (350 mg, yield 48%).

LC-MS: m/z=358.1[M+H] ⁺

The fourth step (S)-2-(cyanomethyl)-4-(3-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl) oxy)-1,7-naphthyridin-4-yl)piperazine-1-carboxylic acid benzyl ester 6e

Compound 6d (350 mg, 0.98 mmol), compound 1a (510 mg, 1.97 mmol), Pd ₂ (dba) ₃ (270 mg, 0.29 mmol), Xantphos (341 mg, 0.59 mmol) and cesium carbonate (958 mg, 2.9 mmol) were added to three ports in turn In the bottle, under nitrogen protection, toluene (20 mL) was added, and the reaction was heated under reflux for 24 hours. The reaction solution was cooled to room temperature, concentrated to remove the solvent, and the crude product was purified by silica gel column to obtain the title compound 6e (150 mg, yield 29%).

LC-MS: m/z=535.3 [M+H] ⁺

The fifth step (S)-2-(cyanomethyl)-4-(3-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl) oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylic acid benzyl ester 6f

Compound 6e (150 mg, 0.28 mmol) was dissolved in acetic acid (2 mL), sodium borohydride (53 mg, 1.39 mmol) was added, and the reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated, a small amount of sodium bicarbonate was added, dichloromethane was added, filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated, and the crude product was purified by silica gel column to obtain the title compound 6f (80 mg, yield 53%).

LC-MS: m/z=539.3[M+H] ⁺

The sixth step (S)-4-(7-(8-chloronaphthalen-1-yl)-3-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidine- 3-yl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester 6g

Compound 6f (80 mg, 0.15 mmol), compound 1-bromo-8-chloronaphthalene (110 mg, 0.45 mmol), Pd ₂ (dba) ₃ (41 mg, 0.04 mmol), Xantphos (51.6 mg, 0.09 mmol) and cesium carbonate ( 193 mg, 0.59 mmol) were successively added to the three-necked flask, and under nitrogen protection, toluene (15 mL) was added, and the reaction was heated under reflux for 4 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, and the crude product was purified by silica gel column to obtain the title compound 6g (60mg, yield 58%).

LC-MS: m/z=699.3[M+H] ⁺

The seventh step 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-3-fluoro-2-(((3R,4R)-4-methoxy-1-methyl Pyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 6h

Compound 6g (60 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), cooled to 0° C., added boron tribromide (215 mg, 0.86 mmol), and reacted at 0° C. for 1 hour. The reaction solution was filtered, and the filter cake was washed with dichloromethane and dried to obtain the title compound 6h (25 mg, crude product), which was directly used in the next step.

LC-MS: m/z=565.3[M+H] ⁺

The eighth step 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-3-fluoro-2-(((3R,4R)-4-methoxy-1-methyl Pyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl) Acetonitrile 6

Compound 6h (25 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), 2-fluoroacrylic acid (8.0 mg, 0.09 mmol), N,N-diisopropylethylamine ( 17 mg, 0.13 mmol) and HATU (25 mg, 0.066 mmol) were reacted at room temperature for 1.5 hours, and TLC showed that the reaction was complete. A small amount of water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 6 (5.0 mg, yield 18%).

LC-MS: m/z=637.3[M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 (d, J=8.4 Hz, 1H), 7.74-7.59 (m, 2H), 7.56-7.42 (m, 2H), 7.41-7.25 (m, 2H) ,5.40-5.22(m,3H),4.31-4.20(m,2H),4.05-4.00(m,1H),3.84-3.69(m,1H),3.66-3.57(m,2H),3.38(d, J=8.4Hz, 3H), 3.27-2.99(m, 8H), 2.95-2.90(m, 1H), 2.78-2.69(m, 1H), 2.56(dd, J=3.2, 9.6Hz, 1H), 2.36 (d, J=5.2Hz, 3H), 1.76-1.67 (m, 1H), 1.49-1.41 (m, 1H). (92.20% purity by HPLC)

Example 7

(S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-2-((1-methylpiperidin-4-yl)oxy)-5,6,7,8- Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 7

The first step (S)-4-(4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((1-methylpiperidin-4-yl) oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate benzyl ester 7a

Compound 3d (120mg, 0.24mmol), 1-methyl-4-piperidinol (82mg, 0.71mmol) and triphenylphosphine (248mg, 0.95mmol) were successively added to the there-necked flask, under nitrogen protection, tetrahydrofuran (5mL) was added. ), cooled to 0° C., added diisopropyl azodicarboxylate (191.2 mg, 0.95 mmol), and the reaction was warmed to room temperature overnight after the addition, and TLC showed that the starting material was consumed. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7a (100 mg, yield 70%).

