TWI847445B - A oxazine compound, its pharmaceutical composition and application - Google Patents

Abstract

The present invention provides a oxazine compound, a pharmaceutical composition and an application thereof. Specifically, the compound has a structure shown in Formula I, which can interfere with the interaction between SOS1 protein and RAS protein, and is expected to be used in the preparation of drugs for treating diseases such as tumors caused by RAS mutations.

Description

A oxazine compound, its pharmaceutical composition and application

The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a oxazine compound, its pharmaceutical composition and application.

Rat sarcoma protein (RAS protein) is an important signal transduction regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration and survival. RAS belongs to guanosine triphosphate hydrolase (GTPase), and regulates multiple important signal pathways such as downstream RAF/MEK/ERK and PI3K/AKT through the cycle of RAS binding to guanosine triphosphate (GTP) in an active state and RAS binding to guanosine diphosphate (GDP) in an inactive state. This cycle includes two processes, in which negative regulation catalyzes the hydrolysis of RAS-GTP to RAS-GDP through GTPase activating protein (GAP), and positive regulation guanylate exchange factor (GEF) catalyzes the dissociation of RAS and GDP, and then RAS will bind to the high concentration of GTP in the cell. SOS1 (Son of Sevenless 1) is one of the most widely expressed and functionally important GEFs in the human body.

The RAS protein family includes KRAS (Kirsten rat sarcoma viral oncogene), NRAS (neuroblastoma RAS viral oncogene) and HRAS (Harvey murine sarcoma viral oncogene), among which KRAS mutation-induced tumors are the most common. KRAS mutation causes the protein to remain in the RAS-GTP state, continuously activating downstream signaling pathways. SOS1 plays an important role in this physiological process of carcinogenesis. Knocking out SOS1 can effectively reduce the growth rate of KRAS mutant tumors and does not affect the growth of KRAS wild-type cell lines.

Small molecule inhibitors bind to the catalytic pocket of SOS1, affecting the binding of SOS1 to RAS proteins, and can effectively inhibit the phosphorylation level of downstream RAS signaling pathways such as ERK (extracellular regulated protein kinases), thereby inhibiting tumor growth. Currently, the small molecule SOS1 inhibitor BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim is in Phase I clinical research, and is collaborating with Mirati's KRAS G12C inhibitor MRTX-849 to develop a combination drug regimen. In addition, Bayer (WO2018172250, WO2019201848) and Revolution (WO2020180770, WO2020180768) have also published multiple patents in this field, but this field still urgently needs to develop effective drugs that can inhibit the interaction between SOS1 and RAS mutant proteins.

The purpose of the present invention is to provide a new oxazine compound and a drug composition containing the same, which can effectively inhibit the interaction between SOS1 and RAS mutant protein.

In a first aspect of the present invention, there is provided a compound of formula I, a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer, a cis-trans isomer, a solvate, a polymorph, a deuterated compound or a combination thereof.

或

；其中，R^1a和R^1b各自獨立地選自：H、任選取代的C1-C6烷基、任選取代的C3-C8碳環基或任選取代的4-8元雜環基；其中，所述取代是指被一個或多個R取代； R²選自：任選取代的C1-C6烷基、任選取代的C3-C16碳環基、任選取代的4-16元雜環基；其中，所述取代是指被一個或多個R取代；A環選自：任選取代的C6-C16芳基、任選取代的5-16元雜芳基、任選取代的C3-C16碳環并C6-C10芳基、任選取代的4-16元雜環并C6-C10芳基、任選取代的C3-C16碳環并5-16元雜芳基或任選取代的4-16元雜環并5-16元雜芳基；其中，所述取代是指被一個或多個R取代；R各自獨立地選自：H、鹵素、氰基、胺基、羥基、氧代基(

)、任選取代的C1-C6烷基、任選取代的C2-C6烯基、任選取代的C2-C6炔基、任選取代的C1-C6烷氧基、-N(任選取代的C₁-C₆烷基)₂、-NH(任選取代的C₁-C₆烷基)、-N(任選取代的C₁-C₆烷基)(任選取代的C₁-C₆烷基苯基)、-NH(任選取代的C₁-C₆烷基苯基)、任選取代的C1-C6烷基-S-、-S(O)₂-任選取代的C1-C6烷基、-S(O)-任選取代的C1-C6烷基、-S(O)₂-任選取代的苯基、-S(O)₂NH₂、-S(O)₂NH(任選取代的C1-C6烷基)、-S(O)₂NH(任選取代的苯基)、-NHS(O)₂(任選取代的C1-C6烷基)、-NHS(O)₂(任選取代的苯基)、任選取代的C3-C16碳環基、任選取代的4-16元雜環基、任選取代的C6-C16芳基或任選取代的5-16元雜芳基；或任意相鄰的2個R和與其相連的原子形成任選 取代的4-8元雜環基或任選取代的C3-C8元碳環基；其中，R中所述取代是指被選自下組的一個或多個基團取代：H、鹵素、氰基、胺基、羥基、氧代基(

)、R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基碸基、R’取代或未取代的C3-C16碳環基、R’取代或未取代的4-16元雜環基、R’取代或未取代的C6-C16芳基、R’取代或未取代的5-16元雜芳基、-N(R’取代或未取代的C1-C6烷基)₂、-CH₂-N(R’取代或未取代的C1-C6烷基)₂，其中，R’選自下組的一個或多個基團：H、鹵素、氘(D)、鹵素、-OH、氧代(=O)、巰基、氰基、-CD₃、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8環烷基和4-8元雜環基，其中所述的烷基、烯基、炔基、環烷基和雜環基中的每一個任選被一個或多個選自以下的取代基進一步取代：H、C1-C6烷基、C1-C6烷氧基、鹵素、-OH、氧代(=O)、-NH₂、-N(R”取代或未取代的C1-C6烷基)₂、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、C3-C8環烷基、4-8元雜環基、C1-C4鹵代烷基-、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4鹵代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)₂、-CONH(C1-C6烷基)、-CONH₂、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、 -SO₂(C1-C6烷基)、-SO₂(苯基)、-SO₂(C1-C6鹵代烷基)、-SO₂NH₂、-SO₂NH(C1-C6烷基)、-SO₂NH(苯基)、-NHSO₂(C1-C6烷基)、-NHSO₂(苯基)、-NHSO₂(C1-C6鹵代烷基)和-C1-C6烷基-NH₂，其中R”選自下組的一個或多個基團：H、鹵素、氰基、胺基、羥基、氧代基(

)、C1-C6烷基和C1-C6烷氧基；

表示基團的連接位置。 wherein ^X1 is selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; preferably, ^X1 is CH; ^X2 is selected from: sulfur atom, oxygen atom, nitrogen atom, ^-NRx- or ^-CRx ; wherein ^Rx is selected from: H, optionally substituted C1-C3 alkyl; preferably, ^X2 is sulfur atom; wherein the substitution refers to substitution by one or more R; ^R1 is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclic group, optionally substituted 4-8 membered heterocyclic group, cyano group,

or

; wherein R ^1a and R ^1b are each independently selected from: H, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 carbocyclic group or an optionally substituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; R ² is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16-membered heterocyclic group; wherein the substitution refers to substitution by one or more R; Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16-membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16-membered heterocyclic and C6-C10 aryl, optionally substituted C3-C16 carbocyclic and 5-16-membered heteroaryl or optionally substituted 4-16-membered heterocyclic and 5-16-membered heteroaryl; wherein the substitution refers to substitution by one or more R; R is independently selected from: H, halogen, cyano, amine, hydroxyl, oxo (

), optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -N(optionally substituted _C1 - _C6 alkyl) ₂ , -NH(optionally substituted _C1 - _C6 alkyl), -N(optionally substituted _C1 - _{C6 alkyl)(optionally substituted C1-C6 alkylphenyl )} , -NH(optionally substituted _C1 - _C6 alkylphenyl), optionally substituted C1-C6 alkyl-S-, -S(O) ₂ -optionally substituted C1-C6 alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O) ₂ -optionally substituted phenyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH(optionally substituted C1-C6 alkyl), -S(O) ₂ NH (optionally substituted phenyl), -NHS (O) ₂ (optionally substituted C1-C6 alkyl), -NHS (O) ₂ (optionally substituted phenyl), optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 membered heteroaryl group; or any two adjacent R and the atoms connected thereto form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amine, hydroxyl, oxo (

), R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , -CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , wherein R' is selected from one or more groups of the following groups: H, halogen, deuterium (D), halogen, -OH, oxo (=O), hydroxyl, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups is optionally further substituted with one or more substituents selected from the following: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), _-NH2 , -N(R" substituted or unsubstituted C1-C6 alkyl) ₂ , -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclic group, C1-C4 halogenated alkyl-, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl) ₂ , -CONH(C1-C6 alkyl), -CONH ₂ , -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , -SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl), -NHSO ₂ (C1-C6 halogenated alkyl) and -C1-C6 alkyl-NH ₂ , wherein R" is one or more groups selected from the group consisting of H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

Indicates the attachment position of the group.

In another preferred example, the R ¹ is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclic group, preferably, R ¹ is selected from: H, halogen or methyl; wherein the substitution refers to substitution by one or more R, and R is defined as above.

