CN115894520A - A macrocyclic K-RAS G12C inhibitor, its preparation method and pharmaceutical application - Google Patents

Abstract

The invention relates to a macrocyclic K-RAS G12C inhibitor, a preparation method and pharmaceutical application thereof. The series of compounds can be widely applied to preparing medicines for treating at least part of cancers or tumors mediated by K-RAS G12C mutation, particularly medicines for treating lung, liver and gall bladder, gastrointestinal tract, blood system, skin, bone, genitourinary tract, nervous system, gynecological and adrenal related malignant tumors or cancers, and are expected to be developed into a new generation of K-RAS G12C inhibitor medicines.

Description

A macrocyclic K-RAS G12C inhibitor and its preparation method and pharmaceutical application

Technical Field

The invention belongs to the field of drug synthesis, and specifically relates to a macrocyclic K-RAS G12C inhibitor and a preparation method thereof and pharmaceutical application thereof.

Background Art

The RAS gene family includes HRAS, KRAS, and NRAS, which are frequently mutated in cancer as oncogenes. 20-30% of human tumors have mutated RAS proteins. Activated RAS proteins lead to the malignant phenotype of cancer cells, including dysregulation of cell growth and programmed cell death, increased invasiveness, and neoangiogenesis. Due to its high affinity for GTP/GDP and the lack of a clear binding pocket, the development of drugs targeting RAS proteins has been slow.

Under normal circumstances, RAS proteins act as molecular switches, alternating between an inactive state bound to GDP and an activated state bound to GTP. After stimulation by exogenous growth factors, RAS proteins are transformed from an inactive GDP-bound form to an activated GTP-bound form, which is able to bind and activate downstream signaling pathways, with the help of its inherent GTPase activity and GTPase activating/accelerating proteins (GAPs). Subsequently, RAS returns to an inactive GDP-bound form.

Missense mutations at codons 12, 13, or 61 lead to abnormal activation of RAS. These mutations prolong the time that RAS proteins remain in the GTP-bound state, leading to sustained activation of downstream signaling pathways. K-RAS is the most common mutation subtype in the RAS family in human cancers, including pancreatic cancer (71%), small intestine cancer (35%), colon cancer (35%), biliary tract cancer (26%), endometrial cancer (17%), and lung cancer (19%). In terms of mutation sites, G12D/G12V/G12C/G13D are the most common mutation types of K-RAS in pancreatic cancer, lung cancer, and colorectal cancer.

The development of inhibitors for K-RAS is challenging because the protein lacks an obvious pocket. Recent studies have found a previously undiscovered pocket in the GDP-bound state of K-RAS. Based on these new findings, covalent binding inhibitors targeting the mutated cysteine at codon 12 have become a hot topic in the development of K-RAS inhibitors. Previously, mutant K-RAS was thought to be locked in the GTP-bound activated state. However, it was later discovered that the G12C mutation still has a relatively high level of GTP hydrolysis activity and is therefore more susceptible to covalent inhibitors of GDP-bound K-RAS. Recently, several covalent inhibitors targeting the K-RAS G12C mutation have entered early clinical trials.

Summary of the invention

The inventors of the present application have developed a macrocyclic K-RAS G12C inhibitor for the first time after extensive and in-depth research, and provided a preparation method and pharmaceutical application thereof. The series of compounds of the present invention have a strong inhibitory effect on K-RAS enzymatic and cellular activity, and can be widely used in the preparation of drugs for treating cancers or tumors mediated at least in part by K-RAS G12C mutations, especially drugs for treating lung, hepatobiliary, gastrointestinal tract, blood system, skin, bone, urogenital tract, nervous system, gynecological and adrenal-related malignant tumors or cancers, and are expected to be developed into a new generation of K-RAS G12C inhibitor drugs.

The first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein X is C(R ₇ ) or N; L is selected from -CR ₈ =CR ₉ -, -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-, -N(R ₁₄ )-C(O)-, -N(R ₁₅ )-C(R ₁₆ R ₁₇ )- and -OC(R ₁₈ R ₁₉ )-;

R ₁ is selected from hydrogen, deuterium, halogen, cyano, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _{1-4 alkoxy, deuterium-substituted C 1-4 alkoxy} , C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido and -SF ₅ ;

Each R ₂ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido and -SF ₅ ;

_R3 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl, _-C0-8 alkyl- _SF5 , _-C0-8 alkyl-S(O) _rR20 , _{-C0-8 alkyl-OR21, -C0-8 alkyl -} C(O) _OR21 , _-C0-8 alkyl-C(O) _R22 , _{-C0-8 alkyl} -OC(O) _R22 , _-C0-8 alkyl _- NR23R24 _{, -C0-8} alkyl-C( _{＝NR23)R22 , -C0-8 alkyl} -N( _R23 )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ , the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, ═O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _{-C 0-8} alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR ₂₃ R ₂₄ , -C _0-8 alkyl-C(═NR ₂₃ )R ₂₂ , -C _0-8 alkyl-N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ ;

Each R ₄ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -SF ₅ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, _cyano substituted C _{1-4 alkyl, hydroxy substituted C 1-4} alkyl, halogen substituted C _1-4 alkyl and deuterium substituted C _1-4 alkyl, or, when m ≥ 2, two R ₄ together with the part to which they are connected form a C _3-12 cycloalkyl or a 3-12 membered heterocyclyl;

R ₅ and R ₆ are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _3-6 cycloalkyl, 4-6 membered heterocyclyl and di-C _1-4 alkylaminomethyl;

_R7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl, _-C0-8 alkyl- _SF5 , _-C0-8 alkyl-S(O) _rR20 , _{-C0-8 alkyl-OR21, -C0-8 alkyl -} C(O) _OR21 , _-C0-8 alkyl-C(O) _R22 , _{-C0-8 alkyl} -OC(O) _R22 , _-C0-8 alkyl _- NR23R24 _{, -C0-8} alkyl-C( _{＝NR23)R22 , -C0-8 alkyl} -N( _R23 )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ , the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, ═O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _{-C 0-8} alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR ₂₃ R ₂₄ , -C _0-8 alkyl-C(═NR ₂₃ )R ₂₂ , -C _0-8 alkyl-N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ ;

_R8 and _R9 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-10 alkyl, _C3-12 cycloalkyl, 4-12 membered heterocyclyl and _-C1-4 alkyl- _NR23R24 , wherein the above groups are optionally further substituted by one or more selected from deuterium, halogen, _cyano , hydroxyl, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, C5-10 aryl, _5-10 membered heteroaryl, =O, _-SF5 , -S(O) _{rR20 , -OR21} , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , _-NR23R24 , -C(═NR ₂₃ )R ₂₂ , -N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ ;

_R10 , _R11 , _R12 , _R13 , _R16 , _R17 , _R18 and _R19 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, C5-10 aryl, _5-10 membered heteroaryl, _-SF5 , -S(O) _rR20 , _{-OR21, -C(O)OR21 ,} -C(O) _R22 , -OC(O _{) R22 , -NR23R24} , -C(＝ _NR23 ) _R22 , -N( _R23 )-C(＝ _NR24 ) _R22 or -C(O) _NR23R24 and -N( _R23 )-C(O _{) R22} ; or, _R10 and _R11 , _R12 and _R13 , _R16 and _R17 , _R18 and _R19 together with the carbon atoms to which they are directly attached form C(O), 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, the above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C5-10 aryl, 5-10 membered heteroaryl, =O _{, -SF5} , -S(O) _rR20 , _-OR21 , -C(O)OR ₂₁ , -C(O)R ₂₂ , -OC(O)R ₂₂ , -NR ₂₃ R ₂₄ , -C(═NR ₂₃ )R ₂₂ , -N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ ;

R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C(O)OR ₂₁ , -C(O)R ₂₂ and -C(O)NR ₂₃ R ₂₄ , wherein the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _0-8 alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR ₂₃ R ₂₄ , -C _0-8 alkyl-C(＝NR ₂₃ )R ₂₂ , -C _0-8 alkyl-N(R ₂₃ )-C(＝NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ substituents;

each R ₂₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and -NR ₂₃ R ₂₄ , which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, =O, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and -NR ₂₃ R ₂₄ ;

each R ₂₁ is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =0, cyano, C _1-10 alkyl, C _1-10 alkoxy, C 3-12 cycloalkyl, C _3-12 cycloalkoxy, _3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₃ R ₂₄ ;

each R ₂₂ is selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _{1-10 alkoxy, C 2-10} alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, _3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₃ R ₂₄ , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _{3-12 cycloalkyl, C 3-12 cycloalkyloxy} , _{3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10} aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 23 R 24 substituted by a substituent selected from the group consisting of _6-10 membered aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₃ R ₂₄ ;

Each of R ₂₃ and R ₂₄ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _1-10 alkoxy, C The alkylene group is substituted with a substituent selected from the group consisting of a C _3-12 cycloalkyl group, a C _3-12 cycloalkyloxy group, a 3-12 membered heterocyclyl group, a 3-12 membered heterocyclyloxy group, a C _6-10 aryl group, a C _6-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, an amino group, a mono-C _1-10 alkylamino group, a di-C _1-10 alkylamino group, and a C _1-10 alkanoyl group,

Alternatively, _R23 and _R24 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C1-10 alkoxy, _C3-12 cycloalkyl, _C3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, _C6-10 aryl, _C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono- _C1-10 alkylamino, di- _C1-10 alkylamino and _C1-10 alkanoyl;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

Each r is independently 0, 1 or 2.