LC-MS: m/z=605.4[M+H] ⁺

The second step (S)-2-(cyanomethyl)-4-(2-((1-methylpiperidin-4-yl)oxy)-5,6,7,8-tetrahydro-1 ,7-Naphthyridin-4-yl)piperazine-1-carboxylate tert-butyl ester 7b

Compound 7a (100 mg, 0.17 mmol) was dissolved in methanol (10 mL), palladium/carbon (60 mg, 10%) was added, and the reaction was carried out at room temperature for 3 hours under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound 7b (75 mg, crude product), which was directly used in the next step.

The third step (S)-4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpiperidin-4-yl)oxy)-5,6,7,8- Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester 7c

Compound 7b (75 mg, crude product), compound 1-bromo-8-chloronaphthalene (125 mg, 0.51 mmol), Pd ₂ (dba) ₃ (47 mg, 0.05 mmol), Xantphos (59 mg, 0.1 mmol) and cesium carbonate (221 mg, 0.68 mmol) was successively added to the three-necked flask, under nitrogen protection, toluene (10 mL) was added, and the reaction was heated under reflux for 4 hours, and TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, and the crude product was purified by silica gel column chromatography to obtain the title compound 7c (40 mg, yield 38% for two steps).

LC-MS: m/z=631.3[M+H] ⁺

The fourth step (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpiperidin-4-yl)oxy)-5,6,7 ,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 7d

Compound 7c (40 mg, 0.06 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC showed that the reaction was complete. The reaction solution was concentrated to remove the solvent, the crude product was added with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7d (20 mg, crude product), which was directly used in the next step.

The fifth step (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpiperidin-4-yl)oxy)-5,6,7 ,8-Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 7

Compound 7d (20 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), 2-fluoroacrylic acid (5.1 mg, 0.06 mmol), N,N-diisopropylethylamine ( 15 mg, 0.12 mmol) and HATU (38 mg, 0.10 mmol) were reacted at room temperature for 1.5 hours, and TLC showed that the reaction was complete. A small amount of water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7 (4.7 mg, yield 12% for two steps).

LC-MS: m/z=603.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.82 (d, J=8.0H _Z , 1H), 7.66 (dd, J=3.2, 8.0H _Z , 1H), 7.53-7.45 (m, 2H), 7.39 -7.29(m, 2H), 6.44-6.29(m, 1H), 5.43-5.21(m, 3H), 4.35(d, J=16.4H _Z , 1H), 3.86-3.65(m, 2H), 3.65- 3.47(m, 4H), 3.46-3.35(m, 3H), 3.24-2.95(m, 6H), 2.91-2.67(m, 6H), 2.45-2.35(m, 1H), 2.33-2.23(m, 1H ),2.12-1.99(m,2H).(97.99%purity by HPLC)

Example 8

2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2- ((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) Methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile mixture 8

The first step (S)-4-(7-benzyl-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5 ,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester and (S)-4-(7-benzyl yl-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-1,7 -Naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester mixture 8a

Compound 3b (250 mg, 0.55 mmol), intermediate IN-4 (230 mg, 1.65 mmol, trans isomer) and tri-n-butylphosphine (668 mg, 3.30 mmol) were weighed and dissolved in dry tetrahydrofuran (5 mL), Diisopropyl azodicarboxylate (668 mg, 3.30 mmol) was added in batches at 50° C., and the reaction was incubated for 1 hour. TLC monitored the complete reaction of the raw materials, and LCMS showed the molecular weights of two target products. The reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (30 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (petroleum Purification with ether/ethyl acetate = 1:1) gave the title compound 8a (94 mg, yield 28.8%) as a colorless oil.

LC-MS: m/z=605.4[M+H] ⁺

¹ HNMR (400MHz, CDCl ₃ ) δ 7.42-7.30(m, 4H), 7.29-7.26(m, 1H), 6.12(s, 1H), 5.30-5.28(s, 0.5H), 5.19-5.14(m ,0.5H),5.01-4.86(m,1H),4.70-4.51(m,1H),4.09-3.99(m,2H),3.95-3.89(m,1H),3.77-3.48(m,4H), 3.30-3.10(m, 6H), 2.99-2.82(m, 4H), 2.75-2.59(m, 4H), 2.16-2.06(m, 2H), 2.03-1.96(m, 1H), 1.94-1.81(m ,3H),1.50(s,9H).

The second step (S)-2-(cyanomethyl)-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy (S)-2-(cyanomethyl)-4 -(2-(((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-1,7 -Naphthyridin-4-yl)piperazine-1-carboxylate tert-butyl ester mixture 8b

Compound 8a (92 mg, 0.14 mmol) was weighed and dissolved in methanol (6 mL), palladium/carbon (50 mg, 10%) and ammonium formate (91 mg, 1.44 mmol) were added successively, the temperature was raised to 60° C. for 3 hours, and the raw materials were monitored by TLC. The reaction is complete. The reaction solution was cooled to room temperature, filtered through a pad of celite, the filtrate was concentrated, diluted with ethyl acetate (15 mL) and water (5 mL), extracted and separated, and the organic layer was successively saturated sodium bicarbonate solution (5 mL) and saturated brine (5 mL). ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 8b (64 mg, 82% yield) as a colorless oil.