In another preferred embodiment, the A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic C6-C10 aryl, optionally substituted 4-8 membered heterocyclic C6-C10 aryl, optionally substituted C3-C8 carbocyclic 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocyclic 5-10 membered heteroaryl; preferably, the A ring is optionally substituted phenyl, 5-6 membered heteroaryl, optionally substituted C3-C8 carbocyclic phenyl, optionally substituted 4-8 membered heterocyclic phenyl, optionally substituted C3-C8 carbocyclic 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic 5-6 membered heteroaryl; more preferably, ring A is selected from: optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl; wherein the substitution refers to substitution by one or more R; R is defined as above.

、

、

、

、

或

；其中，q為0、1、2、3或4，每個R^d各自獨立的選自：H、鹵素、胺基、羥基、氰基、任選取代的C1-C6烷基、任選取代的C1-C6烷氧基、任選取代的C1-C6烷基碸基、任選取代的C3-C16碳環基、任選取代的4-16元雜環基、任選取代的C6-C16芳基或任選取代的5-16元雜芳基，或任意相鄰的2個R^d和與其相連的碳原子形成任選取代的4-8元雜環基或任選取代的C3-C8元碳環基；其中，所述取代是指被選自下組的一個或多個基團取代：H、鹵素、氰基、胺基、羥基、氧代基(

)、R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基碸基、R’取代或未取代的C3-C16碳環基、R’取代或未取代 的4-16元雜環基、-N(R’取代或未取代的C1-C6烷基)₂、-CH₂-N(R’取代或未取代的C1-C6烷基)₂、和-CH₂-(4-8元雜環基)，其中，R’選自下組的一個或多個基團：H、鹵素、氰基、胺基、羥基、氧代基(

)、C1-C6烷基和C1-C6烷氧基；

表示基團的連接位置。 In another preferred embodiment, the A ring is

,

,

,

,

or

; wherein q is 0, 1, 2, 3 or 4, and each R ^d is independently selected from: H, halogen, amine, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heteroaryl, or any two adjacent R ^d and the carbon atom to which they are connected form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo (

), R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , -CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , and -CH ₂ -(4-8 membered heterocyclic group), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

Indicates the attachment position of the group.

其中，R^d1、R^d2、R^d3分別獨立地選自：H、鹵素、胺基、羥基、氰基、任選取代的C1-C6烷基、任選取代的C1-C6烷氧基、任選取代的C1-C6烷基碸基、任選取代的C3-C16碳環基、任選取代的4-16元雜環基、任選取代的C6-C16芳基或任選取代的5-16元雜芳基；R^d4分別獨立地選自：鹵素、任選取代的C1-C6烷基和

；q為0、1、2或3；R^d5選自：氫、任選取代的C6-C10元芳香基或任選取代的5-16元雜芳香環基；Z選自：O或NR^N；R^N選自：H或任選取代的C1-C6烷基； 其中，所述取代是指被選自下組的一個或多個基團取代：H、鹵素、氰基、胺基、羥基、氧代基(

)、R’取代或未取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷基碸基、C3-C16碳環基、4-16元雜環基、-N(R’取代或未取代的C1-C6烷基)₂、-CH₂-N(R’取代或未取代的C1-C6烷基)₂、和-CH₂-(4-8元雜環基)，其中R’選自下組的一個或多個基團：H、鹵素、氰基、胺基、羥基、氧代基(

)、C1-C6烷基和C1-C6烷氧基；

表示基團的連接位置。 In another preferred embodiment, the A ring is selected from:

wherein R ^d1 , R ^d2 , and R ^d3 are independently selected from the group consisting of H, halogen, amine, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl, or optionally substituted 5-16 membered heteroaryl; and R ^d4 are independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, and

; q is 0, 1, 2 or 3; R ^d5 is selected from: hydrogen, optionally substituted C6-C10 aromatic group or optionally substituted 5-16 heteroaromatic ring group; Z is selected from: O or NR ^N ; ^RN is selected from: H or optionally substituted C1-C6 alkyl; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo (

), R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C3-C16 carbocyclic group, 4-16 membered heterocyclic group, -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , -CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , and -CH ₂ -(4-8 membered heterocyclic group), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

Indicates the attachment position of the group.

、

、

、

、

、

、

或

；其中，R^d5a和R^d5b分別獨立地選自：H或取代或未取代的C1-C3烷基，或者R^d5a、R^d5b和相連的N原子形成4-8元雜環基；R^d5c選自：H、鹵素或取代或未取代的C1-C3烷基； 其中，所述取代是指被選自下組的一個或多個基團取代：H、鹵素、氰基、胺基、羥基、氧代基(

)、C1-C6烷基和C1-C6烷氧基；

表示基團的連接位置。 In another preferred embodiment, ring A is

,

,

,

,

,

,

or

; wherein R ^d5a and R ^d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R ^d5a , R ^d5b and the connected N atom form a 4-8 membered heterocyclic group; R ^d5c is selected from: H, halogen or substituted or unsubstituted C1-C3 alkyl; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

Indicates the attachment position of the group.

，其中，X³選自：CR^2’或N；優選地，R²為

；R^2’選自：甲基、乙基、丙基、單氟甲基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、甲硫基、二氟甲硫基、三氟甲硫基、氰基、鹵素、羥甲基或甲氧基甲基；B環選自：任選取代的C3-C16碳環基或任選取代的4-16元雜環基；其中，所述取代是指被一個或多個R取代；R的定義如上所述；

表示基團的連接位置。 In another preferred embodiment, the ^R2 is

, wherein X ³ is selected from: CR ^2' or N; preferably, R ² is

; R ^2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; Ring B is selected from: optionally substituted C3-C16 carbocyclic group or optionally substituted 4-16 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; R is defined as above;

Indicates the attachment position of the group.

)、任選取代的哌啶基(

)；其中，所述取代是指被一個或多個R取代；R的定義如上所述。 In another preferred embodiment, the B ring is selected from: an optionally substituted C3-C11 carbocyclic group or an optionally substituted 4-11 membered heterocyclic group, more preferably, the B ring is selected from: an optionally substituted C5-C11 carbocyclic group or an optionally substituted 5-11 membered heterocyclic group, more preferably, the B ring is selected from: an optionally substituted C5-C8 carbocyclic group or an optionally substituted 5-8 membered heterocyclic group, more preferably, the B ring is an optionally substituted 6 membered heterocyclic group, such as an optionally substituted tetrahydropyranyl (

), optionally substituted piperidinyl (

); wherein the substitution refers to substitution by one or more R; R is defined as above.

In another preferred embodiment, the B ring is selected from: an optionally substituted 4-6 membered monocyclic heterocyclic group or an optionally substituted 7-11 membered spiro heterocyclic group or an optionally substituted 7-11 membered bridged heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the following groups: halogen, hydroxyl, amine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, (CH ₂ ) _1-2 C3-C6 cycloalkyl, (CH ₂ ) _1-2 4-6 membered heterocyclic group, C(O)C1-C6 alkyl, C(O)C1-C6 alkoxy, C(O)C3-C6 cycloalkyl, C(O)4-6 membered heterocyclic group, CONH(C1-C6 alkyl), CON(C1-C6 alkyl) ₂ , 5-8 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl may be optionally substituted with 1-3 groups selected from the following group: halogen, hydroxyl, amine, cyano, NH(C1-C6 alkyl), N(C1-C6 alkyl) ₂ , C1-C6 alkyl, C1-C6 alkoxy.

、

、

、

In another preferred embodiment, ^R2 is selected from:

,

,

,

In another preferred embodiment, X ¹ , X ² , R ¹ , R ² , Ring A, Ring B and R ^2′ are groups corresponding to the specific compounds in the embodiments.

In another preferred embodiment, the compound is selected from the following group:

In a second aspect, the present invention provides a compound of formula II, or a salt, solvate, polymorph or deuterated form thereof,

The third aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more selected from the compound described in the first aspect, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph and deuterated product as an active ingredient; and (2) optionally, a pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides a use of the compound described in the first aspect, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated compound, or the drug composition described in the third aspect in the preparation of a drug for preventing or treating RAS mutation-mediated cancer.

In another preferred embodiment, the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, especially selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

Specific implementation methods

After extensive and in-depth research, the inventors have developed a new oxazine compound that can effectively inhibit the interaction between SOS1 and RAS mutant proteins. On this basis, the present invention was completed.

Terminology

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the field to which the present invention belongs.

As used herein, the term "comprising" or "including" may be open, semi-closed, or closed. In other words, the term also includes "consisting essentially of" or "consisting of."

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

Group Definition

Definitions of standard chemical terms can be found in the reference literature, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are used unless otherwise indicated. Unless specific definitions are provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or as described in the present invention. The above techniques and methods can generally be implemented according to conventional methods known in the art based on the descriptions in the various general and more specific literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by a person skilled in the art to provide stable structural parts and compounds.

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

The section headings used herein are for organizational purposes only and are not to be construed as limitations on the subject matter described. All references or portions of references cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and theses, are incorporated herein by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified notation to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

In addition to the foregoing, when used in the specification and scope of the patent application of this application, unless otherwise specifically indicated, the following terms have the meanings as shown below.

In this application, the term "halogen" means fluorine, chlorine, bromine or iodine.

"Hydroxy" refers to the -OH group.

"Hydroxyalkyl" means an alkyl group as defined below substituted with a hydroxy (-OH) group.

"Carbonyl" refers to the -C(=O)- group.

"Nitro" refers to _-NO2 .

"Cyano" refers to -CN.