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, _R10 , _R11 , _R12 , _R13 , _R16 , _R17 , _R18 and _R19 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, _C2-4 alkenyl, _{C2-4 alkynyl} , _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, -SF5, -S ₍ O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , _-OC (O) _R22 , _-NR23R24 , -C(O) _NR23R24 and -N( _R23 ) _-C (O) _R22 , or, _R10 and _R11 , _R12 and _R13 , _R16 and _R17 , _R18 and _R19 together with the carbon atom to which they are directly attached form C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O _{)R22 ,} -OC(O _{) R22} , _-NR23R24 , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ are substituted;

R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C(O)OR ₂₁ , -C(O)R ₂₂ and -C(O)NR ₂₃ R ₂₄ , wherein the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₂₀ , -C _0-4 alkyl-OR ₂₁ , -C _0-4 alkyl-C(O)OR ₂₁ , -C _0-4 alkyl-C(O)R ₂₂ , -C _0-4 alkyl-OC(O)R ₂₂ , -C _0-4 alkyl-NR ₂₃ R ₂₄ , -C _0-4 alkyl-C(＝NR ₂₃ )R ₂₂ , -C _0-4 alkyl-N(R ₂₃ )-C(＝NR ₂₄ )R ₂₂ , -C _0-4 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-4 alkyl-N(R ₂₃ )-C(O)R ₂₂ ;

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described for the compound of formula (I).

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, _R8 and _R9 are independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, _C3-6 cycloalkyl, 4-6 membered heterocyclyl and _-C1-4 alkyl _{- NR23R24} , and the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, hydroxyl, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , -NR ₂₃ R ₂₄ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ ;

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described for the compound of formula (I).

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, _R7 is selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , _-OC ( _O ) _R22 , _{-NR23R24, -C(＝NR23)R22, -N(R23)-C(＝NR24)R22, -C(O)NR23R24 and -N ( R23 ) -C ( O} ) _R22 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, _5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , _-NR23R24 , -C(= _NR23 ) _R22 , -N( _R23 )-C(= _NR24 ) _R22 , -C(O) _NR23R24 and -N _{( R23} )-C(O)R substituted by a substituent of ₂₂ ;

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described for the compound of formula (I).

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R ₃ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -SF ₅ , -S(O) _r R ₂₀ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ , -OC(O)R ₂₂ , -NR ₂₃ R ₂₄ , -C(＝NR ₂₃ )R ₂₂ , -N(R ₂₃ )-C(＝NR ₂₄ )R ₂₂ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, _5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , _-NR23R24 , -C(= _NR23 ) _R22 , -N( _R23 )-C(= _NR24 ) _R22 , -C(O) _NR23R24 and -N _{( R23} )-C(O)R substituted by a substituent of ₂₂ ;

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described for the compound of formula (I).

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, vinyl, ethynyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, cyclopropyl, acetamido and -SF ₅ .

As a preferred embodiment, each R ₂ in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C _1-4 alkyl, halogen _- substituted C _{1-4 alkyl, deuterium-substituted C 1-4} alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, cyclopropyl, acetamido and -SF ₅ .

As a preferred embodiment, each R ₄ in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -SF ₅ , C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, cyano substituted C _{1-4 alkyl, hydroxyl substituted C 1-4 alkyl} , halogen substituted C _1-4 alkyl and deuterium substituted C _1-4 alkyl.

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R ₅ and R ₆ are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl and dimethylaminomethyl.

As a further preferred embodiment, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof has the following compound structure of formula (II):

wherein X is CH or N, and L is -CR ₈ =CR ₉ - or -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-;

R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido and -SF ₅ ;

R ₂ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido and -SF ₅ ;

_R3 is selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, _diC1-4 alkylaminomethyl and _-SF5 ;

R _4a , R _4b , R _4c are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, cyclopropyl, cyanomethyl, hydroxymethyl, trifluoromethyl, trideuteriomethyl, difluoromethyl and dideuteriomethyl;

R ₈ and R ₉ are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl and cyclopropyl;

_R10 , _R11 , _R12 and _R13 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)rR20, _-OR21 , -C(O)OR21, -C(O)R22, -OC(O)R22, -NR23R24, -C ₍ O) _NR23R24 and -N(R23)-C(O) _R22 ; or, R10, R11, R12 and R13 are each independently selected from hydrogen _, deuterium, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C5-8 aryl, 5-8 membered heteroaryl, _-SF5 , -S(O) _{rR20 , -OR21} , -C(O) _OR21 , -C(O)R22, -OC( _O )R22, _-NR23R24 , -C(O) _NR23R24 and -N( _R23 )-C( _O ) _{R22 13} together with the carbon atom to which it is directly attached forms C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, = _O , _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC(O _{) R22} , _-NR23R24 , -C(O) _NR23R24 and -N( _{R23 )} -C(O) _R22 ;

wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described for the compound of formula (I).

As a further preferred embodiment, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof has the following compound structure of formula (III):

wherein L is -CH=CH- or -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-;

R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl and -SF ₅ ;

R ₂ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl and -SF ₅ ;

R ₃ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, trideuteriomethoxy, cyclopropyl, cyclobutyl, cyclobutyloxy and -SF ₅ ;

_R10 , _R11 , _R12 and _R13 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-8 membered heteroaryl, _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC(O) _R22 and _{-NR23R24 ;} or, _R10 and _R11 , _R12 and _R13 together with the carbon atom to which they are directly attached form C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, which is optionally further substituted with one or more deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, C _substituted by a substituent selected from the group consisting of _5-8 membered aryl, _5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , -OR21, -C(O) _OR21 , -C(O) _R22 , -OC(O) _{R22 , -NR23R24} , -C(O) _NR23R24 and -N( _R23 )-C(O) _{R22 ;}

each R ₂₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl and -NR ₂₃ R ₂₄ , the above groups being independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, =O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;

each R ₂₁ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;

each R ₂₂ is selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₂₃ R ₂₄ , which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;

Each of R ₂₃ and R ₂₄ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C _1-4 alkylamino and C _{1-4 alkanoyl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen _{-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-6 cycloalkyl , C} substituted by a C _3-6 -membered cycloalkyloxy group, a 3-6-membered heterocyclyl group, a 3-6-membered heterocyclyl group, a C _6-8 aryl group, a C _6-8 aryloxy group, a 5-8-membered heteroaryl group, a 5-8-membered heteroaryloxy group, an amino group, a mono-C _1-4 alkylamino group, a di-C _1-4 alkylamino group, and a C _1-4 alkanoyl group,

Alternatively, _R23 and _R24 together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, _C3-6 cycloalkyl, C3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, _C6-8 aryl, _C6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono- _C1-4 alkylamino, di- _C1-4 alkylamino and _C1-4 alkanoyl;

Each r is independently 0, 1 or 2.

As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, L is -CH=CH- or -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-;

R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy and cyclopropyl;

_R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy and cyclopropyl;

_R3 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, trideuteriomethoxy, cyclopropyl, cyclobutyl and cyclobutyloxy;

R ₁₀ is hydrogen;

R ₁₁ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolyl, azolyl, -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R ₂₂ , which are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -SF ₅ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R ₂₂ ;

_R12 is hydrogen;

R ₁₃ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolyl, azopentyl, -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R ₂₂ , wherein the above groups are optionally further substituted by one or more selected from deuterium, fluorine, chlorine, bromine, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -SF ₅ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R substituted by a substituent of ₂₂ ;

Each R ₂₁ is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolyl, azolyl and phenyl, which are independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;

Each R ₂₂ is selected from hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, propoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, oxetanyl, azetidinyl, oxolanyl, azopentyl and phenyl, and the above groups are independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C _1-4 alkyl, C _{1-4 alkoxy, C 3-6 cycloalkyl} , C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy.

As the most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:

The second aspect of the present invention provides a method for preparing a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps: a compound of formula (I') is reacted to obtain a compound of formula (I), and the reaction formula is as follows:

Wherein, R is H or an amino protecting group, preferably, the amino protecting group is tert-butyloxycarbonyl; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , L, X, m and n are as described for the compound of formula (I).

The third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In a fourth aspect, the present invention provides a use of the aforementioned compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition for preparing a medicament for treating a tumor or cancer mediated at least in part by K-RAS G12C mutation.

As a preferred embodiment, the cancer or tumor is selected from lung malignancies or cancers, hepatobiliary malignancies or cancers, gastrointestinal malignancies or cancers, blood system malignancies or cancers, sarcomas, skin malignancies or cancers, bone malignancies or cancers, genitourinary tract malignancies or cancers, nervous system malignancies or cancers, gynecological malignancies or cancers and adrenal malignancies or cancers.