LC-MS: m/z=515.3 [M+H] ⁺

The third step (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester and (S )-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy )-5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester mixture 8c

Compound 8b (40 mg, 0.08 mmol) was weighed, 1-bromo-8-chloronaphthalene (51 mg, 0.21 mmol) was dissolved in toluene (1 mL), Pd ₂ (dba) ₃ (14 mg, 0.015 mmol) was added successively, Xantphos ( 18 mg, 0.03 mmol) and cesium carbonate (104 mg, 0.32 mmol), nitrogen was replaced three times, the temperature was raised to 100° C. and reacted for 16 hours, and the reaction of the raw materials was monitored by TLC for completeness. The reaction solution was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound 8c as a pale yellow solid ( 30 mg, crude product), used directly in the next step.

LC-MS: m/z=675.3[M+H] ⁺

¹ HNMR (400MHz, CDCl ₃ ) δ 7.77-7.71(m,1H), 7.61-7.54(m,1H), 7.53-7.48(m,1H), 7.48-7.38(m,1H), 7.35-7.29( m,1H),7.29-7.26(m,0.55H),7.23-7.19(m,0.45H),6.22(s,0.45H),6.17(s,0.55H),5.32(s,0.45H),5.18 (s,0.55H),4.64(s,1H),4.44-4.37(m,1H),4.21-3.81(m,4H),3.63-3.52(m,1H),3.42-3.03(m,8H), 3.01-2.53(m,6H),2.22-1.97(m,3H),1.96-1.81(m,3H),1.51(s,9H).

The fourth step 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 5H)-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile and 2-((S)-4- (7-(8-Chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5, 6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile mixture 8d

Compound 8c (30 mg, crude product) was weighed and dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was performed at room temperature for 1 hour. TLC monitored the reaction of the raw materials to complete. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (5 mL), the organic phases were combined, concentrated to remove about half of the dichloromethane, extracted with 1N dilute hydrochloric acid (5 mL), the aqueous phases were combined, and the aqueous phase was washed with sodium carbonate The pH was adjusted to 9, extracted with dichloromethane (5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 30 mg of crude product, which was purified by Prep-TLC (dichloromethane/methanol=10:1) to obtain off-white Solid title compound 8d (5 mg, 11% over two steps).

LC-MS: m/z=575.3 [M+H] ⁺

The fifth step 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 5H)-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile mixture 8

Compound 8d (18 mg, 0.031 mmol), N,N-diisopropylethylamine (6 mg, 0.047 mmol) and 2-fluoroacrylic acid (4 mg, 0.044 mmol) were weighed and dissolved in N,N-dimethylformamide ( 3 mL), HATU (15 mg, 0.039 mmol) was added, and the reaction was carried out at room temperature for 2 hours. TLC monitored the reaction of the raw materials to complete. The reaction solution was quenched by adding water (6 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and filtered through Prep-TLC (dichloromethane/methanol=20/ 1) Purification gave the title compound 8 (4 mg, 18.2% yield) as an off-white solid.

LC-MS: m/z=647.3[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ 7.78-7.71 (m, 1H), 7.59 (t, J=8.4Hz, 1H), 7.54-7.48 (m, 1H), 7.48-7.38 (m, 1H), 7.36 -7.29(m,1H),7.29-7.26(m,0.55H),7.23-7.19(m,0.45H),6.25-6.16(m,1H),5.43-5.16(m,3H),4.46-4.35( m,1H),4.19-3.78(m,4H),3.63-3.55(m,1H),3.49-3.37(m,1H),3.34-2.81(m,12H),2.80-2.60(m,2H), 2.19-2.07 (m, 2H), 2.06-1.83 (m, 4H). (99.24% purity by HPLC)

Example 9

(S)-2-(4-(7-(8-Chloronaphthalen-1-yl)-3-fluoro-2-((tetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy) -5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 9

The first step 4-bromo-3-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,7-naphthyridine 9a

Intermediate IN-2 (2.70 g, 17.7 mmol), triphenylphosphine (5.86 g, 22.2 mmol) and compound 5e (2.70 g, 19.1 mmol) were dissolved in anhydrous tetrahydrofuran (72 mL), cooled to 0 °C, nitrogen Diisopropyl azodicarboxylate (6.69 g, 33.3 mmol) was added under protection, and stirred for 0.5 hour after the addition, and TLC detected that the reaction of the raw materials was complete. The reaction solution was quenched by adding water (50 mL), extracted twice with ethyl acetate (50 mL), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (dichloromethane/ammonia of methanol solution = 40/1) to obtain the title compound 9a (1.8 g, yield 45%) as a pale yellow solid.