"Amine" refers to _-NH2 .

"Substituted amino group" refers to an amino group substituted by one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, heteroarylalkyl groups as defined below, for example, monoalkylamino groups, dialkylamino groups, alkylamide groups, arylalkylamino groups, heteroarylalkylamino groups.

"Carboxyl" refers to -COOH.

In this application, as a group or part of other groups (for example, in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by one or more single bonds, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl. For the purpose of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

In this application, as a group or as part of other groups, the term "alkenyl" means a straight or branched alkyl chain group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule through one or more single bonds, such as but not limited to vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

As a group or part of other groups herein, the term "alkynyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule through one or more single bonds, such as but not limited to ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

In the present application, as a group or part of other groups, the term "carbocyclic (base)" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spirocyclic system, having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and which is a saturated or unsaturated ring (i.e., cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule through one or more single bonds via any appropriate carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the carbocyclic group can be optionally oxidized. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindenyl, octahydro-4,7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5,6 ,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

In this application, as a group or part of other groups, the term "cycloalkyl" refers to the above-mentioned fully saturated carbon ring (group), preferably C3-C6 cycloalkyl. Typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

In this application, as a group or part of other groups, the term "cycloalkenyl" refers to a partially unsaturated carbon ring (group), and typical cycloalkenyl groups include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

In the present application, as a group or part of other groups, the term "heterocyclic (base)" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specifically indicated in the specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the nitrogen, carbon or sulfur atom in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or completely saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and via one or more single bonds. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, alkyl, azacyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimide, etc.

In this application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms). For the purpose of the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a carbocyclic or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule through one or more single bonds via atoms on the aromatic ring. Examples of aryl groups include but are not limited to phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.

In this application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered concentric ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a carbocyclic group or a heterocyclic group defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms on the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purpose of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, oxolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriazole yl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4] triazolo[4,3-b]oxazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]oxazine, imidazo[1,2-a]pyrazine, etc.

In this application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

In this application, the term "absent" means that the two sides of the groups defined above are directly connected by chemical bonds. For example, "B is absent in A-B-C" means "A-C".

”中的“

”表示基團R的連接位置。 In this application, “

"middle"

” indicates the attachment position of group R.

In this application, unless otherwise specified in the scope of the application, "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the hydrogen on the aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently substituted with one or more, for example, 1, 2, 3 or 4, substituents independently selected from: deuterium (D), halogen, -OH, oxo (=O), hydroxyl, cyano, -CD ₃ , -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl (preferably C3-C8 carbocyclyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 halogenated alkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclo, -O aryl, -O heteroaryl, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 halogenated alkyl, -NH ₂ , -C1-C6 alkyl-NH ₂ (preferably -C1-C3 alkyl-NH ₂ ), -N(C1-C6 alkyl) ₂ (preferably -N(C1-C3 alkyl) ₂ ), -NH(C1-C6 alkyl)(preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl(preferably -C(O)OC1-C3 alkyl), -CONR ⁱ R ⁱⁱ (wherein R ⁱ and R ⁱⁱ is H, D and C1-6 alkyl, preferably C1-3 alkyl), -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, -C(O) heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 halogenated alkyl, -OC(O)C1-C6 alkyl (preferably -OC(O)C1-C3 alkyl), -S(O) ₂ -C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O) ₂ -phenyl, -S(O) ₂ - _C1 -C6 halogenated alkyl, -S(O) _2NH2 , -S(O) ₂ NH(C1-C6 alkyl), -S(O) ₂ NH(phenyl), -NHS(O) ₂ (C1-C6 alkyl), -NHS(O) ₂ (phenyl) and -NHS(O) ₂ (C1-C6 halogenated alkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclic and heteroaryl groups is optionally further substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH ₂ , carbocyclic group, 3-8 membered heterocyclic group, C1-C4 alkyl, C1-C4 halogenated alkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl) ₂ , -CONH(C1-C6 alkyl), -CONH ₂ , -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , -SO ₂ NH(C1-C6 alkyl), -SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and -NHSO ₂ (C1-C6 halogenated alkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. The terms "part", "structural part", "chemical part", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule. In the present invention, "optionally substituted" and "substituted or unsubstituted" have the same meaning and can be used interchangeably.

、

、

、

或

等。 In the present invention, (C1-C4 alkyl) _2- amino represents an amine substituted with two C1-C4 alkyl groups, for example,

,

,

,

or

wait.

In the present invention, "multiple" means 2, 3 or 4.

，代表C1-C6烷基取代的酯基，例如可以是

、

、

、

、

、

。 In the present invention, -C(O)OC1-C6 alkyl, i.e.

, represents a C1-C6 alkyl substituted ester group, for example,

,

,

,

,

,

.

、

、

、

或

等。 In the present invention, -N(C1-C6 alkyl) ₂ , or (C1-C6 alkyl) ₂ amine, means that the two hydrogen atoms on NH ₂ are replaced by two C1-C6 alkyl atoms, for example

,

,

,

or

wait.

Intermediate

Intermediates refer to semi-finished products, which are products formed in the process of producing the desired products. Usually, inventors can use intermediates as starting materials to produce products. Therefore, screening suitable intermediates can optimize the process route, thereby achieving the purpose of improving yield, saving time and cost.

In the present invention, the intermediate refers to the following compound

Here, R ₁ , X ¹ , and X ² have the same meanings as described above.

Preferably, the intermediate is

Preparation method of intermediates

In the present invention, the preparation method of the intermediate comprises the steps of:

(i) In a solvent (such as N,N -dimethylformamide (DMF)), compound a-1 reacts with a cyaniding agent (such as cuprous cyanide) to obtain compound a-2; (ii) In a solvent (such as ethanol), compound a-2 reacts with hydrazine or its salt (such as hydrazine hydrochloride) to obtain compound a-3; (iii) In a solvent (such as acetonitrile), compound a-3 reacts in the presence of a nitrite (tert-butyl nitrite) and cuprous chloride to obtain compound a.

In the above steps, the reaction time and reaction temperature can be selected according to the specific reactants.

Active ingredients

As used herein, "compounds of the present invention" or "active ingredient" refers to the compound shown in Formula I, and also includes its pharmaceutically acceptable salts, chiral isomers, non-chiral isomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated substances or combinations thereof.

"Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but with different three-dimensional structures. The present invention will cover various stereoisomers and mixtures thereof.

When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, the compounds of the present invention are intended to include E- and Z-geometric isomers.

"Tautomers" refer to isomers formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also included in the scope of the present invention.

The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and thus may produce chiral isomers, non-chiral isomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The preparation of the compounds of the present invention may select racemates, non-chiral isomers or chiral isomers as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/isolating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004 ; A. M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010 ; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991. ,809-816; Heller, Acc.Chem.Res. 1990 ,23,128.

In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable alkali addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or organic acid that can retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include but are not limited to formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, octanoates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates. , maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, appletate, glutamine, pyroglutamine, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: first amines, second amines, and third amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

It should also be understood by those skilled in the art that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amine, alkyl and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amine, amidine and guanidine include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable alkyl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymer resins.

Pharmaceutical compositions and methods of administration

In this application, "drug composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the drug composition is to promote the administration of the organism, facilitate the absorption of the active ingredient, and then exert biological activity.

The compounds described by the general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs at overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

Drugs or active ingredients that can be used in combination with the compound of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.) , KRAS inhibitors (such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, larvatinib, oclatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3 K inhibitors (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as Ibrutinib, Telabutinib, Acalabrutinib, Zebutinib, Vicabrutinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068) or their combinations.

The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any component contained in the composition.

In this application, "pharmaceutically acceptable carriers" include but are not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant government regulatory authorities as acceptable for human or livestock use.

There is no particular limitation on the administration of the compounds or drug compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, enteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, For example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) buffers, such as wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, pills, capsules, pellets and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.

In addition to the active compound, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc.

Compositions for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The "tumor" mentioned in the present invention includes but is not limited to lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer. The terms "preventable", "prevention" and "prevention" used herein include reducing the possibility of the occurrence or deterioration of the disease or condition in the patient.

As used herein, the term "treat" and other similar synonyms include the following meanings: (i) preventing a disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the disease or condition but has not yet been diagnosed with the disease or condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing the disease or condition to regress; or (iv) alleviating the symptoms caused by the disease or condition.

As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be the elimination and/or relief of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant symptom-relieving effect clinically. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

The terms "taking", "administering", "dosing", etc. used herein refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "drug combination", "drug combination", "combination therapy", "administration of other treatments", "administration of other therapeutic agents", etc. refer to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, combined administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount and a pharmacologically acceptable formulation or carrier. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

Preparation method of compound

The following scheme describes a method for preparing the compound of formula I. In some cases, the order of the steps of the reaction scheme can be changed to promote the reaction or avoid unwanted side reaction products. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a technician in the field to which the present invention belongs.

It will also be appreciated by those skilled in the art that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amine, alkyl and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, allyl, etc. Suitable protecting groups for amine, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyloxycarbonyl, p-toluenesulfonyl, t-pentanoyl, trifluoroacetyl, etc. Suitable alkyl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymer resins.

Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5-48 hours.