As a further preferred embodiment, the lung malignancy or cancer is selected from bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma), non-small cell lung cancer, bronchial carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitinoma or mesothelioma; the hepatobiliary malignancy or cancer is selected from liver cancer, bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma or bile duct cancer; the gastrointestinal malignancy or cancer is selected from esophageal malignancy or cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma or lymphoma), gastric malignancy or cancer (carcinoma, lymphoma or leiomyosarcoma), pancreatic malignancy or cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, uveal tumor), small intestine (adenocarcinoma, lymphoma, The invention relates to a malignant tumor or cancer of the colorectal cancer (adenocarcinoma, adenoma, tubular adenoma) or leiomyoma; the malignant tumor or cancer of the blood system is selected from acute or chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease or non-Hodgkin's lymphoma; the sarcoma is selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma or teratoma; the malignant tumor or cancer of the skin is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus nevus, hyperplastic nevus, lipoma, hemangioma, dermatofibroma, keloid or psoriasis. ； The bone malignancy or cancer is selected from osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromucosal fibroma, osteoid osteoma or giant cell tumor; The genitourinary tract malignancy or cancer is selected from renal malignancy or cancer (adenocarcinoma, Wilms' tumor or Wilms' tumor), lymphoma, leukemia, bladder or urethral malignancy or cancer (squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate malignancy or cancer (adenocarcinoma or sarcoma), testicular malignancy or cancer (leukemia, teratoma, embryonal carcinoma or teratoma), choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor or lipoma; The nervous system The systemic malignancy or cancer is selected from osteoma, hemangioma, granuloma, xanthomas, deforming osteitis, meningioma, meningiosarcoma, glioma, astrocytoma, medulloblastoma, glioma, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma or sarcoma; the gynecological malignancy or cancer is selected from endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granulosa-theca cell tumor, testicular interstitial cell tumor, myometrial dysplasia, malignant teratoma, squamous cell carcinoma, fibroepithelial carcinoma, glandular epithelial carcinoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma or fallopian tube carcinoma; the adrenal malignancy or cancer is selected from neuroblastoma.

In a fifth aspect, the present invention provides a compound of the aforementioned formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for use as a drug for treating a tumor or cancer mediated at least in part by K-RAS G12C mutation.

The sixth aspect of the present invention provides a method for preventing and/or treating tumors or cancers mediated at least in part by K-RAS G12C mutation, comprising administering to a patient a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

DETAILED DESCRIPTION

The inventors of the present application have developed a macrocyclic K-RAS G12C inhibitor for the first time after extensive and in-depth research, and provided a preparation method and pharmaceutical application thereof. The series of compounds of the present invention have a strong inhibitory effect on K-RAS enzymatic and cellular activity, and can be widely used in the preparation of drugs for treating cancers or tumors mediated at least in part by K-RAS G12C mutations, especially drugs for treating lung, liver and gallbladder, gastrointestinal tract, blood system, skin, bone, urogenital tract, nervous system, gynecological and adrenal related malignancies or cancers, and are expected to be developed into a new generation of K-RAS G12C inhibitor drugs. On this basis, the present invention has been completed.

Detailed Description: Unless stated to the contrary or specifically indicated, the following terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched alkyl group having 1 to 10, 1 to 6, or 1 to 4 carbon atoms, including, but 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-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched chain isomers thereof, etc. “C _1-10 alkyl” refers to a straight-chain alkyl group and a branched-chain alkyl group having 1 to 10 carbon atoms, “C _1-8 alkyl” refers to a straight-chain alkyl group and a branched-chain alkyl group having 1 to 8 carbon atoms, “C _0-8 alkyl” refers to a straight-chain alkyl group and a branched-chain alkyl group having 0 to 8 carbon atoms, “C _1-4 alkyl” refers to a straight-chain alkyl group and a branched-chain alkyl group having 1 to 4 carbon atoms, and “C ₀ alkyl” refers to a carbon atom number of 0.

The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _{1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl ,} halogen-substituted C _1-10 alkyl, halogen-substituted C _1-10 alkoxy, deuterium-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, =O, -SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, and the cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably a cycloalkyl group including 3 to 10, 3 to 8 or 3 to 6 carbon atoms, for example, "C _3-10 cycloalkyl" refers to a cycloalkyl group including 3 to 10 carbon atoms, "C _3-8 cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms, and "C _3-6 cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms, wherein:

Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl includes cycloalkyl of spiro ring, fused ring and bridged ring. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called spiro atom) is shared between the single rings, which may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl is divided into monospiroalkyl, bispiroalkyl or polyspiroalkyl according to the number of spiro atoms shared between the rings. Spiroalkyl includes but is not limited to:

"Fused cycloalkyl" refers to a full-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and fused cycloalkyl includes but is not limited to:

"Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. Bridged cycloalkyl includes but is not limited to:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _0-8 alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR The group may _be substituted with a substituent selected _{from -C0-8alkyl} -C(= _NR23 ) _R22 , _-C0-8alkyl -N( _R23 )-C(= _NR24 ) _R22 , _-C0-8alkyl -C(O _{) NR23R24} and _-C0-8alkyl -N( _R23 )-C(O) _R22 .

"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) _r (wherein r is an integer 0, 1, 2) heteroatoms, but excluding the ring parts of -OO-, -OS- and -SS-, and the remaining ring atoms are carbon, preferably a heterocyclyl containing 3 to 10 or 3 to 8 or 3 to 6 ring atoms, for example, a "3-6 membered heterocyclyl" refers to a cyclic group containing 3 to 6 ring atoms, a "4-6 membered heterocyclyl" refers to a cyclic group containing 4 to 6 ring atoms, and a "3-10 membered heterocyclyl" refers to a cyclic group containing 3 to 10 ring atoms.

Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called spiro atom) is shared between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) _r (wherein r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into single spiro heterocyclic groups, double spiro heterocyclic groups or multi-spiro heterocyclic groups according to the number of spiro atoms shared between rings. Spiro heterocyclic groups include, but are not limited to:

"Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) _r (wherein r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic alkyl groups, and fused heterocyclic groups include but are not limited to:

"Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) _r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, and bridged heterocyclic groups include but are not limited to:

The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring, including but not limited to:

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, halogen-substituted C _1-10 alkoxy, deuterium-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, =O, -SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably an all-carbon aromatic group containing 5-10 or 5-8 carbons, for example, "C _5-10 aryl" refers to an all-carbon aromatic group containing 5-10 carbons, including but not limited to phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

"Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C1-10 alkoxy, _C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, halogen-substituted _C1-10 alkoxy, deuterium-substituted _C1-10 alkyl, deuterium-substituted C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, _3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, _C5-10 aryl, C5-10 aryloxy, 5-10 membered heteroaryl, _5-10 membered heteroaryloxy _, =O, -SF5, _{-C0-8 alkyl} -S(O) _rR20 , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including nitrogen, oxygen and S(O)r (wherein r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 ring atoms, for example, "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

"Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C1-10 alkoxy, C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, halogen-substituted _C1-10 alkoxy, deuterium-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, _3-10 membered heterocyclyl, _3-10 membered heterocyclyloxy, _C5-10 aryl, C5-10 aryloxy, 5-10 membered heteroaryl _, 5-10 membered heteroaryloxy _, =O, -SF5, _-C0-8 alkyl-S(O) _rR20 , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight chain or branched alkenyl group containing 2-10 or 2-4 carbon atoms, for example, " _C2-10 alkenyl" refers to a straight chain or branched alkenyl group containing 2-10 carbon atoms, and " _C2-4 alkenyl" refers to a straight chain or branched alkenyl group containing 2-4 carbon atoms. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

"Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C1-10 alkoxy, _C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, halogen-substituted _C1-10 alkoxy, deuterium-substituted _C1-10 alkyl, deuterium-substituted C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, _3-10 membered heterocyclyl, _3-10 membered heterocyclyloxy, _C5-10 aryl, C5-10 aryloxy, 5-10 membered heteroaryl _, 5-10 membered heteroaryloxy _, =O, -SF5, _-C0-8 alkyl-S(O) _rR20 , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight chain or branched chain alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C _2-10 alkynyl" refers to a straight chain or branched chain alkynyl group containing 2-10 carbon atoms, and "C _2-4 alkynyl" refers to a straight chain or branched chain alkynyl group containing 2-4 carbon atoms. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

"Alkynyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C1-10 alkoxy, _C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, halogen-substituted _C1-10 alkoxy, deuterium-substituted _C1-10 alkyl, deuterium-substituted C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, _3-10 membered heterocyclyl, _3-10 membered heterocyclyloxy, _C5-10 aryl, C5-10 aryloxy, _5-10 membered heteroaryl, 5-10 membered heteroaryloxy, =O, -SF5- _{C0-8alkyl -S(O)rR20 ,} -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Alkoxy" refers to -O-alkyl, wherein alkyl is as defined above, for example, "C _1-10 alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms, and "C _1-4 alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

"Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C1-10 alkoxy, C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, halogen-substituted _C1-10 alkoxy, deuterium-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, _3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, _C5-10 aryl, _C5-10 aryloxy, 5-10 _membered heteroaryl, 5-10 membered heteroaryloxy _, =O, -SF5, _-C0-8 alkyl-S(O) _rR20 , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Cycloalkoxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above, for example, "C _3-10 cycloalkoxy" refers to cycloalkyloxy containing 3 to 10 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Cycloalkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C1-10 alkoxy, C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, halogen-substituted _C1-10 alkoxy, deuterium-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, _3-10 membered heterocyclyl, _3-10 membered heterocyclyloxy, _C5-10 aryl, C5-10 aryloxy, 5-10 membered heteroaryl _, 5-10 membered heteroaryloxy _, =O, -SF5, _-C0-8 alkyl-S(O) _rR20 , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

"Heterocyclyloxy" refers to an -O-heterocyclyl group, wherein the heterocyclyl group is as defined above, and heterocyclyloxy includes, but is not limited to, azetidinyloxy, oxetanyloxy, azepanyloxy, nitrogen, oxhexyloxy, and the like.

The “heterocyclyloxy” may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, halogen-substituted C _1-10 alkoxy, deuterium-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, =O, -SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C The group may be substituted with a substituent selected from _-C0-8alkyl -OR ₂₁ , _-C0-8alkyl -C(O)OR ₂₁ , _-C0-8alkyl -C(O)R ₂₂ , _-C0-8alkyl -OC(O)R ₂₂ , _-C0-8alkyl -NR ₂₃ R ₂₄ , _-C0-8alkyl -C(＝NR ₂₃ )R ₂₂ , -C0-8alkyl-N(R ₂₃ ) _-C (＝NR ₂₄ )R ₂₂ , _-C0-8alkyl -C(O)NR ₂₃ R ₂₄ and _-C0-8alkyl -N(R ₂₃ )-C(O)R ₂₂ .