LC-MS: m/z=366.1 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ 9.17-9.15 (m, 1H), 8.60-8.58 (m, 1H), 7.83-7.77 (m, 1H), 5.00-4.93 (m, 1H), 4.35-4.34 (m,2H),3.20-3.12(m,2H),2.70-2.68(m,2H),2.05-1.99(m,2H),1.92-1.87(m,4H),1.73-1.72(m,1H) .

The second step (S)-2-(cyanomethyl)-4-(3-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,7 -Naphthyridin-4-yl)piperazine-1-carboxylate benzyl ester 9b

Compound 9a (200 mg, 0.55 mmol) and compound 1a (244 mg, 0.83 mmol) were dissolved in toluene (8 mL), followed by adding Pd ₂ (dba) ₃ (101 mg, 0.11 mmol), Xantphos (127 mg, 0.22 mmol) and cesium carbonate (538 mg, 1.65 mmol), nitrogen was replaced three times, the temperature was raised to 100° C. to react for 16 hours, and the reaction of the raw materials was monitored by TLC for completeness. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was subjected to silica gel column chromatography (dichloromethane/ammonia in methanol solution). =30/1), Prep-TLC purification gave the title compound 9b (40 mg, 13% yield) as a white solid.

LC-MS: m/z=545.3 [M+H] ⁺

¹ HNMR (400MHz, CDCl ₃ )δ9.15(s, 1H), 8.52(d, J=6.4Hz, 1H), 7.68(d, J=6.0Hz, 1H), 7.45-7.33(m, 5H), 5.27-5.19(m, 2H), 4.75(br, 1H), 4.40-4.33(m, 2H), 4.21(br, 1H), 3.72-3.64(m, 1H), 3.49-3.30(m, 3H), 3.25-3.18(m, 3H), 3.05-2.94(m, 2H), 2.74-2.66(m, 2H), 2.09-1.84(m, 7H), 1.73-1.70(m, 1H).

The third step (S)-2-(cyanomethyl)-4-(3-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6 ,7,8-Tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate benzyl ester 9c

Compound 9b (100 mg, 0.18 mmol) was dissolved in acetic acid (2 mL), cooled to 0 °C, sodium borohydride (56 mg, 1.47 mmol) was added in batches, and the reaction was completed at 20 °C for 30 minutes. TLC monitored the reaction of the starting materials. The reaction solution was diluted with dichloromethane (15 mL), a saturated sodium carbonate solution was added dropwise to adjust pH=9, the layers were separated, the organic layer was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a light brown solid The title compound 9c (76 mg, 75% yield).

LC-MS: m/z=549.3 [M+H] ⁺

The fourth step (S)-4-(7-(8-chloronaphthalen-1-yl)-3-fluoro-2-((tetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy) -5,6,7,8-Tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester 9d

Compound 9c (76 mg, 0.14 mmol) and 1-bromo-8-chloronaphthalene (68 mg, 0.28 mmol) were dissolved in toluene (8 mL), followed by adding Pd ₂ (dba) ₃ (13 mg, 0.014 mmol), Xantphos (16 mg, 0.014 mmol) 0.03 mmol) and cesium carbonate (91 mg, 0.28 mmol), nitrogen was replaced three times, the temperature was raised to 100° C. to react for 16 hours, and the reaction of the raw materials was monitored by TLC for completeness. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (dichloromethane/ammonia in methanol = 30/1) was purified to give the title compound 9d (32 mg, 33% yield) as a light brown solid.

LC-MS: m/z=709.3[M+H] ⁺

The fifth step (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-3-fluoro-2-((tetrahydro-1H-pyrroazine-7a(5H)-yl)methyl oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 9e

Compound 9d (32 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), cooled to -10 °C in an ice-salt bath, and a solution of boron tribromide in dichloromethane (0.45 mL, 0.45 mmol, 1 M) was added dropwise. The reaction was carried out at the temperature for 30 minutes, and the reaction of the starting materials was monitored by TLC for completeness. The reaction was added dropwise to a mixture of dichloromethane and saturated sodium carbonate (v/v=1/1, 20 mL), stirred for 5 minutes, and the layers were separated. The organic phase was washed with saturated brine (10 mL), and anhydrous sodium sulfate Dry, filter, and concentrate the filtrate to give the title compound 9e (24 mg, crude) as a yellow solid, which is used directly in the next step.