Preferably, the compound of formula I can be prepared by the following method:

(1) Compound a and b-1 undergo Friedel-Crafts acylation in the presence of a Lewis acid to generate compound c, wherein the Lewis acid is selected from the group consisting of aluminum trichloride, tin dichloride, zinc chloride, boron trifluoride, titanium tetrachloride, tetraisopropyl titanium oxide, etc.; or compound a reacts with compound b-2 in the presence of a strong base to generate compound c, wherein the strong base is selected from the group consisting of n-butyl lithium, lithium diisopropylamide, tert-butyl lithium, sec-butyl lithium, lithium hexamethyldisilazide, or a combination thereof; (2) Compound c reacts with compound d in the presence of a base to generate an aromatic nucleophilic substitution reaction. Compound I, wherein the base is selected from the group consisting of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate, potassium phosphate, triethylamine, diisopropylethylamine, 1.8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof; or compound c and compound d undergo a Buchwald-Hartwig reaction to generate compound I; wherein X ¹ , X ² , R ¹ , R ² , and ring A are as defined above.

The main advantages of the invention are:

1. The compound in this application has a novel structure; 2. The compound in this application can effectively inhibit the binding of SOS1 to RAS protein; 3. The compound in this application has good pharmacokinetics and efficacy.

The technical solution of the present invention is further explained below through a specific implementation method. Those skilled in the art should understand that the embodiments described are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

In each example, ¹ H NMR was recorded by a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm); liquid chromatography mass spectrometry (LCMS) was recorded by a Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, LCMS-2020 mass spectrometer; and preparative HPLC separation was performed using a Gilson-281 liquid chromatograph.

Embodiment

Preparation of intermediates

1. Preparation of intermediate A

(1) Add cuprous cyanide (8.73 g, 97.5 mmol) to a solution of compound A-1 (10.0 g, 48.8 mmol) in N,N -dimethylformamide (100 mL). Stir the reaction mixture at 100 °C for 16 hours under nitrogen. Add water (100 mL) to the reaction mixture, extract with ethyl acetate (200 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product is separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 5:1) to obtain compound A-2 .

¹ H NMR (400 MHz, DMSO- d 6 ) δ 8.15 (d, J =5.2 Hz, 1H), 7.69 (d, J =5.2 Hz, 1H), 2.65 (s, 3H).

(2) Add hydrazine hydrochloride (2.92 g, 27.78 mmol) to a solution of compound A-2 (3.50 g, 23.2 mmol) in ethanol (20.0 mL). Stir the reaction solution at 80 °C for 12 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure, add water (50.0 mL), extract with ethyl acetate (50.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain crude compound A-3 .

MS-ESI [M+H] ⁺ , calcd. 166, found 166.

(3) Add tert-butyl nitrite (2.50 g, 24.2 mmol) and cuprous chloride (2.40 g, 24.2 mmol) to a solution of compound A-3 (2.00 g, 12.1 mmol) in acetonitrile (30.0 mL). Stir the reaction solution at 60 °C for 12 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure, add water (30.0 mL), extract with ethyl acetate (50.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to obtain compound A-4 .

MS-ESI [M+H] ⁺ , calcd. 185, found 185.

(4) Compound A - 5 (1.52 g, 6.50 mmol), sodium acetate (122 mg, 542 μmol), cesium carbonate (3.53 g, 10.8 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (675 mg, 1.08 mmol) were added to a toluene (10.0 mL) solution of compound A-4 (1.00 g, 5.42 mmol). The reaction solution was stirred at 105 °C for 2 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain compound A.

MS-ESI [M+H] ⁺ , calcd. 383, found 383.

2. Preparation of intermediate B

(1) To a solution of compound B-1 (2.00 g, 20.0 mmol) in bromoform (10.0 mL) at 0°C, add a solution of potassium hydroxide (3.36 g, 59.9 mmol) in methanol (2.43 mL). The reaction solution was stirred at 25°C for 12 hours under nitrogen protection. Dichloromethane (30.0 mL) was added to the reaction solution, extracted with water (15.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound B-2 .

¹ H NMR (400 MHz, DMSO- d 6 ) δ 3.69 (s, 3H), 3.57 (dd, J =7.2, 3.2 Hz, 4H), 3.16 (s, 3H), 1.84-1.92 (m, 2H), 1.71-1.76 (m, 2H).

(2) Lithium hydroxide monohydrate (3.61 g, 86.1 mmol) and water (10.0 mL) were added to a solution of compound B-2 (5.00 g, 28.7 mmol) in tetrahydrofuran (30 mL). The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, water (10.0 mL) was added, the pH was adjusted to 5 with dilute hydrochloric acid, and extracted with ethyl acetate (15.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound B-3 .

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.74-3.78 (m, 4H), 3.33 (s, 3H), 2.11-2.14 (m, 1H), 2.05-2.11 (m, 1H), 1.86-1.89 (m, 1H), 1.82-1.86 (m, 1H).

(3) Add diisopropylethylamine (7.99 g, 61.8 mmol), the hydrochloride of compound B-4 (2.01 g, 20.6 mmol) and propylphosphonic anhydride (26.2 g, 41.2 mmol, 50%) to a solution of compound B-3 (3.30 g, 20.6 mmol) in dichloromethane (30.0 mL). Stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Add dichloromethane (20.0 mL) to the reaction solution, wash with water (10.0 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 2:1) to obtain compound B.

MS-ESI [M+H] ⁺ , calcd. 204, found 204.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.73-3.79 (m, 4H), 3.72 (s, 3H), 3.32 (s, 3H), 3.23 (s, 3H), 2.05-2.15 (m, 2H), 1.92-2.00 (m, 2H).

Example 1 Synthesis of Compound 1

(1) To a solution of intermediate A (100 mg, 262 μmol) in tetrahydrofuran (6.0 mL) was added lithium diisopropylamide (2.0 mol/L, 523 μL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection, and a solution of dimethyl carbonate (70.7 mg, 785 μmol) in tetrahydrofuran (6.0 mL) was added. The reaction solution was stirred at 0°C for 2 hours under nitrogen protection, and then a saturated aqueous ammonium chloride solution (100 mL) was added. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 10:1) to obtain compound 1-1 .

(2) Lithium hydroxide monohydrate (6.53 mg, 2.73 μmol) and water (1.0 mL) were added to a solution of compound 1-1 (40.0 mg, 90.8 μmol) in tetrahydrofuran (30. mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, water (50.0 mL) was added, and the solution was washed with ethyl acetate (50.0 mL × 2). The pH of the aqueous phase was adjusted to 5 with dilute hydrochloric acid, and the solution was extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-2 .

MS-ESI [M+H] ⁺ , calcd. 427, found 427.

(3) Compound 1-3 (9.68 mg, 56.3 μmol), propylphosphonic anhydride (74.6 mg, 117 μmol, 50%) and diisopropylethylamine (30.3 mg, 235 μmol) were added to a solution of compound 1-2 (20.0 mg, 46.9 μmol) in dichloromethane (4.0 mL). The reaction solution was stirred at 25°C for 2 hours, then a saturated sodium bicarbonate aqueous solution (30.0 mL) was added, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-4 .

MS-ESI [M+H] ⁺ , calcd. 508, found 508.

(4) Palladium carbon (0.05 g, 10%) was added to a solution of compound 1-4 (20.0 mg, 39.4 μmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15 psi), filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 25%-60%: 12 minutes) to obtain compound 1 .

MS-ESI [M+H] ⁺ , calcd. 478, found 478.

¹ H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 6.97 (s, 2H), 6.77 (s, 1H), 5.31-5.45 (m, 2H), 4.08-4.34 (m, 4H), 3.81 (d, J =13.6 Hz, 1H), 2.65 (s, 3H), 2.19 (t, J =7.6 Hz, 1H), 1.96 (d, J =9.2 Hz, 1H), 1.62 (d, J =7.2 Hz, 3H).

Example 2 Synthesis of Compound 2

(1) To a solution of intermediate A (250 mg, 654 μmol) in tetrahydrofuran (3.0 mL) was added lithium diisopropylamide (2.0 mol/L, 1.31 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection, and a solution of compound B (399 mg, 1.96 mmol) in tetrahydrofuran (3.0 mL) was added. The reaction solution was stirred at 0°C for 2 hours under nitrogen protection, and then a saturated aqueous ammonium chloride solution (100 mL) was added, and water (100 mL) was added, and extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography (Welch Xtimate C18, 150 mm×30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 40%-80%: 12 minutes) to obtain compound 2-1 .

MS-ESI [M+H] ⁺ , calcd. 525, found 525.

(2) Palladium carbon (0.10 g, 10%) was added to a solution of compound 2-1 (100 mg, 191 μmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15 psi), filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 37%-74%: 12 minutes) to obtain compound 2 .

MS-ESI [M+H] ⁺ , calcd. 495, found 495.

¹ H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 6.98 (d, J =5.6 Hz, 2H), 6.78 (s, 1H), 5.41 (q, J =6.8 Hz, 1H), 3.76-3.92 (m, 4H), 3.32-3.34 (m, 3H),, 2.66 (s, 3H), 2.04-2.14 (m, 4H), 1.63 (d, J =7.2 Hz, 3H).

Example 3 Synthesis of Compound 3

(1) Compound 3-2 (2.31 g, 12.4 mmol), tris[dibenzylideneacetone]dipalladium (569 mg, 621 μmol), sodium tert-butoxide (1.19 g, 12.4 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (244 mg, 621 μmol) were added to a toluene (10.0 mL) solution of compound 3-1 (1.00 g, 6.21 mmol). The reaction solution was stirred at 100°C for 10 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 10:1) to obtain compound 3-3 . MS-ESI [M+H] ⁺ , calculated value 267, found value 267.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (s, 1H), 6.97 (s, 1H), 3.83 (s, 3H), 3.51-3.60 (m, 4H), 2.83-2.92 (m, 4H), 1.474 (s, 9H).