“C _1-10 alkanoyl” refers to the monovalent atomic group remaining after removing the hydroxyl group from a C _1-10 alkyl acid, and is also commonly represented as “C _0-9 -C(O)-”, for example, “C ₁ -C(O)-” refers to acetyl; “C ₂ -C(O)-” refers to propionyl; and “C ₃ -C(O)-” refers to butyryl or isobutyryl.

" _-C0-8alkyl -S(O) _rR20 " means _that the sulfur atom in -S(O) _rR20 is bonded to _{a C0-8alkyl group} . The _C0-8alkyl group is as defined above.

"-C _0-8 alkyl-OR ₂₁ " means that the oxygen atom in -OR ₂₁ is bonded to a C _0-8 alkyl group. The definition of C _0-8 alkyl group is as described above.

" _-C0-8alkyl -C(O) _OR21 " means that the carbonyl group in -C(O) _OR21 is bonded to a _C0-8alkyl group. The definition of _C0-8alkyl group is as described above.

“—C _0-8 alkyl—C(O)R ₂₂ ” means that the carbonyl group in —C(O)R ₂₂ is bonded to a C _0-8 alkyl group. The C _0-8 alkyl group is as defined above.

" _-C0-8alkyl -OC(O) _R22 " means that the oxygen atom in -OC(O) _R22 is bonded to a _C0-8alkyl group. The definition of _C0-8alkyl group is as described above.

" _{-C0-8alkyl - NR23R24} " means that the nitrogen atom in _{-NR23R24 is bonded to a C0-8alkyl group .} The definition of _C0-8alkyl group is as described above.

" _-C0-8alkyl -C(= _NR23 ) _R22 " means that the nitrogen atom in -C(= _NR23 ) _R22 is bonded to a _C0-8alkyl group. The definition of _C0-8alkyl group is as described above.

“—C _0-8 alkyl-N(R ₂₃ )—C(═NR ₂₄ )R ₂₂ ” means that the nitrogen atom in —N(R ₂₃ )—C(═NR ₂₄ )R ₂₂ is bonded to a C _0-8 alkyl group. The definition of C _0-8 alkyl group is as described above.

" _-C0-8alkyl -C(O) _NR23R24 " means _that the carbonyl group in -C(O) _NR23R24 is bonded to a _C0-8alkyl group. _{The C0-8alkyl group} is as defined above.

“—C _0-8 alkyl—N(R ₂₃ )—C(O)R ₂₂ ” means that the nitrogen atom in —N(R ₂₃ )—C(O)R ₂₂ is bonded to a C _0-8 alkyl group. The C _0-8 alkyl group is as defined above.

"Halogen-substituted C _1-4 alkyl" refers to an alkyl group of 1-4 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl (-CHF ₂ ), dichloromethyl (-CHCl ₂ ), dibromomethyl (-CHBr ₂ ), trifluoromethyl (-CF ₃ ), trichloromethyl (-CCl ₃ ), tribromomethyl (-CBr ₃ ) and the like.

"Halogen-substituted C _1-4 alkoxy" refers to an alkoxy group with 1 to 4 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

"Deuterium-substituted C _1-4 alkyl" refers to an alkyl group of 1 to 4 carbon atoms in which hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl (-CH ₂ D), dideuteriomethyl (-CHD ₂ ), trideuteriomethyl (-CD ₃ ) and the like.

"Deuterium-substituted C _1-4 alkoxy" refers to an alkyl group of 1 to 4 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethoxy, dideuteriomethoxy, trideuteriomethoxy and the like.

"Halogen" refers to fluorine, chlorine, bromine or iodine. "MeOH" refers to methanol. "KF" refers to potassium fluoride. "KHMDS" refers to potassium hexamethyldisilazide. "NBS" refers to N-bromosuccinimide. "DMF" refers to N,N-dimethylformamide. "Grubbs 2nd generation catalyst" refers to Grubbs 2nd generation catalyst. "IBX" refers to 2-iodobenzoic acid.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes the occasions where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted situations are included. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the situation where the heterocyclic group is substituted with an alkyl group and the situation where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more "hydrogen atoms" in a group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the valence bond theory in chemistry, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefin).

"Stereoisomers" are called stereoisomers in English. They refer to isomers produced by different spatial arrangements of atoms in molecules. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in molecules, rings, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. If the compound of the present invention contains a double bond, it can be understood to include E and/or Z forms unless otherwise specified. Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers, which are divided into R and S configurations. In the present invention, the "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.

"Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

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

The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400/500 nuclear magnetic spectrometer, the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard is tetramethylsilane (TMS).

Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

Preparation of intermediates

Intermediate 1: Preparation of 2,5,6-trichloronicotinyl chloride

Dissolve 2,5,6-trichloronicotinic acid (5.1 g, 22.5 mmol) in dichloromethane (50 mL), add N,N-dimethylformamide (0.5 mL). Add oxalyl chloride (4.29 g, 33.8 mmol) dropwise to the above solution under nitrogen protection. After the addition is completed, stir at 25°C for 1 hour, and the reaction solution is concentrated under reduced pressure to remove the solvent to obtain 2,5,6-trichloronicotinyl chloride (5.52 g, yield: 100%). The crude product is directly used for the next step reaction.

The preparation of intermediate 2 can be obtained by referring to the synthesis method of intermediate 1:

Preparation of Examples

Example 1: Preparation of 2 ⁴ -(4-acryloylpiperazine-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy- ¹ 2 -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

Step 1: Synthesis of 2-cyano-N-(2-isopropyl-4-vinylpyridin-3-yl)acetamide

2-Isopropyl-4-vinylpyridin-3-amine (5g, 30.8mmol) was dissolved in 1,2-dichloroethane (50mL), and 2-cyanoacetic acid (5.24g, 61.6mmol) and triethylamine (17.1mL, 123mmol) were added respectively. Under nitrogen protection, tri-n-propyl cyclophosphoric anhydride (50% ethyl acetate solution, 39g, 61.6mmol) was added dropwise, and the reaction solution was stirred at 50°C for 1 hour. 1,2-dichloroethane was removed by concentration under reduced pressure, and 300mL saturated sodium bicarbonate aqueous solution was added to the residue, and extracted with ethyl acetate (300mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column to obtain 2-cyano-N-(2-isopropyl-4-vinylpyridin-3-yl)acetamide (3.75g, yield: 53%). ESI-MS 230[M+H] ⁺ .

Step 2: Synthesis of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

Dissolve 2-cyano-N-(2-isopropyl-4-vinylpyridin-3-yl)acetamide (5.05 g, 22.0 mmol) in tetrahydrofuran (50 mL), slowly add sodium hydride (1.32 g, 33.0 mmol) in batches at 0°C under nitrogen protection, and stir at 0°C for 30 minutes after adding sodium hydride. Dissolve 2,5,6-trichloronicotinyl chloride (5.39 g, 22.0 mmol) in 50 mL tetrahydrofuran and dropwise add it to the above solution under nitrogen protection. After the dropwise addition, the reaction solution was reacted at 70°C for 6 hours. The reaction solution was slowly poured into 200 mL of water, extracted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by a rapid silica gel column to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (2 g, yield: 22.6%). ESI-MS 401[M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate

Dissolve 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (3.13 g, 7.80 mmol) in acetonitrile (35 mL), slowly add N,N-diisopropylethylamine (3.87 mL, 23.4 mmol) and oxychlorophosphine (1.09 mL, 11.7 mmol) under nitrogen protection at 0°C. The mixture is reacted at 80°C for 1 hour. LC-MS detected 60% of the product in the reaction solution, and N,N-diisopropylethylamine (2.23 mL, 13.7 mmol) and tert-butylpiperazine-1-carboxylate (0.85 g, 4.57 mmol) were added to the reaction solution at room temperature. The mixture was reacted overnight at room temperature. The reaction solution was slowly poured into 200 mL of water, extracted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by rapid silica gel column to obtain tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (2.12 g, yield: 81.4%). ESI-MS 569[M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-(6-chloro-3-cyano-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate

Tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.89 g, 3.57 mmol) was dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (5 mL). Trifluoro(2-fluoro-6-hydroxyphenyl)borate (1.01 g, 4.64 mmol), potassium acetate (0.7 g, 7.14 mmol) and Pd(dppf)Cl ₂ (0.26 g, 0.357 mmol) were added respectively, and the mixture was reacted at 90°C for 1 hour under nitrogen protection. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by rapid silica gel column to obtain tert-butyl 4-(6-chloro-3-cyano-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.42 g, yield: 65.7%). ESI-MS 645[M+H] ⁺ .

Step 5: Synthesis of tert-butyl 4-(7-(2-(allyloxy)-6-fluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate

Dissolve tert-butyl 4-(6-chloro-3-cyano-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.42 g, 3.57 mmol) in acetonitrile (20 mL). Add 3-bromoprop-1-ene (0.58 mL, 6.60 mmol) and potassium carbonate (608 mg, 4.40 mmol) respectively and react at 70°C for 1 hour. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by rapid silica gel column to obtain tert-butyl 4-(7-(2-(allyloxy)-6-fluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.34 g, yield: 89.2%). ESI-MS 685[M+H] ⁺ .

Step 6: Synthesis of tert-butyl (Z)-4-(2 ⁶ -chloro-2 ³ -cyano-3 ⁶ -fluoro- ^{1 2} -isopropyl- ² 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 4} -yl)piperazine-1-carboxylate

Tert-butyl 4-(7-(2-(allyloxy)-6-fluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-vinylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.24 g, 1.82 mmol) was dissolved in 1,2-dichloroethane (500 mL), Grubbs second generation catalyst (0.23 g, 0.36 mmol) was added under nitrogen protection, and the reaction was carried out at 60°C overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by rapid silica gel column to obtain tert-butyl (Z)-4-(2 ⁶ -chloro- ^{2 3} -cyano- ^{3 6} -fluoro- ^{1 2} -isopropyl- ² 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene-2 ⁴ -yl)piperazine-1-carboxylate (1.1 g, purity: 80%, yield: 73.6%). ESI-MS 657 [M+H] ⁺ .

Step 7: Synthesis of tert-butyl 4-(2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6,7-dihydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate

Dissolve tert-butyl (Z)-4-(2 ⁶ -chloro-2 ³ -cyano- ^{3 6} -fluoro-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene-2 ⁴ -yl)piperazine-1-carboxylate (400 mg, 0.609 mmol) in acetone (5 mL), and add ethylene glycol (151 mg, 2.43 mmol) and sodium bicarbonate (153 mg, 1.83 mmol) respectively. Under nitrogen protection, the mixture was cooled to -20°C, and potassium permanganate (96.2 mg, 0.609 mmol) was added in batches. The reaction solution was slowly heated to 0°C and reacted for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by rapid silica gel column to obtain tert-butyl 4-(2 ⁶ -chloro-2 ³ -cyano- ^{3 6} -fluoro-6,7-dihydroxy- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-2 ⁴ -yl)piperazine-1-carboxylate (267 mg, yield: 63.5%). ESI-MS 691[M+H] ⁺ .

Step 8: Synthesis of 2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy- ^{1 2} -isopropyl-2 2 -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

Dissolve tert-butyl 4-(2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6,7-dihydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate (135 mg, 0.195 mmol) in dichloromethane (5 mL), cool the solution to 0°C, and add trifluoroacetic acid (0.8 mL) dropwise under nitrogen protection. React at 0°C for 1 hour. The reaction solution is directly concentrated under reduced pressure to remove the solvent to obtain a crude product, which is directly used in the next step. ESI-MS 591[M+H] ⁺ .

Step 9: Synthesis of 2 ⁴ -(4-acryloylpiperazine-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy- ^{1 2 -isopropyl} -2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

Dissolve 2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy-1 ² -isopropyl- ^{2 2} -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile (100 mg, 0.169 mmol) in anhydrous dichloromethane (5 mL), add triethylamine (85.6 mg, 0.846 mmol), cool to -10°C, add prop-2-enoyl chloride (15.3 mg, 0.169 mmol) dropwise under nitrogen protection, and react for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride aqueous solution (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by reverse phase column to obtain 2 ⁴ -(4-acryloylpiperazine-1-yl)-2 ⁶ -chloro- ^{3 6} -fluoro-6,7-dihydroxy- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile (24 mg, yield: 22.0%, purity: 98.84%). ESI-MS 645[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.55-8.48 (m, 2H), 8.01 (br d, J = 4.8Hz, 1H), 7.46 (q, J = 8.0Hz, 1H), 7.12 (br d,J＝8.5Hz,1H),7.03-6.87(m,2H),6.21(br d,J＝16.6Hz,1H),5.83-5.73(m,2H),5.19(br d,J＝8.5Hz ,1H),4.48(br dd,J＝4.8,8.0Hz,1H),4.05-3.69(m,10H),3.33-3.28(m,1H),2.88(td,J＝6.3,13.1Hz,1H) ,1.18(br d,J＝6.3Hz,3H),0.83(br d,J＝6.5Hz,3H).

Example 2: Preparation of (Z)-2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro- ^{1 2} -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 3} -carbonitrile

Step 1: Synthesis of (Z)-2 ⁶ -chloro-3 ⁶ -fluoro- ¹ 2 -isopropyl- ^{2 2} -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 3} -carbonitrile

Tert-butyl (Z)-4-(2 ⁶ -chloro-2 ³ -cyano-3 ⁶ -fluoro-1 ² -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 4} -yl)piperazine-1-carboxylate (80 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0°C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen protection, and the mixture was reacted at 0°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain a crude product which was directly used in the next step. ESI-MS557[M+H] ⁺ .

Step 2: Synthesis of (Z)-2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 3} -carbonitrile

Dissolve (Z)-2 ⁶ -chloro-3 ⁶ -fluoro- ¹ 2 -isopropyl- ^{2 2} -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 3} -carbonitrile (67 mg, 0.120 mmol) in anhydrous dichloromethane (3 mL), add triethylamine (60.8 mg, 0.60 mmol), cool to -10°C, add prop-2-enoyl chloride (10.8 mg, 0.12 mmol) dropwise under nitrogen protection, and react for 1 hour. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride aqueous solution (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by reverse phase column to obtain (Z)-2 ⁴ -(4-acryloylpiperazine-1-yl)-2 ⁶ -chloro- ^{3 6} -fluoro- ^{1 2} -isopropyl- ² 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene- ^{2 3} -carbonitrile (7 mg, yield: 9.52%, purity: 97.34%). ESI-MS 611 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.54 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.56-7.41 (m, 1H), 7.18-6.86 (m, 1H), 7.20-6.86(m,3H),6.38(d,J＝11.3Hz,1H),6.21(dd,J＝2.1,16.7Hz,1H),5.85-5.70(m,2H),4.75(dd,J＝ 2.9,9.7Hz,1H),3.98-3.76(m,8H),3.33(br s,1H),2.87(td,J＝6.5,13.4Hz,1H),1.18(d,J＝6.5Hz,3H),0.83(d,J＝6.5Hz,3H).

Examples 4 and 5: Preparation of 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-7-ethoxy-3 ⁶ -fluoro-6-hydroxy-1 ² -isopropyl- ² 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile and 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-6-ethoxy-3 ⁶ -fluoro-7-hydroxy- ^{1 2 -isopropyl-2} 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

Step 1: Synthesis of tert-butyl 4-(2 ⁶ -chloro-2 ³ -cyano-7-ethoxy-3 ⁶ -fluoro-6-hydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate and tert-butyl 4-(2 ⁶ -chloro-2 ³ -cyano-6-ethoxy-3 ⁶ -fluoro-7-hydroxy-1 ² -isopropyl-2 ² -oxo- ^{2 1} ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-2 ⁴ -yl)piperazine-1-carboxylate

Dissolve tert-butyl 4-(2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6,7-dihydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate (80 mg, 0.17 mmol) in ethyl acetate (3 mL), and add iodoethane (144 mg, 0.93 mmol), copper acetylacetonate (9.1 mg, 0.04 mmol), silver oxide (21.4 mg, 0.09 mmol), and tetrabutylammonium bromide (22.4 mg, 0.07 mmol) respectively. Stir at 60°C overnight under nitrogen protection. The reaction solution was diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by rapid silica gel column to obtain tert-butyl 4-( ^2,6 -chloro- ^2,3 -cyano- ⁷ -ethoxy- ^3,6 -fluoro-6-hydroxy- ^1,2 -isopropyl- ^2,2 -carbonyl-2,1,2,2-dihydro-4-oxa-2(1,7)-naphthyridine ^- 1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^2,4 -yl)piperazine-1-carboxylate and tert-butyl 4-( ^2,6 -chloro- ^2,3 -cyano- ⁶ -ethoxy-3,6-fluoro-7-hydroxy- ^1,2 -isopropyl- ^2,2 -oxo ^{- 2,1,2,2} -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate (74 mg, yield: 84.1%). ESI-MS 719 [M+H] ⁺ .

Step ² : Synthesis of ^2,6 -chloro-7-ethoxy- ^3,6 -fluoro- ⁶ -hydroxy-1,2-isopropyl- ^2,2 -oxo- ^2,4- (piperazin-1-yl)-2,1,2,2-dihydro- ⁴ -oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^2,3 -carbonitrile and ^2,6 -chloro-6-ethoxy- ^3,6 -fluoro-7-hydroxy- ^1,2 -isopropyl- ^2,2 -oxo- ^2,4- (piperazin- ¹ -yl)-2,1,2,2-dihydro-4-oxa- ² (1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^2,3 -carbonitrile

tert-Butyl 4-(2 ⁶ -chloro-2 ³ -cyano-7-ethoxy-3 ⁶ -fluoro-6-hydroxy-1 ² -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate and tert-butyl 4-(2 ⁶ -chloro- ^{2 3} -cyano-6-ethoxy-3 ⁶ -fluoro-7-hydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate mixture (70 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0°C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen protection, and the reaction was carried out at 0°C for 2 hours. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain a crude product which was directly used in the next step. ESI-MS 619 [M+H] ⁺ .

Step 3: Synthesis of 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-7-ethoxy-3 ⁶ -fluoro-6-hydroxy-1 ² -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile and 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-6-ethoxy-3 ⁶ -fluoro- ⁷ -hydroxy-1 ² -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

The mixture from the previous step (50 mg, 0.081 mmol) was dissolved in anhydrous dichloromethane (3 mL), and triethylamine (40.8 mg, 0.40 mmol) was added. The mixture was cooled to -20°C, and prop-2-enoyl chloride (7.15 mg, 0.08 mmol) was added dropwise under nitrogen protection, and the reaction was continued for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by reverse phase column to give 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-7-ethoxy-3 ⁶ -fluoro-6-hydroxy- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile (9.5 mg, yield: 17.3%, purity: 98.93%) and 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-6-ethoxy-3 ⁶ -fluoro-7-hydroxy- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile (7.8 mg, yield: 13.9%, purity: 97.10%). ESI-MS 673 [M+H] ⁺ .

Example 4: 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-6-ethoxy-3 ⁶ -fluoro-7-hydroxy- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.50 (s, 1H), 7.89 (d, J = 5.0Hz, 1H), 7.51-7.43 (m, 1H), 7.15 (d, J = 8.3Hz, 1H),7.02-6.88(m,2H),6.21(dd,J＝2.4,16.7Hz,1H),5.81-5.75(m,1H),5.30(d,J＝9.0Hz,1H),4.62(dd ,J＝4.6,8.7Hz,1H),3.99(br dd,J＝3.8,9.0Hz,4H),3.82-3.67(m,6H),3.47-3.37(m,2H),3.32-3.29(m,1H),2.89(quin,J＝6.7Hz,1H) ,1.21-1.16(m,6H),0.84(d,J=6.8Hz,3H).

Example 5: 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-7-ethoxy-3 ⁶ -fluoro-6-hydroxy- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.56 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.53-7.42 (m, 1H),7.14(d,J＝8.3Hz,1H),7.05-6.87(m,2H),6.21(dd,J＝2.4,16.7Hz,1H),5.82-5.74(m,1H),5.70(d ,J＝4.8Hz,1H),4.46(dd,J＝4.9,8.7Hz,1H),4.25(qd,J＝4.7,9.3Hz,1H),4.04-3.71(m,10H),3.33(br d,J＝2.5Hz,1H),3.17-3.09(m,1H),2.87(td,J＝6.7,13.3Hz,1H),1.18(d,J＝6.8Hz,3H),0.94(t,J ＝6.9Hz,3H),0.83(d,J＝6.8Hz,3H).

Example 14: Preparation of 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6-hydroxy-1 ² -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-7-yl acetate

Step 1: Synthesis of tert-butyl 4-(7-acetoxy-2 ⁶ -chloro-2 ³ -cyano-3 ⁶ -fluoro-6-hydroxy- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-2 ⁴ -yl)piperazine-1-carboxylate

Tert-butyl 4-(2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6,7-dihydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate (80 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (35.1 mg, 0.35 mmol), acetyl chloride (9.1 mg, 0.04 mmol), silver oxide (21.4 mg, 0.09 mmol), and tetrabutylammonium bromide (27.3 mg, 0.35 mmol) were added at 0°C. The mixture was stirred at 0°C overnight under nitrogen protection. The reaction solution was diluted with ethyl acetate (20 mL), filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was directly used in the next step. ESI-MS719[M+H] ⁺ .

Step 2: Synthesis of 2 ⁶ -chloro-2 ³ -cyano-3 ⁶ -fluoro-6 -hydroxy- ^{1 2} -isopropyl-2 2 -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptan-7-yl acetate

Tert-butyl 4-(7-acetoxy-2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6-hydroxy- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 4} -yl)piperazine-1-carboxylate (45 mg, 0.06 mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0°C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen protection, and the mixture was reacted at 0°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain a crude product which was directly used in the next step. ESI-MS 619[M+H] ⁺ .

Step 3: Synthesis of 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6-hydroxy-1 ² -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane-7-yl acetate

Dissolve 2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6-hydroxy- ^{1 2} -isopropyl-2 2 -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridin-1(3,4)-pyridine-3(1,2)-benzocycloheptane-7-yl acetate (35 mg, 0.06 mmol) in anhydrous dichloromethane (3 mL), add triethylamine (16.7 mg, 0.17 mmol), cool to -20°C, add prop-2-enoyl chloride (4.98 mg, 0.06 mmol) dropwise under nitrogen protection, and react for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride aqueous solution (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by reverse phase column to obtain 2 ⁴ -(4-acryloylpiperazine-1-yl)-2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro-6-hydroxy- ^{1 2 -isopropyl-2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-7-yl acetate (6 mg, yield: 14.5%, purity: 91.20%). ESI-MS 687 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.62(d,J＝5.0Hz,1H),8.54(s,1H),8.17(d,J＝5.0Hz,1H),7.53-7.42(m,1H),7.12(d,J＝8.3Hz,1H),7.02-6.86(m,2H),6.27-6.12(m,2H),5.82-5.7 4(m,1H),5.35(d,J＝3.3Hz,1H),4.57(dd,J＝5.3,8.8Hz,1H),4.21-4.08(m,1H),4.06-3.72(m,10H),1.87(s,3H),1.16(d,J＝6.5Hz,3H),0.89-0.84(m, 3H).

Example 16: Preparation of 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

Step 1: Synthesis of tert-butyl 4-(2 ⁶ -chloro- ^{2 3} -cyano-3 ⁶ -fluoro- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-2 ⁴ -yl)piperazine-1-carboxylate

Tert-butyl (Z)-4-(2 ⁶ -chloro-2 ³ -cyano-3 ⁶ -fluoro-1 ² -isopropyl- ² 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-6-ene-2 ⁴ -yl)piperazine-1-carboxylate (30 mg, 0.05 mmol) was dissolved in methanol (10 mL) and added to a hydrogenation bottle. Tris(triphenylphosphine)rhodium chloride (I) (4.2 mg, 0.01 mmol) was added under nitrogen protection. The above solution was replaced with hydrogen several times and stirred at 50°C overnight under a hydrogen atmosphere (50 psi). The reaction solution was filtered through celite, concentrated under reduced pressure, and the crude product was used directly in the next step. ESI-MS 659 [M+H] ⁺ .

Step 2: Synthesis of 2 ⁶ -chloro-3 ⁶ -fluoro- ^{1 2 -isopropyl-2 2} -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

The crude product tert-butyl 4-(2 ⁶ -chloro-2 ³ -cyano- ^{3 6} -fluoro-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane-2 ⁴ -yl)piperazine-1-carboxylate (20 mg, 0.030 mmol) obtained from the previous step was dissolved in dichloromethane (3 mL), the solution was cooled to 0°C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen protection, and the mixture was reacted at 0°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain a crude product which was directly used in the next step. ESI-MS 559[M+H] ⁺ .

Step 3: Synthesis of 2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

Dissolve 2 ⁶ -chloro-3 ⁶ -fluoro- ^{1 2} -isopropyl-2 2 -oxo- ^{2 4} -(piperazin-1-yl)-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile (15 mg, 0.03 mmol) in anhydrous dichloromethane (3 mL), add triethylamine (10.8 mg, 0.11 mmol), cool to -10°C, add prop-2-enoyl chloride (2.43 mg, 0.03 mmol) dropwise under nitrogen protection, and react for 1 hour. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride aqueous solution (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by reverse phase column to obtain 2 ⁴ -(4-acryloylpiperazine-1-yl)-2 ⁶ -chloro- ^{3 6} -fluoro-1 2 -isopropyl- ² 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-, naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile (1.8 mg, yield: 10.9%, purity: 100%). ESI-MS 613 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.58-8.41(m,2H),7.53-7.41(m,1H),7.33(d,J＝5.1Hz,1H),7.10(d,J＝8.4 Hz,1H),7.02-6.85(m,2H),6.21(dd,J＝2.3,16.6Hz,1H),5.77(dd,J＝2.2,10.4Hz,1H),4.46(br d,J＝5.8Hz,1H),4.09-3.66(m,8H),2.90(td,J＝6.6,13.3Hz,1H),2.40-2.23(m,3H),2.05-1.98(m,2H) ,1.17(d,J＝6.6Hz,3H),0.86(d,J＝6.6Hz,3H).

Example 17: Preparation of (R)-2 ⁴ -(4-acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy- ^{1 2} -isopropyl- ^{2 2} -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile

2 ⁴ -(4-Acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy-1 ² -isopropyl-2 ² -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile was resolved by SFC to obtain compound (R)-2 ⁴ -(4-Acryloylpiperazin-1-yl)-2 ⁶ -chloro-3 ⁶ -fluoro-6,7-dihydroxy- ^{1 2} -isopropyl-2 2 -oxo-2 ¹ ,2 ² -dihydro-4-oxa-2(1,7)-naphthyridine-1(3,4)-pyridine-3(1,2)-benzocycloheptane- ^{2 3} -carbonitrile.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.55-8.47 (m, 2H), 8.00 (d, J = 5.0 Hz, 1H), 7.51-7.42 (m, 1H), 7.12 (d, J = 8.4 Hz,1H),7.02-6.88(m,2H),6.21(dd,J＝2.2,16.7 Hz,1H),5.81-5.74(m,2H),5.19(d,J＝8.6 Hz,1H),4.52 -4.44(m,1H),4.06-3.67(m,10H),2.93-2.84(m,1H),1.18(d,J＝6.6 Hz,3H),0.83(br d,J＝6.6 Hz,4H) .

The preparation of the compounds of Examples 3, 6 to 13, and 15 can be obtained by referring to the synthesis methods of Examples 1, 2 or 4 and 5, or by preparing the compounds of Example 1 or 2 by conventional synthesis methods:

Biological test evaluation

1. Anti-proliferation 2D CTG test of H358 and MiaPaCa-2 cell lines

1. Experimental steps

1) Day 0 plating:

When the cell confluence is about 80%, detach the cells with 0.25% trypsin. Resuspend the detached cells in 5 mL of fresh cell culture medium and centrifuge to collect the cells. Count the number of cells at the same time. Then suspend the cells in medium concentration medium. Place the cells in a 96-well plate, 1500 cells/well for H358 and 500 cells/well for MIAPACA-2. Place the 96-well plate in a 37°C incubator and incubate overnight.

2) First day compound treatment:

Serially dilute 10 points at a ratio of 1:3 from the 2mM stock solution. Transfer the 5X compound-containing medium to the corresponding wells of the 96-well plate. The final top point compound concentration is 10μM and the final DMSO concentration is 0.5%. Place the 96-well plate in a 37℃ incubator and incubate for 5 days.

3) Baseline reading.

4) Read the signal on the sixth day, add 50 μL/well of detection reagent (CTG), and read the signal in the Envision machine.

2. Data processing

The percentage inhibition (%) at each compound concentration was calculated based on the signals in the HPE and ZPE control wells contained in each assay plate and the fluorescent signals in the individual compound wells. The inhibition rate for the ZPE control wells containing enzyme and substrate was 0%, and the inhibition rate for the HPE control wells containing only substrate was 100%. The concentration of the compound required to inhibit 50% (IC ₅₀ ) was determined using a four-parameter logarithmic dose-response equation based on the concentration of the test compound and the value of the inhibition percentage. The endpoint value (IC ₅₀ ) of the reference compound was evaluated in each experiment as a quality control measure. If the endpoint value was within three times of the expected value, the experiment was considered acceptable.

Table 1: Biological test results

From the activity data of the compounds in the specific examples, it can be seen that the series of compounds of the present invention have a strong inhibitory effect on the activity of K-RAS cells.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as references separately. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (18)

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein X is C(R ₇ ) or N; L is selected from -CR ₈ =CR ₉ -, -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-, -N(R ₁₄ )-C(O)-, -N(R ₁₅ )-C(R ₁₆ R ₁₇ )- and -OC(R ₁₈ R ₁₉ )-; R ₁ is selected from hydrogen, deuterium, halogen, cyano, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _{1-4 alkoxy, deuterium-substituted C 1-4 alkoxy} , C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido and -SF ₅ ; Each R ₂ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido and -SF ₅ ; _R3 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl, _-C0-8 alkyl- _SF5 , _-C0-8 alkyl-S(O) _rR20 , _{-C0-8 alkyl-OR21, -C0-8 alkyl -} C(O) _OR21 , _-C0-8 alkyl-C(O) _R22 , _{-C0-8 alkyl} -OC(O) _R22 , _-C0-8 alkyl _- NR23R24 _{, -C0-8} alkyl-C( _{＝NR23)R22 , -C0-8 alkyl} -N( _R23 )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ , the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, ═O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _{-C 0-8} alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR ₂₃ R ₂₄ , -C _0-8 alkyl-C(═NR ₂₃ )R ₂₂ , -C _0-8 alkyl-N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ ; Each R ₄ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -SF ₅ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, _cyano substituted C _{1-4 alkyl, hydroxy substituted C 1-4} alkyl, halogen substituted C _1-4 alkyl and deuterium substituted C _1-4 alkyl, or, when m ≥ 2, two R ₄ together with the part to which they are connected form a C _3-12 cycloalkyl or a 3-12 membered heterocyclyl; R ₅ and R ₆ are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _3-6 cycloalkyl, 4-6 membered heterocyclyl and di-C _1-4 alkylaminomethyl; _R7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl, _-C0-8 alkyl- _SF5 , _-C0-8 alkyl-S(O) _rR20 , _{-C0-8 alkyl-OR21, -C0-8 alkyl -} C(O) _OR21 , _-C0-8 alkyl-C(O) _R22 , _{-C0-8 alkyl} -OC(O) _R22 , _-C0-8 alkyl _- NR23R24 _{, -C0-8} alkyl-C( _{＝NR23)R22 , -C0-8 alkyl} -N( _R23 )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ , the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, ═O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ , -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _{-C 0-8} alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR ₂₃ R ₂₄ , -C _0-8 alkyl-C(═NR ₂₃ )R ₂₂ , -C _0-8 alkyl-N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ ; _R8 and _R9 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-10 alkyl, _C3-12 cycloalkyl, 4-12 membered heterocyclyl and _-C1-4 alkyl- _NR23R24 , wherein the above groups are optionally further substituted by one or more selected from deuterium, halogen, _cyano , hydroxyl, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, C5-10 aryl, _5-10 membered heteroaryl, =O, _-SF5 , -S(O) _{rR20 , -OR21} , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , _-NR23R24 , -C(═NR ₂₃ )R ₂₂ , -N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ ; _R10 , _R11 , _R12 , _R13 , _R16 , _R17 , _R18 and _R19 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, C5-10 aryl, _5-10 membered heteroaryl, _-SF5 , -S(O) _rR20 , _{-OR21, -C(O)OR21 ,} -C(O) _R22 , -OC(O _{) R22 , -NR23R24} , -C(＝ _NR23 ) _R22 , -N( _R23 )-C(＝ _NR24 ) _R22 or -C(O) _NR23R24 and -N( _R23 )-C(O _{) R22} ; or, _R10 and _R11 , _R12 and _R13 , _R16 and _R17 , _R18 and _R19 together with the carbon atoms to which they are directly attached form C(O), 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, the above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C5-10 aryl, 5-10 membered heteroaryl, =O _{, -SF5} , -S(O) _rR20 , _-OR21 , -C(O)OR ₂₁ , -C(O)R ₂₂ , -OC(O)R ₂₂ , -NR ₂₃ R ₂₄ , -C(═NR ₂₃ )R ₂₂ , -N(R ₂₃ )-C(═NR ₂₄ )R ₂₂ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ ; R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C(O)OR ₂₁ , -C(O)R ₂₂ and -C(O)NR ₂₃ R ₂₄ , wherein the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₂₀ -C _0-8 alkyl-OR ₂₁ , -C _0-8 alkyl-C(O)OR ₂₁ , -C _0-8 alkyl-C(O)R ₂₂ , -C _0-8 alkyl-OC(O)R ₂₂ , -C _0-8 alkyl-NR ₂₃ R ₂₄ , -C _0-8 alkyl-C(＝NR ₂₃ )R ₂₂ , -C _0-8 alkyl-N(R ₂₃ )-C(＝NR ₂₄ )R ₂₂ , -C _0-8 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-8 alkyl-N(R ₂₃ )-C(O)R ₂₂ substituents; each R ₂₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and -NR ₂₃ R ₂₄ , which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, =O, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and -NR ₂₃ R ₂₄ ; each R ₂₁ is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =0, cyano, C _1-10 alkyl, C _1-10 alkoxy, C 3-12 cycloalkyl, C _3-12 cycloalkoxy, _3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₃ R ₂₄ ; each R ₂₂ is selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _{1-10 alkoxy, C 2-10} alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, _3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₃ R ₂₄ , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxy, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _{3-12 cycloalkyl, C 3-12 cycloalkyloxy} , _{3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10} aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 23 R 24 substituted by a substituent selected from the group consisting of _6-10 membered aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₂₃ R ₂₄ ; Each of R ₂₃ and R ₂₄ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _1-10 alkoxy, C The alkylene group is substituted with a substituent selected from the group consisting of a C _3-12 cycloalkyl group, a C _3-12 cycloalkyloxy group, a 3-12 membered heterocyclyl group, a 3-12 membered heterocyclyloxy group, a C _6-10 aryl group, a C _6-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, an amino group, a mono-C _1-10 alkylamino group, a di-C _1-10 alkylamino group, and a C _1-10 alkanoyl group, Alternatively, _R23 and _R24 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C1-10 alkoxy, _C3-12 cycloalkyl, _C3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, _C6-10 aryl, _C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono- _C1-10 alkylamino, di- _C1-10 alkylamino and _C1-10 alkanoyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; Each r is independently 0, 1 or 2. 2. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized _in that R ₁₀ , R ₁₁ , R 12, R ₁₃ , R ₁₆ , R ₁₇ , R ₁₈ and R ₁₉ are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _{2-4 alkynyl, C 3-6 cycloalkyl} , 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -SF ₅ , -S(O) _r R ₂₀ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ , -OC(O)R ₂₂ , -NR ₂₃ R ₂₄ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ , or, _R10 and _R11 , _R12 and _R13 , _R16 and _R17 , _R18 and _R19 together with the carbon atom to which they are directly attached form C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O _{)R22 ,} -OC(O _{) R22} , _-NR23R24 , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ are substituted; R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C(O)OR ₂₁ , -C(O)R ₂₂ and -C(O)NR ₂₃ R ₂₄ , wherein the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₂₀ , -C _0-4 alkyl-OR ₂₁ , -C _0-4 alkyl-C(O)OR ₂₁ , -C _0-4 alkyl-C(O)R ₂₂ , -C _0-4 alkyl-OC(O)R ₂₂ , -C _0-4 alkyl-NR ₂₃ R ₂₄ , -C _0-4 alkyl-C(＝NR ₂₃ )R ₂₂ , -C _0-4 alkyl-N(R ₂₃ )-C(＝NR ₂₄ )R ₂₂ , -C _0-4 alkyl-C(O)NR ₂₃ R ₂₄ and -C _0-4 alkyl-N(R ₂₃ )-C(O)R ₂₂ ; wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described in claim 1. 3. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R ₈ and R ₉ are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl and -C _1-4 alkyl-NR ₂₃ R ₂₄ , and the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, hydroxyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -SF ₅ , -S(O) _r R ₂₀ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ , -OC(O)R ₂₂ , -NR ₂₃ R ₂₄ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ ; wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described in claim 1. 4. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _R7 is selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O _{) R22} , -OC(O) _{R22 , -NR23R24} , -C(＝ _NR23 ) _R22 , -N( _R23 )-C(＝ _NR24 ) _R22 , -C(O) _NR23R24 and -N _{(R23 )} -C(O) _R22 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, _5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , _-NR23R24 , -C(= _NR23 ) _R22 , -N( _R23 )-C(= _NR24 ) _R22 , -C(O) _NR23R24 and -N _{( R23} )-C(O)R substituted by a substituent of ₂₂ ; wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described in claim 1. 5. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R ₃ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _{2-4 alkynyl, C 3-6 cycloalkyl} , 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -SF ₅ , -S(O) _r R ₂₀ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ , -OC(O)R ₂₂ , -NR ₂₃ R ₂₄ , -C(＝NR ₂₃ )R ₂₂ , -N(R ₂₃ )-C(＝NR ₂₄ )R ₂₂ , -C(O)NR ₂₃ R ₂₄ and -N(R ₂₃ )-C(O)R ₂₂ The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, _5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC( _O ) _R22 , _-NR23R24 , -C(= _NR23 ) _R22 , -N( _R23 )-C(= _NR24 ) _R22 , -C(O) _NR23R24 and -N _{( R23} )-C(O)R substituted by a substituent of ₂₂ ; wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described in claim 1. 6. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _R1 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, vinyl, ethynyl, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, cyclopropyl, acetamido and _-SF5 . 7. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that each R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, cyclopropyl, acetamido and -SF ₅ . 8. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that each R ₄ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -SF ₅ , C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, cyano substituted C _1-4 alkyl, hydroxyl substituted C _1-4 alkyl, halogen substituted C _1-4 alkyl and deuterium substituted C _1-4 alkyl. 9. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that R ₅ and R ₆ are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl and dimethylaminomethyl. 10. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following compound structure of formula (II):

wherein X is CH or N, and L is -CR ₈ =CR ₉ - or -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-; R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido and -SF ₅ ; R ₂ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido and -SF ₅ ; _R3 is selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, _diC1-4 alkylaminomethyl and _-SF5 ; R _4a , R _4b , R _4c are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, cyclopropyl, cyanomethyl, hydroxymethyl, trifluoromethyl, trideuteriomethyl, difluoromethyl and dideuteriomethyl; R ₈ and R ₉ are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl and cyclopropyl; _R10 , _R11 , _R12 and _R13 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)rR20, _-OR21 , -C(O)OR21, -C(O)R22, -OC(O)R22, -NR23R24, -C ₍ O) _NR23R24 and -N(R23)-C(O) _R22 ; or, R10, R11, R12 and R13 are each independently selected from hydrogen _, deuterium, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C5-8 aryl, 5-8 membered heteroaryl, _-SF5 , -S(O) _{rR20 , -OR21} , -C(O) _OR21 , -C(O)R22, -OC( _O )R22, _-NR23R24 , -C(O) _NR23R24 and -N( _R23 )-C( _O ) _{R22 13} together with the carbon atom to which it is directly attached forms C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C5-8 aryl, 5-8 membered heteroaryl, = _O , _-SF5 , -S(O) _rR20 , _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC(O _{) R22} , _-NR23R24 , -C(O) _NR23R24 and -N( _{R23 )} -C(O) _R22 ; wherein R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and r are as described in claim 1. 11. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: the compound of formula (I) has the following compound structure of formula (III):

wherein L is -CH=CH- or -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-; R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl and -SF ₅ ; R ₂ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl and -SF ₅ ; R ₃ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, trideuteriomethoxy, cyclopropyl, cyclobutyl, cyclobutyloxy and -SF ₅ ; _R10 , _R11 , _R12 and _R13 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-8 membered heteroaryl, _-OR21 , -C(O) _OR21 , -C(O) _R22 , -OC(O) _R22 and _{-NR23R24 ;} or, _R10 and _R11 , _R12 and _R13 together with the carbon atom to which they are directly attached form C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, which is optionally further substituted with one or more deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, C _substituted by a substituent selected from the group consisting of _5-8 membered aryl, _5-8 membered heteroaryl, =O, _-SF5 , -S(O) _rR20 , -OR21, -C(O) _OR21 , -C(O) _R22 , -OC(O) _{R22 , -NR23R24} , -C(O) _NR23R24 and -N( _R23 )-C(O) _{R22 ;} each R ₂₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl and -NR ₂₃ R ₂₄ , the above groups being independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, =O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy; each R ₂₁ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy; each R ₂₂ is selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₂₃ R ₂₄ , which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy; Each of R ₂₃ and R ₂₄ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C _1-4 alkylamino and C _{1-4 alkanoyl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen _{-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-6 cycloalkyl , C} substituted by a C _3-6 -membered cycloalkyloxy group, a 3-6-membered heterocyclyl group, a 3-6-membered heterocyclyl group, a C _6-8 aryl group, a C _6-8 aryloxy group, a 5-8-membered heteroaryl group, a 5-8-membered heteroaryloxy group, an amino group, a mono-C _1-4 alkylamino group, a di-C _1-4 alkylamino group, and a C _1-4 alkanoyl group, Alternatively, _R23 and _R24 together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, _C3-6 cycloalkyl, C3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, _C6-8 aryl, _C6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono- _C1-4 alkylamino, di- _C1-4 alkylamino and _C1-4 alkanoyl; Each r is independently 0, 1 or 2. 12. The compound of formula (I) according to claim 1 or 11, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L is -CH=CH- or -C(R ₁₀ R ₁₁ )-C(R ₁₂ R ₁₃ )-; R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy and cyclopropyl; _R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, methoxy and cyclopropyl; _R3 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, trideuteriomethoxy, cyclopropyl, cyclobutyl and cyclobutyloxy; R ₁₀ is hydrogen; R ₁₁ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolyl, azolyl, -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R ₂₂ , which are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -SF ₅ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R ₂₂ ; _R12 is hydrogen; R ₁₃ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolyl, azopentyl, -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R ₂₂ , wherein the above groups are optionally further substituted by one or more selected from deuterium, fluorine, chlorine, bromine, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -SF ₅ , -OR ₂₁ , -C(O)OR ₂₁ , -C(O)R ₂₂ and -OC(O)R substituted by a substituent of ₂₂ ; Each R ₂₁ is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolyl, azolyl and phenyl, which are independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy; Each R ₂₂ is selected from hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, propoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, oxetanyl, azetidinyl, oxolyl, azopentyl and phenyl, and the above groups are independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C _1-4 alkyl, C _{1-4 alkoxy, C 3-6 cycloalkyl} , C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy. 13. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:

14. A method for preparing the compound of formula (I) according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps: the compound of formula (I') is reacted to obtain the compound of formula (I), and the reaction formula is as follows:

Wherein, R is H or an amino protecting group, preferably, the amino protecting group is tert-butyloxycarbonyl; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , L, X, m and n are as described in claim 1. 15. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 16. Use of the compound of formula (I) according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, characterized in that it is used for the preparation of a medicament for treating a tumor or cancer mediated at least in part by K-RAS G12C mutation. 17. The use according to claim 16, characterized in that the cancer or tumor is selected from lung malignancies or cancers, hepatobiliary malignancies or cancers, gastrointestinal malignancies or cancers, blood system malignancies or cancers, sarcomas, skin malignancies or cancers, bone malignancies or cancers, genitourinary tract malignancies or cancers, nervous system malignancies or cancers, gynecological malignancies or cancers and adrenal malignancies or cancers. 18. The use according to claim 17, characterized in that the lung malignancy or cancer is selected from bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma), non-small cell lung cancer, bronchial carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitinoma or mesothelioma; The hepatobiliary malignancy or cancer is selected from the group consisting of liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer or cholangiocarcinoma; The gastrointestinal malignancy or cancer is selected from the group consisting of esophageal malignancies and cancers (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, or lymphoma), gastric malignancies and cancers (carcinoma, lymphoma, or leiomyosarcoma), pancreatic malignancies and cancers (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, uveal tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal malignancies or cancers (adenocarcinoma, adenoma, adenoma, tubular adenoma), or leiomyoma; The hematological malignancy or cancer is selected from acute or chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease or non-Hodgkin's lymphoma; The sarcoma is selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma or teratoma; The skin malignancy or cancer is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus nevus, hyperplastic nevus, lipoma, hemangioma, dermatofibroma, keloid or psoriasis; The bone malignancy or cancer is selected from osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign enchondroma, chondroblastoma, chondromycofibroma, osteoid osteoma or giant cell tumor; The genitourinary tract malignancy or cancer is selected from the group consisting of a renal malignancy or cancer (adenocarcinoma, Wilms' tumor or Wilms' tumor), a lymphoma, a leukemia, a bladder or urethral malignancy or cancer (squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), a prostate malignancy or cancer (adenocarcinoma or sarcoma), a testicular malignancy or cancer (leukemia, teratoma, embryonal carcinoma or teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor or lipoma; The nervous system malignancy or cancer is selected from osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibromas, meningiomas, gliomas or sarcomas; The gynecological malignancy or cancer is selected from endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granulosa-thecal cell tumor, testicular interstitial cell tumor, myometrial dysplasia, malignant teratoma, squamous cell carcinoma, fibroepithelial carcinoma, glandular epithelial carcinoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma or fallopian tube carcinoma; The adrenal gland malignancy or cancer is selected from neuroblastoma.