LC-MS: m/z=575.3 [M+H] ⁺

The sixth step (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-3-fluoro-2-((tetrahydro-1H-pyrroazine-7a(5H)-yl)methyl oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 9

Compound 9e (24 mg, crude), N,N-diisopropylethylamine (10 mg, 0.08 mmol) and 2-fluoroacrylic acid (4.5 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (2 mL) In the solution, HATU (19.0 mg, 0.05 mmol) was added, and the reaction was carried out at room temperature for 30 minutes. TLC monitored the reaction of the raw materials to complete. The reaction solution was quenched by adding water (6 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and filtered through Prep-TLC (dichloromethane/methanol). =20/1) was purified to give the title compound 9 (6 mg, 21% yield for two steps) as a pale yellow solid.

LC-MS: m/z=647.3[M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76-7.73 (m, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.48-7.40 (m, 1H), 7.33 (t, J＝8.4Hz, 1H), 7.28-7.26(m, 0.5H), 7.21-7.20(m, 0.5H), 5.45-5.30(m, 1.5H), 5.26-2.21(m, 1H), 4.98(br,0.5H),4.34-4.24(m,3H),3.93-3.80(m,1H),3.70(s,1H),3.66-3.58(m,2H),3.48-2.95(m,10H) , 2.83-2.67 (m, 3H), 2.17-1.86 (m, 8H). (96.02% purity by HPLC)

IC ₅₀ Determination of the Compound of Test Example 1 for Inhibition of MIAPaCa-2 Cell Proliferation

Human pancreatic cancer MIAPaCa-2 cells (CRL-1420) used in the present invention were purchased from American Type Culture Collection (ATCC). Cells were grown in DMEM medium containing 2.5% horse serum, 10% fetal bovine serum, and 1% dual antibodies at 37°C in a 5% CO ₂ environment.

The inhibitory effect of compounds on the proliferation of MIAPaCa-2 cells cultured in vitro was determined by the following methods:

1) Cell seeding: Take pancreatic cancer MIAPaCa-2 cells in good logarithmic growth phase and resuspend them in complete medium, and seed 3000 cells/well into a 96-well plate, 180 μL per well, at 37°C, 5% CO ₂ . Incubate overnight under conditions.

2) Dosing: Dilute the compound to be tested in the complete medium in a gradient manner, and add 20 μL of the diluted compound to 180 μL of cells, so that the final concentration of the compound is 10000, 3000, 1000, 300, 100, 30, 10, 3 , 1nM, and set the corresponding solvent control at the same time. Place in a 37°C, 5% _CO2 cell incubator for 120 hours.

3) Detection: fix the cells with 10% trichloroacetic acid, remove the supernatant and wash, add 100 μL of 4 mg/mL SRB solution to each well for 15 minutes (Sigma, S1402-25g), and finally add 150 μL of 10 mM Tris solution to dissolve SRB, TECAN SPARK multi-function microplate reader reads the OD510 value.

4) Calculation: Calculate the cell growth inhibition rate with the following formula: inhibition rate=(OD value control well-OD value administration well)/OD value control well×100%. _IC50 values were calculated from compound concentrations and corresponding inhibition ratios using Graphpad prism 5.0 software. The test results are shown in Table 1:

Table 1 IC ₅₀ (nM) of the compounds of the present invention for inhibiting the proliferation of MIAPaCa-2 cells

Compound number MIAPaCa-2 Compound number MIAPaCa-2 MRTX849 1.9 1 132.5 2 2640 3 30.7 4 92.4 5 2.7 6 412.7 7 3208 8 12.35 9 377.2

Conclusion: The compounds of the examples of the present invention can inhibit the proliferation of MIAPaCa-2 cells, and the activity of compound 5 is comparable to that of MRTX849.

The effect of the compound of test example 2 on the phosphorylation level of KRAS downstream signaling molecule ERK1/2 in MIAPaCa-2 cells

The effect of the compounds of the present invention on the phosphorylation level of ERK1/2 in MIAPaCa-2 cells was detected by the following methods:

1) Cell seeding: MIAPaCa-2 cells in good logarithmic growth phase were seeded into a six-well plate at 1*10 ⁶ cells/well, and cultured overnight at 37° C. and 5% CO 2 .

2) Dosing: After the compound to be tested is serially diluted in complete medium, it is added to the cells so that the final concentration of the compound is 1000, 100, 10, and 1 nM. Place in a 37°C, 5% _CO2 cell incubator for 24 hours.

3) Protein sample preparation: trypsin digestion, collect cells, centrifuge at 500g for 5 minutes, discard the supernatant, wash 3 times with PBS, and use 1×SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) 100 μL of lysed cells. Cell lysates were denatured by heating at 100°C for 10 minutes.