(2) Add trifluoroacetic acid (214 mg, 1.88 mmol) to a solution of compound 3-3 (100 mg, 375 μmol) in dichloromethane (2.0 mL). Stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 3-4 . MS-ESI [M+H] ⁺ , calculated value 167, found value 167.

(3) Compound 3-4 (46.8 mg, 281 μmol), propylphosphonic anhydride (373 mg, 586 μmol, 50%) and diisopropylethylamine (151 mg, 1.17 μmol) were added to a solution of compound 1-2 (100 mg, 234 μmol) in dichloromethane (4.0 mL). The reaction solution was stirred at 25°C for 2 hours, then a saturated sodium bicarbonate aqueous solution (30.0 mL) was added, and the mixture was extracted with ethyl acetate (50.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-5 . MS-ESI [M+H] ⁺ , calculated value 575, found value 575.

(4) Palladium carbon (0.1 g, 10%) was added to a solution of compound 3-5 (80.0 mg, 139 μmol) in tetrahydrofuran (2.0 mL). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15 psi), filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 15%-45%: 10 minutes) to obtain the formate salt of compound 3. MS-ESI [M+H] ⁺ , calculated value 545, found value 545.

¹ H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 7.29 (d, J =14.0 Hz, 3H), 6.75-7.00 (m, 2H), 3.87-3.97 (m, 5H), 3.81 (s, 3H), 3.03-3.08 (m, 4H), 2.65 (s, 3H), 1.54-1.72 (m, 3H).

Example 4 Synthesis of Compound 4

(1) Add diisopropylamine lithium (2.00 mol/L, 1.22 mL) to a solution of compound A-4 (150 mg, 812 mmol) in tetrahydrofuran (6.0 mL). Stir the reaction mixture at -78°C for 1 hour under nitrogen protection, add compound B (330 mg, 1.62 mmol), stir the reaction mixture at -78°C for 1 hour under nitrogen protection, slowly raise the temperature to room temperature, and continue stirring for 2 hours. Add saturated aqueous ammonium chloride solution (5.0 mL), add water (5.0 mL), extract with dichloromethane (5.0 mL × 2), combine the organic phases, wash with saturated brine (5.0 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 1:1) to obtain compound 4-1 .

MS-ESI [M+H] ⁺ , calcd. 327, found 327.

(2) Synthesis of compound 4-2 : Patent WO2021127429. Compound 4-1 (100 mg, 306 μmol), palladium acetate (7.91 mg, 35.2 μmol), diisopropylethylamine (45.2 mg, 350), cesium carbonate (228 mg, 699 μmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (43.9 mg, 70.4 μmol) were added to a toluene (1.0 mL) solution of compound 4-2 (160 mg, 35.0 μmol). The reaction solution was stirred at 100 °C for 4 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 20:1) to obtain compound 4-3 .

MS-ESI [M+H] ⁺ , calcd. 748, found 748.

(3) Tetrabutylammonium fluoride (1.00 mol/L, 88.2 μL) was added to a solution of compound 4-3 (44.0 mg, 58.8 μmol) in tetrahydrofuran (1.0 mL) at 0°C. The reaction solution was stirred at 25°C for 1 hour. Water (5.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5.0 mL × 2). The organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Phenomenex C18, 75 mm × 30 mm 3 μm, A: water (ammonium bicarbonate); B: acetonitrile, 31%-61%: 10 minutes) to obtain compound 4 . MS-ESI [M+H] ⁺ , calcd. 510, found 510.

¹ H NMR (400 MHz, MeOD) δ 9.00 (s, 1H), 7.54 (t, J =7.2 Hz, 1H), 7.42 (t, J =7.2 Hz, 1H), 7.15 (t, J =7.6 Hz, 1H), 5.72 (q, J =6.8 Hz, 1H), 4.03 (t, J =14.0 Hz, 2H), 3.77-3.93 (m, 4H), 3.32 (br s, 3H), 2.64 (s, 3H), 2.03-2.14 (m, 4H), 1.67 (d, J =6.8 Hz, 3H).

Example 5 Synthesis of Compound 5

(1) To a solution of compound 5-1 (1.70 g, 6.56 mmol) in dichloromethane (5.0 mL), diisopropylethylamine (4.24 g, 32.8 mmol), the hydrochloride of compound B-4 (959 mg, 9.83 mmol) and propylphosphonic anhydride (10.4 g, 16.4 mmol, 50%) were added. The reaction solution was stirred at 25°C for 1 hour under nitrogen protection. The reaction solution was diluted with dichloromethane (30.0 mL) and washed with saturated sodium bicarbonate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 5-2 . MS-ESI [M-Boc+H] ⁺ , calculated value 203, found value 203.

(2) Add diisopropylamino lithium (2.00 mol/L, 5.42 mL) to a solution of compound 5-2 (500 mg, 2.71 mmol) in tetrahydrofuran (6.0 mL). The reaction mixture was stirred at -78 °C for 1 hour under nitrogen protection, and intermediate A-4 (983 mg, 3.25 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours under nitrogen protection, and a saturated aqueous ammonium chloride solution (100.0 mL) was added. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain compound 5-3 . MS-ESI [M+H] ⁺ , calcd. 426, found 426.

(3) Compound A-5 (90.7 mg, 388 μmol), palladium acetate (7.91 mg, 35.2 μmol), cesium carbonate (229 mg, 704 μmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine ) (43.9 mg, 70.4 μmol) were added to a solution of compound 5-3 (150 mg, 352 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 80°C for 2 hours under nitrogen protection. Water (100.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain compound 5-4 . MS-ESI [M+H] ⁺ , calculated value 624, found value 624.

(4) Trifluoroacetic acid (128 mg, 1.12 mmol) was added to a solution of compound 5-4 (70.0 mg, 112 μmol) in dichloromethane (5.0 mL). The reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 5-5 . MS-ESI [M+H] ⁺ , calculated value 524, found value 524.

(5) To a solution of compound 5-5 (50.0 mg, 78.4 μmol) in ethanol (5.0 mL) were added paraformaldehyde (11.8 mg, 392 μmol), triethylamine (7.94 mg, 78.4 μmol), acetic acid (471 μg, 7.84 μmol) and sodium cyanoborohydride (7.39 mg, 118 μmol). The reaction solution was stirred at 25°C for 10 hours, water (100.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5-6 . MS-ESI [M+H] ⁺ , calculated value 538, found value 538.

(6) Iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) were added to a solution of compound 5-6 (20.0 mg, 37.2 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 60°C for 1 hour, water (100.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (C18-1, 150 mm×30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 25%-65%: 25 minutes) to obtain compound 5 . MS-ESI [M+H] ⁺ , calcd. 508, found 508.

¹ H NMR (400 MHz, MeOD) δ 8.94 (s, 1H), 6.97 (br d, J =6.4 Hz, 2H), 6.77 (s, 1H), 5.40 (q, J =7.2 Hz, 1H), 3.28 (s, 3H), 2.76 (br d, J =10.8 Hz, 2H), 2.65 (s, 3H), 2.46-2.56 (m, 2H), 2.34 (s, 3H), 2.15-2.24 (m, 2H), 2.01-2.12 (m, 2H), 1.62 (d, J =7.2 Hz, 3H).

Example 6 Synthesis of Compound 6

(1) Synthesis of compound 6-1 : Refer to patent WO2021127429. Compound 5-3 (107 mg, 250 μmol), palladium acetate (5.11 mg, 22.6 μmol), cesium carbonate (148 mg, 455 μmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (28.3 mg, 45.5 μmol) were added to a solution of compound 6-1 (100 mg, 227 μmol) in dioxane (2.0 mL). The reaction solution was stirred at 80°C for 1 hour under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5.0 mL × 2). The organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain compound 6-2 .

MS-ESI [M+H] ⁺ , calcd. 829, found 829.

(2) Add trifluoroacetic acid (138 mg, 1.21 mmol) to a solution of compound 6-2 (100 mg, 121 μmol) in dichloromethane (3.0 mL). Stir the reaction mixture at 25° C. for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain the trifluoroacetic acid salt of compound 6-3 .

MS-ESI [M+H] ⁺ , calcd. 729, found 729.

(3) To a solution of the trifluoroacetic acid salt of compound 6-3 (60.0 mg, 82.3 μmol) in ethanol (2.0 mL) were added paraformaldehyde (2.4 mg, 412 μmol), triethylamine (8.33 mg, 82.3 μmol), acetic acid (4.94 mg, 82.3 μmol) and sodium cyanoborohydride (5.17 mg, 82.3 μmol). The reaction solution was stirred at 25°C for 1 hour, water (100.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-4 .

MS-ESI [M+H] ⁺ , calcd. 743, found 743.

(4) Tetrabutylammonium fluoride (1.00 mol/L, 101 μL) was added to a solution of compound 6-4 (50.0 mg, 67.3 μmol) in tetrahydrofuran (1.0 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL × 2). The organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Welch Xtimate C18, 150 mm × 25 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 5%-35%: 25 min) to obtain compound 6 .

MS-ESI [M+H] ⁺ , calcd. 505, found 505.

¹ H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 7.64 (s, 1H), 7.57 (br d, J =6.8 Hz, 1H), 7.33-7.44 (m, 2H), 5.53 (q, J =7.2 Hz, 1H), 3.86 (t, J =13.6 Hz, 2H), 3.17-3.23 (m, 2H), 2.99-3.09 (m, 2H), 2.72 (s, 3H), 2.66 (s, 3H), 2.37 (br d, J =14.0 Hz, 2H), 2.15-2.25 (m, 2H), 1.67 (d, J =7.2 Hz, 3H).

Example 7 Synthesis of Compound 7

(1) Synthesis of compound 7-1 : Refer to patent WO2021127429. Compound 5-3 (50.2 mg, 118 μmol), palladium acetate (2.65 mg, 11.8 μmol), cesium carbonate (76.9 mg, 236 μmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (14.7 mg, 23.6 μmol) were added to a solution of compound 7-1 (35.0 mg, 141 μmol) in dioxane (2.0 mL). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5.0 mL × 2). The organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 20:1) to obtain compound 7-2 .

MS-ESI [M+H] ⁺ , calcd. 637, found 637.

(2) Add trifluoroacetic acid (154 mg, 1.35 mmol) to a solution of compound 7-2 (20.0 mg, 31.4 μmol) in dichloromethane (1.0 mL). Stir the reaction mixture at 25° C. for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain the trifluoroacetic acid salt of compound 7-3 .

MS-ESI [M+H] ⁺ , calcd. 537, found 537.

(3) To a solution of the trifluoroacetic acid salt of compound 7-3 (30.0 mg, 55.9 μmol) in ethanol (0.5 mL) were added paraformaldehyde (5.04 mg, 168 μmol), triethylamine (8.33 mg, 82.3 μmol), acetic acid (4.94 mg, 82.3 μmol) and sodium cyanoborohydride (3.51 mg, 55.9 μmol). The reaction solution was concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Welch Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 15%-35%: 10 min) to give compound 7. MS-ESI [M+H] ⁺ , calculated value 551, found value 551.

¹ H NMR (400 MHz, MeOD) δ 9.02 (d, J =8.4 Hz, 1H), 7.53 (t, J =6.8 Hz, 1H), 7.35 (t, J =6.8 Hz, 1H), 7.12 (t, J =8.0 Hz, 1H), 5.73 (q, J =6.8 Hz, 1H), 3.35 (d, J =11.2 Hz, 6H), 3.00-3.19 (m, 2H), 2.69-2.83 (m, 2H), 2.59-2.67 (m, 3H), 2.32-2.50 (m, 2H), 2.13-2.28 (m, 2H), 1.62-1.71 (m, 3H), 1.29 (br s, 6H).

Example 8 Synthesis of Compound 8

(1) Add diisopropylethylamine (4.48 g, 34.7 mmol), the hydrochloride of compound 8-2 (1.01 g, 10.4 mmol) and propylphosphonic anhydride (6.62 g, 10.4 mmol, 50%) to a solution of compound 8-1 (1 g, 6.94 mmol) in dichloromethane (30.0 mL). Stir the reaction solution at 25 °C for 2 hours under nitrogen protection. Add dichloromethane (20.0 mL) to the reaction solution, wash with water (10.0 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (dichloromethane/methanol = 1:0 to 50:1) to obtain compound 8-3 . MS-ESI [M+H] ⁺ , calculated value: 188, found value: 188.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.73-3.81 (m, 2H), 3.66 (s, 3H), 3.58-3.66 (m, 2H), 3.21 (s, 3H), 2.14-2.23 (m, 2H), 1.52-1.61 (m, 2H), 1.29 (s, 3H).

(2) To a solution of intermediate A (50 mg, 130 μmol) in tetrahydrofuran (1.0 mL) was added lithium diisopropylamide (2.0 mol/L, 0.26 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection, and a solution of compound 8-3 (73.4 mg, 392 mmol) in tetrahydrofuran (1.0 mL) was added. The reaction solution was stirred at -78°C to 0°C under nitrogen protection for 2 hours, and then a saturated aqueous ammonium chloride solution (10.0 mL) was added, and water (10.0 mL) was added. It was extracted with ethyl acetate (10.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography (Welch Xtimate C18, 100mm×30mm 10μm, A: water (0.225% formic acid); B: acetonitrile, 30%-60%: 30 minutes) to obtain the formate salt of compound 8-4 . MS-ESI [M+H] ⁺ , calcd. 509, found 509.

(2) Iron powder (5.49 mg, 98.3 μmol) and hydrochloric acid (1 mol/L, 100 μL) were added to a solution of the formate salt of compound 8-4 (5 mg, 9.83 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 65°C for 1 hour, filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC (Welch Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 20%-50%: 25 minutes) to obtain the formate salt of compound 8. MS-ESI [M+H] ⁺ , calculated value 479, found value 479.

¹ H NMR (400 MHz, MeOD) δ 8.76 (s, 1H), 6.97 (s, 2H), 6.78 (s, 1H), 5.39 (q, J = 6.8 Hz, 1H), 3.77-3.87 (m, 2H), 3.61 (ddd, J = 11.6, 8.8, 3.2 Hz, 2H), 2.65 (s, 3H), 2.31-2.41 (m, 2H), 1.78-1.88 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H), 1.61 (s, 3H).

Example 9 Synthesis of Compound 9

(1) Add diisopropylamino lithium (2.00 mol/L, 0.61 mL) to a solution of compound A-4 (150 mg, 812 μmol) in tetrahydrofuran (6.0 mL). Stir the reaction mixture at -78°C for 1 hour under nitrogen protection, add compound 9-1 (203 mg, 894 μmol), stir the reaction mixture at 0°C for 2 hours under nitrogen protection, add saturated aqueous ammonium chloride solution (100 mL), add water (100 mL), extract with ethyl acetate (100 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound 9-2 . MS-ESI [M+H] ⁺ , calcd. 412, found 412.

(2) Manganese dioxide (633 mg, 7.28 mmol) was added to a solution of compound 9-2 (300 mg, 728 μmol) in dichloroethane (3.0 mL). The reaction solution was stirred at 25°C for 10 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 9-3 . MS-ESI [M+H] ⁺ , calculated value 410, found value 410.

(3) Compound A-5 (31.4 mg, 134 μmol), palladium acetate (2.74 mg, 12.2 μmol), cesium carbonate (79.5 mg, 244 μmol) and 1,1' - binaphthyl-2,2'-bis(diphenylphosphine) (15.19 mg, 24.4 μmol) were added to a solution of compound 9-3 (50.0 mg, 122 μmol) in dioxane (2.00 mL). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain compound 9-4 . MS-ESI [M+H] ⁺ , calculated value 608, found value 608.

(4) Add trifluoroacetic acid (93.8 mg, 823 mmol) to a solution of compound 9-4 (50.0 mg, 82.3 μmol) in dichloromethane (5.0 mL). Stir the reaction solution at 25°C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the trifluoroacetic acid salt of compound 9-5 . MS-ESI [M+H] ⁺ , calculated value 508, found value 508.

(5) To a solution of compound 9-5 (40.0 mg, 64.4 μmol) in ethanol (5.0 mL) were added paraformaldehyde (9.66 mg, 322 μmol), triethylamine (6.51 mg, 64.4 μmol), acetic acid (387 μg, 6.44 μmol) and sodium cyanoborohydride (6.07 mg, 96.5 μmol). The reaction solution was stirred at 25°C for 10 hours, water (100.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9-6 . MS-ESI [M+H] ⁺ , calculated value 524, found value 524.

(6) Iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) were added to a solution of compound 9-6 (19.4 mg, 37.2 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 60°C for 1 hour, water (100.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (C18-6, 100 mm×30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 8%-38%: 15 minutes) to obtain the formate salt of compound 9 . MS-ESI [M+H] ⁺ , calcd. 492, found 492.

¹ H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 6.98 (s, 2H), 6.79 (s, 1H), 5.41 (q, J=7.2 Hz, 1H), 3.20-3.28 (m, 2H), 2.90-3.04 (m, 2H), 2.72 (s, 3H), 2.54-2.69 (m, 5H), 1.96-2.09 (m, 2H), 1.62-1.69 (m, 6H).

Example 10 Synthesis of Compound 10

(1) Compound 10-1 (28.7 mg, 155 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonate (21.1 mg, 25.3 μmol) and cesium carbonate (103 mg, 316 μmol) were added to a solution of compound 9-3 (51.8 mg, 126 μmol) in dioxane (2.00 mL). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL×2). The organic phases were combined, washed with saturated brine (10.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 2:3) to obtain compound 10-2 . MS-ESI [M+H] ⁺ , calculated value 563, found value 563.

(2) Trifluoroacetic acid (0.1 mL) was added to a solution of compound 10-2 (22.0 mg, 39.1 μmol) in dichloromethane (1.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 10-3 . MS-ESI [M+H] ⁺ , calculated value 463, found value 463.