4) Western blot: perform SDS-PAGE electrophoresis on the protein samples, after electrophoresis, transfer the protein to PVDF membrane with a wet transfer system, and place the PVDF membrane in blocking solution (5% nonfat milk powder diluted in TBS/T) to block at room temperature 1 hour, then I, II anti-reaction; after washing the membrane, use Immobilon Western HRP Substrate luminal reagent reagent to develop color, and take pictures with Western Blot imager (Tanon, 4600). The following is the antibody information used: p-ERK1/2 (CST:4370); ERK1/2 (CST:9102); β-tubulin (CST:2146).

The results of compound effects on ERK1/2 phosphorylation levels in MIAPaCa-2 cells are shown in Figure 1 .

Conclusion: Compound 5 in the examples of the present invention has a significant inhibitory effect on the phosphorylation of ERK1/2 in MIAPaCa-2 cells, and the inhibitory activity is concentration gradient dependent, and the activity is roughly equivalent to MRTX849.

Rat Pharmacokinetic Properties of the Compound of Test Example 3

The compound of Example 5 (10 mg/kg) was orally administered to overnight fasted SD rats (male, n=3/time point). Rats were fed after 2 h of administration. Blood samples were collected before administration and 1.5 hours, 4 hours, and 8 hours after administration, respectively, and centrifuged at 4° C. (4500 rpm) for 10 min to obtain serum. Livers were collected before and 1.5 hours, 4 hours, and 8 hours after dosing, respectively. Liver samples were then snap frozen and stored at -80°C. The mixture was pelleted by adding 100 μL of MeOH/ACN (1:1, v/v) to 10 μL of serum, followed by vortexing for 1 min and centrifugation (11000 rpm) for 5 min to obtain the supernatant. 20 μL of the supernatant was dissolved in 20 μL ACN/H2O (1:1, v/v) and analyzed by ultra-high performance liquid chromatography. The liver samples were added with 10 times the weight of MeOH/ACN (1:1, v/v), and then homogenized with a homogenizer at 50 Hz for 120 s to obtain a homogenate. The homogenate was centrifuged (11000 rpm) for 5 minutes and the supernatant was collected. 20 μL of the supernatant was then redissolved in 20 μL ACN/H2O (1:1, v/v) and analyzed by ultra-high performance liquid chromatography. The results are shown in Table 2:

Table 2 Pharmacokinetic properties of compound 5 in rats

It can be seen from the above table that compound 5 has better plasma exposure and better half-life in rats.

Tissue distribution of the compound of Test Example 4 in mice

Compound 5 and MRTX849 were administered intravenously at a dose of 5 mg/kg. The mice tested were 7-8 week old ICR male mice. The sampling time points were 0.083h, 0.5h, 1h, 2h, and the sampling tissues were plasma, brain, lung, colorectum, pancreas, gallbladder and bile duct. The specific operation process is as follows:

blood collection

The time was recorded after the administration was completed, and samples were collected at the set time point.

Blood was collected from the mouse heart, thoroughly mixed, placed on ice, and centrifuged within 30 min to separate the plasma (4°C, 8000 rpm for 5 min), and the plasma was stored at -80°C until measurement. The brain, lung, colorectum, pancreas, gallbladder and bile duct were collected from mice on ice, perfused with normal saline, rinsed, blotted dry with filter paper, and finally stored at -80°C until measurement. Blood, brain, lung, colorectum, pancreas, gallbladder and bile duct were collected from blank animals without administration of carbon dioxide after euthanasia, as blank matrix.

end of experiment

Euthanasia: The experimental animals were euthanized by inhaling excess _CO2 after the experiment.

Reserve sample

Accurately weigh 1-2 mg of the test substance. Reserve 100 μL of the prepared preparation and freeze it for dose retesting.

Sample Analysis Method

Standard preparation

Weigh the compound to be tested to prepare a stock solution of the analyte to obtain a stock solution of the analyte with a concentration of 1 mg/mL. The stock solution was diluted to 50,000 ng/mL with acetonitrile as an intermediate concentration diluent. Use serial dilution to prepare calibration standard samples with gradient concentrations such as: 5000, 1000, 750, 500, 250, 100, 50, 10, 5, 1 ng/mL.

LC-MS/MS analysis of blood samples

The blood-brain drug concentration was measured at different time points, and the pharmacokinetic software WinNonlin was used to fit and calculate the metabolic parameters of the sample, such as the area under the drug-time curve (AUC), peak concentration (Cmax), time to peak (Tmax), half-life ( T1/2) and other parameters.

Table 3 Tissue distribution of compound 5 in mice

Table 4 Tissue distribution of MRTX849 in mice

Through the comparison of the two groups of data, it was unexpectedly found that the half-life of compound 5 was significantly prolonged compared with MRTX849, and its maximum drug exposure in the lung was nearly 1.4 times that of MRTX849, and the area under the plasma concentration-time curve ( AUC) were 2.2-fold and 4.63-fold higher than MRTX849, respectively. At the same time, the plasma exposure and the area under the plasma concentration-time curve of compound 5 were also significantly higher than those of MRTX849.

In vivo antitumor activity of the compound of Test Example 5

Female BALB/c mice (6-8 weeks) were injected subcutaneously with MIAPaCa-2 cells (1.0E+07 cells) and Corning's Matrigel mixture on the right side. Compound 5 and MRTX849 were administered by gavage at doses of 3 mg/kg and 10 mg/kg, respectively, for 36 consecutive days. Mice were monitored daily and caliper measurements were initiated when tumors became visible. The volume of the tumor was calculated by measuring two perpendicular diameters using the formula: (L*W ² )/2, where L and W refer to the length and width of the tumor diameter. When the mean tumor volume reached 100 ^mm3 , mice were grouped (n=5/group) and administered compound. During the dosing period (36 days), tumor volume and mouse weight were measured every 3 days. The result is shown in Figure 2-3.

The experimental results showed that the anti-tumor activity of compound 5 at a dose of 3 mg/kg was significantly better than that of MRTX849, and the two exhibited comparable anti-tumor activity at a dose of 10 mg/kg. Moreover, compound 5, like MRTX849, had no significant effect on the body weight of mice at two doses, showing good safety. In conclusion, the area under the curve (AUC) of compound 5 in pancreas was better than that of MRTX849 at the dose of 3 mg/kg, and its antitumor activity against pancreatic cancer was also better than that of MRTX849. These data all suggest that compound 5 has better therapeutic prospects.

The applicant declares that the present invention is to illustrate a class of tetrahydronaphthyridine derivatives as KRAS mutant G12C inhibitors of the present invention, the preparation method and the application thereof through the above-mentioned examples, but the present invention is not limited to the above-mentioned examples. , that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

The preferred embodiments of the present invention are described in detail above, but the present invention is not limited to the specific details of the above-mentioned embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention. These simple modifications All belong to the protection scope of the present invention.

In addition, it should be noted that the specific technical features described in the above-mentioned specific embodiments can be combined in any suitable manner under the condition of no contradiction. In order to avoid unnecessary repetition, the present invention has The combination method will not be specified otherwise.

Claims (10)

A tetrahydronaphthyridine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, It is characterized in that, the structure of described tetrahydronaphthyridine derivatives is shown in formula (I):

in: R ¹ is selected from H or F; R ² is selected from 6-12-membered aryl or 5-12-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1-4 R ^c ; R ^c is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl or 3-8 membered heterocycle group, wherein said alkyl, alkenyl, cycloalkyl, R ^a , R ^b or heterocyclyl is optionally substituted with 1-3 R ^c1 ; R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group; R ^c1 is selected from halogen, hydroxyl, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy; L ¹ is selected from bond, O, S, NH or NCH ₃ ; R ³ is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8-membered heterocyclic group, 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group cyclic group, 5-10-membered spiro heterocyclic group, 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl group, alkenyl group, cycloalkyl group, heterocyclic group, fused heterocyclic group cyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl or heteroaryl may be optionally substituted with 1-4 R ^c2 ; R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ; L ² is selected from C3-C8 cycloalkyl, C5-C10 spirocycloalkyl, C4-C10 fused cycloalkyl, C5-C10 bridged cycloalkyl, 3-8-membered heterocyclyl, 5-10-membered Condensed heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, 6-12-membered aryl group, 5-12-membered heteroaryl group, wherein the cycloalkyl, spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl, heteroaryl optionally surrounded by 1-4 R ^c replaced; R ⁴ is selected from -C(O)R ^d or -S(O) ₂ R ^d ; R ^d is selected from C2-C4 alkenyl or C2-C4 alkynyl, wherein the alkenyl and alkynyl can be optionally further substituted by 1-3 R ^d1 ; R ^d1 is selected from halogen, cyano, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl is optionally replaced by 1- 3 R ^c substitutions; The heteroatoms in the heterocyclic group and the heteroaryl group in the formula (I) are 1-4 and are selected from one or more of oxygen, nitrogen and sulfur. The tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof according to claim 1, wherein: The structure of the tetrahydronaphthyridine derivatives is shown in formula (II):

Wherein, R ¹ , R ² , R ³ , R ^c and L ¹ have the same limited range as claim 1; n=0-4; R ^e1 , R ^e2 or R ^e3 are independently selected from H, halogen, cyano, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclic group, and the above-mentioned alkyl, ring Alkyl or heterocyclyl is optionally substituted with 1-3 halogens, C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, hydroxy or amino; The heteroatoms in the heterocyclic group are 1-3 one or more selected from oxygen, nitrogen and sulfur; And/or, R ² is selected from 6-12-membered aryl or 5-12-membered heteroaryl, wherein said aryl or ^heteroaryl is optionally substituted by 1-4 R; wherein, R ^c is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl or 3-8 membered heterocycle group, wherein said alkyl, alkenyl, cycloalkyl, R ^a , R ^b or heterocyclyl is optionally substituted with 1-3 R ^c1 ; R ^c1 is selected from halogen, hydroxyl, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy; And/or, R ³ is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused heterocyclyl, 5-10 membered heterocyclyl Bridged heterocyclyl with 5-10 members, spiro heterocyclyl with 5-10 members, aryl with 6-12 members or heteroaryl with 5-12 members, wherein the alkyl, alkenyl, cycloalkyl, heterocycle base, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl or heteroaryl may be optionally substituted with 1-4 R ^c2 ; R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ; R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c 2 , when the R ^c 2 is 2-4, the R ^c 2 are the same or different; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heteroatom of the heterocyclic group is nitrogen or oxygen; And/or, when the R ³ is a 4-8 membered heterocyclic group optionally substituted by 1-4 R ^c2 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different. The tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof according to claim 1 or 2, wherein the tetrahydronaphthyridine derivatives are derived from The structure of the compound is shown in formula (III):

Wherein, R ¹ , R ³ and L ¹ have the same limited scope as claim 1 ; R ^e1 , R ^e2 , R ^e3 have the same limited scope as claim 2 ; Preferably, for compounds of formula (III), wherein ^R is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused Heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered spiro heterocyclyl, 6-12-membered aryl or 5-12-membered heteroaryl, wherein the alkyl, alkenyl , cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl can be optionally replaced by 1-4 R replaced by ^c2 ; R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ; R ^c1 is selected from halogen, hydroxyl, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy; R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c 2 , when the R ^c 2 is 2-4, the R ^c 2 are the same or different; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ³ is a 4-8 membered heterocyclic group optionally substituted by 1-4 R ^c2 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different. The tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof according to any one of claims 1 to 3, wherein the tetrahydronaphthyridine derivatives are The structure of naphthyridine derivatives is shown in formula (IV):

Wherein, R ³ and L ¹ have the same limited scope as claim 1 ; R ^e1 , R ^e2 , R ^e3 have the same limited scope as claim 2; Preferably, for compounds of formula (IV), wherein R ³ is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused Heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered spiro heterocyclyl, 6-12-membered aryl or 5-12-membered heteroaryl, wherein the alkyl, alkenyl , cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl can be optionally replaced by 1-4 R replaced by ^c2 ; R ^c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR ^a R ^b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R ^c1 , -C(O)NR ^a R ^b , - NR ^a C(O)R ^b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R ^a , R ^b , aryl or heteroaryl optionally substituted with 1-3 R ^c1 ; R ^c1 is selected from halogen, hydroxyl, -NR ^a R ^b , cyano, C1-C3 alkyl or C1-C3 alkoxy; R ^a and R ^b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R ^a and R ^b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c 2 , when the R ^c 2 is 2-4, the R ^c 2 are the same or different; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ³ is a 4-8-membered heterocyclic group optionally substituted by 1-4 R ^c2 , the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ³ is a 4-8 membered heterocyclic group optionally substituted by 1-4 R ^c2 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different. The tetrahydronaphthyridine derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer according to claim 1, wherein the tetrahydronaphthyridine derivative is selected from from any of the following structures:

A method for preparing a tetrahydronaphthyridine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof according to any one of claims 1-5, which is selected from the group consisting of The following method:

In the first step, the compound of general formula (I-A) reacts with the compound of general formula (I-B) to obtain the compound of general formula (I-C); In the second step, the compound of general formula (I-C) reacts with the compound of general formula (I-D) to obtain the compound of general formula (I); Wherein, R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² have the same limited range as in claim 1; X is halogen or OTs, preferably bromine. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the tetrahydronaphthyridine derivatives according to any one of claims 1-5, pharmaceutically acceptable salts thereof, tautomers thereof or a stereoisomer thereof; preferably, the pharmaceutical composition further includes a pharmaceutically acceptable carrier and/or excipient. The tetrahydronaphthyridine derivatives according to any one of claims 1-5, their pharmaceutically acceptable salts, their tautomers or their stereoisomers, or the medicaments according to claim 7 Use of the composition in the manufacture of a medicament for the treatment of cancer or as a KRAS mutant G12C inhibitor. The use according to claim 8, wherein the cancer is but not limited to astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma , laryngeal cancer, pancreatic cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, kidney cancer and bile duct cancer; preferably lung cancer, pancreatic cancer or colorectal cancer. A method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of a tetrahydronaphthyridine derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 to a human being , its tautomer or its stereoisomer or the pharmaceutical composition of claim 7 .

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