(3) To a solution of the trifluoroacetate of compound 10-3 (30.0 mg, 52.0 μmol) in ethanol (1.0 mL) were added paraformaldehyde (15.6 mg, 520 μmol), triethylamine (6.51 mg, 64.4 μmol), acetic acid (387 μg, 6.44 μmol) and sodium cyanoborohydride (8.17 mg, 130 μmol). The reaction solution was stirred at 25°C for 10 hours, water (30.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Welch Xtimate C18, 150 mm×30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 50%-85%: 14 minutes) to obtain compound 10. MS-ESI [M+H] ⁺ , calculated value 477, found value 477. ¹ H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.59 (t, J =8.0 Hz, 1H), 7.42-7.51 (m, 1H), 7.19 (t, J =7.6 Hz, 1H), 6.83-7.15 (m, 1H), 5.71 (q, J =7.2 Hz, 1H), 2.67 (d, J =6.4 Hz, 2H), 2.61-2.64 (m, 3H), 2.42-2.51 (m, 2H), 2.31-2.41 (m, 2H), 2.28 (s, 3H), 1.82-1.91 (m, 2H), 1.69 (d, J =7.2 Hz, 3H), 1.57 (s, 3H).

Examples 11, 13, 18 Synthesis of Compounds 11, 13 and 18

The synthesis method in Example 10 was used to synthesize compounds 11, 13 and 18 using corresponding raw materials.

Example 12 Synthesis of Compound 12

(1) Add diisopropylamino lithium (2.00 mol/L, 1.84 mL) to a solution of compound A-4 (400 mg, 2.17 mmol) in tetrahydrofuran (8.0 mL). Stir the reaction mixture at -78 °C for 1 hour under nitrogen protection, add compound 12-1 (305 mg, 2.38 mmol), stir the reaction mixture at -65 °C for 2 hours under nitrogen protection, add saturated aqueous ammonium chloride solution (30.0 mL), add water (30.0 mL), extract with ethyl acetate (30.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 1:1) to obtain compound 12-2 . MS-ESI [M+H] ⁺ , calcd. 313, found 313.

(2) Manganese dioxide (1.89 g, 21.7 mmol) was added to a solution of compound 12-2 (170 mg, 543 μmol) in dichloroethane (2.0 mL). The reaction solution was stirred at 70°C for 48 hours. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1) to obtain compound 12-3 . MS-ESI [M+H] ⁺ , calculated value 311, found value 311.

(3) Compound 12-4 (18.3 mg, 96.5 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonate (13.5 mg, 16.1 μmol), and cesium carbonate (52.4 mg, 161 μmol) were added to a solution of compound 12-3 (13.5 mg, 16.1 μmol) in dioxane (2.00 mL). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 100 mm×30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 38%-58%: 10 min) to obtain compound 12. MS-ESI [M+H] ⁺ , calculated value 464, found value 464. ¹ H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 7.59 (t, J =7.2 Hz, 1H), 7.45 (t, J =6.8 Hz, 1H), 7.19 (t, J =7.6 Hz, 1H), 6.83-7.14 (m, 1H), 5.68 (q, J =6.8 Hz, 1H), 3.82 (ddd, J =11.6, 6.0, 3.6 Hz, 2H), 3.61 (ddd, J =11.2, 8.4, 2.8 Hz, 2H), 2.63 (s, 3H), 2.37 (dd, J =13.9, 1.3 Hz, 2H), 1.79-1.88 (m, 2H), 1.69 (d, J =6.8 Hz, 3H), 1.62 (s, 3H).

Examples 14, 15, 17 Synthesis of Compounds 14, 15 and 17

The synthesis method in Example 12 was used to synthesize compounds 14, 15 and 17 using corresponding raw materials.

Example 16 Synthesis of Compound 16

The synthesis method in Example 8 was used to synthesize compound 16 using corresponding raw materials.

Example 19 Synthesis of Compound 19

(1) Compound 13-1 (356 mg, 1.76 mmol), diisopropylethylamine (945 mg, 7.32 mmol) and potassium fluoride (850 mg, 14.64 mmol) were added to a solution of compound 9-3 (600 mg, 1.46 mmol) in dimethyl sulfoxide (10.0 mL). The reaction solution was stirred at 100 °C for 12 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30.0 mL × 2). The organic phases were combined, washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 1:1) to obtain compound 19-1 . MS-ESI [M+H] ⁺ , calcd. 577, found 577.

(2) Add trifluoroacetic acid (2.0 mL) to a solution of compound 19-1 (700 mg, 1.21 mmol) in dichloromethane (10.0 mL). Stir the reaction mixture at 25°C for 1 hour. Reduce the pressure and concentrate the reaction mixture. Add sodium bicarbonate aqueous solution to adjust the pH to 8-9. Add water (30.0 mL) and extract with dichloromethane (30.0 mL×2). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound 19-2 . MS-ESI [M+H] ⁺ , calculated value 477, found value 477.

(3) Diisopropylethylamine (65.1 mg, 503 μmol), compound 19-3 (18.2 mg, 202 μmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (95.7 mg, 252 μmol) were added to a solution of compound 19-2 (18.2 mg, 202 μmol) in dichloromethane (3.0 mL). The reaction solution was stirred at 25°C for 1 hour under nitrogen protection. The reaction solution was diluted by adding dichloromethane (30.0 mL) and washed with water (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 14%-54%: 25 minutes) to give the formate salt of compound 19. MS-ESI [M+H] ⁺ , calculated value 549, found value 549. ¹ H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.73 (q, J = 3.2 Hz, J =10.0Hz,1H),4.10-4.22(m,2H),3.92-4.02(m,1H),3.62-3.72(m,1H),3.39(s,3H),3.32-3.38(m,1H),3.21-3.28(m,1H),2.59-2.65(m,6H),2.37-2.47(m,2H),1.74-1.85(m,2H),1.58-1.68(m,6H).

Example 20-29 Synthesis of Compound 20-29

The synthesis method in Example 19 was used to synthesize compounds 20-29 using corresponding raw materials.

Example 30 Synthesis of Compound 30

Compound 19-2 was separated by preparative HPLC (Xtimate C18, 150 mm×30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 16%-54%: 25 min) to give the formate salt of compound 30. MS-ESI [M+H] ⁺ , calculated value 477, found value 477. ¹ H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.75 (d, J =7.6 Hz, 1H), 7.59 (d, J =7.6 Hz, 1H), 7.34 (t, J =8.0 Hz, 1H), 5.54 (q, J =7.2 Hz, 1H), 3.35-3.40 (m, 2H), 3.09-3.15 (m, 2H), 2.76 (s, 3H), 2.60 (s, 3H), 1.72 (s, 6H), 1.22-1.33 (m, 4H).

Example 31 Synthesis of Compound 31

At 0°C, triethylamine (14.8 mg, 146 μmol) and compound 31-1 (23.6 mg, 220 μmol) were added to a solution of compound 19-2 (70.0 mg, 146 μmol) in dichloromethane (5.0 mL). The reaction solution was stirred at 0°C for 1 hour under nitrogen protection. The reaction solution was diluted with water (30.0 mL) and extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 18%-58%: 25 minutes) to obtain the formate salt of compound 31 . MS-ESI [M+H] ⁺ , calculated value 548, found value 548. ¹ H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.71 (q, J = 4.8 Hz, J = 6.8 Hz, 1H), 3.41-3.47 (m, 2H), 3.12 (t, J = 10.8 Hz, 2H), 2.84 (s, 6H), 2.57-2.64 (m, 6H), 2.34-2.41 (m, 2H), 1.81 (t, J = 10.4 Hz, 2H), 1.56-1.66 (m, 6H).

Example 32 Synthesis of Compound 32

The synthesis method in Example 31 was used to synthesize compound 32 using corresponding raw materials.

Example 33 Synthesis of Compound 33

Triethylamine (21.7 mg, 168 μmol) and compound 33-1 (77.9 mg, 336 μmol) were added to a solution of compound 19-2 (80.0 mg, 168 μmol) in N,N-dimethylformamide (1.0 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours under nitrogen protection. The reaction solution was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 34%-74%: 25 minutes) to obtain the formate salt of compound 33 . MS-ESI [M+H] ⁺ , calcd. 559, found 559. ¹ H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 7.71 (d, J =7.6 Hz, 1H), 7.53 (d, J =7.6 Hz, 1H), 7.28 (d, J =8.0 Hz, 1H), 5.61-5.74 (m, 1H), 3.05 (q, J =5.2 Hz, J =15.2 Hz, 2H), 2.81-2.88 (m, 2H), 2.66 (s, 3H), 2.61 (s, 3H), 2.54-2.60 (m, 2H), 2.36-2.47 (m, 2H), 1.83-1.93 (m, 2H), 1.65 (d, J =6.8 Hz, 3H), 1.57 (s, 3H).

Example 34 Synthesis of Compound 34

Compound 34-1 (15.8 mg, 220 μmol), acetic acid (1.76 mg, 29.3 μmol) and sodium cyanoborohydride (13.8 mg, 220 μmol) were added to a solution of compound 19-2 (70.0 mg, 146 μmol) in methanol (5.0 mL). The reaction solution was stirred at 25°C for 1 hour, water (15.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15.0 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (Phenomenex C18, 75 mm×30 mm 3 μm, A: water (ammonium bicarbonate); B: acetonitrile, 34%-74%: 25 minutes) to obtain compound 34 . MS-ESI [M+H] ⁺ , calculated value 533, found value 533. ¹ H NMR (400 MHz, MeOD) δ 8.77 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 5.72 (q, J = 4.8 Hz, J = 6.8 Hz, 1H), 4.68 (t, J =6.4Hz,2H),4.56-4.60(m,2H),3.42-3.46(m,1H),3.42-3.52(m,1H),2.62(s,6H),2.52-2.56(m,2H),2.43-2.48(m,2H),2.16-2.24(m,2H),1.87(t,J=10.0Hz,2H),1.62(d,J=6.8Hz,3H),1.57(s,3H).

Example 35 Synthesis of Compound 35

The synthesis method in Example 33 was adopted and the corresponding raw materials were used to synthesize compound 35 .

Example 36-38 Synthesis of Compound 36-38

The synthesis method in Example 34 was used to synthesize compounds 36-38 using corresponding raw materials.

Test example

Determination of the inhibitory effect of compounds on the binding of SOS1 to KRAS (G12C) mutant protein (HTRF method)

1. Experimental principle: The homogeneous time resolved fluorescence (HTRF) method is used to detect the inhibitory effect of the compound on the binding of SOS1 and KRAS (G12C) mutant protein.

2. Experimental materials: KRAS (G12C) mutant protein was purchased from Pujian Biotechnology Co., Ltd.; SOS1 protein was purchased from Cytoskeleton Co., Ltd.; labeled antibodies Mab Anti 6HIS-XL665 and Mab Anti GST-Eu cryptate were purchased from Cisbio.

3. Experimental method: Preparation of 1x concentration buffer (prepare immediately for use): 4-hydroxyethylpiperazineethanesulfonic acid (Hepes): 5mmol/L; Sodium chloride: 150mmol/L; Ethylenediaminetetraacetic acid: 10mmol/L; Ethylphenylpolyethylene glycol (Igepal): 0.0025%; Potassium fluoride: 100mmol/L; Dithiothreitol (DTT): 1mmol/L; Bovine serum albumin (BSA): 0.05%.

Prepare a compound stock solution containing the test compound with dimethyl sulfoxide (DMSO), and start with a test compound concentration of 1000 μmol/L in the compound stock solution, dilute 5 times, set 8 gradient concentrations, use 1-fold concentration buffer to dilute each gradient of the test compound into a working solution containing the test compound and 2 vol% DMSO, 5 μL/well is added to the corresponding well, and duplicate well detection is set for each concentration. Prepare a mixed working solution of KRAS (G12C) mutant protein (200nM) and Mab Anti GST-Eu cryptate (1μg/uL) with 1-fold concentration buffer. Incubate the mixed working solution at 25°C for 5 minutes, and add 2.5 μL/well to the corresponding well. Use 1x concentration buffer to prepare a mixed working solution of SOS1 protein (80nM) and Mab Anti 6HIS-XL665 (8μg/uL), and add 2.5μL/well to the corresponding wells. Add 2.5μL of Mab Anti 6HIS-XL665 (8μg/μL) dilution to the blank well. The reaction system was placed at 25℃ for 60 minutes. After the reaction, the HTRF was read using a multi-label analyzer.

4. Data processing:

The IC ₅₀ of the compounds was calculated using Graphpad software. The results are shown in Table 1.

From the test data in Table 1, it can be seen that the compound of formula I described in the present invention has a good inhibitory effect on the binding of SOS1 to KRAS (G12C) mutant protein, and has the potential to be used in the preparation of tumor drugs for the treatment of RAS mutations.

The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the oxazine compounds, the pharmaceutical compositions containing the same and their applications, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. The technical personnel in the relevant technical field should understand that any improvement of the present invention, the equivalent replacement of the raw materials of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

without.

Claims (13)

A compound of formula I, a pharmaceutically acceptable salt thereof, a chiral isomer, a non-chiral isomer, a cis-trans isomer, or a combination thereof,

wherein ^X1 is CH; ^X2 is selected from: sulfur atom, oxygen atom, ^-NRx- ; wherein ^Rx is selected from: H, optionally substituted C1-C3 alkyl; wherein said substitution refers to substitution by one or more R; ^R1 is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclic group; wherein said substitution refers to substitution by one or more R; ^R2 is

, wherein X ³ is selected from: CR ^2' or N; R ^2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; The B ring is selected from: an optionally substituted C3-C8 carbocyclic group or an optionally substituted 4-8-membered heterocyclic group; wherein the substitution refers to substitution by one or more R; the A ring is selected from: an optionally substituted phenyl group, a 5-6-membered heteroaryl group, an optionally substituted C3-C8 carbocyclic phenyl group, an optionally substituted 4-8-membered heterocyclic phenyl group, an optionally substituted C3-C8 carbocyclic 5-6-membered heteroaryl group or an optionally substituted 4-8-membered heterocyclic 5-6-membered heteroaryl group; wherein the substitution refers to substitution by one or more R; R is independently selected from: H, halogen, cyano, amine, hydroxyl, oxo (

), optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -N(optionally substituted _C1 - _C6 alkyl) ₂ , -NH(optionally substituted _C1 - _C6 alkyl), -N(optionally substituted _C1 - _{C6 alkyl)(optionally substituted C1-C6 alkylphenyl )} , -NH(optionally substituted _C1 - _C6 alkylphenyl), optionally substituted C1-C6 alkyl-S-, -S(O) ₂ -optionally substituted C1-C6 alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O) ₂ -optionally substituted phenyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH(optionally substituted C1-C6 alkyl), -S(O) ₂ NH (optionally substituted phenyl), -NHS (O) ₂ (optionally substituted C1-C6 alkyl), -NHS (O) ₂ (optionally substituted phenyl), optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 membered heteroaryl group; or any two adjacent R and the atoms connected thereto form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amine, hydroxyl, oxo (

), R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , -CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , wherein R' is selected from one or more groups of the following groups: H, halogen, deuterium (D), halogen, -OH, oxo (=O), hydroxyl, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups is optionally further substituted with one or more substituents selected from the following: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), _-NH2 , -N(R" substituted or unsubstituted C1-C6 alkyl) ₂ , -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclic group, C1-C4 halogenated alkyl-, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl) ₂ , -CONH(C1-C6 alkyl), -CONH ₂ , -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , -SO ₂ NH(C1-C6 alkyl), -SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl), -NHSO ₂ (C1-C6 halogenated alkyl) and -C1-C6 alkyl-NH ₂ , wherein R" is one or more groups selected from the group consisting of H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

Indicates the connection position of the group; wherein the "4-8 membered heterocyclic (base)" contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and the "5-6 membered heteroaryl" contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. A compound as described in claim 1, a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a cis-trans isomer, or a combination thereof, wherein the R ¹ is selected from: H, a halogen, an optionally substituted C1-C3 alkyl; wherein the substitution refers to substitution by one or more R, and R is defined as described in claim 1. The compound as described in claim 1, its pharmaceutically acceptable salt, isomer, cis-trans isomer, or combination thereof, wherein the A ring is selected from: optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl; wherein the substitution refers to substitution by one or more R; R is defined as described in claim 1. The compound according to claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, cis-trans isomer, or a combination thereof, wherein the A ring is selected from:

wherein R ^d1 , R ^d2 , and R ^d3 are independently selected from the group consisting of H, halogen, amine, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl, or optionally substituted 5-16 membered heteroaryl; and R ^d4 are independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, and

; q is 0, 1, 2 or 3; R ^d5 is selected from: hydrogen, optionally substituted C6-C10 aromatic group or optionally substituted 5-16 heteroaromatic ring group; Z is selected from: O or NR ^N ; ^RN is selected from: H or optionally substituted C1-C6 alkyl; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo (

), R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C3-C16 carbocyclic group, 4-16 membered heterocyclic group, -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , -CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , and -CH ₂ -(4-8 membered heterocyclic group), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

Indicates the attachment position of the group; wherein the "heterocyclic group" contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and the "heteroaryl group" contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. The compound of claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, cis-trans isomer, or a combination thereof, wherein the A ring is

,

,

,

,

or

; wherein R ^d5a and R ^d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R ^d5a , R ^d5b and the connected N atom form a 4-8 membered heterocyclic group; R ^d5c is selected from: H, halogen or substituted or unsubstituted C1-C3 alkyl; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo (

), C1-C6 alkyl and C1-C6 alkoxy;

represents the attachment position of the group; wherein the "4-8 membered heterocyclic group" contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, cis-trans isomer, or a combination thereof, wherein the B ring is an optionally substituted 6-membered heterocyclic group, wherein the "6-membered heterocyclic group" contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the substitution refers to substitution by one or more R; R is defined as described in claim 1. The compound of claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, cis-trans isomer, or a combination thereof, wherein the B ring is an optionally substituted tetrahydropyranyl (

), optionally substituted piperidinyl (

); wherein the substitution refers to substitution by one or more R; R is defined as described in claim 1. The compound as claimed in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, cis-trans isomer, or a combination thereof, wherein R ² is selected from:

,

,

,

,

,

The compound as claimed in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, cis-trans isomer, or a combination thereof, wherein the compound is selected from the group consisting of:

A compound represented by formula II, or a salt thereof,

A pharmaceutical composition, wherein the pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more of the compounds selected from any one of claims 1 to 9, their pharmaceutically acceptable salts, chiral isomers, non-chiral isomers, and cis-trans isomers as active ingredients; and (2) optionally, a pharmaceutically acceptable carrier. Use of a compound as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a chiral isomer, a non-chiral isomer, a cis-trans isomer, or a drug composition as described in claim 11 in the preparation of a drug for preventing or treating RAS mutation-mediated cancer. The use as described in claim 12, wherein the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal carcinoma, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer.