TW202136243A - Zeste enhancer homologue 2 inhibitor and use thereof - Google Patents

Abstract

Provided are a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate and a eutectic crystal thereof, or a pharmaceutical composition containing same, and the use thereof as an EZH2 inhibitor in the preparation of a drug for treating related diseases. Each group in formula (I) is as defined in the description.

Description

ZESTE enhancer homolog 2 inhibitor and its use

The invention belongs to the field of medicine, and in particular relates to a compound with EZH2 inhibitory activity, its stereoisomers, pharmaceutically acceptable salts, solvates or co-crystals, and its use in the preparation of drugs for treating related diseases.

Cancer treatment methods currently mainly include radiotherapy, surgical therapy, and drug therapy. Drug therapy targeting lesions has become the main method of clinical tumor treatment. However, due to the rapid development of drug resistance in tumor cells, people at this stage are concerned with tumor metastasis. The recurrence is basically helpless.

Lysine methyltransferase can methylate histones and non-histone proteins, and its abnormal performance is closely related to the occurrence of a variety of tumors. It has become a hot spot in the field of epigenetics for more than ten years. Targeting lysine methyltransferase and reversing abnormal histone or non-histone methylation levels is regarded as another new method for tumor treatment. PRC2 (polycomb repressive complex 2) is a multi-subunit protein complex composed of EZH1 (Enhancer of zeste homologue 1, KMT6B) or EZH2 (Enhancer of zeste homologue 2, KMT6A), SUZ12 (Suppressor of zeste 12), EED ( Embyronic ectoderm development), used to catalyze the trimethylation of H3K27. The PCR2 complex modifies the methylation of the lysine at position 27 and H3K9 of the nucleosome protein through the SET domain of EZH2. Then the PCR1 complex is triggered to gather at a specific gene site to silence the target gene (CDKN1C, CDH1, RUNX3, etc.) and promote cell proliferation. Studies have shown that whether EZH2 overexpression or mutations in the SET region (Y641F, Y641N, A687V, A677G point mutations) lead to an abnormal increase in H3K27me3, it promotes the growth and development of many types of tumors, such as breast cancer, prostate cancer, and leukemia.

The present invention provides a compound with EZH2 inhibitory activity, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated compound, and the compound is represented by formula (I),

Wherein, R _{1 is} selected from H, C _1-4 alkyl, halogenated C _1-4 alkyl and halogen;

R _{2 is} selected from C _1-4 alkyl;

The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;}

W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)-, -C(=S)- and bond;

Each R _La and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R _La and R _Lb on the carbon atom are formed together with the carbon atom to which they are attached C _3-6 carbon ring;

Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl;

m, n, p, q are independently selected from an integer of 0-4;

Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom;

Each R _{X1 is} independently selected from H, C _1-4 alkyl and C _3-6 cycloalkyl;

Each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1-3 halogens;

、

、

、

、

、含有0-3個選自N、S、O雜原子的五元碳環或五元雜環，或含有0-3個選自N、S、O雜原子的六元非芳香碳環或六元非芳香雜環，或者不存在； Ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Non-aromatic heterocyclic ring, or non-existent;

Each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, CN, halogen, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the alkyl group, Cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy and NH ₂ ;

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 ring Alkyl groups and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic rings are optionally selected from 1-3 C _1-4 alkyl groups, Halogen and -C(O)C _1-4 alkyl group substitution;

Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and The heterocycle is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl;

t is an integer of 0-3;

Each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or forms with R ₄ and R ₅ on the carbon atom together with the carbon atom to which they are attached C _3-6 carbocyclic ring; the C _1-4 alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen;

s is an integer of 0-3;

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基、胺基、-C(O)C_1-4烷基、羥基和鹵素的基團取代；作為選擇，所述碳環或雜環同碳原子上的兩個取代基與連接的碳原子一起形成C_3-6碳環； A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl group, amino group, -C(O)C _1-4 alkyl group, hydroxyl group and halogen group substitution; alternatively, the two substituents on the same carbon atom and the connected carbon atom of the carbocyclic or heterocyclic ring Together to form a C _3-6 carbon ring;

L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, =NO-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond;

R _L2 is H or C _1-4 alkyl;

r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time;

Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen;

R ₇ is C _1-4 alkyl, -Si(R ₆₃ ) ₃ , halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, halogenated C _{1 -4} alkoxy, phenyl or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, wherein the C _1-4 alkyl group is optionally substituted by 1-2 -Si (R ₆₄ ) ₃ substitution, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkane Oxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _{1- 4} Alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted;

Each of R ₆₃ and R _{64 is} independently H, C _1-4 alkyl or halogen;

或

時，L₂和R₇不存在；當A為取代或未取代的哌啶基時，滿足L₂是-C(O)-或-C(O)NH-，或 者滿足R₇是-Si(R₆₃)₃或R₇是被1-2個-Si(R₆₄)₃取代的C_1-4烷基；並且，當式(I)的化合物為

時，不符合以下(1)-(5)的任一情形： The condition is that when A is substituted or unsubstituted

or

When, L ₂ and R ₇ does not exist; when A is a substituted or unsubstituted piperidinyl group, satisfies L ₂ is -C (O) -, or -C (O) NH-, R ₇ is satisfied or -Si ( R ₆₃ ) ₃ or R _{7 is C 1-4} alkyl substituted with 1-2 -Si(R ₆₄ ) ₃ ; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(5):

，L₂為-NH-，R₇為取代或未取代的

、取代或未取代的

，且

的取代基為1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基的基團；

的取代基為C_1-4烷基；或者A為

，L₂為-N(CH₃)-，R₇為取代或未取代的

、或C_1-4烷基，且

的取代基為1-3個C_1-4烷基； (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl; or A is

, L ₂ is -N(CH ₃ )-, R ₇ is substituted or unsubstituted

, Or C _1-4 alkyl, and

The substituents of are 1-3 C _1-4 alkyl groups;

，L₂為鍵時，R₇為鹵代C_1-4烷氧基、或者取代或未取代的

，所述取代是被1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷氧基、鹵素、羥基、氰基、-S(O)₂-C_1-4烷基的基團取代；或者R₇為取代或未取代的

、

，所述取代是被1-3個選自=O、鹵素的基團取代；或者R₇為

、

、C_1-4烷基； (2) A is

, When L ₂ is a bond, R ₇ is a halogenated C _1-4 alkoxy group, or substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S(O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl;

，L₂為-O-，R₇為C_1-4烷基、環丙基、鹵代C_1-4烷基或

； (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

；

； (4) -AL ₂ -R ₇ is

；

，L₂为-NH-时，R₇为

。 (5) When A is

, When L ₂ is -NH-, R ₇ is

.

In some embodiments, R _{1 is} selected from H, C _1-4 alkyl, halo C _1-4 alkyl, and halogen; in some embodiments, R _{1 is} selected from C _1-4 alkyl; in some embodiments In the examples, R ₁ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; in some embodiments, R ₁ is a deuterated C _1-4 alkyl group, such as -CD ₃ ；

In some embodiments, R _{2 is} selected from C _1-4 alkyl; in some embodiments, R ₂ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; in some embodiments In the example, R ₁ is a deuterated C _1-4 alkyl group, such as -CD ₃ ;

、

或-C(O)-NR_Lc-CH₂-；在一些實施例中，L₁为

；在一些實施例中，L₁為-CH₂-NH-C(O)-、-NH-NH-C(O)-、-CH₂-N(CF₃)-C(O)-、-CH₂-NH-CH(環丙基)-(即

)、-CH₂-NH-SO₂-、-CH₂-NH-CH₂-或

。在進一步實施例中，L₁為-CH₂-NH-C(O)-； In some embodiments, L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N , S, O heteroatom 3-6 membered heterocyclic ring, the heterocyclic ring is optionally _{substituted by 1-3 R Lc} , W is selected from -C(O)-, -S(O) ₂ -, -C =N(CN)-, -C(=S) _{-and bond, each R La} and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or the same R _La and R _Lb on the carbon atom together with the carbon atom to which they are attached form a C _3-6 carbocyclic ring, and each R _{Lc is} independently selected from H, C _1-4 alkyl and halogenated C _1-4 alkyl, m, n, p, and q are independently selected from an integer of 0-4; in some embodiments, L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -( CR _La R _Lb ) _q -, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the heterocyclic ring is optionally _{substituted by 1-3 R Lc} , and W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)- and bond, each of R _La and R _Lb is H, or R _La and R _Lb on the same carbon atom are connected to them The carbon atoms of together form a C _3-6 carbocyclic ring, each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl, m, n, p, q are independently selected from 0 -4; In some embodiments, L ₁ is -CH ₂ NHW-; W is selected from -C(O)-, -S(O) ₂ -and -C(=S)-; in some embodiments In some embodiments, L ₁ is -CH ₂ NHC(O)-; in some embodiments, L ₁ is not -CH ₂ -NH-C(O)-; in some embodiments, L ₁ contains 1-2 options A 3-6 membered heterocyclic ring from N, S, O heteroatoms, the heterocyclic ring is optionally _{substituted by 1-3 R LC} , R _LC is H or C _1-4 alkyl; or L ₁ is -( NH) ₂ -C(O)-, -CH ₂ -N(R _Lc )-C(O)-, -CH ₂ -C(O)-N(R _Lc )-, -CH ₂ -NR _Lc -S (O) ₂ -、

,

Or -C(O)-NR _Lc -CH ₂ -; In some embodiments, L ₁ is

; In some embodiments, L ₁ is -CH ₂ -NH-C(O)-, -NH-NH-C(O)-, -CH ₂ -N(CF ₃ )-C(O)-,- CH ₂ -NH-CH(cyclopropyl)-(i.e.

), -CH ₂ -NH-SO ₂ -, -CH ₂ -NH-CH ₂ -or

. In a further embodiment, L ₁ is -CH ₂ -NH-C(O)-;

為

、

、

、

或

，所述R_X1為H或C_1-4烷基；或者

為

，R_X2為鹵素； In some embodiments, each X is independently C, N, NR _X1 or CR _X2 , and has at least one N atom; each R _{X1 is} independently selected from H, C _1-4 alkyl, and C _3-6 Cycloalkyl; each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, the alkyl and cycloalkyl are optionally substituted with 1-3 halogens; In some embodiments, each X is independently C, N, NR _X1, or CR _X2 , and has at least one N atom; each R _{X1 is} independently selected from H and C _1-4 alkyl; each R _X2 Independently selected from H, halogen, and C _1-4 alkyl; in some embodiments,

for

,

,

,

or

, Said R _X1 is H or C _1-4 alkyl; or

for

, R _X2 is halogen;

In some embodiments, _{at least one of R 1} , R ₂ , L ₁ and R _X2 contains a deuterium atom;

、

、

、

、

、 含有0-3個選自N、S、O雜原子的五元碳環或五元雜環，或含有0-3個選自N、S、O雜原子的六元非芳香碳環或六元非芳香雜環，或者不存在；在一些實施例中，環B為

、

、

、

，或者不存在；在一些實施例中，環B 為

、

、

，或者不存在；本發明的化合物，環B與

按照左側與左側連接點、右側與右側連接點連接的方式形成稠和環； In some embodiments, ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Membered non-aromatic heterocycle, or not present; in some embodiments, ring B is

,

,

,

, Or not present; in some embodiments, ring B is

,

,

, Or not present; the compound of the present invention, ring B and

A condensed ring is formed according to the connection point between the left side and the left side, and the right side and the right side connection point;

、

，所述雜環任選的被1個C_1-2烷基或C_1-2烷氧基取代；在一些實施例中，R_B為含有1个选自N和O雜原子的4-8元雜環，是指選自

、

或

，所述雜環任选地被1个-C(O)C_1-4烷基取代； In some embodiments, each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, -NR _B1 R _B2 , -C(O) NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkane Group, cycloalkyl, heterocycle are optionally substituted by 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, NH ₂ , R _B1 , R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 cycloalkyl and containing 1 -3 4-10 membered heterocycles selected from N, S, O heteroatoms, the cycloalkyl and heterocycles are optionally selected from 1-3 C _1-4 alkyl, halogen and -C( O) _{Substitution of C 1-4} alkyl group, R _B3 is C _1-4 alkyl, C _3-6 cycloalkyl or 4-10 member containing 1-3 heteroatoms selected from N, S, O Heterocycles, the cycloalkyl and heterocycles are optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen, and -C(O)C _1-4 alkyl; in some embodiments Where R _{B is} selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C( O) OR _B3 , -OR _B3 , -C(O)R _B3 and 4-6 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, and heterocycles Optionally substituted by 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, NH ₂ and each R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 cycloalkyl and containing 1-3 selected from N , S, O heteroatoms of 4-10 membered heterocycles, the cycloalkyl and heterocycles are optionally 1-3 selected from C _1-4 alkyl, halogen and -C (O) C _1-4 Alkyl group substitution, each R _{B3 is} independently C _1-4 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O , The cycloalkyl and heterocyclic ring are optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl; in some embodiments, R _{B is} selected from H, -NR _B1 R _B2 , -OR _B3 and a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the heterocyclic ring is optionally composed of 1-3 Substitution by a group selected from C _1-4 alkyl and C _{1-4 alkoxy; each R B1} and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 Alkyl; R _B3 is C _1-4 alkyl, C _3-6 cycloalkyl; in some embodiments, each R _{B is} independently selected from H, -NR _B1 R _B2 and -OR _B3 ; R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S( O) ₂ C _1-4 alkyl; R _B3 is C _3-6 cycloalkyl or a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, the heterocyclic ring is optionally divided by 1- C(O)C _1-4 alkyl substitution; in some embodiments, R _B is -NR _B1 R _B2 or -OR _B3 , R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl,- C(O)C _1-4 alkyl, -S(O) ₂ C _1-4 alkyl; R _B3 is C _3-6 cycloalkyl or 4-8 membered with one heteroatom selected from N and O heterocyclic ring optionally substituted with one -C (O) C _1-4 alkyl; in some embodiments, R _B containing 1-3 heteroatoms selected from N, S, O heteroatoms 4-6 membered heterocycles, including but not limited to

,

, The heterocyclic ring is optionally substituted with a C _1-2 alkyl group or a C _1-2 alkoxy group; in some embodiments, R _B is a 4-8 group containing one heteroatom selected from N and O Membered heterocyclic ring means selected from

,

or

, The heterocyclic ring is optionally substituted with 1 -C(O)C _1-4 alkyl;

In some embodiments, t is an integer from 0 to 3; in some embodiments, t is 1;

為

、

、

、

、

、

、

、

、

或

；在進一步實施例中，

為

、

、

、

、

、

、

、

或

； In some embodiments

for

,

,

,

,

,

,

,

,

or

; In a further embodiment,

for

,

,

,

,

,

,

,

or

；

In some embodiments, each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R ₄ and R ₅ on the same carbon atom and their The connected carbon atoms together form a C _3-6 carbocyclic ring, the C _1-4 alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkane Group or halogen, s is an integer from 0 to 3; in some embodiments, each of R ₄ and R _{5 is} independently selected from H and C _1-4 alkyl, and s is 1 or 2; in some embodiments, R ₄ and R _{5 are} independently selected from H and C _1-2 alkyl, s is 1; in some embodiments, s is 1, R ₄ and R ₅ are H; or s is 2, R ₄ and R ₅ Are independently selected from H and methyl; in some embodiments, s is 1, _{and at least one of R 4} and R _{5 is a C 1-4} alkyl substituted with 1-2 -Si(Rs) ₃ , each Rs is independently H, C _1-4 alkyl or halogen; in some embodiments, s is 1, R ₄ and R _{5 are} independently H, substituted or unsubstituted with 1-2 -Si(Rs) ₃ C _1-2 alkyl, each Rs is independently C _1-2 alkyl or halogen; in some embodiments, s is 1, R ₄ is H, and R ₅ is methyl; or s is 1, R ₄ And R ₅ are both H;

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基、胺基、-C(O)C_1-4烷基、羥基和鹵素的基團取代；作為選擇，所述碳環或雜環同碳原子上的兩個取代基與連接的碳原子一起形成C_3-6碳環；在一些實施例中，A為含有0-3個選自N、S雜原子的5-12元碳環或雜環，所述碳環不是苯環或

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、羥基和鹵素的基團取代；作為選擇，或者所述碳環同碳原子上的兩個取代基與連接的碳原子一起形成C_{3- 6}碳環；在一些實施例中，A为

、

、

、

、

、

或

；在一些實施例中，A為

、

或

；在一些會施例中，A为

，且环A上同碳原子上的两个取代基与连接的碳原子一起形成C_3-6碳环；在另一些實施例中，A为含有0-2個N原子的7-10元螺環或橋環；在另一些實施例中，A为含有0-2個N原子的7-10元並環；在另一些實施例中，A为

、

、

、或

，这些基团任选地被=O取代；在另一些實施例中，A为含有0-3个选自N、S雜原子的4-6元碳环或雜環；在另一些實施例中，A为含有0-1个选自N、S雜原子的4元碳环或雜環；在另一些實施例中，A为亚环丁基或亚氮雜環丁基；在一些實施例中，A为

；在一些實施例中，A为

； In some embodiments, A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl group, amino group, -C(O)C _1-4 alkyl group, hydroxyl group and halogen group substitution; alternatively, the two substituents on the same carbon atom and the connected carbon atom of the carbocyclic or heterocyclic ring Together to form a C _3-6 carbocyclic ring; in some embodiments, A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, and the carbocyclic or heterocyclic ring is optionally substituted with 1-3 _{groups selected from =0, C 1-4} alkyl, hydroxyl and halogen; alternatively, or carbocyclic ring carbon atom substituents on the same carbon atom form two C _{3- 6} carbocyclic ring; in some embodiments, a is

,

,

,

,

,

or

; In some embodiments, A is

,

or

; In some cases, A is

, And the two substituents on the same carbon atom on ring A together with the connected carbon atom form a C _3-6 carbocyclic ring; in other embodiments, A is a 7-10 membered spiro containing 0-2 N atoms Ring or bridged ring; in other embodiments, A is a 7-10 membered ring containing 0-2 N atoms; in other embodiments, A is

,

,

,or

, These groups are optionally substituted by =0; in other embodiments, A is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S; in other embodiments , A is a 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N and S; in other embodiments, A is cyclobutylene or azetidine; in some embodiments , A is

; In some embodiments, A is

；

In some embodiments, L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, =NO-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond, R _L2 is H or C _{1- 4} alkyl; r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time; in some embodiments, L ₂ is -C(O)-(NR _L2 ) _r -,- NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -; in some embodiments Where L ₂ is -C(O)-(NH) _r -, -NR _L2 -C(O)-, -O-,-(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -( CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -; r is 0 or 1, y is 0 or 1; R _L2 is H or C _1-2 alkyl; in some embodiments, L ₂ is -C( O)-(NH) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y- (NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond, r is 0 or 1, y is an integer from 0 to 3, and r and y are not both 0, each Each R ₆₁ and R _{62 are} independently selected from H, C _1-4 alkyl and halogen; in some embodiments, L ₂ is -C(O)-(NH) _r -, -NH-C(O)- , -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond, each of R ₆₁ and R _{62 is} independently selected from H and C _1-4 alkyl; in some embodiments, L ₂ is -NH-C(O)-, -C( O)-(NH) _r -, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -, when L ₂ is =NO- When L ₂ and A are connected by a double bond, r is 0 or 1, y is an integer of 1-3, R ₆₁ and R ₆₂ are H; in some embodiments, L ₂ is -NH-, -N(CH ₃ )-, =NO-, bond, -C(O)-, -C(O)-NH-, -NH-C(O)-, -NH-CH ₂ -or -CH ₂ -;

、

、

、

和

，所述取代是指被1-2个选自选自C_1-2烷基、氰基、羟基、卤素、卤代C_1-2烷氧基、-C(O)-C_1-2烷基和-S(O)₂-C_1-2烷基的基团取代；在一些實施例中，R₇为C_5-8二环桥环烷基，所述二环桥环烷基任选地被1-2个卤素取代，所述二环桥环烷基包括但不限於

；在一些實施例中，R₇为-Si(R₆₃)₃或被1-2个-Si(R₆₄)₃取代的C_1-4烷基，每个R₆₃和R₆₄独立地为H、C_1-4烷基或卤素；在一些實施例中，R₇為C_1-4烷基、鹵代C_1-4烷基、C_3-6環烷基、鹵代C_1-4烷氧基或含有1-2個選自N、S、O雜原子的4-10元雜環，所述環烷基和雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、單C_1-4烷基胺基、鹵代C_1-4烷基、氰基取代的C_1-4烷基、氰基、羥基、鹵素、鹵代C_1-4烷氧基、-C(O)-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4烷基-O-鹵代C_1-4烷基、-C_1-4烷基-OC(O)-C_1-4烷基、C_2-4烯基和C_2-4炔基的基團取代；在一些實施例中，R₇為C_3-6環烷基或含有1-2個選自N、S、O雜原子的4-6元單環雜環或4-6元橋環雜環，所述環烷基、單環雜環和橋環雜環被1-3個選自氰基取代的C_1-4 烷基、氰基、鹵素、鹵代C_1-4烷氧基、-C_1-4烷基-O-鹵代C_1-4烷基、-S(O)₂-C_1-4烷基、-C(O)-C_1-4烷基、-C_1-4烷基-OC(O)-C_1-4烷基、羥基、C_2-4烯基和C_2-4炔基的基團取代，或者R₇為含有1-2個選自N、S、O雜原子的7-10元螺環雜環，所述螺環雜環任選地被1-3個選自=O、C_1-4烷氧基、單C_1-4烷基胺基和C_1-4烷基的基團取代；在一些實施例中，所述桥环雜環为

、所述螺环雜環为

、

、

、

、

； In some embodiments, R ₇ is C _1-4 alkyl, -Si(R ₆₃ ) ₃ , halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkane Group, halogenated C _1-4 alkoxy, phenyl or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the C _1-4 alkyl group is optionally substituted by 1 -2 -Si(R ₆₄ ) ₃ substitution, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _{1- 4} alkoxy, -C (O) -C _1-4 alkyl, -S (O) ₂ -C _1-4 alkyl, -C _1-4 haloalkyl C _1-4 alkyl group -O- , -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted, each of R ₆₃ and R _{64 is} independently H , C _1-4 alkyl or halogen; in some embodiments, R ₇ is C _3-6 cycloalkyl, -Si(R ₆₃ ) ₃ , C substituted with 0-2 -Si(R ₆₄ ) _{3 1-4} alkyl group, C _5-8 bicyclic bridged cycloalkyl group, or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring optionally Ground is substituted by 1-3 selected from =O, C _1-4 alkyl, C _1-4 alkoxy, mono-C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxy, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl, -S (O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-O-halogenated C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 Alkynyl group substitution; each of the R ₆₃ and R _{64 is} independently H, C _1-4 alkyl or halogen; in some embodiments, R ₇ is C _3-6 cycloalkyl or contains 1- Two 4-6 membered heterocycles selected from N, S, O heteroatoms, the cycloalkyl and heterocycles are optionally selected from =0, C _1-4 alkyl, C _{1- 4} alkoxy, mono C _1-4 alkylamino, halo C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxy, halo, halogenated C _1-4 alkoxy Group, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _{Substitution of 1-4} alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl; in some embodiments, R ₇ is a C _3-6 ring Alkyl group or 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring are optionally selected from 1-3 C _1-4 alkyl groups, Cyano, hydroxyl, halogen, halogenated C _{1 -4} alkoxy, -C(O)-C _1-4 alkyl and -S(O) ₂ -C _1-4 alkyl group; in some embodiments, R _{7 is} selected from substituted or unsubstituted Substituted groups:

,

,

,

with

, The substitution refers to being selected from C _1-2 alkyl, cyano, hydroxyl, halogen, halogenated C _1-2 alkoxy, -C(O)-C _1-2 alkane Group and -S(O) ₂ -C _1-2 alkyl group; in some embodiments, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, the bicyclic bridged cycloalkyl group optionally Ground is substituted with 1-2 halogens, and the bicyclic bridged cycloalkyl includes but is not limited to

In some embodiments, R ₇ is -Si(R ₆₃ ) ₃ or C _1-4 alkyl substituted with 1-2 -Si(R ₆₄ ) ₃ , each of R ₆₃ and R _{64 is} independently H , C _1-4 alkyl or halogen; in some embodiments, R ₇ is C _1-4 alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl, halo C _1-4 alkane Oxy group or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and heterocyclic ring are optionally selected from 1-3 selected from =0, C _1-4 Alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halo C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-O-haloC _{1- 4} alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted; in some embodiments, R ₇ It is a C _3-6 cycloalkyl group or a 4-6 membered monocyclic heterocyclic ring or 4-6 membered bridged ring heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl, monocyclic ring Heterocycles and bridged heterocycles are substituted with 1-3 C _1-4 alkyl groups selected from cyano groups, cyano groups, halogens, halogenated C _1-4 alkoxy groups, -C _1-4 alkyl-O- Halogenated C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _{Substitution of 1-4} alkyl, hydroxy, C _2-4 alkenyl and C _2-4 alkynyl groups, or R ₇ is a 7-10 membered spiro containing 1-2 heteroatoms selected from N, S and O A cyclic heterocycle, the spirocyclic heterocycle is optionally substituted by 1-3 _{groups selected from the group consisting of =0, C 1-4} alkoxy, mono C _1-4 alkylamino and C _1-4 alkyl Substituted; In some embodiments, the bridged heterocyclic ring is

, The spirocyclic heterocycle is

,

,

,

,

；

In some embodiments, each of R ₆₃ and R _{64 is} independently H, C _1-4 alkyl or halogen; in some embodiments, R ₆₃ and R _{64 are} independently methyl, ethyl, propyl, F, Cl, Br, I;

)、3-(氰基甲基)氧雜環丁-3-基、3-((三氟甲氧基)甲基)氧雜環丁-3-基、3-((乙醯氧基)甲基)氧雜環丁-3-基、3-氰基氧雜環丁-3-基、3-乙炔基氧雜環丁-3-基、氧雜環丁-3-基或3-三氟甲基氧雜環丁-3-基；在一些實施例中，R₇為四氫呋喃-3-基(

)；在一些實施例中，R₇為1-乙醯基-3-甲基氮雜環丁-3-基、3-甲基-1-(甲磺醯基)氮雜環丁-3-基、氮雜環丁-3-基、1-乙醯基-氮雜環丁-3-基或1-(甲磺醯基)氮雜環丁-3-基；在一些實施例中，R₇為 3,3-二氟吡咯烷-1-基；在一些實施例中，R₇為2-氧雜-7-氮雜螺[4.4]壬-7-基(

)、7-氧雜-2-氮雜螺[3.5]壬-2-基(

)、8-氧雜-2,7-二氮雜螺[4.4]壬-2-基(

)、7-異丙氧基-2-氮雜螺[3.5]壬-2-基(

)、2,2,-二氧化-2-硫雜-7-氮雜螺[4.4]壬-7-基(

)、7-(異丙基胺基)-2-氮雜螺[3.5]壬-2-基 (

)、7-甲基-2,7-二氮雜螺[4.4]壬-2-基(

)、2-乙醯基-2-氮雜二環[2.1.1]己-4-基(

)、1-氮雜螺[4.5]癸-8-基(

)、2-側氧基-1-氮雜螺[4.5]癸-8-基(

)、3-側氧基-2-氮雜螺[4.5]癸-8-基(

)、1-側氧基-2-氮雜螺[4.5]癸-8-基(

)、2-氮雜螺[4.5]癸-8-基或(

)；在一些實施例中，R₇為2-甲基噻唑-4-基(

)、5-氟-2-甲基噁唑-4-基(

)、1H-吡唑-1-基(

)、4-甲基噻唑-2-基(

)、6-(三氟甲基)吡啶-3-基(

)、2-(三氟甲基)吡啶-4-基(

)、6-氰基吡啶-3-基(

)、2-(三氟甲基)嘧啶-5-基(

)或1-甲基-1H-吡唑-4-基(

)；在一些實施例中，R₇為3-氟二環[1.1.1]戊-1-基(

)。 In some embodiments, R ₇ is methyl, ethyl, or isopropyl; in some embodiments, R ₇ is 2,2,2-trifluoroethyl or trifluoromethyl; in some embodiments, R ₇ is trifluoromethoxy; in some embodiments, R ₇ is -Si(CH ₃ ) ₃ ; in some embodiments, R ₇ is 3-cyano-1-methylcyclobutyl, 3, 3-Difluoro-1-methylcyclobutyl, 3-trifluoromethoxy-1-methylcyclobutyl, 3,3-difluorocyclobutyl, 3-hydroxy-1-methylcyclobutyl , 1-methyl-3-(2-methylprop-1-enyl)cyclobutyl, 3-ethynyl-1-methylcyclobutyl, 3-cyanocyclobutyl, 3-hydroxy-cyclobutyl Butyl, 3-(2-methylprop-1-enyl)cyclobutyl, 3-ethynyl-cyclobutyl, or 3-difluoromethoxycyclobutyl; in some embodiments, R ₇ is 2,2-Difluorocyclopropyl, 1-fluorocyclopropyl or cyclopropyl; in some embodiments, R ₇ is 3-methyloxetan-3-yl (

), 3-(cyanomethyl)oxetan-3-yl, 3-((trifluoromethoxy)methyl)oxetan-3-yl, 3-((acetoxy) (Methyl)oxetan-3-yl, 3-cyanooxetan-3-yl, 3-ethynyloxetan-3-yl, oxetan-3-yl or 3-tri Fluoromethyloxetan-3-yl; in some embodiments, R ₇ is tetrahydrofuran-3-yl (

); In some embodiments, R ₇ is 1-acetyl-3-methylazetidin-3-yl, 3-methyl-1-(methylsulfonyl)azetidin-3-yl R ₇ is 3,3-difluoropyrrolidin-1-yl; in some embodiments, R ₇ is 2-oxa-7-azaspiro[4.4]non-7-yl (

), 7-oxa-2-azaspiro[3.5]non-2-yl(

), 8-oxa-2,7-diazaspiro[4.4]non-2-yl(

), 7-isopropoxy-2-azaspiro[3.5]non-2-yl(

), 2,2,-dioxide-2-thia-7-azaspiro[4.4]non-7-yl(

), 7-(isopropylamino)-2-azaspiro[3.5]non-2-yl(

), 7-methyl-2,7-diazaspiro[4.4]non-2-yl(

), 2-Acetyl-2-azabicyclo[2.1.1]hex-4-yl(

), 1-azaspiro[4.5]dec-8-yl(

), 2-Pendant oxy-1-azaspiro[4.5]dec-8-yl(

), 3-oxo-2-azaspiro[4.5]dec-8-yl(

), 1-Pendant oxy-2-azaspiro[4.5]dec-8-yl(

), 2-azaspiro[4.5]dec-8-yl or (

); In some embodiments, R ₇ is 2-methylthiazol-4-yl (

), 5-fluoro-2-methyloxazol-4-yl (

), 1H-pyrazol-1-yl (

), 4-methylthiazol-2-yl (

), 6-(trifluoromethyl)pyridin-3-yl(

), 2-(trifluoromethyl)pyridin-4-yl(

), 6-cyanopyridin-3-yl(

), 2-(trifluoromethyl)pyrimidin-5-yl(

) Or 1-methyl-1H-pyrazol-4-yl (

); In some embodiments, R ₇ is 3-fluorobicyclo[1.1.1]pent-1-yl (

).

In some embodiments, the compound of formula (I) has the structure of formula (VI)

或

時，L₂和R₇不存在，當A為哌啶基時，L₂是-C(O)-；並且，當式(I)的化合物為

時，不符合以下(1)-(4)的任一情形： The condition is that when A is substituted or unsubstituted

or

When L ₂ and R ₇ do not exist, when A is piperidinyl, L ₂ is -C(O)-; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(4):

，L₂為-NH-，R₇為取代或未取代的

、取代或未取代的

，且

的取代基為1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基的基團；

的取代基為C_1-4烷基； (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl;

，L₂為鍵時，R₇為取代或未取代的

，所述取代是被1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷氧基、鹵素、羥基、氰基、-S(O)₂-C_1-4烷基的基團取代；或者R₇為取代或未取代的

、

，所述取代是被1-3個選自=O、鹵素的基團取代；或者R₇為

、

、C_1-4烷基， (2) A is

, When L ₂ is a bond, R ₇ is substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S(O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl,

，L₂為-O-，R₇為C_1-4烷基、環丙基、鹵代C_1-4烷基 或

； (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

；

。 (4) -AL ₂ -R ₇ is

.

The "condition" in the present invention is only a restriction on the compound, and when the compound is a pharmaceutically acceptable salt, solvate, co-crystal or deuterated compound, it is not restricted by the condition.

As a more specific first technical solution of the present invention, the compound represented by formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds,

Wherein, R _{1 is} selected from H, C _1-4 alkyl, halogenated C _1-4 alkyl and halogen;

R _{2 is} selected from C _1-4 alkyl;

The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;}

W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)-, -C(=S)- and bond;

Each R _La and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R _La and R _Lb on the carbon atom are formed together with the carbon atom to which they are attached C _3-6 carbon ring;

Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl;

m, n, p, q are independently selected from an integer of 0-4;

Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom;

Each R _{X1 is} independently selected from H, C _1-4 alkyl and C _3-6 cycloalkyl;

Each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1-3 halogens;

、

、

、

、

、含有0-3個選 自N、S、O雜原子的五元碳環或五元雜環，或含有0-3個選自N、S、O雜原子的六元非芳香碳環或六元非芳香雜環，或者不存在； Ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Non-aromatic heterocyclic ring, or non-existent;

Each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 ,- C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, The heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy and NH ₂ ;

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 ring Alkyl groups and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic rings are optionally selected from 1-3 C _1-4 alkyl groups, Halogen and -C(O)C _1-4 alkyl group substitution;

Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and The heterocycle is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl;

t is an integer of 0-3;

Each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or forms with R ₄ and R ₅ on the carbon atom together with the carbon atom to which they are attached C _3-6 carbocyclic ring; the C _1-4 alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen;

s is an integer of 0-3;

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基、胺基、-C(O)C_1-4烷基、羥基和鹵素的基團取代；作為選擇，所述碳環或雜環同碳原子上的兩個取代基與連接的碳原子一 起形成C_3-6碳環； A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl group, amino group, -C(O)C _1-4 alkyl group, hydroxyl group and halogen group substitution; alternatively, the two substituents on the same carbon atom and the connected carbon atom of the carbocyclic or heterocyclic ring Together to form a C _3-6 carbon ring;

L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, =NO-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond;

R _L2 is H or C _1-4 alkyl;

r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time;

Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen;

R ₇ is C _1-4 alkyl, -Si(R ₆₃ ) ₃ , halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, halogenated C _{1 -4} alkoxy, phenyl or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, wherein the C _1-4 alkyl group is optionally substituted by 1-2 -Si (R ₆₄ ) ₃ substitution, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkane Oxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _{1- 4} Alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted;

Each of R ₆₃ and R _{64 is} independently H, C _1-4 alkyl or halogen;

或

時，L₂和R₇不存在；當A為取代或未取代的哌啶基時，滿足L₂是-C(O)-或-C(O)NH-，或者滿足R₇是-Si(R₆₃)₃或R₇是被1-2個-Si(R₆₄)₃取代的C_1-4烷基；並且，當式(I)的化合物為

時，不符合以下(1)-(5)的任一情形： The condition is that when A is substituted or unsubstituted

or

When, L ₂ and R ₇ does not exist; when A is a substituted or unsubstituted piperidinyl group, satisfies L ₂ is -C (O) -, or -C (O) NH-, R ₇ is satisfied or -Si ( R ₆₃ ) ₃ or R _{7 is C 1-4} alkyl substituted with 1-2 -Si(R ₆₄ ) ₃ ; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(5):

，L₂為-NH-，R₇為取代或未取代的

、取代或 未取代的

，且

的取代基為1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基的基團；

的取代基為C_1-4烷基；或者A為

，L₂為-N(CH₃)-，R₇為取代或未取代的

、或C_1-4烷基，且

的取代基為1-3個C_1-4烷基； (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl; or A is

, L ₂ is -N(CH ₃ )-, R ₇ is substituted or unsubstituted

, Or C _1-4 alkyl, and

The substituents of are 1-3 C _1-4 alkyl groups;

，L₂為鍵時，R₇為鹵代C_1-4烷氧基、或者取代或未取代的

；所述取代是被1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷氧基、鹵素、羥基、氰基、-S(O)₂-C_1-4烷基的基團取代；或者R₇為取代或未取代的

、

，所述取代是被1-3個選自=O、鹵素的基團取代；或者R₇為

、

、C_1-4烷基； (2) A is

, When L ₂ is a bond, R ₇ is a halogenated C _1-4 alkoxy group, or substituted or unsubstituted

; The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S (O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl;

，L₂為-O-，R₇為C_1-4烷基、環丙基、鹵代C_1-4烷基或

； (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

；

； (4) -AL ₂ -R ₇ is

；

，L₂为-NH-时，R₇为

。 (5) When A is

, When L ₂ is -NH-, R ₇ is

.

As the second technical solution of the present invention, the compound represented by formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds,

Wherein, R _{1 is} selected from H, C _1-4 alkyl, halogenated C _1-4 alkyl and halogen;

R _{2 is} selected from C _1-4 alkyl;

The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;}

W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)- and bond;

Each R _La and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R _La and R _Lb on the carbon atom are formed together with the carbon atom to which they are attached C _3-6 carbon ring;

Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl;

m, n, p, q are independently selected from an integer of 0-4;

Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom;

Each R _{X1 is} independently selected from H, C _1-4 alkyl and C _3-6 cycloalkyl;

Each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, the alkyl and cycloalkyl are optionally substituted with 1-3 halogens;

、

、

、

、

、含有0-3個選自N、S、O雜原子的五元碳環或五元雜環，或含有0-3個選自N、S、O雜原子的六元非芳香碳環或六元非芳香雜環，或者不存在； Ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Non-aromatic heterocyclic ring, or non-existent;

Each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 ,- C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, The heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, cyano, OH, NH _2;

R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 cycloalkyl And a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic ring are optionally selected from C _1-4 alkyl, halogen and -C(O)C _1-4 alkyl group substitution;

R _B3 is a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring optionally Ground is substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl;

t is an integer of 0-3;

Each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or forms with R ₄ and R ₅ on the carbon atom together with the carbon atom to which they are attached C _3-6 carbon ring;

s is an integer of 0-3;

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基、鹵素、胺基、-C(O)C_1-4烷基、羥基和鹵素的基團取代；作為選擇，所述碳環或雜環同碳原子上的兩個取代基與連接的碳原子一起形成C_3-6碳環； A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl, halogen, amine, -C(O)C _1-4 alkyl, hydroxyl and halogen groups are substituted; alternatively, the two substituents on the carbocyclic or heterocyclic ring and carbon atoms are connected to the The carbon atoms together form a C _3-6 carbocyclic ring;

L ₂ is -C(O)-(NH) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond;

r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time;

Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen;

R ₇ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, halogenated C _1-4 alkoxy, phenyl, or contains 1-2 selected from N, S 4-10 membered heterocyclic ring of O heteroatom, the cycloalkyl, phenyl and heterocyclic ring are optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy , Mono-C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _1-4 alkyl -OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted;

或

時，L₂和R₇不存在；當A為取代或未取代的哌啶基時，L₂是-C(O)-；並且，當式(I)的化合物為

時，不符合以下(1)-(4)的任一情形： The condition is that when A is substituted or unsubstituted

or

When L ₂ and R _{7 are} not present; when A is a substituted or unsubstituted piperidinyl group, L ₂ is -C(O)-; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(4):

，L₂為-NH-，R₇為取代或未取代的

、取代或未取代的

，且當取代時，

的取代基為1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基的基團；

的取代基為C_1-4烷基； (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

, And when replaced,

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl;

，L₂為鍵時，R₇為取代或未取代的

，所述取代是被1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷氧基、鹵素、羥基、氰基、-S(O)₂-C_1-4烷基的基團取代；或者R₇為取代或未取代的

、

，所述取代是被1-3個選自=O、鹵素的基團取代；或者R₇為

、

、C_1-4烷基； (2) A is

, When L ₂ is a bond, R ₇ is substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S(O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl;

，L₂為-O-，R₇為C_1-4烷基、環丙基、鹵代C_1-4烷基或

； (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

；

。 (4) -AL ₂ -R ₇ is

.

As the third technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate or co-crystal, wherein:

R _{1 is} selected from C _1-4 alkyl;

The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;}

W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)- and bond;

Each of R _La and R _Lb is H, or the R _La and R _Lb on the carbon atom together with the carbon atom to which they are connected form a C _3-6 carbocyclic ring;

Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl;

m, n, p, q are independently selected from an integer of 0-4;

Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom;

Each R _{X1 is} independently selected from H and C _1-4 alkyl;

Each R _{X2 is} independently selected from H, halogen, and C _1-4 alkyl, which is optionally substituted with 1-3 deuteriums;

、

、

、

，或者不存在； Ring B is

,

,

,

, Or does not exist;

Each R _{B is} independently selected from H, -NR _B1 R _B2 and -OR _B3 ;

R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl, and -S(O) ₂ C _1-4 alkyl;

R _B3 is a C _3-6 cycloalkyl group or a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, the heterocyclic ring is optionally substituted by 1 -C(O)C _1-4 alkyl replace;

t is 0 or 1;

Each R ₄ and R _{5 is} independently selected from H and C _1-4 alkyl;

s is 1 or 2;

A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkane Substitution of the group, hydroxyl and halogen; alternatively, or the two substituents on the carbon atom and the two substituents on the carbon atom together with the connected carbon atom form a C _3-6 carbocycle;

L ₂ is -C(O)-(NH) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond;

Each R ₆₁ and R _{62 is} independently selected from H and C _1-4 alkyl;

R ₇ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, halogenated C _1-4 alkoxy or containing 1-2 selected from N, S, O hetero A 4-10 membered heterocyclic ring, the cycloalkyl and heterocyclic ring are optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 Alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxy, halogen, halogenated C _1-4 alkoxy, -C(O)-C _{1 -4} alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halogenated C _1-4 alkyl, -C _1-4 alkyl -OC(O) -Substitution of C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups;

The remaining groups are as defined in the aforementioned second technical solution.

As the fourth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has formula (IIa) or Structure of (IIb):

The remaining groups are as defined in the aforementioned second or third technical solution.

As the fifth technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated substances, wherein R ₁ , R ₂ , L ₁ and At least one group in R _X contains a deuterium atom, and the remaining groups are as defined in the foregoing fourth technical solution.

、

、

，或者不存在，其餘基團如前述第四技術方案之定義。 As the sixth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein ring B is

,

,

, Or not present, and the remaining groups are as defined in the foregoing fourth technical solution.

As the seventh technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

為

、

、

、

或

，所述R_X為H或C_1-4烷基；或者

for

,

,

,

or

, The R _X is H or C _1-4 alkyl; or

為

，R_X為鹵素；

for

, R _X is halogen;

The remaining groups are as defined in the foregoing fourth technical solution.

As the eighth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₁ is not -CH ₂ -NH- C(O)-, and the remaining groups are as defined in the second or third technical solution mentioned above.

As the ninth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has formula (IIIa) or (IIIb) Structure:

The remaining groups are as defined in the aforementioned eighth technical solution.

As a tenth technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

L ₁ is a 3-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the heterocyclic ring is optionally _{substituted by 1-3 R Lc} , R _Lc is H or C _1-4 Alkyl; or

、

或-C(O)-NR_Lc-CH₂-； L ₁ is -(NH) ₂ -C(O)-, -CH ₂ -NR _Lc -C(O)-, -CH ₂ -C(O)-NR _Lc -, -CH ₂ -NR _Lc -S( O) ₂ -、

,

Or -C(O)-NR _Lc -CH ₂ -;

The remaining groups are as defined in the aforementioned ninth technical solution.

，其餘基團如前述第十技術方案之定義。 As the eleventh technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₁ is

, And the remaining groups are as defined in the tenth technical solution mentioned above.

As the twelfth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has formula (IVa) Or the structure of (IVb):

The remaining groups are as defined in the aforementioned second or third technical solution.

As the thirteenth technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products, wherein:

t is 1, R _B is -NR _B1 R _B2 or -OR _B3 , R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl, -S( O) ₂ C _1-4 alkyl;

R _B3 is a C _3-6 cycloalkyl group or a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, the heterocyclic ring is optionally substituted by 1 -C(O)C _1-4 alkyl replace,

The remaining groups are as defined in the aforementioned twelfth technical solution.

、

或

，所述雜環任选地被1个-C(O)C_1-4烷基取代，其餘基團如前述第十三技術方案之定義。 As the fourteenth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein said R _B3 contains 1 A 4-8 membered heterocycle selected from N and O heteroatoms, the heterocycle is

,

or

, The heterocyclic ring is optionally substituted by a -C(O)C _1-4 alkyl group, and the remaining groups are as defined in the thirteenth technical solution mentioned above.

As the fifteenth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein s is 1, R ₄ and R ₅ is H; or s is 2, R ₄ and R _{5 are} independently selected from H and methyl, and the remaining groups are as defined in the aforementioned twelfth technical solution.

As the sixteenth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has formula (V) Structure:

The remaining groups are as defined in the aforementioned second or third technical solution.

As the seventeenth technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products, wherein:

、

、

、

、

、

或

；或者 A is

,

,

,

,

,

or

;or

、

或

；或者 A is

,

or

;or

，且环A上同碳原子上的两个取代基与连接的碳原子一起形成C_3-6碳环；或者 A is

, And the two substituents on the same carbon atom on ring A form a C _3-6 carbocyclic ring together with the connected carbon atom; or

A is a 7-10 membered spiro ring or bridged ring containing 0-2 N atoms; or

A is a 7-10 membered bridged ring containing 0-2 N atoms;

The remaining groups are as defined in the aforementioned sixteenth technical solution.

As a preferred embodiment of the seventeenth technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products, wherein:

，且环A上同碳原子上的两个取代基与连接的碳原子 一起形成C_3-6碳环；或者 A is

, And the two substituents on the same carbon atom on ring A form a C _3-6 carbocyclic ring together with the connected carbon atom; or

A is a 7-10 membered spiro ring or bridged ring containing 0-2 N atoms; or

A is a 7-10 membered bridged ring containing 0-2 N atoms;

The remaining groups are as defined in the aforementioned sixteenth technical solution.

、

、

、或

，这些基团任选地被=O取代，其餘基團如前述第十七技術方案之定義。 As the eighteenth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein A is

,

,

,or

, These groups are optionally substituted by =0, and the remaining groups are as defined in the seventeenth technical solution mentioned above.

As the nineteenth technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₂ is -NH-C( O)-, -C(O)-(NH) _r -, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -, When L ₂ is =NO-, L ₂ and A are connected through a double bond;

r is 0 or 1, and y is an integer of 1-3;

R ₆₁ and R ₆₂ are both H,

The remaining groups are as defined in the aforementioned sixteenth technical solution.

As the twentieth technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products, wherein R ₇ is a C _3-6 ring Alkyl group or 4-6 membered monocyclic heterocyclic ring or 4-6 membered bridged ring heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl, monocyclic heterocyclic ring and bridged ring heterocyclic ring _{The ring is C 1-4} alkyl substituted by 1-3 selected from cyano, cyano, halogen, halogenated C _1-4 alkoxy, -C _1-4 alkyl-O-halo C _1-4 Alkyl, -S(O) ₂ -C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, Substitution of hydroxyl, C _2-4 alkenyl and C _2-4 alkynyl groups; or

R ₇ is a 7-10 membered spiro heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from =0, C _1-4 Alkoxy, mono-C _1-4 alkylamino and C _1-4 alkyl group substitutions,

The remaining groups are as defined in the aforementioned sixteenth technical solution.

、所述螺环雜環为

、

、

、

、

，其餘基團如前述第二十技術方案之定義。 As the twenty-first technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the bridged ring heterocycle is

, The spirocyclic heterocycle is

,

,

,

,

, And the remaining groups are as defined in the twentieth technical solution mentioned above.

As the twenty-second technical solution of the present invention, the compound of formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has the formula (VI )Structure,

The remaining groups are as defined in the aforementioned second or third technical solution.

As the twenty-third technical solution of the present invention, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, has the formula (Ia) structure,

Wherein, L ₁ is -CH ₂ NHW-;

W is selected from -C(O)-, -S(O) ₂ -and -C(=S)-;

R _X2 is C _1-4 alkyl or halogenated C _1-4 alkyl;

R _{B is} selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C(O) OR _B3 , -OR _B3 , -C(O)R _B3 and 4-6 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, and heterocycles are optional Is substituted with 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, NH ₂ ;

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 ring Alkyl groups and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic rings are optionally selected from 1-3 C _1-4 alkyl groups, Halogen and -C(O)C _1-4 alkyl group substitution;

Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and The heterocycle is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl;

R ₄ and R _{5 are} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen; or R ₄ and R ₅ together with the carbon atom to which they are attached form a C _3-6 carbocyclic ring; The alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen;

A is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S;

L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -;

R ₇ is C _3-6 cycloalkyl, -Si(R ₆₃ ) _{3 , C 1-4} alkyl substituted with 0-2 -Si(R ₆₄ ) ₃ , C _5-8 bicyclic bridged cycloalkyl , Or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally selected from 1-3 = O, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, Hydroxy, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-O -Group substitution of halogenated C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl; each Said R ₆₃ and R _{64 are} independently H, C _1-4 alkyl or halogen;

The rest is as described in the aforementioned first technical solution.

As the twenty-fourth technical solution of the present invention, the compound of formula (I) or formula (Ia), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein A is A 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N and S, and the remaining groups are as defined in the aforementioned first or twenty-third technical solution.

As the twenty-fifth technical solution of the present invention, the compound of formula (I) or formula (Ia), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated substances,

Wherein, R _X2 is C _1-4 alkyl or halogenated C _1-4 alkyl;

R ₄ and R _{5 are} independently selected from H and C _1-4 alkyl;

R _{B is} selected from H, -NR _B1 R _B2 , -OR _B3 and a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the heterocyclic ring is optionally composed of 1-3 Substitution by a group selected from C _1-4 alkyl and C _{1-4 alkoxy;}

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl;

R _B3 is C _1-4 alkyl, C _3-6 cycloalkyl;

L ₂ is -C(O)-(NH) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or-(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -;

r is 0 or 1, y is 0 or 1;

R _L2 is H or C _1-2 alkyl;

R ₇ is a C _3-6 cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring are optionally selected from 1-3 From =O, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano Group, hydroxy, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl -O-halogenated C _1-4 alkyl, -C _1-4 alkyl, -OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl group substitutions,

The remaining groups are as defined in the aforementioned twenty-fourth technical solution.

As the twenty-sixth technical solution of the present invention, the compound of formula (I) or formula (Ia), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated substances,

Wherein, R _X2 is C _1-2 alkyl or halogenated C _1-2 alkyl;

R ₄ and R _{5 are} independently selected from H and C _1-2 alkyl;

A is cyclobutylene or azetidine;

L ₂ is -C(O)-(NH) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NH) _r -;

R ₇ is a C _3-6 cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring are optionally selected from 1-3 From C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl and -S (O) ₂ -C _1-4 alkane Group substitution,

The remaining groups are as defined in the aforementioned twenty-fifth technical solution.

As the twenty-seventh technical solution of the present invention, the compound of formula (I) or formula (Ia), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products,

、

、

、

和

，所述取代是指被1-2个选自选自C_1-2烷基、氰基、羟基、卤素、卤代C_1-2烷氧基、-C(O)-C_1-2烷基和-S(O)₂-C_1-2烷基的基团取代， Wherein, R _{7 is} selected from substituted or unsubstituted groups:

,

,

,

with

, The substitution refers to being selected from C _1-2 alkyl, cyano, hydroxyl, halogen, halogenated C _1-2 alkoxy, -C(O)-C _1-2 alkane Group and -S(O) ₂ -C _1-2 alkyl group,

The remaining groups are as defined in the twenty-sixth technical solution mentioned above.

As the twenty-eighth technical solution of the present invention, the compound of formula (Ia), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₁ is -CH ₂ NHC (O)-, R ₄ and R _{5 are} independently selected from H and C _1-2 alkyl, A is cyclohexyl, L ₂ is -NH-, R ₇ is C _5-8 bicyclic bridged cycloalkyl, so The bicyclic bridged cycloalkyl group is optionally substituted with 1-2 halogens, and the remaining groups are as defined in the aforementioned 23rd technical solution.

As the thirty-ninth technical solution of the present invention, the compound of formula (I) or formula (Ia), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated substances,

Wherein, _{at least one of R 4} and R _{5 is C 1-4} alkyl substituted with 1-2 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen; or,

R ₇ is -Si(R ₆₃ ) ₃ or C _1-4 alkyl substituted by 1-2 -Si(R ₆₄ ) ₃ , each of R ₆₃ and R _{64 is} independently H, C _1-4 alkyl Or halogen,

The remaining groups are as defined in the aforementioned first or twenty-third technical solution.

As the thirtieth technical solution of the present invention, the compound of formula (I) or formula (Ia), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products,

Among them, L ₁ is -CH ₂ NHW-,

W is selected from -C(O)-, -S(O) ₂ -and -C(=S)-,

R ₄ and R _{5 are independently H, C 1-2} alkyl substituted or unsubstituted by 1-2 -Si(Rs) ₃ , and each Rs is independently C _1-2 alkyl or halogen;

A is a 6-membered carbocyclic or heterocyclic ring containing 0-2 heteroatoms selected from N and S,

L ₂ is -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -NR _L2 -C(O)-, or -C(O)-(NR _L2 ) _r -,

r is 0 or 1, y is 0 or 1,

R _L2 is H or C _1-2 alkyl,

R ₆₁ and R _{62 are} independently H or C _1-2 alkyl,

The remaining groups are as defined in the aforementioned twenty-ninth technical solution.

As the thirty-first technical solution of the present invention, the compound represented by formula (VII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products,

Wherein, R _{1 is} selected from H, D, C _1-4 alkyl, deuterated C _1-4 alkyl, halo C _1-4 alkyl and halogen;

R _{2 is} selected from C _1-4 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, halogenated C _1-4 alkyl and Deuterated C _1-4 alkyl;

R _La and R _{Lb are} independently selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterated C _1-4 alkyl and halogen, or R _La and R _Lb are connected to them The carbon atoms together form a C _3-6 carbocyclic ring, or R _La and R _Lb together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O;

M is -CR' _{La R'Lb} -, -C(=S)-, -C(=N-CN)-, -C(=O)-, -S(O)- or -S(O) ₂ -;

_R'La and _{R'Lb are} independently selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterated C _1-4 alkyl and halogen, or _R'La and _R'Lb Together with the carbon atoms to which they are connected, they form a C _3-6 carbocyclic ring, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O;

R _{X2 is} selected from H, D, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, the alkyl and cycloalkyl are optionally substituted with 1-3 halogens or D;

Each R _{B is} independently selected from OH, halogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, CN, C _3-9 cycloalkyl, phenyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C _1-4 alkylene-R _B3 , -C(O)R _B3 and containing 1 -4 4-10 membered heterocycles selected from N, S, O heteroatoms, the alkyl, cycloalkyl, phenyl, and heterocycles are optionally selected from 1-3 halogen, =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, CN, OH, C _3-6 cycloalkyl, containing 1-3 4-7 membered heterocyclic ring selected from N, S, O heteroatoms, NH ₂ and -C(O)C _1-4 alkyl group substitution;

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl, -C (O) C _1-4 alkyl, -C (O) C _3-6 Cycloalkyl, -S (O) ₂ C _1-4 alkyl, -S (O) C _1-4 alkyl, C _3-6 cycloalkyl and containing 1-3 selected from N, S, O hetero A 4-10 membered heterocyclic ring, the cycloalkyl and heterocyclic ring are optionally substituted by 1-3 _{groups selected from the group consisting of C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl replace;

Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the alkyl group, ring The alkyl group and the heterocyclic ring are optionally selected from the group consisting of C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogen , CN, OH, NH ₂ and -C(O)C _1-4 alkyl group substitution;

t is an integer of 0-3;

R _{5 is} independently selected from H, D, C _1-4 alkyl, deuterated C _1-4 alkyl, halo C _1-4 alkyl and halogen;

s is an integer of 1-3;

z is an integer of 0-2, when z is 0, the key represented by ----- does not exist;

R _A and R _A 'are independently selected from H, halogen, CN, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, NH ₂ , -C(O)C _1-4 alkyl and OH;

Y is CH or N, Y is CH, H atoms may be optionally substituted with RA or R _A 'substituents;

L ₂ is QT;

Q is a bond, -C(O)-, -NR _L2 -, -O-, =N-, -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, or contains 1- 3 4-7 membered heterocycles selected from N, S, O heteroatoms, when Q is =N-, Q and Y are connected through a double bond;

T is a bond, -C(O)-, -NR _L2 -, -C(O)NR _L2 -, -NR _L2 C(O)-, -O-, -(CR ₆₁ R ₆₂ ) _y -, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, -(CR ₆₁ R ₆₂ ) _y -O-, -O-(CR ₆₁ R ₆₂ ) _y -, or contain 1- 3 4-7 membered heterocycles selected from N, S, O heteroatoms;

表示單鍵或雙鍵；

Represents a single bond or a double bond;

R _L2 is H, C _1-4 alkyl or halogenated C _1-4 alkyl;

Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen;

y is an integer of 0-3;

R ₇ is H, C _1-4 alkyl, halogen, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _3-6 monocycloalkyl, C _5-8 bicyclic bridged cycloalkyl , Halogenated C _1-4 alkoxy, C _2-4 alkenyl, -NHC(O)C _1-4 alkyl, phenyl or 4-containing 1-3 heteroatoms selected from N, S, O A 12-membered heterocyclic ring, _{when R 7} is an alkyl group, optionally one to three selected from C _1-4 alkoxy, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, CN, OH, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, or 4-7 membered heteroatoms containing 1-3 heteroatoms selected from N, S, O When R ₇ is a monocyclic alkyl group, a phenyl group, a bicyclic bridged cycloalkyl group and a heterocyclic ring, it is optionally substituted by 1-3 selected from =0, C _1-4 alkyl,- C _1-4 alkyl -OH, C _1-4 alkoxy, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _{1- 4} alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S (O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 Alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group substitution .

As the thirty-second technical solution of the present invention, the compound of formula (VII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

i. At least one hydrogen atom in the compound is replaced by a deuterium atom; or

ii, z is 1 or 2; or s is 1, and R ₅ is H; or s is an integer of 2-3; or

iii. M is -CR' _{La R'Lb} -, -C(=N-CN)-, C(=S), -S(O)- or -S(O) ₂ -;

R _'La and R' and the carbon atom to which they are attached together _Lb C _3-6 carbocyclic ring or contains 1-3 heteroatoms selected from N, S, 4-7 membered heterocycle O heteroatom; or

iv, t is an integer of 1-3;

Each R _{B is} independently selected from C _3-9 cycloalkyl, -NR _B1 R _B2 , -C (O) NR _B1 R _B2 , -C (O) OR _B3 , -OR _B3 , -C _1-4 sub Alkyl -R _B3 , -C(O)R _B3 and 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring are optionally substituted by 1- 3 selected from halogen, =O, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, CN, OH, C _{3- 6} cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, NH ₂ and -C(O)C _1-4 alkyl group substitution;

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl, -C (O) C _1-4 alkyl, -C (O) C _3-6 Cycloalkyl, -S (O) ₂ C _1-4 alkyl, -S (O) C _1-4 alkyl, C _3-6 cycloalkyl and containing 1-3 selected from N, S, O hetero A 4-10 membered heterocyclic ring, the cycloalkyl and heterocyclic ring are optionally substituted by 1-3 _{groups selected from the group consisting of C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl replace;

Each R _{B3 is} independently a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the cycloalkyl group and the heterocyclic ring are optionally substituted by 1 -3 selected from C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogen, CN, OH, NH ₂ and -C (O) _{Substitution of C 1-4} alkyl group; or

v, L ₂ =NO-, -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, -(CR ₆₁ R ₆₂ ) _y C(O )NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 C(O)-, -C(O)NR _L2 (CR ₆₁ R ₆₂ ) _y -, containing 1-3 selected from N, S, O Atomic 4-7 membered heterocyclic ring-C(O)-, containing 1-3 heteroatoms selected from N, S, O, 4-7 membered heterocyclic ring-C(O)NR _L2 -, containing 1-3 4-7 membered heterocyclic ring selected from N, S, O heteroatoms-NR _L2 C(O)-, 4-7 membered heterocyclic ring containing 1-3 selected N, S, O heteroatoms-(CR ₆₁ R ₆₂ ) _y -O-, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S and O-(CR ₆₁ R ₆₂ ) _y -NR _L2 -, y is not 0, R ₇ C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, halogenated C _1-4 Alkoxy, phenyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, _{when R 7} is alkyl, optionally 1-3 selected from C _{1- 4} alkoxy, halo C _1-4 alkyl, C _3-6 cycloalkyl, CN, OH, -C (O ) -C 1-4 alkyl, -S (O) ₂ -C _1-4 Alkyl group, or a 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, phenyl, bicyclic bridged cycloalkyl and hetero The ring is optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _1-4 alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-haloC _{1 -4} alkyl, -C _1-4 alkylene, -OC(O)-C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, containing 1-3 selected from N, S, O heteroatoms 4-7 membered heterocyclic ring and C _2-4 alkynyl group substitution; or

L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -, 4-7 containing 1-3 heteroatoms selected from N, S, O -Membered heterocyclic ring -NR _L2 -, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O -NR _L2 (CR ₆₁ R ₆₂ ) _y -, containing 1-3 heteroatoms selected from N, S, O heteroatoms 4-7 membered heterocyclic ring -(CR ₆₁ R ₆₂ ) _y -, or containing 1-3 selected from N, S, O heteroatoms 4-7 membered heterocyclic ring -O-(CR ₆₁ R ₆₂ ) _y -, y is not 0, R ₇ is C _2-4 alkenyl, -NHC(O)C _1-4 alkyl, C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged ring Alkyl group, or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group, bicyclic bridged cycloalkyl group and heterocyclic ring are optionally further selected from 1-3 From halogen, =O, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, mono C _1-4 alkylamino, -N (C _1-4 alkyl ) ₂ , halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, CN, OH, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _{1 -4} alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group Group replacement; or

L ₂ is -NR _L2 -, or a 4-7 membered heterocycle -O- containing 1-3 heteroatoms selected from N, S, O, R ₇ is C _2-4 alkenyl, C _3-6 monocyclic ring Alkyl, C _5-8 bicyclic bridged cycloalkyl or 4-12 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl And non-aromatic heterocyclic ring substituted by 1-3 selected from halogen, mono-C _1-4 alkylamino, -N(C _1-4 alkyl) _{2 , C 1-4} alkyl substituted with cyano group, CN, OH , Halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halo Substituted C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups, and optionally Is 1-3 selected from C _1-4 alkyl, =O, C _1-4 alkoxy, -C _1-4 alkyl-OH, C _3-6 cycloalkyl, containing 1-3 selected from N, S, O heteroatoms of 4-7 membered heterocyclic ring and halogenated C _1-4 alkyl group substitution; or

L ₂ is -NR _L2 -, R ₇ is a 4-7 membered heteroaromatic ring or phenyl containing 1-3 heteroatoms selected from N, S, O, and the heteroaromatic ring and phenyl are optionally substituted by 1 -3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -NHC _1-4 alkyl, -N (C _1-4 alkyl ) _2. Halogenated C _1-4 alkyl, -C _1-4 alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy , -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene, -O-halo C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 4 containing 1-3 heteroatoms selected from N, S, O Substitution of -7 membered heterocyclic ring and C _2-4 alkynyl group; or

L ₂ is -O-, R ₇ is C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, phenyl or 4-12 containing 1-3 heteroatoms selected from N, S, O -Membered heterocyclic ring, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are substituted by 1-3 halogens, =O, C _1-4 alkoxy, mono C _1-4 alkylamino, Halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, CN, OH, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S( O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkane Group, C _2-4 alkenyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group; or

L ₂ is -O-(CR ₆₁ R ₆₂ ) _y -, y is not 0, R ₇ is C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, C _{2 -4} alkenyl, -NHC(O)C _1-4 alkyl, C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl, phenyl or containing 1-3 selected from N, S , O heteroatom of 4-12 membered heterocycle, when R ₇ is C _1-4 alkyl, 1-3 are selected from C _3-6 cycloalkyl, CN, OH, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, or a 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, said R ₇ is a monocyclic alkyl group, a phenyl group, a bicyclic bridged cycloalkyl group and a heterocyclic ring, optionally by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -C _1-4 alkyl-OH, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _{1 -4} alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl,- S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _{1- 4} alkyl group, C _2-4 alkenyl group, C _3-6 cycloalkyl group, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group Replace; or

L ₂ is a bond, R ₇ is a C _3-6 cycloalkyl group or a C _5-8 bicyclic bridged cycloalkyl group, and the cycloalkyl group and the bicyclic bridged cycloalkyl group are 1-3 selected from -NHC _{1- 4} alkyl, -N (C _1-4 alkyl) ₂ , halo C _1-4 alkyl, -C _1-4 alkylene -NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O- Halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl, containing 1-3 selected from N, S, O hetero A 4-7 membered heterocyclic ring of atoms and a C _2-4 alkynyl group; or

L ₂ is a bond, R ₇ is a 4-12 membered monocyclic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the monocyclic heterocyclic ring is connected to Y through a ring carbon atom, the monocyclic The heterocyclic ring is selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _1-4 alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O) -C _{1-4 alkyl, -S (O) 2 -C 1-} 4 alkyl, -C _1-4 haloalkyl alkylene -O- C _1-4 alkyl, -C _1-4 alkylene -OC(O)-C _1-4 alkyl, C _2-4 alkenyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O and C _2-4 alkynyl group Group replacement; or

L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocycle, bridged heterocycle or conjugated heterocycle containing 1-3 heteroatoms selected from N, S, O, the spiro heterocycle, bridge The cyclic heterocyclic ring and the bicyclic heterocyclic ring are optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -NHC _{1 -4} alkyl, -N(C _1-4 alkyl) ₂ , halo C _1-4 alkyl, -C _1-4 alkylene -NH ₂ , cyano substituted C _1-4 alkyl, CN , OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene -O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, containing 1 -3 substitutions of 4-7 membered heterocycles selected from N, S, O heteroatoms and C _2-4 alkynyl groups; or

L ₂ is -O-, R ₇ is C _1-4 alkyl, R _X2 is halogenated C _1-4 alkyl;

The rest of the groups are as described in the 31st technical solution mentioned above.

As the thirty-third technical solution of the present invention, the compound of formula (VII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, further has the formula ( The structure of VIII),

Each group is as defined in the aforementioned thirty-second technical solution.

As the thirty-fourth technical solution of the present invention, the compound of formula (VIII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

Y is CH; t is selected from 0 or 1;

R _{B is} independently selected from halogen, -NR _B1 R _B2 , CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, and the heterocyclic ring is optionally composed of 1-3 Substitution with a group selected from halogen, C _1-4 alkyl, and halogenated C _{1-4 alkyl;}

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl;

L ₂ is -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, y is selected from 1 or 2, R ₇ is C _3-6 cycloalkyl , C _5-8 bicyclic bridged cycloalkyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, bicyclic bridged cycloalkyl and The heterocyclic ring is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl and halogen; or

L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, y is selected from 1 or 2, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkane Group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally further selected from 1-3 halogens , C _1-4 alkyl group substitution; or

L ₂ is -NR _L2 -, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl or 4-12 member containing 1-3 heteroatoms selected from N, S, O Non-aromatic heterocycle, the cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle are substituted by 1-3 groups selected from halogen, OH, -S(O) ₂ -C _1-4 alkyl ;or

L ₂ is a bond, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, the bicyclic bridged cycloalkyl group is substituted with 1-3 halogenated C _1-4 alkyl groups, -C(O)-C _{1- 4} alkyl group substitution; or

L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from C _{1 -4} Alkyl, halogen group substitution;

R _L2 is H, C _1-2 alkyl or halogenated C _1-2 alkyl;

The remaining groups are as described in the aforementioned 33rd technical scheme.

As the thirty-fifth technical solution of the present invention, the compound of formula (VIII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

R _{B is} independently selected from F, Cl, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , CN, 5 containing 1-4 heteroatoms selected from N, S, and O -6 membered heteroaryl group, the heteroaryl group is optionally selected from 1-3 selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ group substitution;

、

、

或

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代；或者 L ₂ is -NHC(O)-, -C(O) _{NH-, -CH 2} NH-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or

、

或

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代；或者 L ₂ is -C(O)-, -NHCH ₂ -, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or

，所述R₇為環丙基、環丁基、環戊基、環己基時被1-3個選自F、Cl、OH、-S(O)₂-CH₃、-S(O)₂-CH₂CH₃、-S(O)₂-CH₂CH₂CH₃、-S(O)₂-CH(CH₃)CH₃的基團取代；或者 L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or

When the R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, 1-3 are selected from F, Cl, OH, -S(O) ₂ -CH ₃ , -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -CH ₂ CH ₂ CH ₃ , -S(O) ₂ -CH(CH ₃ )CH ₃ group substitution; or

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代； L ₂ is the bond, R ₇ is

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;

The remaining groups are as described in the aforementioned 34th technical scheme.

As the thirty-sixth technical solution of the present invention, the compound of formula (VII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

R _{1 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl;

R _{2 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl;

R _La and R _{Lb are} independently selected from H and D;

M is -C(=O)-;

R _{X2 is} selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterium halo C _1-4 alkyl;

R _A and R _A 'are independently selected from H;

表示單鍵；

Represents a single key;

i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and,

t is 0 or 1; s is 1; Y is CH or N; z is selected from 0, 1, 2;

R _{5 is} selected from H, D, C _1-4 alkyl, and deuterated C _1-4 alkyl;

R _{B is} independently selected from halogen, CN, -NR _B1 R _B2 and a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, the heterocyclic ring is optionally composed of 1-3 Substitution by a group selected from halogen and C _{1-4 alkyl;}

Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl;

L ₂ is -NR _L2 -, -O-;

R _L2 is H or C _1-4 alkyl;

R ₇ is a C _1-4 alkyl group, a C _3-6 monocyclic alkyl group, and when R ₇ is a monocyclic alkyl group, optionally 1-3 _{groups selected from C 1-4} alkyl group and halogen Replace; or

ii, z is 1 or 2; s is 1; Y is N; t is 0 or 1;

R _{B is} selected from halogen, CN, -NR _B1 R _B2 and 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally composed of 1-3 Substitution by a group selected from halogen and C _{1-2 alkyl;}

Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl;

R _{5 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl;

L ₂ is a bond, -C(O)-, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, R ₇ is H, halogen, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl; or

iii, s is 1, R _{5 is} selected from H; z is selected from 0; t is 0 or 1; Y is CH;

R _{B is} selected from halogen, CN, -NR _B1 R _B2 and 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally composed of 1-3 Substitution by a group selected from halogen and C _{1-2 alkyl;}

Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl;

L ₂ is -NR _L2 -;

R _L2 is H or C _1-4 alkyl;

R ₇ is a C _3-6 monocyclic alkyl group, a 4-12 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, said R ₇ is a monocyclic alkyl group, a non-aromatic heterocyclic ring When optionally substituted by 1-3 _{groups selected from halogen and C 1-4} alkyl; or

iv and t are 1 or 2, Y is CH or N; s is 1; z is 0;

R _{5 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl;

R _{B is} independently selected from -NR _B1 R _B2 and a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the heterocyclic ring is optionally selected from 1-3 halogen, Substitution of C _1-4 alkyl groups;

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl;

L _{2 is} selected from -O-;

R _{7 is} selected from C _1-4 alkyl; or

v and z are 0, Y is selected from CH or N, t is selected from 0 or 1; s is 1;

R _{5 is} selected from H, D, C _1-4 alkyl, and deuterated C _1-4 alkyl;

R _{B is} selected from halogen, -NR _B1 R _B2 , CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, the heterocyclic ring is optionally selected from 1-3 Substitution of halogen, C _1-4 alkyl, and halogenated C _{1-4 alkyl;}

Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl;

L ₂ is -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, y is selected from 1 or 2, R ₇ is C _3-6 cycloalkyl , C _5-8 bicyclic bridged cycloalkyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, bicyclic bridged cycloalkyl and The heterocyclic ring is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl and halogen; or

L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, y is selected from 1 or 2, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkane Group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally further selected from 1-3 halogens , C _1-4 alkyl group substitution; or

L ₂ is -NR _L2 -, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl or 4-12 member containing 1-3 heteroatoms selected from N, S, O Non-aromatic heterocycle, the cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle are substituted by 1-3 groups selected from halogen, OH, -S(O) ₂ -C _1-4 alkyl ;or

L ₂ is a bond, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, the bicyclic bridged cycloalkyl group is substituted with 1-3 halogenated C _1-4 alkyl groups, -C(O)-C _{1- 4} alkyl group substitution; or

L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from C _{1 -4} Alkyl, halogen group substitution; or

L ₂ is -O-, R ₇ is C _1-4 alkyl, R _X2 is halogenated C _1-4 alkyl;

The remaining groups are as described in the aforementioned thirty-second technical solution.

Further, the compound of formula (VII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

R _{1 is} selected from C _1-2 alkyl;

R _{2 is} selected from C _1-2 alkyl and deuterated C _1-2 alkyl;

R _La and R _{Lb are} independently selected from H and D;

M is -C(=O)-;

R _{X2 is} selected from C _1-2 alkyl and halogenated C _1-2 alkyl;

R _A and R _A 'are independently selected from H;

表示單鍵；

Represents a single key;

i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and,

t is 0 or 1; s is 1; Y is CH; z is selected from 0;

R _{5 is} selected from H, C _1-2 alkyl;

R _{B is} independently selected from halogen, CN, -NR _B1 R _B2 and 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally substituted by 1- Substitution with 2 groups selected from C _{1-4 alkyl;}

Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl;

L ₂ is -NH-, -O-;

R ₇ is C _1-2 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and when R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally 1 -3 groups selected from halogen substitution; or

ii. z is 1; s is 1; Y is N; t is 0;

R _{5 is} selected from C _1-2 alkyl;

L ₂ is a bond, -C(O)-, C _1-2 alkyl, fluoro C _1-2 alkyl, R ₇ is H, C _1-2 alkyl; or

iii, s is 1, R _{5 is} selected from H; z is selected from 0; t is 0; Y is CH;

L ₂ is -NH-;

R ₇ is a C _4-5 monocyclic alkyl group, a 4-6 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, said R ₇ is a monocyclic alkyl group, a non-aromatic heterocyclic ring When optionally substituted by 1-3 _{groups selected from halogen and C 1-2} alkyl; or

iv and t are 1, Y is CH; s is 1; z is 0;

R _{5 is} selected from C _1-2 alkyl;

R _{B is} selected from -NR _B1 R _B2 and a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally selected from 1-3 halogen, Substitution of C _1-2 alkyl groups;

Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl;

L _{2 is} selected from -O-;

R _{7 is} selected from C _1-2 alkyl; or

v and z are 0, Y is selected from CH or N, t is selected from 0 or 1; s is 1;

R _{5 is} selected from H, C _1-2 alkyl;

R _{B is} selected from halogen, -NR _B1 R _B2 , CN, 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O, and the heteroaromatic ring is optionally composed of 1-3 Substitution by a group selected from C _{1-2 alkyl;}

Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl;

L ₂ is -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, y is selected from 1, R ₇ is C _4-5 cycloalkyl, C _5-6 bicyclic bridged cycloalkyl or 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring When optionally substituted by 1-3 _{groups selected from C 1-2} alkyl and halogen; or

L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, y is selected from 1, R ₇ is C _4-5 monocyclic alkyl, C _5-6 bicyclic bridged cycloalkyl or A 4-6 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocyclic ring may be further optionally substituted by 1-3 Substitution with a group selected from halogen and C _1-2 alkyl; or

L ₂ is -NR _L2 -, R ₇ is a C _4-5 monocyclic alkyl group or a 4-6 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group, The bicyclic bridged cycloalkyl group and non-aromatic heterocyclic ring are substituted with 1-3 groups selected from halogen, OH, -S(O) ₂ -C _1-2 alkyl; or

L ₂ is a bond, R ₇ is an 8-10 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from C _{1 -2} Alkyl, halogen group substitution; or

L ₂ is -O-, R ₇ is C _1-2 alkyl, R _X2 is halogenated C _1-2 alkyl;

The remaining groups are as described in the aforementioned thirty-sixth technical scheme.

As the thirty-seventh technical solution of the present invention, the compound of formula (VII), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated compounds, wherein:

R _{1 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ;

R _{2 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ;

R _{X2 is} selected from methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ;

i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and,

t is 0 or 1; s is 1; Y is CH or N; z is selected from 0 or 1;

R _{5 is} selected from H, methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ;

R _{B is} independently selected from F, Cl, CN, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ and 5 containing 1-4 heteroatoms selected from N, S, O -6-membered heteroaryl, said heteroaryl is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;

L ₂ is -NH-, -N(CH ₃ )-, -O-;

R ₇ is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said R ₇ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl When optionally substituted by 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or

ii. z is 1; s is 1; Y is N; t is 0 or 1;

R _{B is} independently selected from F, Cl, CN, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ and 5 containing 1-4 heteroatoms selected from N, S, O -6-membered heteroaryl, said heteroaryl is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;

R _{5 is} selected from H methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ;

L ₂ is a bond, -C(O)-, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , R ₇ is H, F, Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ;or

iii, s is 1, R _{5 is} selected from H; z is selected from 0; t is 0 or 1; Y is CH;

R _{B is} independently selected from F, Cl, CN, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ and 5 containing 1-4 heteroatoms selected from N, S, O -6-membered heteroaryl, said heteroaryl is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;

或

，所述R₇任選被1-3個選自F、Cl的基團取代；或者 L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F and Cl; or

iv and t are 1, Y is CH or N; s is 1; z is 0;

R _{5 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ;

R _{B is} selected from -NH-C _1-4 alkyl, -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , 5-6 containing 1-2 heteroatoms selected from N, S, O -Membered heteroaromatic ring, said heteroaromatic ring is optionally substituted by 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;

L _{2 is} selected from -O-;

R _{7 is} selected from methyl, ethyl, propyl, isopropyl; or

v and z are 0, Y is selected from CH or N, t is selected from 0 or 1, and s is 1;

R _{5 is} selected from H, D, methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ;

R _{B is} selected from F, Cl, -NH-CH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , CN, 5 containing 1-4 heteroatoms selected from N, S, O -6 membered heterocyclic ring, the heterocyclic ring is optionally selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ group substitution;

、

、

或

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代；或者 L ₂ is -NHC(O)-, -C(O) _{NH-, -CH 2} NH-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or

、

或

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代；或者 L ₂ is -C(O)-, -NHCH ₂ -, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or

，所述R₇為環丙基、環丁基、環戊基或環己基時被1-3個選自F、Cl、OH、-S(O)₂-CH₃、-S(O)₂-CH₂CH₃、-S(O)₂-CH₂CH₂CH₃、-S(O)₂-CH(CH₃)CH₃的基團取代；或者 L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or

When R ₇ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 1-3 are selected from F, Cl, OH, -S(O) ₂ -CH ₃ , -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -CH ₂ CH ₂ CH ₃ , -S(O) ₂ -CH(CH ₃ )CH ₃ group substitution; or

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基、CF₃、CHF₂、CH₂F、CH₂CF₃的基團取代；或者 L ₂ is the bond, R ₇ is

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ;or

L ₂ is -O-, R ₇ is methyl, ethyl, propyl, isopropyl, R _X2 is CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ;

The remaining groups are as described in the aforementioned thirty-sixth technical scheme.

Further, the compound of formula (VII), its stereoisomers, pharmaceutically acceptable The salt, solvate, co-crystal or deuterated substance of, in which:

R _{1 is} selected from methyl;

R _{2 is} selected from methyl, CD ₃ ;

R _{X2 is} selected from methyl, CHF ₂ ;

i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and,

t is 0 or 1; s is 1; Y is CH; z is selected from 0;

R _{5 is} selected from methyl;

R _{B is} independently selected from F and pyrazolyl, and the pyrazolyl is optionally substituted with 1 or 2 groups selected from methyl;

L ₂ is -NH-, -O-;

R ₇ is methyl or cyclobutyl, and _{when R 7} is cyclobutyl, it is optionally substituted with 1 or 2 or 3 groups selected from F; or

ii. z is 1; s is 1; Y is N; t is 0;

R _{5 is} selected from methyl;

L ₂ is a bond, -C(O)-, CH- ₂ CF ₃ , and R ₇ is H, methyl; or

iii, s is 1, R _{5 is} selected from H; z is selected from 0; t is 0; Y is CH;

，所述R₇為環丁基時任選被1或2個選自F的基團取代；或者 L ₂ is -NH-, R ₇ is cyclobutyl or

, When R ₇ is cyclobutyl, it is optionally substituted with 1 or 2 groups selected from F; or

iv and t are 1, Y is CH or N; s is 1; z is 0;

R _{5 is} selected from methyl;

R _B is selected from -NH-C _1-4 alkyl, -NHC (O) CH ₃ or pyrazolyl group, a pyrazolyl optionally substituted with 1 or 2 substituents selected from methyl groups;

L _{2 is} selected from -O-;

R _{7 is} selected from methyl; or

v and z are 0, Y is selected from CH or N, t is selected from 0 or 1, and s is 1;

R _{5 is} selected from methyl;

R _{B is} selected from F, -NH-CH ₃ , -NHC(O)CH ₃ , CN or pyrazolyl, said pyrazolyl is optionally substituted with 1 or 2 groups selected from methyl;

、

、

或

，所述R₇任選地被1或2個選自F、甲基的基團取代；或者 L ₂ is -NHC(O)-, -C(O) _{NH-, -CH 2} NH-, R ₇ is cyclobutyl,

,

,

or

, Said R _{7 is} optionally substituted with 1 or 2 groups selected from F and methyl; or

、

或

，所述R₇任選地被1或2個選自F、甲基的基團取代；或者 L ₂ is -C(O)-, -NHCH ₂ -, R ₇ is cyclobutyl,

,

or

, Said R _{7 is} optionally substituted with 1 or 2 groups selected from F and methyl; or

，所述R₇為環丁基時被1或2個選自F的基團取代；或者 L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclobutyl or

, When R ₇ is cyclobutyl, it is substituted by 1 or 2 groups selected from F; or

；或者 L ₂ is the bond, R ₇ is

;or

L ₂ is -O-, R ₇ is methyl, and R _X2 is CHF ₂ ;

The remaining groups are as described in the aforementioned 37th technical scheme.

In any technical scheme of the present invention, R _{1 is} selected from H, D, C _1-4 alkyl, deuterated C _1-4 alkyl, halogenated C _1-4 alkyl and halogen; further, R _{1 is} selected from C _1-4 alkyl, deuterated C _1-4 alkyl, halogenated C _1-4 alkyl; further, R _{1 is} selected from C _1-4 alkyl, deuterated C _1-4 alkyl; further, R _{1 is} selected from C _1-2 alkyl, deuterated C _1-2 alkyl; R _{1 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; Further, R _{1 is} selected from C _1-4 alkyl; further, R _{1 is} selected from methyl.

In any technical scheme of the present invention, R _{2 is} selected from C _1-4 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, Halogenated C _1-4 alkyl and deuterated C _1-4 alkyl; further, R _{2 is} selected from C _1-4 alkyl, halogenated C _1-4 alkyl, and deuterated C _1-4 alkyl; further , R _{2 is} selected from C _1-4 alkyl, deuterated C _1-4 alkyl; further, R _{2 is} selected from C _1-2 alkyl, deuterated C _1-2 alkyl; further, R _{2 is} selected from methyl Group, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; further, R _{2 is} selected from methyl, CD ₃ .

In any technical solution of the present invention, R _La and R _{Lb are} independently selected from H, D, C _1-4 alkyl, halogenated C _1-4 alkyl, deuterated C _1-4 alkyl and halogen, or R _La and R _Lb together with the carbon atoms to which they are connected form a C _3-6 carbon ring, or R _La and R _Lb together with the carbon atoms to which they are connected form a 4 containing 1-3 heteroatoms selected from N, S, and O -7 membered heterocycle; further, R _La and R _{Lb are} independently selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterated C _1-4 alkyl and halogen; further, R _La and R _{Lb are} independently selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, and deuterated C _1-4 alkyl; further, R _La and R _{Lb are} independently selected from H , D.

In any technical scheme of the present invention, M is -CR' _{La R'Lb} -, -C(=S)-, -C(=N-CN)-, -C(=O)-, -S(O )-Or -S(O) ₂ -; further, M is -C(=O)-.

In any technical scheme of the present invention, R _{X2 is} selected from H, D, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally grouped by 1-3. Halogen or D substitution; further, R _{X2 is} selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterium halo C _1-4 alkyl; further, R _{X2 is} selected from C _{1- 4} alkyl, the alkyl is optionally substituted by 1-3 halogens or D; further, R _{X2 is} selected from C _1-2 alkyl, the alkyl is optionally substituted by 1-3 halogens or D ; Further, R _{X2 is} selected from methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ; further, R _{X2 is} selected from methyl, CHF ₂ .

In any technical scheme of the present invention, each R _{B is} independently selected from OH, halogen, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, CN, C _{3 -9} cycloalkyl, phenyl, -NR _B1 R _B2 ,-C(O)NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C _1-4 alkylene-R _B3 ,- C(O)R _B3 and a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, phenyl, and heterocyclic ring are optionally 1-3 One is selected from halogen, =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, CN, OH, C _3-6 Cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, NH ₂ and -C(O)C _1-4 alkyl group substitution; further, R _{B is} independent Is selected from halogen, -NR _B1 R _B2 , CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, the heterocyclic ring is optionally selected from 1-3 halogen , C _1-4 alkyl, halogenated C _1-4 alkyl groups; further, R _{B is} independently selected from halogen, -NR _B1 R _B2 , CN, containing 1-4 selected from N, S, A 5-6 membered heteroaromatic ring of O heteroatom, the heteroaromatic ring is optionally substituted by 1-3 _{groups selected from halogen, C 1-4} alkyl, and halogenated C _1-4 alkyl; further , R _{B is} independently selected from halogen, -NR _B1 R _B2 , CN, 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally 1 -3 substituents selected from halogen, C _1-2 alkyl, halo C _1-2 alkyl; further, R _{B is} independently selected from F, Cl, -NHC(O)CH ₃ , -NHC( O) CH ₂ CH ₃ , CN, a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, the heteroaryl group is optionally selected from 1-3 F, Cl , Methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ group substitution;

In any technical solution of the present invention, t is an integer from 0 to 3; further, t is 0, 1 or 2; further, t is 0, 1.

In any technical scheme of the present invention, R _{5 is} independently selected from H, D, C _1-4 alkyl, deuterated C _1-4 alkyl, halogenated C _1-4 alkyl and halogen; further, R ₅ It is selected from H, D, C _1-4 alkyl, and deuterated C _1-4 alkyl; further, R _{5 is} selected from H, D, C _1-2 alkyl, and deuterated C _1-2 alkyl; further, R _{5 is} selected from C _1-4 alkyl, deuterated C _1-4 alkyl; further, further, R _{5 is} selected from C _1-2 alkyl, deuterated C _1-2 alkyl; further, R _{5 is} selected from H, methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; further, R _{5 is} selected from methyl, ethyl, propyl, isopropyl, CD _3. CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; further, R _{5 is} selected from methyl.

In any technical solution of the present invention, s is an integer of 1-3; further, s is 1, 2; further, s is 1.

In any technical solution of the present invention, z is an integer of 0-2; further, z is 1, 2; further, z is 0.

Any aspect of the present invention, R _A and R _A 'are independently selected from H, halo, the CN, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo Substituted C _1-4 alkoxy, NH ₂ , -C(O)C _1-4 alkyl and OH; further, R _A and R _A 'are independently selected from H, halogen, CN, C _1-4 alkyl ; Further, R _A and R _A 'are independently selected from H.

In any technical solution of the present invention, Y is CH or N; further, Y is CH.

、

、

或

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代。 In any technical solution of the present invention, L ₂ is -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, y is selected from 1 or 2, R ₇ is a C _3-6 cycloalkyl group, a C _5-8 bicyclic bridged cycloalkyl group, or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and R ₇ is a cycloalkane Group, bicyclic bridged cycloalkyl and heterocycle are optionally substituted by 1-3 _{groups selected from C 1-4} alkyl and halogen; further, L ₂ is -NHC(O)-, -C( O) _{NH-, -CH 2} NH-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

or

The R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, and isopropyl.

、

或

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基的基團取代。 In any technical solution of the present invention, L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, y is selected from 1 or 2, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring optionally It is further substituted by 1-3 _{groups selected from halogen and C 1-4} alkyl; further, L ₂ is -C(O)-, -NHCH ₂ -, R ₇ is cyclopropyl, cyclobutyl, ring Pentyl, cyclohexyl,

,

or

The R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, and isopropyl.

，所述R₇為環丙基、環丁基、環戊基或環己基時被1-3個選自F、Cl、OH、-S(O)₂-CH₃、-S(O)₂-CH₂CH₃、-S(O)₂-CH₂CH₂CH₃、-S(O)₂-CH(CH₃)CH₃的基團取代。 In any technical solution of the present invention, L ₂ is -NR _L2 -, R ₇ is a C _3-6 monocyclic alkyl group, a C _5-8 bicyclic bridged cycloalkyl group or contains 1-3 selected from N, S , O heteroatom of 4-12 membered non-aromatic heterocyclic ring, the cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocyclic ring are selected from 1-3 halogen, OH, -S(O) ₂ -C _{Substitution of 1-4} alkyl groups; further, L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or

When R ₇ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 1-3 are selected from F, Cl, OH, -S(O) ₂ -CH ₃ , -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -CH ₂ CH ₂ CH ₃ , -S(O) ₂ -CH(CH ₃ )CH ₃ group substitution.

In any technical scheme of the present invention, L ₂ is a bond, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, and the bicyclic bridged cycloalkyl group is substituted by 1-3 halogenated C _1-4 alkyl groups, -C(O)-C _1-4 alkyl group substitution;

，所述R₇任選地被1-3個選自F、Cl、甲基、乙基、丙基、異丙基、CF₃、CHF₂、CH₂F、CH₂CF₃的基團取代。 In any technical scheme of the present invention, L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally Substituted by 1-3 groups selected from C _1-4 alkyl and halogen; L ₂ is a bond, R ₇ is

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ .

In any technical scheme of the present invention, L ₂ is -O-, R ₇ is C _1-4 alkyl, R _X2 is halogenated C _1-4 alkyl; further, L ₂ is -O-, R ₇ is Methyl, ethyl, propyl, isopropyl, R _X2 is CF ₃ , CHF ₂ , CH ₂ F and CH ₂ CF ₃ .

As the thirty-eighth technical solution of the present invention, formulas (I), (Ia), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (V), (VI ), or a compound of formula (VII), its stereoisomers, pharmaceutically acceptable Accepted salts, solvates, co-crystals or deuterated compounds, the compound selected from one of the following structures:

The deuterated substance is selected from one of the following structures:

As yet another aspect, the present invention provides a pharmaceutical composition, which contains the compound described in any one of the first to thirty-eighth technical solutions, its stereoisomers, pharmaceutically acceptable salts, and solvates. Substances, co-crystals or deuterated substances, and pharmaceutically acceptable excipients and/or carriers.

In addition, the present invention also provides the technical solutions described in any one of the first to thirty-eighth technical solutions The compound, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterium, or the use of the foregoing composition in the preparation of a medicament for the treatment of EZH2-mediated diseases; and

The compound described in any one of the foregoing technical schemes 1 to 38, its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals, or deuterated substances, or the foregoing composition in the treatment of EZH2-mediated Use in disease.

In the aforementioned use, the EZH2-mediated diseases are tumors or cancers (for example, breast cancer, prostate cancer, leukemia, etc.) or autoimmune diseases.

The compound of formula (I) with EZH2 inhibitory activity, its stereoisomer, pharmaceutically acceptable salt, solvate or co-crystal,

或

時，L₂和R₇不存在；當A為取代或未取代的哌啶基時，滿足L₂是-C(O)-或-C(O)NH-，或者滿足R₇是-Si(R₆₃)₃或R₇是被1-2個-Si(R₆₄)₃取代的C_1-4烷基；並且，當式(I)的化合物為

時，不符合以下(1)-(5)的任一情形： It satisfies: when A is substituted or unsubstituted

or

When, L ₂ and R ₇ does not exist; when A is a substituted or unsubstituted piperidinyl group, satisfies L ₂ is -C (O) -, or -C (O) NH-, R ₇ is satisfied or -Si ( R ₆₃ ) ₃ or R _{7 is C 1-4} alkyl substituted with 1-2 -Si(R ₆₄ ) ₃ ; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(5):

，L₂為-NH-，R₇為取代或未取代的

、取代或未取代的

，且

的取代基為1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷 基的基團；

的取代基為C_1-4烷基；或者A為

，L₂為-N(CH₃)-，R₇為取代或未取代的

、或C_1-4烷基，且

的取代基為1-3個C_1-4烷基； (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl; or A is

, L ₂ is -N(CH ₃ )-, R ₇ is substituted or unsubstituted

, Or C _1-4 alkyl, and

The substituents of are 1-3 C _1-4 alkyl groups;

，L₂為鍵時，R₇為鹵代C_1-4烷氧基、或者取代或未取代的

，所述取代是被1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷氧基、鹵素、羥基、氰基、-S(O)₂-C_1-4烷基的基團取代；或者R₇為取代或未取代的

、

，所述取代是被1-3個選自=O、鹵素的基團取代；或者R₇為

、

、C_1-4烷基； (2) A is

, When L ₂ is a bond, R ₇ is a halogenated C _1-4 alkoxy group, or substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S(O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl;

，L₂為-O-，R₇為C_1-4烷基、環丙基、鹵代C_1-4烷基或

； (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

；

； (4) -AL ₂ -R ₇ is

；

，L₂为-NH-时，R₇为

。 (5) When A is

, When L ₂ is -NH-, R ₇ is

.

或

時，L₂和R₇不存在，當A為取代或未取代的哌啶基時， L₂是-C(O)-；並且，當式(I)的化合物為

時，不符合以下(1)-(4)的任一情形： In some embodiments, the compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates or co-crystals, satisfy: when A is substituted or unsubstituted

or

When L ₂ and R ₇ do not exist, when A is a substituted or unsubstituted piperidinyl group, L ₂ is -C(O)-; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(4):

，L₂為-NH-，R₇為取代或未取代的

、取代或未取代的

，且

的取代基為1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基的基團；

的取代基為C_1-4烷基； (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl;

，L₂為鍵時，R₇為取代或未取代的

，所述取代是被1-3個選自C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷氧基、鹵素、羥基、氰基、-S(O)₂-C_1-4烷基的基團取代；或者R₇為取代或未取代的

、

，所述取代是被1-3個選自=O、鹵素的基團取代；或者R₇為

或

， (2) A is

, When L ₂ is a bond, R ₇ is substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S(O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

or

,

，L₂為-O-，R₇為C_1-4烷基、鹵代C_1-4烷基或

； (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, halogenated C _1-4 alkyl or

；

。 (4) -AL ₂ -R ₇ is

.

In some embodiments, R _{1 is} selected from H, C _1-4 alkyl, halo C _1-4 alkyl, and halogen; in some embodiments, R _{1 is} selected from C _1-4 alkyl; in some embodiments In the example, R ₁ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl.

In some embodiments, R _{2 is} selected from C _1-4 alkyl; in some embodiments, R ₂ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl.

、

或-C(O)-NR_Lc-CH₂-；在一些實施例中，L₁为

。 In some embodiments, L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N , S, O heteroatom 3-6 membered heterocyclic ring, the heterocyclic ring is optionally _{substituted by 1-3 R Lc} , W is selected from -C(O)-, -S(O) ₂ -, -C =N(CN)-, -C(=S) _{-and bond, each R La} and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or the same R _La and R _Lb on the carbon atom together with the carbon atom to which they are attached form a C _3-6 carbocyclic ring, and each R _{Lc is} independently selected from H, C _1-4 alkyl and halogenated C _1-4 alkyl, m, n, p, and q are independently selected from an integer of 0-4; in some embodiments, L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -( CR _La R _Lb ) _q -, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the heterocyclic ring is optionally _{substituted by 1-3 R Lc} , and W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)- and bond, each of R _La and R _Lb is H, or R _La and R _Lb on the same carbon atom are connected to them The carbon atoms of together form a C _3-6 carbocyclic ring, each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl, m, n, p, q are independently selected from 0 -4; In some embodiments, L ₁ is -CH ₂ NHW-; W is selected from -C(O)-, -S(O) ₂ -and -C(=S)-; in some embodiments In some embodiments, L ₁ is -CH ₂ NHC(O)-; in some embodiments, L ₁ is not -CH ₂ -NH-C(O)-; in some embodiments, L ₁ contains 1-2 options A 3-6 membered heterocyclic ring from N, S, O heteroatoms, the heterocyclic ring is optionally _{substituted by 1-3 R LC} , R _LC is H or C _1-4 alkyl; or L ₁ is -( NH) ₂ -C(O)-, -CH ₂ -N(R _Lc )-C(O)-, -CH ₂ -C(O)-N(R _Lc )-, -CH ₂ -NR _Lc -S (O) ₂ -、

,

Or -C(O)-NR _Lc -CH ₂ -; In some embodiments, L ₁ is

.

為

、

、

、

或

，所述R_X1為H或C_1-4烷基；或者

為

，R_X2為鹵素。 In some embodiments, each X is independently C, N, NR _X1 or CR _X2 , and has at least one N atom; each R _{X1 is} independently selected from H, C _1-4 alkyl, and C _3-6 Cycloalkyl; each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, the alkyl and cycloalkyl are optionally substituted with 1-3 halogens; In some embodiments, each X is independently C, N, NR _X1, or CR _X2 , and has at least one N atom; each R _{X1 is} independently selected from H and C _1-4 alkyl; each R _X2 Independently selected from H, halogen, and C _1-4 alkyl; in some embodiments,

for

,

,

,

or

, Said R _X1 is H or C _1-4 alkyl; or

for

, R _X2 is halogen.

In some embodiments, _{at least one of R 1} , R ₂ , L ₁ and R _X2 contains a deuterium atom.

、

、

、

、

、含有0-3個選自N、S、O雜原子的五元碳環或五元雜環，或含有0-3個選自N、S、O雜原子的六元非芳香碳環或六元非芳香雜環，或者不存在；在一些實施例中，環B為

、

、

、

，或者不存在；在一些實施例中，環B為

、

、

，或者不存在。 In some embodiments, ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Membered non-aromatic heterocycle, or not present; in some embodiments, ring B is

,

,

,

, Or not present; in some embodiments, ring B is

,

,

, Or does not exist.

、

，所述雜環任選的被1個C_1-2烷基或C_1-2烷氧 基取代；在一些實施例中，R_B為含有1个选自N和O雜原子的4-8元雜環，是指選自

、

或

，所述雜環任选地被1个-C(O)C_1-4烷基取代。 In some embodiments, each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, -NR _B1 R _B2 , -C(O) NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkane Group, cycloalkyl, heterocycle are optionally substituted by 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, NH ₂ , R _B1 , R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 cycloalkyl and containing 1 -3 4-10 membered heterocycles selected from N, S, O heteroatoms, the cycloalkyl and heterocycles are optionally 1-3 selected from C _1-4 alkyl, halogen and -C( O) _{Substitution of C 1-4} alkyl group, R _B3 is C _1-4 alkyl, C _3-6 cycloalkyl or 4-10 member containing 1-3 heteroatoms selected from N, S, O Heterocycles, the cycloalkyl and heterocycles are optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen, and -C(O)C _1-4 alkyl; in some embodiments Where R _{B is} selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C( O) OR _B3 , -OR _B3 , -C(O)R _B3 and 4-6 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, and heterocycles Optionally substituted by 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, NH ₂ and each R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 cycloalkyl and containing 1-3 selected from N , S, O heteroatoms of 4-10 membered heterocycles, the cycloalkyl and heterocycles are optionally 1-3 selected from C _1-4 alkyl, halogen and -C (O) C _1-4 Alkyl group substitution, each R _{B3 is} independently C _1-4 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O , The cycloalkyl and heterocyclic ring are optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl; in some embodiments, R _{B is} selected from H, -NR _B1 R _B2 , -OR _B3 and a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the heterocyclic ring is optionally composed of 1-3 Substitution by a group selected from C _1-4 alkyl and C _{1-4 alkoxy; each R B1} and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 Alkyl; R _B3 is C _1-4 alkyl, C _3-6 cycloalkyl; in some embodiments, each R _{B is} independently selected from H, -NR _B1 R _B2 and -OR _B3 ; R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl; R _B3 is C _3-6 cycloalkyl or a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, the heterocyclic ring is optionally divided by 1 -C(O)C _1-4 alkyl substitution; in some embodiments, R _B is -NR _B1 R _B2 or -OR _B3 , R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl, -S(O) ₂ C _1-4 alkyl; R _B3 is C _3-6 cycloalkyl or 4-8 containing one heteroatom selected from N and O membered heterocyclic ring optionally substituted with one -C (O) C _1-4 alkyl; in some embodiments, R _B containing 1-3 heteroatoms selected from N, S, O heteroatoms的4-6 membered heterocycles, including but not limited to

,

, The heterocyclic ring is optionally substituted with a C _1-2 alkyl group or a C _1-2 alkoxy group; in some embodiments, R _B is a 4-8 group containing one heteroatom selected from N and O Membered heterocyclic ring means selected from

,

or

, The heterocyclic ring is optionally substituted with 1 -C(O)C _1-4 alkyl.

In some embodiments, t is an integer from 0 to 3; in some embodiments, t is 1.

In some embodiments, each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R ₄ and R ₅ on the same carbon atom and their The connected carbon atoms together form a C _3-6 carbocyclic ring, the C _1-4 alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkane Group or halogen, s is an integer from 0 to 3; in some embodiments, each of R ₄ and R _{5 is} independently selected from H and C _1-4 alkyl, and s is 1 or 2; in some embodiments, R ₄ and R _{5 are} independently selected from H and C _1-2 alkyl, s is 1; in some embodiments, s is 1, R ₄ and R ₅ are H; or s is 2, R ₄ and R ₅ Are independently selected from H and methyl; In some embodiments, s is 1, _{and at least one of R 4} and R _{5 is a C 1-4} alkyl substituted with 1-2 -Si(Rs) ₃ , each Each Rs is independently H, C _1-4 alkyl or halogen; in some embodiments, s is 1, R ₄ and R _{5 are} independently H, substituted with 1-2 -Si(Rs) ₃ or not Substituted C _1-2 alkyl, each Rs is independently C _1-2 alkyl or halogen.

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、鹵代C_1-4烷基、鹵素、胺基、-C(O)C_1-4烷基、羥基和鹵素的基團取代；作為選擇，所述碳環或雜環同碳原子上的兩個取代基與連接的碳原子一起形成C_3-6碳環；在一些實施例中，A為含有0-3個選自N、S雜原子的5-12元碳環或雜環，所述碳環不是苯環或

，所述雜環不是嘧啶環，所述碳環或雜環任選地被1-3個選自=O、C_1-4烷基、羥基和鹵素的基團取代；作為選擇，或者所述碳環同碳原子上的兩個取代基與連接的碳原子一起 形成C_3-6碳環；在一些實施例中，A为

，且环A上同碳原子上的两个取代基与连接的碳原子一起形成C_3-6碳环；在另一些實施例中，A为含有0-2個N原子的7-10元螺環或橋環；在另一些實施例中，A为

、

、

、或

，这些基团任选地被=O取代；在另一些實施例中，A为含有0-3个选自N、S雜原子的4-6元碳环或雜環；在另一些實施例中，A为含有0-1个选自N、S雜原子的4元碳环或雜環；在另一些實施例中，A为亚环丁基或亚氮雜環丁基；在一些實施例中，A为

。 In some embodiments, A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl, halogen, amine, -C(O)C _1-4 alkyl, hydroxyl and halogen groups are substituted; alternatively, the two substituents on the carbocyclic or heterocyclic ring and carbon atoms are connected to the The carbon atoms together form a C _3-6 carbocyclic ring; in some embodiments, A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, and the carbocyclic or heterocyclic ring is optionally substituted with 1-3 _{groups selected from =0, C 1-4} alkyl, hydroxyl and halogen; alternatively, or The two substituents on the carbocyclic ring and carbon atoms together with the connected carbon atoms form a C _3-6 carbocyclic ring; in some embodiments, A is

, And the two substituents on the same carbon atom on ring A together with the connected carbon atom form a C _3-6 carbocyclic ring; in other embodiments, A is a 7-10 membered spiro containing 0-2 N atoms Ring or bridge ring; in other embodiments, A is

,

,

,or

, These groups are optionally substituted by =0; in other embodiments, A is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S; in other embodiments , A is a 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N and S; in other embodiments, A is cyclobutylene or azetidine; in some embodiments , A is

.

In some embodiments, L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, =NO-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond, R _L2 is H or C _{1- 4} alkyl; r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time; in some embodiments, L ₂ is -C(O)-(NR _L2 ) _r -,- NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -; in some embodiments Where L ₂ is -C(O)-(NH) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -( CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -; r is 0 or 1, y is 0 or 1; R _L2 is H or C _1-2 alkyl.

In some embodiments, L ₂ is -C(O)-(NH) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r- (CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond, r is 0 or 1, and y is 0-3 an integer, and r, y are not simultaneously 0, and each R ₆₁ and R ₆₂ are independently selected from H, C _{1- 4} alkyl and halogen; in some embodiments, L ₂ is -C (O) - (NH ) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r- Or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond, and each R ₆₁ and R _{62 is} independently selected from H and C _1-4 alkyl; in some embodiments, L ₂ is -NH-C(O)-, -C(O)-(NH) _r -, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -( NH) _r -, when L ₂ is =NO-, L ₂ and A are connected by a double bond, r is 0 or 1, y is an integer of 1-3, and R ₆₁ and R ₆₂ are H.

、

、

、

和

，所述取代是指被1-2个选自选自C_1-2烷基、氰基、羟基、卤素、卤代C_1-2烷氧基、-C(O)-C_1-2烷基和-S(O)₂-C_1-2烷基的基团取代；在一些實施例中，R₇为C_5-8二环桥环烷基，所述二环桥环烷基任选地被1-2个卤素取代，所述二环桥环烷基包括但不限於

；在一些實施例中，R₇为-Si(R₆₃)₃或被1-2个-Si(R₆₄)₃取代的C_1-4烷基，每个R₆₃和R₆₄独立地为H、C_1-4烷基或卤素；在一些實施例中，R₇為C_1-4烷基、鹵代C_1-4烷基、C_3-6環烷基、鹵代C_1-4烷氧基或含有1-2個選自N、S、O雜原子的4-10元雜環，所述環烷基和雜環任選地被1-3個選自=O、C_1-4烷基、C_1-4烷氧基、單C_1-4烷基胺基、鹵代C_1-4烷基、氰基取代的C_1-4烷基、氰基、羥基、鹵素、鹵代C_1-4烷氧基、-C(O)-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4烷基-O-鹵代C_1-4烷基、-C_1-4烷基-OC(O)-C_1-4烷基、C_2-4烯基和C_2-4炔基的基團取代；在一些實施例中，R₇為C_3-6環烷基或含有1-2個選自N、S、O雜原子的4-6元單環雜環或4-6元橋環雜環，所述環烷基、單環雜環和橋環雜環被1-3個選自氰基取代的C_1-4烷基、氰基、鹵素、鹵代C_1-4烷氧基、-C_1-4烷基-O-鹵代C_1-4烷基、-S(O)₂-C_1-4烷基、-C(O)-C_1-4烷基、-C_1-4烷基-OC(O)-C_1-4烷基、羥基、C_2-4烯基和C_2-4炔基的基團取代，或者R₇為含有1-2個選自N、S、O雜原子的7-10元螺環雜環，所述螺環雜環任選地被1-3個選自=O、C_1-4烷氧基、單C_1-4烷基胺基和C_1-4烷基的基團取代；在一些實施例中，所述桥环雜環为

、所述螺环雜環为

、

、

、

、

。 In some embodiments, R ₇ is C _1-4 alkyl, -Si(R ₆₃ ) ₃ , halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkane Group, halogenated C _1-4 alkoxy, phenyl or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the C _1-4 alkyl group is optionally substituted by 1 -2 -Si(R ₆₄ ) ₃ substitution, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _{1- 4} alkoxy, -C (O) -C _1-4 alkyl, -S (O) ₂ -C _1-4 alkyl, -C _1-4 haloalkyl C _1-4 alkyl group -O- , -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl group substitution; each R ₆₃ and R _{64 is} independently H , C _1-4 alkyl or halogen; in some embodiments, R ₇ is C _3-6 cycloalkyl, -Si(R ₆₃ ) ₃ , C substituted with 0-2 -Si(R ₆₄ ) _{3 1-4} alkyl group, C _5-8 bicyclic bridged cycloalkyl group, or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring optionally Ground is substituted by 1-3 selected from =O, C _1-4 alkyl, C _1-4 alkoxy, mono-C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxy, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl, -S (O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-O-halogenated C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 Alkynyl group substitution; each of the R ₆₃ and R _{64 is} independently H, C _1-4 alkyl or halogen; in some embodiments, R ₇ is C _3-6 cycloalkyl or contains 1- Two 4-6 membered heterocycles selected from N, S, O heteroatoms, the cycloalkyl and heterocycles are optionally selected from =0, C _1-4 alkyl, C _{1- 4} alkoxy, mono C _1-4 alkylamino, halo C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxy, halo, halogenated C _1-4 alkoxy Group, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _1-4 alkyl group -OC (O) -C _{1- 4} alkyl, C _2-4 alkenyl and C _2-4 alkynyl substituted; in some embodiments, R ₇ is a C _3-6 cycloalkyl Alkyl group or 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring are optionally selected from 1-3 C _1-4 alkyl groups, Cyano, hydroxyl, halogen, halogenated C _{1 -4} alkoxy, -C(O)-C _1-4 alkyl and -S(O) ₂ -C _1-4 alkyl group; in some embodiments, R _{7 is} selected from substituted or unsubstituted Substituted groups:

,

,

,

with

, The substitution refers to being selected from C _1-2 alkyl, cyano, hydroxyl, halogen, halogenated C _1-2 alkoxy, -C(O)-C _1-2 alkane Group and -S(O) ₂ -C _1-2 alkyl group; in some embodiments, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, the bicyclic bridged cycloalkyl group optionally Ground is substituted with 1-2 halogens, and the bicyclic bridged cycloalkyl includes but is not limited to

In some embodiments, R ₇ is -Si(R ₆₃ ) ₃ or C _1-4 alkyl substituted with 1-2 -Si(R ₆₄ ) ₃ , each of R ₆₃ and R _{64 is} independently H , C _1-4 alkyl or halogen; in some embodiments, R ₇ is C _1-4 alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl, halo C _1-4 alkane Oxy group or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and heterocyclic ring are optionally selected from 1-3 selected from =0, C _1-4 Alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halo C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-O-haloC _{1- 4} alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted; in some embodiments, R ₇ It is a C _3-6 cycloalkyl group or a 4-6 membered monocyclic heterocyclic ring or 4-6 membered bridged ring heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl, monocyclic ring Heterocycles and bridged heterocycles are substituted with 1-3 C _1-4 alkyl groups selected from cyano groups, cyano groups, halogens, halogenated C _1-4 alkoxy groups, -C _1-4 alkyl-O- Halogenated C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _{Substitution of 1-4} alkyl, hydroxy, C _2-4 alkenyl and C _2-4 alkynyl groups, or R ₇ is a 7-10 membered spiro containing 1-2 heteroatoms selected from N, S and O A cyclic heterocycle, the spirocyclic heterocycle is optionally substituted by 1-3 _{groups selected from the group consisting of =0, C 1-4} alkoxy, mono C _1-4 alkylamino and C _1-4 alkyl Substituted; In some embodiments, the bridged heterocyclic ring is

, The spirocyclic heterocycle is

,

,

,

,

.

In some embodiments, the compound of formula (I) has the structure of formula (VI)

synthetic route

Patent document WO2019094552A1 introduces a method for preparing a class of EZH2 inhibitors. Those familiar with the art can combine this document and known organic synthesis techniques to prepare the compounds of the present invention. The starting materials are commercially available chemicals and/or chemistry. Compounds described in the literature. "Commercially available chemicals" are obtained from formal commercial sources. Suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Medicine Stone, WuXi AppTec, and Bailingwei Technology, etc. company.

Reference books and monographs in the industry detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation methods for reference. These reference books and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SRSandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000 ) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

The index of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society can selectively identify specific and similar reactants. These indexes are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, where many standard chemical supply plants (for example, those listed above) provide custom synthesis services. The reference for preparing and selecting pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

the term

Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

"Halogen" herein refers to F, Cl, Br, I, or their isotopes.

"Halo" or "halogen substitution" refers to substitution by more than one selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group, Without special limitation, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they can be substituted with the same or different halogens.

"Alkyl" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably It is an alkyl group of 1 to 6 carbon atoms, more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, neobutyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl Base and its various branched chain isomers.

"Deuteration" refers to the situation where the hydrogen atom on alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl and other groups is replaced by at least one isotope deuterium, and the upper limit of the number of deuteration It is equal to the sum of the number of hydrogens that can be substituted for the substituted group. Without special limitation, the number of deuteration is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, more preferably 1- Substitution with 10 deuterium atoms, more preferably with 1 to 6 deuterium atoms, and even more preferably with 1 to 3 deuterium atoms. Preferably, the alkyl group is substituted with at least one isotope deuterium, such as -CD ₃ or -CD ₂ -.

"Alkylene" refers to a divalent linear and branched saturated alkyl group. Examples of alkylene include but are not limited to methylene, ethylene, propylene, butylene and the like.

"Cycloalkyl" refers to a monovalent saturated, substituted or unsubstituted carbocyclic hydrocarbon group. Unless otherwise specified, it usually has 3 to 10 carbon atoms, preferably 3-6 carbon atoms, and more preferably 3 -4 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like.

"Cycloalkylene" refers to a divalent saturated, substituted or unsubstituted carbocyclic hydrocarbon group, and non-limiting examples include cyclopropylene, cyclobutylene and the like.

、

、

等，二環並環包括

、

、

、

和

等，二環螺環包括

、

、

、

、

和

等。 "Carbocyclic" or "carbocyclic group" refers to substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic groups, including monocyclic carbocyclic rings, bicyclic bridged rings, bicyclic and bicyclic rings Cyclospiro rings, etc., when not specifically stated, have 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. The definition of "carbocyclic" or "carbocyclic group" includes cycloalkyl, cycloalkylene, aromatic carbocyclic, and non-aromatic monocyclic and bicyclic carbocyclic groups containing one or more carbon-carbon double bonds. In non-limiting examples, monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc., and bicyclic bridged rings include

,

,

And so on, the two-ring ring includes

,

,

,

with

Etc., the bicyclic spiro ring includes

,

,

,

,

with

Wait.

、

、

、

、

、

、

、

、

、

、

等。 "Heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, and when not specifically limited, it contains 1 to 3 heteroatoms selected from N, O or S, Including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles, etc., when not specifically limited, they are 3 to 12 membered heterocycles, more preferably 4-12 membered heterocycles, more preferably It is a 4-10 membered heterocyclic ring. The selectively substituted N and S in the heterocyclic ring can be oxidized to various oxidation states. The heterocyclic group may be attached to a hetero atom or a carbon atom. Non-limiting examples include oxirane ethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolane , 1,4-dioxolane, 1,3-dioxanyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, Pyrazinyl, pyrazolyl, tiazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiol, dihydrofuranyl, dihydropyran Group, dithipentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzo Imidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclic [5.3.1.1] Dodecyl, azaadamantyl and oxaspiro[3.3] heptyl,

,

,

,

,

,

,

,

,

,

,

Wait.

"Heteroaromatic ring" or "heteroaryl" refers to a substituted or unsubstituted aromatic ring. When not specifically limited, it contains 1 to 3 heteroatoms selected from N, O or S, including monocyclic heteroaromatic rings, fused The bicyclic heteroaromatic ring and fused tricyclic heteroaromatic ring of and, when not specifically limited, are 4-12 membered heteroaromatic ring, more preferably 4-7 membered heteroaromatic ring, further 5-6 membered heteroaromatic ring . Non-limiting examples of heteroaromatic rings include pyridine, pyrimidine, imidazole, oxazole, pyrazole, thiazole, tiazine, indole, indazole, quinoline, benzimidazole, and the like.

"Alkynyl" refers to a linear or branched monovalent unsaturated group containing more than one carbon-carbon triple bond Hydrocarbyl groups, unless otherwise specified, alkynyl groups contain 2-6 carbon atoms, preferably 2-4 carbon atoms, non-limiting examples are ethynyl, propynyl, propargyl and the like.

"Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing more than one carbon-carbon double bond. Unless otherwise specified, an alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples are vinyl, propenyl, allyl, 2-butenyl, 1-butenyl and the like.

"Alkoxy" or "alkyloxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, third butoxy, n-pentoxy, n-hexoxy, cyclo Propoxy and cyclobutoxy, etc.

"Haloalkoxy" refers to -O-haloalkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

"Alkylamino" or "alkylamino" refers to an amino group substituted by a single or two alkyl groups, also written as -N-(alkyl) ₂ or -NH-alkyl, the latter is also written as monoalkylamine base. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, and the like.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example: "Alkyl group optionally substituted by F" means that the alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or organic base, and the free base is passed with the non-toxic inorganic base or organic base. The salt obtained by the reaction of inorganic acid or organic acid.

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals, and other constituents, wherein the other components It contains physiologically/pharmaceutically acceptable carriers and/excipients.

"Carrier" refers to: does not cause obvious stimulation to the organism, does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the human body and the distribution in the body, control the release rate of the drug, and Non-limiting examples of systems for delivering drugs to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.

"Excipient" refers to: it is not a therapeutic agent itself, it is used as a diluent, adjuvant, binder and/or vehicle, used to add to a pharmaceutical composition to improve its handling or storage properties or to allow or promote The compound or pharmaceutical composition forms a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives , Surface active agent, coloring agent, flavoring agent and sweetening agent. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g. croscarmellose sodium) ; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oil, such as peanut oil, cottonseed oil , Safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as Ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyester, polycarbonate and/or polyanhydride; and (22) Other non-toxic used in pharmaceutical preparations Compatible substances.

"Stereoisomers" refer to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, and conformational isomers.

"Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent combined with intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.

The content of the present invention will be described in detail below through examples. If the specific conditions are not indicated in the examples, it shall be carried out in accordance with the experimental methods of conventional conditions. The examples given are to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the examples. Generally, those skilled in the art make non-essential improvements and adjustments to the embodiments based on the content of the above-mentioned invention, which still belongs to the protection scope of the present invention.

Test Methods

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), internal standard It is tetramethylsilane (TMS);

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4 mm-0.5mm;

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

Abbreviation description:

Ruphos: 2-Dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl

2 ^nd Gen Ruphos precatalyst: Chlorine (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl) (2-amino-1,1'- Biphenyl-2-yl)palladium(II)

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate

DCE: 1,2-Dichloroethane

DIPEA: N,N-Diisopropylethylamine

Compound preparation

The present invention prepares a compound with the following structure:

Intermediate 1: (R)-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylic acid methyl ester

methyl( R )-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylate

The first step: (1 R )-N-(1-(1,4-dioxaspiro[4.5]decane-8-yl)ethyl)-1-benzylethyl-1-amine

(1R)-N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-1-phenylethan-1-amine

Add substrate 1a (8.0g, 43.4mmol) in a 250mL single-necked flask, dissolve it with dichloromethane (100mL), add (R)-methylphenethylamine (5.3g, 43.4mmol), acetic acid (1.3g, 21.7mmol), stirred at room temperature for 0.5h, added NaBH(OAc) ₃ (11.5g, 54.3mmol), stirred at room temperature overnight. It was quenched with water, adjusted to pH 8-9 with saturated sodium bicarbonate, extracted with DCM (2×100 mL), the combined organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (DCM:MeOH=10: 1) Obtain a colorless oil 1b (11.0 g, yield 87.5%). LC-MS(ESI): m/z=290.3[M+H] ⁺ .

The second step: 1-(1,4-dioxaspiro[4.5]decane-8-yl)ethyl-1-amine

1-(1,4-dioxaspiro[4.5]decan-8-yl)ethan-1-amine

The starting material 1b (8.0g, 27.6mmol) was added to a 250mL single-mouth flask, dissolved with methanol (80mL), palladium carbon (8.0g, 10%) was added, replaced with hydrogen three times, kept at 20atm room temperature and stirred overnight. Diatomite was suction filtered, and the filtrate was concentrated to obtain a white solid 1c (3.7 g, yield 72%). LC-MS(ESI): m/z=186.3[M+H] ⁺ .

The third step: (Z)-3-((1-(1,4-dioxaspiro[4.5]decane-8-yl)ethyl)imino)-2-(2-bromophenyl) Methyl butyrate

methyl(Z)-3-((1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)imino)-2-(2-bromophenyl)butanoate

Add the starting material 1c (2.5g, 13.5mmol) in a 100mL single-necked flask, dissolve it with tertiary butanol (50mL), and add methyl 2-(2-bromophenyl)-3-oxobutyrate ( 4.0g, 14.8mmol), acetic acid (1.1g, 17.5mmol), stirred at 85°C overnight. After the reaction solution was concentrated, dichloromethane (50mL) was added to dissolve, washed with saturated sodium bicarbonate solution until alkaline, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (PE:EA=5:1) to obtain Colorless oil 1e (2.7g, yield 46%). LC-MS(ESI): m/z=438.2[M+H] ⁺ .

The fourth step: ( R )-1-(1-(1,4-dioxaspiro[4.5]decane-8-)ethyl)-2-methyl-1H-indole-3-carboxylic acid methyl ester

methyl( R )-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-methyl-1H-indole-3-carboxylate

Add the starting material 1e (2.5g, 5.7mmol) in a 100mL single-necked flask, dissolve it with dioxane (25mL), add sodium methoxide (0.46g, 8.6mmol), Ruphos (0.53g, 1.1mmol), 2 ^nd Gen Ruphos precatalyst (0.89g, 1.1mmol), under nitrogen protection, stirred at 100°C for 5h. The reaction solution was filtered through Celite, the filtrate was diluted with water (30mL), and extracted with EA (30mL×2). The combined organic phases were dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (PE:EA=4: 1) Obtain 2.4g of yellow solid, which is prepared by hand-to-hand preparation (Conditions for hand-to-hand preparation: instrument: MG Ⅱ preparation SFC (SFC-14), chromatography column: ChiralPak AY, 250×30mm ID, 5μm, mobile Phase: A is CO ₂ , B is ethanol, mobile phase: B 30%, flow rate: 60 mL/min, back pressure: 100 bar, column temperature: 38 ℃, wavelength: 254 nm, period: 11 min) to obtain the R configuration product 1f- 1 (peak 2, retention time: 4.25 min, 1.6 g, yellow solid) and 1f-2 (peak 1, retention time: 3.01 min, 0.4 g). LC-MS(ESI): m/z=358.2[M+H] ⁺ .

The fifth step: (R)-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylic acid methyl ester

methyl(R)-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylate

Add the starting material 1f-1 (1.6g, 4.5mmol) in a 100mL single-necked flask, dissolve it with tetrahydrofuran THF (16mL), add HCl (6M, 16mL), stir at room temperature for 48h, and adjust the reaction solution with saturated sodium bicarbonate The pH was 8-9, extracted with DCM (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain yellow solid intermediate 1 (1.2 g, yield 86%). LC-MS (ESI): m/z=314.2 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ 8.22-8.15 (d, 1H), 7.55 (d, 1H), 7.30-7.16 (m, 2H), 4.23 (m, 1H), 3.94 (s, 3H), 2.78 (s,3H),2.56-2.35(m,3H),2.26-2.11(m,2H),1.74(s,3H),1.67-1.54(m,1H),1.42-1.22(m,3H).

Intermediate 2: 3-(Aminomethyl)-6-methyl-4-(methylthio)pyridine-2(1H)-one

3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one

Intermediate 2 is prepared by referring to the method of patent WO2019094552.

Compound synthesis

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-( 2-(2,2,2-Trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole-3-carboxamide ( Compound 47 )

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(2-(2,2,2- trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole-3-carboxamide

The first step: 5-(1-ethoxy-1-oxopropan-2-ylmethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate ( 47C )

Under the protection of nitrogen, ethyl 2-(diethoxyphosphinyl)propionate (2.38g, 10mmol) was dissolved in dry tetrahydrofuran (20mL), and sodium hydride (400mg, 10mmol) was added in batches under cooling in an ice-water bath. After the addition, after stirring for 1 hour, add 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (2.0g, 8.8mmol) into the reaction solution, stir and react for 1 hour Afterwards, the reaction solution was slowly poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography (petroleum ether: ethyl acetate=3:1) Later, 47C (800mg, 29.4%) was obtained.

LC-MS(ESI): m/z=310.2[M+H] ⁺ .

The second step: 5-(1-ethoxy-1-oxopropan-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate ( 47D )

Add 47C (800mg, 2.59mmol) to methanol (20ml) at room temperature, and add a catalytic amount of 10% palladium on carbon. After the addition, H _{2 was} replaced 3 times, the _{reaction was kept under H 2} balloon and stirred for 18 hours, filtered with a small amount of celite, and the filtrate was concentrated to obtain 47D (600 mg, 75%). LC-MS(ESI): m/z=312.2[M+H] ⁺ .

The third step: 2-(2-(Third-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)propionic acid ( 47E )

At room temperature, 47D (600mg, 1.92mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL), methanol (4mL) and water (2mL), lithium hydroxide monohydrate (250mg, 6.0mmol) was added, and the reaction was stirred at room temperature. After 16 hours, the reaction solution was concentrated, and the residue was diluted with water, then extracted with ethyl acetate, and the aqueous phase was retained. The retained aqueous phase was adjusted to pH=3 with dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 47E (500mg, 95%). LC-MS(ESI): m/z=284.2[M+H] ⁺ .

The fourth step: 5-(1-aminoethyl)hexahydrocyclopenta[c]pyrrole-2(1H) -tert- butyl carboxylate (47F)

To 47E (400mg, 1.4mmol) at room temperature were added toluene (4mL), triethylamine (200mg, 2.0mmol), and diphenyl azide phosphate (550mg, 2.0mmol) in sequence. The reaction was stirred at 70°C for 2 hours. After the reaction was cooled to room temperature, the reaction solution was concentrated, and tetrahydrofuran (5 mL), water (5 mL), lithium hydroxide monohydrate (100 mg, 2.4 mmol) were added to the residue in sequence, and the reaction was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, the residue was extracted with ethyl acetate, the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 47F (260 mg, 71.8%). LC-MS(ESI): m/z=255.2[M+H] ⁺ .

The fifth step: (E)-5-(1-(3-(2-bromophenyl)-4-methoxy-4-oxobut-2-en-2-ylamino)ethyl) Hexahydrocyclopenta[c]pyrrole-2(1H) -tert- butyl carboxylate (47G)

Add 47F (260mg, 1.0mmol) and (2-(2-bromophenyl)-3-oxobutyric acid methyl ester (280mg, 1.0mmol) to tertiary butanol (5mL) at room temperature, dropwise Glacial acetic acid (60mg, 0.1mmol). The temperature was raised to 90°C and the reaction was stirred. After 16 hours, the reaction solution was concentrated. The residue was diluted with ethyl acetate and washed with saturated sodium carbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography separation (ethyl acetate: petroleum ether=1: 2), 47G (280mg, 55.3%) was obtained. LC-MS(ESI): m/z=508.2[M+H] ⁺ .

Step 6: (1-(1-(2-(Third-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-2-methyl-1H-indole-3 -Methyl carboxylate (47H)

Add 47G (280mg, 0.55mmol) to dioxane (5mL), add a catalytic amount (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl) [ 2-(2-Aminoethylphenyl))palladium(II) methyl tertiary butyl ether complex and catalytic amount of 2-dicyclohexylphosphorus-2',6'-diisopropoxy -1,1'-biphenyl, and sodium methoxide (54 mg, 1.0 mmol). After nitrogen replacement 3 times, the reaction was heated to 100°C and stirred for 12 hours. After the reaction solution was cooled to room temperature, the filtrate was filtered through Celite, concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain 47H (110 mg, 46.9%). LC-MS (ESI): m/z=427.2[M+H] ⁺ .

The seventh step: 2-methyl-1-(1-(octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole-3-carboxylic acid methyl ester ( 47I )

47I (110mg, 0.26mmol) was added to ethyl acetate (2mL), and a dioxane solution of hydrogen chloride (6mol/L, 0.5mL) was added dropwise. After stirring for 2 hours at room temperature, the reaction solution was concentrated to dryness. The hydrochloride salt of compound 47I (90 mg, 98%) was obtained. LC-MS(ESI): m/z=327.2[M+H] ⁺ .

The eighth step: 2-methyl-1-(1-(2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole Methyl Dole -3-carboxylate (47J)

To 47I hydrochloride (90mg, 0.25mmol) was added tetrahydrofuran (2mL), diisopropylethylamine (130mg, 1.0mmol) was added dropwise, under an ice water bath, 2,2,2-trifluoroethyl trifluoroacetate was added dropwise After the addition of the fluoromethanesulfonate, it was naturally raised to room temperature and reacted for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain 47J (70mg, 68.9%). LC-MS(ESI): m/z=409.2[M+H] ⁺ .

The ninth step: 2-methyl-1-(1-(2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole Dole -3-carboxylic acid (47K)

To 47J (70mg, 0.17mmol) was added ethanol (1mL), sodium hydroxide aqueous solution (6mol/L, 1mL) was added dropwise, the temperature was raised to 80℃ and the reaction was stirred for 12 hours, the reaction solution was concentrated, and diluted hydrochloric acid was added dropwise to adjust the reaction solution The pH was around 8. The neutralized residue was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 47K (50 mg, 74.6%). LC-MS(ESI): m/z=395.2[M+H] ⁺ .

The tenth step: 2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1- (1-(2-(2,2,2-Trifluoroethyl)octahydrocyclopenta(c)pyrrol-5-yl)ethyl)-1H-indole-3-carboxamide ( Compound 47 )

To 47K (50mg, 0.12mmol) and 3-(aminomethyl)-6-methyl-4-(methylthio)pyridine-2(1H)-one ( intermediate 2 , 33mg, 0.18mmol) was added two To methyl chloride (1mL), add diisopropylethylamine (0.1mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea in sequence Hexafluorophosphate (76mg, 0.2mmol), the reaction was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane and then extracted with water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (ethyl acetate: petroleum ether=1:1) to obtain compound 47 (25mg ,36.9%).

LC-MS(ESI): m/z=561.2[M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ) δ 11.98(s,1H),7.83(d,1H),7.52-7.48(m,1H ), 7.09-7.02 (m, 2H), 5.99 (s, 1H), 4.79-4.65 (m, 2H), 4.26-4.21 (m, 1H), 3.01-2.94 (m, 2H), 2.74 (s, 3H) ), 2.72-2.68(m, 2H), 2.62-2.52(m, 2H), 2.47(s, 3H), 2.44-2.40(m, 1H), 2.35-30(m, 2H), 2.20(s, 3H) ), 1.42-1.12 (m, 5H), 1.26 (s, 3H).

( R )-1-(1-(4-(7-oxa-2-azaspiro[3.5]non-2-yl)cyclohexyl)ethyl)-2-methyl-N-((6- Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( compound 50 )

( R )-1-(1-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio )-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

Intermediate 1 (200mg, 0.64mmol) was dissolved in DCE (6.4mL), 7-oxa-2-azaspiro[3.5]nonane (244mg, 1.91mmol) was added, and tetraisopropyl titanate ( 0.48ml, 1.92mmol), stirred at room temperature overnight. Sodium borohydride (145mg, 3.83mmol) was added and stirred for 2 hours. Add saturated sodium bicarbonate aqueous solution (50mL), extract with dichloromethane (50mL×2), combine the organic phases, wash once with water (100mL), dry with anhydrous sodium sulfate, filter and spin dry to obtain a light butter Crude product 50A (310mg). LC-MS(ESI): m/z=425.3[M+H] ⁺ .

The second step:

The crude product 50A (310 mg) was dissolved in methanol (2 mL), THF (2 mL) was added, and a water (2 mL) solution of KOH (107 mg, 1.92 mmol) was added, and the mixture was heated to reflux and stirred overnight. Cool, add water (50mL), adjust the pH to about 6 with dilute hydrochloric acid (2moL/L), extract with ethyl acetate (50mL×2), extract the combined organic phase, wash once with water (100mL), anhydrous sodium sulfate Dry, filter and spin dry to obtain crude product 50B (320 mg) as a light buttery substance. LC-MS(ESI): m/z=411.6[M+H] ⁺ .

third step:

The crude product 50B (320mg) was dissolved in DMF (3mL), HATU (445mg, 1.17mmol) was added, then Intermediate 2 (258mg, 1.17mmol) was added, and then triethylamine (1.08mL, 7.79mmol) was added dropwise. After stirring at room temperature overnight. Add water (50mL), adjust the pH to about 6 with dilute hydrochloric acid (2moL/L), extract with ethyl acetate (50mL×2), and extract the combined organic phases, wash once with water (100mL), dry with anhydrous sodium sulfate, Filter and spin dry to obtain crude compound 50 (350 mg) as a light buttery substance. LC-MS(ESI): m/z=577.3[M+H]+.

The crude compound 50 (350 mg) was subjected to HPLC preparative analysis, and the preparative analysis conditions were as follows: instrument: Waters 2767 preparative liquid phase; chromatography column: XBridge C18 5 μm, 19*250 mm. The sample was dissolved in water and filtered with a 0.45μm filter to prepare a sample solution. Preparative chromatography conditions: a. Composition of mobile phase A and B: mobile phase A: acetonitrile, mobile phase B: water (containing 1% TFA). Gradient elution, mobile phase A content from 10%-55%, time 15min; flow rate 12ml/min. The elution time is 20min. The component with a residence time of 14.02 min is isomer 1 (30 mg), and the component with a residence time of 14.51 min is isomer 2 (23 mg).

Isomer 1: ¹ H NMR (400MHz, CDCl ₃ ) δ 13.07 (br, 1H), 7.74 (d, J=5.5 Hz, 1H), 7.48-7.38 (m, 1H), 7.19-7.09 (m, 2H) ), 6.92 (br, 1H), 6.33 (s, 1H), 4.81-4.60 (m, 2H), 4.31-4.07 (m, 3H), 4.06-3.95 (m, 1H), 3.68-3.57 (m, 2H) ), 3.57-3.50 (m, 2H), 3.49-3.37 (m, 2H), 2.80-2.72 (m, 1H), 2.66 (s, 3H), 2.54 (s, 3H), 2.39 (s, 3H), 2.32-2.13(m,2H),2.10-2.02(m,1H),2.01-1.93(m,2H),1.77-1.65(m,3H),1.60(d,3H),1.31-1.17(m,1H) ), 1.16-0.96 (m, 2H), 0.80-0.65 (m, 1H).

Isomer 2: ¹ H NMR (400MHz, CDCl ₃ ) δ 12.83 (br, 1H), 7.79 (s, 1H), 7.46-7.34 (m, 1H), 7.16-7.02 (m, 2H), 6.75 (br ,1H),6.33(s,1H),4.81-4.60(m,3H),4.52(s,1H),4.38-4.20(m,2H),3.64-3.52(m,4H),3.49-3.35(m ,2H), 2.78(s, 1H), 2.68(s, 3H), 2.53(s, 3H), 2.41(s, 3H), 2.06-1.97(m, 2H), 1.96-1.90(m, 1H), 1.84-1.77 (m, 2H), 1.77-1.71 (m, 3H), 1.59-1.53 (m, 3H), 1.47-1.17 (m, 3H), 0.92-0.80 (m, 1H).

( R )-2-Methyl-N-((6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1- (1-(4-(((3-Methyloxetan-3-yl)methyl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide ( Compound 68 , Isomer 1 and Isomer 2 )

( R )-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-((( 3-methyloxetan-3-yl)methyl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide

first step:

Using intermediate 1 and 3-methyl-3-aminomethyl-1-oxetane as raw materials, referring to the synthesis method of compound 104 , compound 68 ( isomer 1 and isomer 2 ) is obtained.

LC-MS: m/z=551.3[M+H] ⁺ .

Isomer 1: ¹ H NMR (400MHz, CDCl ₃ ) δ 12.06 (brs, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29-7.23 ( m, 1H), 7.09-7.00 (m, 2H), 5.99 (s, 1H), 4.80-4.61 (m, 2H), 4.46-4.42 (m, 2H), 4.37-4.35 (m, 2H), 4.24 4.15 (m, 1H), 2.77-2.65 (m, 5H), 2.47 (s, 3H), 2.36-2.27 (m, 1H), 2.20 (s, 3H), 1.81-1.70 (m, 3H), 1.62- 1.56 (m, 5H), 1.49-1.41 (m, 2H), 1.30-1.26 (m, 4H), 1.14-1.06 (m, 1H), 0.88-0.73 (m, 1H).

Isomer 2: ¹ H NMR (400MHz, CDCl ₃ ) δ 12.42 (brs, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.32-7.30 ( m,1H),7.09-7.00(m,2H),6.00(s,1H),4.74-4.68(m,2H),4.42-4.39(m,2H),4.34-4.32(m,2H),4.10- 4.02 (m, 1H), 2.81-2.71 (m, 3H), 2.71 (s, 2H), 2.48 (s, 3H), 2.38-2.30 (m, 1H), 2.19 (s, 3H), 2.11-2.06 ( m, 2H), 1.71-1.60 (m, 5H), 1.31-1.25 (m, 4H), 1.17-1.04 (m, 3H), 0.88-0.74 (m, 2H).

( R )-2-Methyl-N-((6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1- (1-(4-((oxetan-3-yl-amino)methyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide ( compound 71 , isomer 1 and Isomer 2 )

( R )-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-((oxetan -3-ylamino)methyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide

first step:

(Methoxymethyl)triphenylphosphonium chloride (514.2mg, 1.5mmol) was added to anhydrous THF (8mL), and potassium tert-butoxide (168.3mg, 1.5mmol) was added in batches under the protection of nitrogen at 0°C. ), stirring was continued for 10 min, and a solution of intermediate 1 (313 mg, 1.0 mmol) in THF (2 mL) was added dropwise at 0° C., after dropping, it was naturally warmed to room temperature and stirred overnight. Add 5mL water, extract with EA (5mL×3), wash the organic phase with saturated sodium chloride (5mL×1), dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography (PE:EA=5:1 to 2: 1) to obtain compound 71A (150 mg, yield 44%). LC-MS: m/z=342.3[M+H] ⁺ .

The second step:

Compound 71A (150 mg, 0.44 mol) was dissolved in THF (3 mL) at room temperature, then hydrochloric acid (3M, 3 mL) was added, and the mixture was stirred at room temperature overnight. EA extraction (5mL×3), the organic phase was washed with water (5mL×1), saturated sodium bicarbonate (5mL×1), saturated sodium chloride (5mL×1), dried with anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (PE:EA=10:1 to 2:1) to obtain compound 71B (140mg, yield 95%). LC-MS: m/z=328.3[M+H] ⁺ .

third step:

Using compound 71B and 3-oxetanamine as raw materials, according to the synthesis method of compound 104, compound 71 (isomer 1 and isomer 2) was obtained.

Preparative HPLC separation conditions: instrument Waters 2767 preparative liquid phase; preparative column SunFire C18 5μm, 19*250mm; mobile phase system: mobile phase A acetonitrile, mobile phase B: water (containing 1% TFA); elution gradient: mobile phase A ranges from 5% to 50%; the retention time of isomer 1 is 11.2 min, and the retention time of isomer 2 is 13.5 min.

LC-MS: m/z=537.3[M+H] ⁺ .

Isomer 1: ¹ H NMR (400MHz, CDCl ₃ ) δ 11.74 (brs, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.23-7.20 ( m,1H),7.08-7.01(m,2H),6.01(s,1H),4.82-4.78(m,2H),4.63-4.59(m,2H),4.05-3.95(m,2H),3.50- 3.45 (m, 1H), 2.79-2.68 (m, 3H), 2.48 (s, 3H), 2.38-2.36 (m, 2H), 2.24 (s, 3H), 2.05-1.97 (m, 3H), 1.56- 1.53(m,4H),1.30-1.19(m,4H),0.90-0.84(m,4H).

Isomer 2: ¹ H NMR(400MHz, CDCl ₃ )δ 12.52(br s, 1H), 7.82(d, J =7.6Hz,1H), 7.44(d, J =7.6Hz,1H), 7.30-7.28 (m,1H),7.09-7.01(m,2H),6.00(s,1H),4.80-4.77(m,2H),4.77-4.65(m,2H),4.45-4.42(m,2H),4.07 -4.02(m,1H),3.95-3.88(m,1H), 2.80-2.70(m,3H), 2.48(s,3H),2.36-2.34(m,2H), 2.20(s,3H), 2.10 -2.07(m,1H),1.95-1.91(m,1H),1.58-1.51(m,4H),1.35-1.25(m,1H),1.05-0.97(m,2H),0.9-0.83(m, 3H), 0.76-0.69 (m, 2H).

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4- (Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1hydro-indole-3-amide ( compound 104 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

The first step: ( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-1H-indole-3- Methyl carboxylate ( 104B )

Methyl( R )-1-(1-(4-((3,3- difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-1H-indole-3-carboxylate

Dissolve 1A (136.6mg, 3.0eq.) in (5mL) DCM _{at room temperature, add Et 3} N (97.6mg, 3.0eq.) and stir at room temperature for 0.5h. Then add Intermediate 1 (100mg, 1.0eq.) .), add acetic acid (19.2mg, 1.0eq.). Stir at room temperature for 16h, add NaBH(OAc) ₃ (203.2mg, 3.0eq.) and continue stirring for 0.5h. TLC detects that the reaction is complete, add saturated sodium bicarbonate aqueous solution (100mL), stir for 10min, use dichloromethane (50mL× 2) Extraction, the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography to obtain 104B (120 mg, 93%). LC-MS(ESI): m/z=405.2[M+H] ⁺ .

The second step: (R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-1H-indole-3- Carboxylic acid ( 104C )

(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-1H-indole-3-carboxylic acid

At room temperature, compound 104B (120 g, 0.3 mmol) was dissolved in ethanol (2 mL), NaOH (2 mL, 6M aqueous solution), and the temperature was raised to 80° C. to react for 16 h. Stop the reaction, spin off the ethanol in the reaction solution, add water (2mL), adjust the pH of the reaction solution to 6-7 with hydrochloric acid (2M), extract with dichloromethane (50mL×2), and use the combined organic phase It was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 104C (110 mg, 95%). LC-MS(ESI): m/z=391.4[M+H] ⁺ .

The third step: ( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1hydro-indole-3-carboxamide ( compound 104 , isomer 1 and isomers 2 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

Compound 104C (110mg, 0.28mmol) was dissolved in N,N-dimethylformamide (2mL), HATU (128mg, 1.2eq.), DIPEA (72.8mg, 2eq.) were added and Intermediate 2 ( Prepared with reference to WO2019094552, 92.7mg, 1.5eq.), add water (5mL) to quench the reaction after stirring for 1 hour at room temperature, extract with dichloromethane (20mL×2), and dry the combined organic phase with anhydrous sodium sulfate After concentration under reduced pressure, the mixture obtained by column chromatography was further separated by preparative HPLC to obtain compound 104 ( isomer 1 , isomer 2 ).

Preparative HPLC separation conditions: instrument Waters 2767 preparative liquid phase; preparative column SunFire C18 5μm, 19*250mm; mobile phase system: mobile phase A acetonitrile, mobile phase B: water (containing 1% TFA); elution gradient: mobile phase A ranges from 5% to 50%; the retention time of isomer 1 is 13.2 min, and the retention time of isomer 2 is 13.4 min.

LC-MS(ESI): m/z=557.7[M+H] ⁺ .

Isomer 1 : ¹ H NMR (400MHz, CDCl ₃ ) δ 12.09 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.35-7.32 ( m, 1H), 7.07-7.03 (m, 2H), 5.99 (s, 1H), 4.78-4.65 (m, 2H), 3.22-3.21 (m, 1H), 2.82-2.77 (m, 1H), 2.73 ( s, 3H), 2.47 (s, 3H), 2.21 (s, 3H), 1.62 (s, 3H), 1.58-1.54 (m, 12H), 0.90-0.83 (m, 3H).

Isomer 2 : ¹ H NMR (400MHz, CDCl ₃ ) δ 11.95 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.20-7.12 ( m,1H),7.07-7.03(m,2H),6.00(s,1H),4.73-4.62(m,2H),3.15-3.13(m,1H),2.75-2.73(m,1H),2.71( s, 3H), 2.43 (s, 3H), 2.15 (s, 3H), 1.58 (s, 3H), 1.56-1.49 (m, 12H), 0.87-0.84 (m, 3H).

( R )-2-Methyl-N-((6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1- (1-(4-((1-(Methylsulfonyl)azacyclobutan-3-yl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide ( Compound 106 )

( R )-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-((1 -(methylsulfonyl)azetidin-3-yl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide

first step:

Dissolve 3-N-tertiary butoxycarbonylaminocyclobutylamine ( 106A ) (0.5g, 2.9mmol), triethylamine (0.35g, 3.5mmol) in dichloromethane (20mL) and place in an ice bath Methanesulfonyl chloride (0.4g, 3.48mmol) was added dropwise, and then the reaction was stirred at room temperature for two hours. After the completion of the reaction, the reaction was cooled to room temperature, the organic phase was washed with distilled water, the layers were separated, and the organic phase was concentrated under reduced pressure to obtain the target compound ( 106B ) as a white solid (0.6 g, 82.6%). LC-MS(ESI): m/z=196.1[M-55] ⁺

The second step:

To a solution of compound 106B (0.6 g, 2.4 mmol) in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutral, and then extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 106C as a white oil (0.3 g, 83%). LC-MS(ESI): m/z=151.3[M+H] ⁺

third step:

In a single-neck flask, add compound 106C (0.3g, 2mmol), intermediate 1 (0.31g, 1mmol), dichloromethane (10mL), a few drops of acetic acid, stir and react for 15 minutes, then add triacetoxyborohydride Sodium (0.64g, 3mmol), continue to stir and react at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added dropwise to quench the reaction, and the residue was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 106D as a pale yellow solid (0.27 g, 30.2%). LC-MS(ESI): m/z=448.2[M+H] ⁺

the fourth step:

To a solution of compound 106D (0.27 g, 0.6 mmol) in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide (0.12 g, 3 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was treated with 10% citric acid aqueous solution to adjust pH=6, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with ether to obtain the target compound 106E as a white solid (0.27g, 84.1%). LC-MS(ESI): m/z=434.3[M +H] ⁺

the fifth step:

( R )-2-Methyl-N-((6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1- (1-(4-((1-(Methylsulfonyl)azacyclobutan-3-yl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide ( Compound 106 )

At room temperature, to compound 106E (0.22g, 0.51mmol) was added N,N-dimethylformamide (10mL), HATU (0.23g, 0.61mmol), N,N-diisopropylethyl Amine (0.13g, 1mmol), Intermediate 2 (0.13g, 0.61mmol), the reaction was stirred at room temperature for 3h. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the mixture and further separated by preparative HPLC to obtain compound 106 (isomer 1 and isomer 2) .

The analysis conditions of Isomer 1 and Isomer 2 are as follows:

Instrument: Waters 2767; Column type: SunFire C18 5μm, 250*19mm; for samples Methanol dissolves, mobile phase: A is 1% TFA aqueous solution, B is acetonitrile; gradient: mobile phase B: 10%~60%; flow rate: 12mL/min; column pressure: 100bar; column temperature: 40℃, column length: 254nm ; The elution time is 25 min; the retention time is 17.5 min for isomer 1 and 20.1 min for isomer 2; injection: 2 mL/time.

Isomer 1 : LC-MS (ESI): m/z=600.2[M+H] ⁺

¹ H NMR (400MHz, DMSO) δ 11.8 (s, 1H), 7.84-7.82 (m, 1H), 7.42-7.41 (m, 1H), 7.09-7.03 (m, 2H), 6.0 (s, 1H), 4.76-4.66(m,2H),4.21(s,1H),4.02(s,2H),3.76-3.62(m,3H),3.48(s,1H),2.88(s,3H),2.73(s, 3H), 2.46 (s, 3H), 2.22 (s, 4H), 1.74-1.55 (m, 12H).

Isomer 2 : LC-MS (ESI): m/z=600.2[M+H] ⁺

¹ H NMR (400MHz, DMSO) δ 12.1 (s, 1H), 7.81-7.79 (m, 1H), 7.42-7.41 (m, 1H), 7.22 (s, 1H), 7.09-7.02 (m, 2H), 6.01 (s, 1H), 4.76-4.66 (m, 2H), 4.01 (s, 3H), 3.76 (s, 3H), 3.48 (s, 1H), 2.67 (s, 3H), 2.73 (s, 3H) , 2.48(s,3H),2.22(s,4H),2.12-1.55(m,12H).

1-(( R )-1-(4-((1 r, 3 R )-3-hydroxycyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 107-1 )

1-(( R )-1-(4-((1 r ,3 R )-3-hydroxycyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

The synthesis of compound 107-1 uses 107-1A and intermediate 1 as starting materials. Reference compound 104's synthesis method.

LC-MS(ESI): m/z=537.7[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 12.09 (s, 1H), 7.82 (d, J=7.6Hz, 1H), 7.44 (d, J=7.8Hz, 1H), 7.30-7.29 (m, 1H), 7.06-7.01(m,2H),5.99(s,1H), 4.80-4.63(m,2H), 4.48-4.43(m,1H),4.24-4.20(m,1H),3.57-3.51(m,1H) ),2.72(s,3H),2.47(s,3H),2.14(s,3H),1.75-1.64(m,10H),1.55(s,3H),1.17-1.03(m,2H),0.90- 0.83(m,3H).

1-(( R )-1-(4-((1 s ,3 S )-3-hydroxycyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 107-2 )

1-(( R )-1-(4-((1 s ,3 S )-3-hydroxycyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

The synthesis of compound 107-2 uses 107-2A and Intermediate 1 as starting materials and refers to the synthesis method of compound 104.

LC-MS(ESI): m/z=537.7[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 12.09 (s, 1H), 7.83 (d, 1H), 7.44 (d, 1H), 7.30-7.29 (m, 1H), 7.06-7.01 (m, 2H), 5.99 (s, 1H), 4.80-4.62 (m, 2H), 4.24-4.19 (m, 1H), 4.00-3.94 (m, 1H), 3.75-3.73 (m, 1H), 2.74 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H), 1.76-1.62 (m, 10H), 1.55 (s, 3H), 1.11-1.03 (m, 2H), 0.89-0.83 (m, 3H).

2-Methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((4- (Oxetan-3-ylamino)cyclohexyl)methyl)-1H-indole-3-carboxamide ( compound 111 )

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((4-(oxetan-3-ylamino)cyclohexyl) methyl)-1H-indole-3-carboxamide

first step:

Compound 111A (500.0 mg, 2.9 mmol) was added to DCM (10 mL) at room temperature, followed by triphenylphosphine (1.2 g, 4.4 mmol) and imidazole (395 mg, 5.8 mmol). At 0°C, a solution of carbon tetrabromide (1.4 g, 4.4 mmol) in DCM (5 mL) was added under nitrogen protection, and the reaction was warmed to room temperature and stirred overnight. Add water (5mL), extract with DCM (10mL×3), wash the organic phase with saturated sodium chloride (5mL×1), dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography (PE:EA=10:1 to 5:1) to obtain compound 111B (480 mg, 70%). LC-MS: m/z=235.1[M+H] ⁺ .

The second step:

Compound 111C (338 mg, 1.78 mol) was dissolved in DMF (10 mL) at room temperature, cesium carbonate (1.7 g, 5.3 mmol) and compound 111B (460 mg, 1.96 mol) were sequentially added, and the reaction was heated to 100° C. and reacted for 2 hours. After the reaction is cooled to room temperature, filter, add water (10mL), extract with EA (25mL×3), wash the organic phase with saturated sodium chloride (5mL×1), dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography ( PE:EA=10:1 to 4:1) to obtain compound 111D (240mg, 36%). LC-MS: m/z=344.3[M+H] ⁺ .

third step:

Compound 111D (200 mg, 0.58 mol) was dissolved in THF (10 mL) at room temperature, then hydrochloric acid (6M, 3 mL) was added, and the mixture was stirred at room temperature overnight. Add water (10mL), extract with ethyl acetate (EA) (15mL×3), wash the organic phase with saturated sodium bicarbonate (15mL×1), saturated sodium chloride (15mL×1), and dry with anhydrous sodium sulfate , Filtration, concentration and column chromatography (PE:EA=10:1 to 2:1) to obtain compound 111E (110mg, 63%). LC-MS: m/z=300.2[M+H] ⁺ .

the fourth step:

Using compound 111E and 3-oxetanamine as raw materials, according to the synthesis method of compound 104, compound 111 was obtained.

LC-MS: m/z=509.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 12.67 (br s, 1H), 7.82 (d, J =8.0Hz, 1H), 7.37-7.34 (m, 1H), 7.28-7.23 (m, 1H), 7.15 7.11(m,1H),7.07-7.04(m,1H),6.00(s,1H),4.84-4.72(m,4H),4.45-4.35(m,2H),4.06-3.91(m,3H), 2.75-2.64 (m, 3H), 2.47 (s, 3H), 2.22 (s, 3H), 2.04 (s, 2H), 1.81-1.77 (m, 1H), 1.54-1.38 (m, 6H), 1.13- 0.88(m,2H).

2-Methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((1 R ) -1-(4-(oxetan-3-ylaminomethanyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide ( compound 118 )

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((1 R )-1-(4-(oxetan -3-ylcarbamoyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide

first step:

At room temperature, compound 71A (505 mg, 1.48 mmol) was dissolved in ethanol (4 mL), NaOH (4 mL, 6M aqueous solution), and the temperature was raised to 80° C. to react for 16 h. Stop the reaction, spin off the ethanol in the reaction solution, add water (2mL), adjust the pH of the reaction solution to 6-7 with hydrochloric acid (2M), extract with dichloromethane (50mL×2), and saturate the combined organic phase. It was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 118A (479 mg, 94.9%). LC-MS(ESI): m/z=328.2[M+H] ⁺ .

The second step:

Compound 118A (479mg, 1.46mmol) was dissolved in N,N-dimethylformamide (4mL), HATU (666mg, 1.2eq.), DIPEA (379.6mg, 2eq.) was added and Intermediate 2 (403mg, 1.5eq.), add water (10mL) to quench the reaction after adding room temperature and stirring for 1 hour, extract twice with dichloromethane (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure Column chromatography separated compound 118B (482.5mg, 67%). LC-MS(ESI): m/z=494.3[M+H] ⁺ .

third step:

Compound 118B (482.5 mg, 0.98 mmol) was dissolved in THF (3 mL) at room temperature, then formic acid (3 mL) was added, and the mixture was stirred at room temperature overnight. EA extraction (5mL×3), the combined organic phase was washed with water (5mL×1), saturated sodium bicarbonate (5mL×1), saturated sodium chloride (5mL×1), dried with anhydrous sodium sulfate, filtered Column chromatography (PE:EA=10:1 to 2:1) after concentration to obtain compound 118C (433mg, 92%). LC-MS(ESI): m/z=480.3[M+H] ⁺ .

the fourth step:

Compound 118C (433mg, 0.90mmol) was dissolved in tertiary butanol (10mL) at room temperature, and then 2-methyl-2-butene (630mg, 9mmol), sodium chlorite (244mg , 2.7mmol), dissolve sodium dihydrogen phosphate (648mg, 5.4mmol) in water (2mL) and drop it into the reaction solution at room temperature. Stir at room temperature for 2h. Add saturated ammonium chloride (20mL) to quench the reaction The residue was extracted with EA (25mL×3), the combined organic phase was washed with water (15mL×1), saturated sodium chloride (15mL×1), dried over anhydrous sodium sulfate, and filtered to obtain crude compound 118D (330mg , Yield 74%). LC-MS(ESI): m/z=496.2[M+H] ⁺ .

Step 6: Compound 118 (Isomer 1 and Isomer 2)

2-Methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((1 R ) -1-(4-(oxetan-3-ylaminomethanyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((1 R )-1-(4-(oxetan -3-ylcarbamoyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide

Compound 118D (150mg, 0.3mmol) was dissolved in N,N-dimethylformamide (2mL), and HATU (137mg, 1.2eq.), DIPEA (78mg, 2eq.), 3-oxygen were added to it in turn. Etidine (33mg, 1.5eq.), stirred at room temperature for 1 hour, then added water (5mL) to quench the reaction, extracted with dichloromethane (20mL×2) twice, and the combined organic phases were dried with anhydrous sodium sulfate After concentration under reduced pressure, the mixture obtained by column chromatography was further separated by preparative HPLC to obtain compound 118 (isomer 1, isomer 2).

Preparative HPLC separation method: instrument: Waters 2767 preparative liquid phase; chromatography column: SunFire C18 5μm, 19*250mm. Mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (Containing 1% TFA), elution gradient: mobile phase A from 50% to 80% peak position: isomer 1: 14.4 min, isomer 2: 14.6 min

LC-MS(ESI): m/z=551.3[M+H] ⁺ .

Isomer 1: ¹ H NMR (400MHz, CDCl ₃ ) δ 11.74 (br s, 1H), 7.82-7.81 (m, 1H), 7.43-7.42 (m, 1H), 7.23-7.20 (m, 1H), 7.08-7.01 (m, 2H), 6.25 (s, 1H), 6.04 (s, 1H), 5.02-4.92 (m, 2H), 4.74-4.66 (m, 2H), 4.47-4.45 (m, 2H), 4.22-4.21(m,1H), 2.6(s,3H), 2.48(s,3H),2.35-2.33(m,2H),2.24(s,3H),1.61-1.55(m,5H),1.33- 1.25 (m, 4H), 0.90-0.87 (m, 3H).

Isomer 2: ¹ H NMR (400MHz, CDCl ₃ ) δ 11.70 (br s, 1H), 7.79-7.77 (m, 1H), 7.50-7.44 (m, 1H), 7.23-7.21 (m, 1H), 7.11-7.09(m,2H),6.35(s,1H),6.11(s,1H),4.91-4.87(m,2H),4.79-4.60(m,2H),4.50-4.47(m,2H), 4.07-4.02 (m, 1H), 2.68 (s, 3H), 2.50 (s, 3H), 2.29 (s, 3H), 2.14-2.10 (m, 2H), 1.58-1.56 (m, 4H), 1.30- 1.25 (m, 5H), 0.90-0.87 (m, 3H).

( R )-2-Methyl-N-((6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1- (1-(4-(3-Methyloxetane-3-carboxamide)cyclohexyl)ethyl)-1H-indole-3-carboxamide (Compound 127)

( R )-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-(3- methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxamide

The first step: ( R )-1-(1-(4-aminocyclohexyl)ethyl)-2-methyl-1H-indole-3-carboxylic acid methyl ester ( 127A )

methyl-( R )-1-(1-(4-aminocyclohexyl)ethyl)-2-methyl-1H-indole-3- carboxylate( 127A )

Intermediate 1 (1 g, 3.2 mmol) was dissolved in (15 mL) DCM at room temperature, and ammonium acetate (2.46 g, 32 mmol) was added and stirred at room temperature for 0.5 h. Then NaBH(OAc) ₃ (954 mg, 4.5 mmol) was added and stirring continued for 0.5 h. TLC detected the completion of the reaction, added saturated aqueous sodium bicarbonate solution (100 mL), stirred for 10 minutes, extracted with dichloromethane (50 mL×2), washed the combined organic phase with saturated brine (100 mL), dried over anhydrous sodium sulfate, and reduced pressure After concentration, the residue was separated and purified by silica gel column chromatography to obtain 127A (480mg, 47.8%). LC-MS(ESI): m/z=315.2[M+H] ⁺ .

The second step: ( R )-2-methyl-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole Methyl-3-carboxylate ( 127B )

Methyl-(R)-2-methyl-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxylate( 127B )

Dissolve 3-methyloxetane-3-carboxylic acid (80mg, 0.69mmol) in N,N-dimethylformamide (2mL) at room temperature, add HATU (314mg, 0.83mmol), DIPEA (180mg, 1.4mmol) and then 127A (200mg, 0.66mmol) was added. After the addition, stirring was continued for 2 hours at room temperature, and then water (5 mL) was added to quench the reaction. The dichloromethane (20 mL×2) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography. Compound 127B (250 mg, 92.4%) was obtained. LC-MS(ESI): m/z=413.3[M+H] ⁺ .

The third step: ( R )-2-methyl-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole -3-carboxylic acid ( 127C )

( R )-2-methyl-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxylic acid( 127C )

At room temperature, compound 127B (250 mg, 0.6 mmol) was dissolved in ethanol (2 mL), NaOH (2 mL, 6M aqueous solution), and the temperature was raised to 80° C. to react for 16 h. The reaction was stopped, the reaction solution was concentrated under reduced pressure and most of the ethanol was removed. Water (2mL) was added to the residue. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid (2M) and extracted with dichloromethane (50mL×2) The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 127C (200 mg, 82.8%). LC-MS(ESI): m/z=399.1[M+H] ⁺ .

The fourth step : ( R )-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl )-1-(1-(4-(3-Methyloxetane-3-carboxamide)cyclohexyl)ethyl)-1H-indole-3-carboxamide ( Compound 127 )

( R )-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-(3- methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxamide

Compound 7C (200mg, 0.5mmol) was dissolved in N,N-dimethylformamide (2mL), HATU (228mg, 0.6mmol), DIPEA (190mg, 1.5mmol) were added and Intermediate 2 (110mg, 0.6mmol) was added mmol), add water (5mL) to quench the reaction after adding to room temperature and stirring for 2 hours, extract twice with dichloromethane (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and pass through column chromatography After separation, compound 127 (100 mg, 35.28%) was obtained.

LC-MS(ESI): m/z=565.3[M+H] ⁺ .

1H NMR (400MHz, CDCl ₃ ) δ 12.7 (brs, 1H), 7.93-7.71 (m, 1H), 7.45 (d, 1H), 7.20-7.09 (m, 3H), 6.15 (s, 1H), 5.96 ( d, 1H), 4.83(t, 2H), 4.71(q, 2H), 4.48(d, 2H), 4.21(t, 1H), 4.07(s, 1H), 2.74(s, 2H), 2.51(s ,3H),2.34(s,3H),2.26-2.01(m,3H),1.92(t,2H),1.73-1.70(m,1H),1.67-1.59(m,2H),1.53-1.26(m ,4H),0.98-0.86(m,2H).

1-((1 R )-1-4-((3,3-Difluorocyclobutyl)carboxamido)cyclohexyl)ethyl)-2-methyl-N-((6-methyl- 4-(Methylthio)-2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 129 )

1-((1 R )-1-(4-((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-1H- indole-3-carboxamide

Compound 129 is obtained by condensation of intermediate 118D and 3,3-difluorocyclobutylamine hydrochloride as starting materials with reference to compound 118.

Preparative HPLC separation method: instrument: Waters 2767 preparative liquid phase; chromatography column: SunFire C18 5μm, 19*250mm. Mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (containing 1% TFA), elution gradient: mobile phase A from 50% to 80%, peak position: isomer 1: 13.5min, Isomer 2: 14.6min

LC-MS(ESI): m/z=585.3[M+H] ⁺ .

Isomer 1: ¹ H NMR (400MHz, CDCl ₃ ) δ 12.50 (br s, 1H), 7.70-7.68 (m, 1H), 7.50-7.48 (m, 1H), 7.21-7.16 (m, 3H), ,6.46(s,1H),6.09(s,1H),4.75-4.62(m,2H),4.22-4.20(m,2H),4.08-4.07(m,1H),2.66(s,3H),2.59 (s,3H),2.53(s,3H),2.46-2.44(m,1H),2.21-2.15(m,6H),2.01-1.96(m,6H),1.25(s,3H).

Isomer 2: ¹ H NMR (400MHz, CDCl ₃ ) δ 12.52 (br s, 1H), 7.81-7.80 (m, 1H), 7.44-7.42 (m, 1H), 7.08-7.04 (m, 3H), ,6.30(s,1H),6.02(s,1H),4.77-4.63(m,3H),4.25-4.23(m,2H),2.69(s,3H),2.49(s,3H),2.28(s ,3H), 2..03-2.00 (m, 5H), 1.57-1.55 (m, 4H), 1.29-1.26 (m, 4H), 0.90-0.87 (m, 3H).

( R )-1-(1-(4-(3-Fluorobicyclo[1.1.1]pentane-1-carboxamido)cyclohexyl)ethyl)-2-methyl-N-((6 -Methyl-4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 182)

( R )-1-(1-(4-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)cyelohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

At room temperature, ethanol (44 mL) was added to the intermediate 1f-1 (1.0 g, 2.8 mmol), then potassium hydroxide (1.5 g, 28 mmol) was added, and the mixture was refluxed and stirred at 80° C. for 20 h. The pH was adjusted to 5-6 with 6N HCl, water and EA were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 182A (0.9g, 94%). LC-MS(ESI): m/z=344.3[M+H] ⁺ .

The second step:

At room temperature, to intermediate 2 (0.82g, 4.45mmol), compound 182A (0.9g, 2.62mmol) was added DMF (10mL), HATU (1.1g, 2.88mmol), N,N-diisopropyl Ethylamine (1.4 g, 10.5 mmol). Stir at room temperature for 2 hours, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine (10 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 182B (1.1 g, 83%). LC-MS(ESI): m/z=510.3[M+H] ⁺ .

third step:

At room temperature, tetrahydrofuran (6 mL) and 6N HCl (6 mL) were sequentially added to 182B (1.0 g, 1.96 mmol), and the mixture was stirred at room temperature for 20 h. After concentration under reduced pressure, 182C (0.8g, 89%) was obtained. LC-MS(ESI): m/z=466.3[M+H] ⁺ .

the fourth step:

At room temperature, to compound 182C (0.3g, 0.64mmor) were added methanol (10mL), ammonium acetate (0.25g, 3.22mmol), glacial acetic acid (2 drops), stirred for 30 minutes, and added triacetyl borohydride Sodium (0.28g, 1.28mmol), stirred at room temperature for 16h. The reaction was quenched by adding water dropwise, extracted with ethyl acetate, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 182D (0.14 g, 46.7%).

the fifth step:

At room temperature, to 182D (0.12g, 0.26mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (0.036g, 0.26mmol) was added DMF (4mL), HATU (0.1g , 0.26mmol), N,N-diisopropylethylamine (0.12g, 0.78mmol). Stir at room temperature for 2 hours, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine (10 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is prepared, separated and purified to obtain compound 182, isomer 1 (0.02g) , 13.5%), compound 182, isomer 2 (0.04g, 27%).

Preparative HPLC separation conditions: preparative instrument W/J0407, preparative column Xbridge C18, mobile phase system: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1 : 15.05 min, isomer 2 : 15.88 min.

Isomer 1: ¹ H NMR(400MHz, CDCl ₃ )δ7.76-7.75(d,1H),7.45-7.44(d,1H),7.16-7.14(m,2H), 6.84(s,1H), 6.38(s,1H),5.30(s,1H),4.73-4.72(m,2H),4.07-4.05(m,1H), 3.67(s,1H), 2.80-2.68(m,3H), 2.54( s, 3H), 2.44 (s, 3H), 2.28 (s, 6H), 2.16-2.10 (m, 3H), 1.72 (s, 1H), 1.60-1.59 (d, 3H), 1.20-1.14 (m, 2H), 1.09-1.03 (m, 1H), 0.95-0.85 (m, 2H).

LC-MS(ESI): m/z=579.3[M+H] ⁺ .

Isomer 2: ¹ H NMR (400MHz, CDCl ₃ ) δ7.73-7.72(d,1H), 7.47-7.46(d,1H), 7.18-7.14(m,2H), 6.82(s,1H), 6.46(s,1H),5.59(s,1H),4.77-4.68(m,2H),4.22(s,1H),3.99(s,1H),2.80-2.72(m,3H),2.56(s, 3H), 2.49 (s, 3H), 2.42-2.32 (m, 7H), 1.94-1.83 (m, 2H), 1.71-1.29 (m, 7H), 1.03-1.00 (m, 1H), 0.86-0.82 ( m,1H).

LC-MS(ESI): m/z=579.3[M+H] ⁺ .

1-((4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)methyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 183 )

1-((4-((3,3-difluorocyclobutyl)amino)cyclohexyl)methyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3 -yl)methyl)-1H-indole-3-carboxamide

Using compound 111E and 3,3-difluorocyclobutylamine hydrochloride as raw materials, according to the synthesis method of compound 104 , compound 183 (isomer 1, isomer 2) was obtained .

The preparation and separation conditions of Compound 183 Isomer 1 and Isomer 2 are as follows:

Preparation instrument: Waters 2767 preparative liquid phase; preparation column: SunFire C185μm, 19*250mm; mobile phase system: mobile phase A acetonitrile, mobile phase B water (containing 5mM ammonium acetate); elution gradient: mobile phase A from 10% To 70%; peak position: isomer 1:14.43min, isomer 2:17.33min.

LC-MS: m/z=543.3[M+H] ⁺ .

Isomer 1 : ¹ H NMR (400MHz, CDCl ₃ ) δ 12.57 (br s, 1H), 7.81 (d, 1H), 7.35-7.33 (m, 1H), 7.26-7.25 (m, 1H), 7.14 7.10(m,1H),7.07-7.03(m,1H),6.01(s,1H),4.73-4.72(m,2H),3.95-3.94(m,2H), 3.27(s,1H), 2.82- 2.73 (m, 6H), 2.48 (s, 3H), 2.30-2.24 (m, 4H), 1.89 (s, 1H), 1.59-1.26 (m, 10H).

Isomer 2 : ¹ H NMR (400MHz, CDCl ₃ ) δ 12.73 (br s, 1H), 7.82 (d, 1H), 7.37-7.34 (m, 1H), 7.26-7.23 (m, 1H), 7.14 7.11(m,1H),7.07-7.03(m,1H),6.00(s,1H),4.73-4.72(m,2H),3.93-3.91(m,2H),3.33-3.27(m,1H), 2.84-2.73 (m, 5H), 2.47-2.40 (m, 4H), 2.33-2.22 (m, 5H), 1.87-1.63 (m, 6H), 1.26-0.96 (m, 4H).

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4- (Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1hydro-indole-3-sulfonamide ( compound 184 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1H-indole-3-sulfonamide

first step:

At room temperature, ethanol (44 mL) was added to the intermediate 1f-1 (1.0 g, 2.8 mmol), then potassium hydroxide (1.5 g, 28 mmol) was added, and the mixture was refluxed and stirred at 80° C. for 20 h. After the reaction was cooled to room temperature, the pH was adjusted to 5-6 with 6N HCl, water and EA were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 184A (0.9g, 94%). LC-MS(ESI): m/z=344.2[M+H] ⁺ .

The second step:

At room temperature, bromobenzene (30 mL) was added to compound 184A (0.9 g, 2.6 mmol), and the mixture was stirred at 165° C. for 6 h. The residue was directly concentrated under reduced pressure with an oil pump to obtain 184B (0.78g, 100%). LC-MS(ESI): m/z=300.2[M+H] ⁺ .

third step:

To compound 184B (0.78 g, 2.6 mmol) were added pyridine (10 mL) and pyridine sulfur trioxide (0.85 g, 5.2 mmol), protected by nitrogen, and stirred at 110°C under reflux for 2 hours. The residue was concentrated under reduced pressure to obtain 184C (0.9g, 81%). LC-MS(ESI): m/z=380.2[M+H] ⁺ .

the fourth step:

At room temperature, tetrahydrofuran (6 mL) and 6N HCl (6 mL) were sequentially added to 184C (0.6 g, 1.3 mmol), and the mixture was stirred at room temperature for 20 h. The residue was concentrated under reduced pressure to obtain 184D (0.4g, 92%). LC-MS(ESI): m/z=336.2[M+H] ⁺ .

the fifth step:

At room temperature, add dichloromethane (10mL), 4 drops of DMF, and nitrogen protection to compound 184D (0.4g, 1.2mmol) in sequence. The temperature was lowered to 0°C, and oxalic chloride (0.46g, 3.6mmol, room temperature) was added dropwise. After stirring for 2 hours, water was added dropwise to quench the reaction, extracted with dichloromethane, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 184E (0.4g, 95%).LC-MS(ESI): m/z=350.2[M+H+MeOH-HCl] ⁺ .

The sixth step:

At room temperature, to compound 184E (0.04 g, 0.11 mmol) was sequentially added dichloromethane (4 mL), intermediate 2 (0.042 g, 0.22 mmol), and DIEA (0.07 g, 0.55 mmol). Stir at room temperature for 2 hours, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine (20 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the residue to obtain 184F (0.06 g, 100%). LC-MS(ESI): m/z=502.2[M+H]+.

Step 7: Compound 184 ( Isomer 1 and Isomer 2 )

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4- (Methylthio)-2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-sulfonamide

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1H-indole-3-sulfonamide

At room temperature, to compound 184F (0.06g, 0.12mmol) was sequentially added dichloromethane (2mL), 3,3-difluorocyclobutane-1-amine (0.048g, 0.3mmol), glacial acetic acid (0.1mL ), stirred at room temperature for 18 hours, then added sodium triacetoxyborohydride (0.06 g, 0.24 mmol), and stirred at room temperature for 2 hours. The reaction was quenched by adding water dropwise, extracted with dichloromethane, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture obtained by column chromatography was further separated and purified by preparative HPLC to obtain compound 184 , which is isomerized. Compound 1 and compound 184 , isomer 2 .

Preparative HPLC separation conditions: preparative instrument W/J0407, preparative column Xbridge C18, mobile phase system: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1 : 15.70 min, isomer 2 : 18.18 min.

Isomer 1 : ¹ HNMR (400MHz, CDCl ₃ ) δ 12.12 (s, 1H), 7.99-7.97 (d, 1H), 7.40-7.38 (d, 1H), 7.16-7.06 (m, 2H), 6.30- 6.26(t,1H),5.77(s,1H),4.08-4.01(m,3H),3.34-3.29(m,1H),2.83-2.74(m,3H),2.68(s,2H),2.47- 2.31(m,6H),2.16-2.11(m,4H),2.06(s,2H),2.03-2.00(m,1H),1.70-1.68(m,1H),1.62-1.60(d,3H), 1.28-0.74(m,5H).

Isomer 2 : ¹ HNMR (400MHz, CDCl ₃ ) δ 11.97 (s, 1H), 8.00-7.98 (d, 1H), 7.41-7.39 (d, 1H), 7.14-7.06 (m, 2H), 6.32 6.29(t,1H),5.77(s,1H),4.26-4.21(m,1H),4.07-4.05(d,2H),3.28-3.26(m,1H),2.82-2.71(m,6H), 2.32-2.28(m,5H), 2.18(s,3H), 2.08(s,1H), 1.78-1.76(m,2H), 1.62-1.58(m,5H), 1.50-147(m,1H), 1.34-1.10 (m, 3H), 0.84-0.80 (m, 1H).

LC-MS(ESI): m/z=593.2[M+H] ⁺ .

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4- (Methylthio)-2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide ( Compound 185 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide

first step:

To sodium tert-butoxide (16.6 g, 172 mmol) was added 30 mL of toluene, and replaced with nitrogen three times. At 0°C, compound 185A (5.00 g, 86 mmol) was added dropwise, and after dropping, carbon disulfide (6.6 g, 86 mmol) was slowly added dropwise at a temperature of 0-5°C. After the addition, the temperature was controlled at 0°C to react for 4 hours. After the reaction was completed, it was filtered and the filter cake was dried to obtain compound 185B (12.8 g, crude product), which was directly put into the next step without further purification.

The second step:

Compound 185B (12.8g, 72mmol) was dissolved in 100ml of methanol, and methyl iodide (20.5g, 142mmol) was slowly added dropwise. After the addition, the temperature was raised to 70°C and reacted for 2 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to remove the methanol. 200 mL of water was added to the residue, extracted with ethyl acetate (100 mL×2), the combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure and crystallized with petroleum ether to obtain compound 185C (5.3 g, 45%). LC-MS(ESI): m/z=163.1[M+H] ⁺

third step:

Compound 185C (5.3g, 32.7mmol) and cyanoacetamide (2.75g, 32.7mmol) were dissolved in 50mL tertiary butanol, then potassium tertiary butoxide (4.03g, 36.0mmol) was added, and the temperature was raised after the addition was completed Stir at 80°C for 12 hours, add 20 mL of water after the reaction is completed, then adjust the pH to 5-6 with 1N hydrochloric acid, stir for 30 minutes, filter, and dry the filter cake to obtain compound 185D (4.6 g, 78%). LC-MS(ESI): m/z =181.1[M+H] ⁺

the fourth step:

Compound 185D (1.0g, 5.5mmol) was dissolved in tetrahydrofuran (10ml), and the temperature was lowered to 0℃ under nitrogen protection. Then, tetradeuterium aluminum lithium (236.0mg, 5.6mmol) was added. After the addition, it was stirred for 30 minutes, and 10% hydrogen was slowly added dropwise. The reaction was quenched with an aqueous sodium oxide solution (1 mL), the reaction solution was filtered, and the filtrate was concentrated to obtain compound 185E (0.9 g). LC-MS(ESI): m/z=187.1[M+H]+

the fifth step:

Compound 185E (0.9g, 4.8mmol) was dissolved in tetrahydrofuran (10mL), followed by adding triethylamine (0.97g, 9.6mmol), (Boc) ₂ O (1.26g, 5.8mmol), and reacting at room temperature for 15 hours After the reaction was completed, 10 mL of water was added, the residue was extracted with ethyl acetate (50 mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure and isolated to obtain compound 185F (0.9 g, 65%). LC-MS(ESI): m/z=287.1[M+H] ⁺

The sixth step:

Compound 185F (0.9g, 3.1mmol) was dissolved in dichloromethane (5mL), added with hydrogen chloride in dioxane solution (5mL), added to room temperature and stirred for 5 hours, after the reaction was filtered, the filter cake was dried to obtain compound 185G ( 310mg, 45%). LC-MS(ESI): m/z=187.1[M+H] ⁺

¹ H NMR (400MHz, D ₂ O) δ 6.49 (s, 1H), 2.63 (s, 3H), 2.40 (s, 3H).

The seventh step: ( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N((6-methyl -4-(Methylthio)-2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide ( Compound 185 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide

At room temperature, to intermediate 104C (0.2g, 0.5mmol), compound 185G (0.23g, 1.03mmol) was added DMF (4mL), HATU (0.3g, 0.75mmol), N,N-diisopropyl Ethylamine (0.2g, 1.5mmol). Stir at room temperature for 2 hours, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine (20 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated and purified by column chromatography to obtain compound 185 (0.1g, 35%). ).

¹ H NMR (400MHz, CDCl ₃ ) δ 12.68 (s, 1H), 7.79-7.77 (d, 1H), 7.92-7.90 (d, 1H), 7.09 (s, 1H), 7.06-7.01 (t, 1H) ,6.97-6.93(t,1H),6.06(s,1H),3.97-3.92(m,1H),3.49-3.47(m,1H),2.97-2.72(m,5H),2.60(s,3H) ,2.49(s,3H),2.33(s,3H),2.13-2.10(d,3H),1.87(m,1H),1.66-1.62(m,1H),1.49-1.48(d,4H),1.06 -0.91(m,3H),0.71-0.60(m,1H).

LC-MS(ESI): m/z=559.3[M+H]+.

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4- ((Methyl-d3)sulfanyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 186 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyl-d3)thio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

At room temperature, dissolve compound 185B (6.0g, 32.8mmol) in methanol (30mL), add deuterated methyl iodide (9.5g, 65.6mmol) dropwise, reflux at 70°C for 1 hour, concentrate under reduced pressure and use silica gel column layer Separate and purify to obtain 186A (1.8g, 33%). LC-MS(ESI): m/z=169[M+H] ⁺ .

The second step:

Compound 186A (1.8 g, 10.7 mmol) was dissolved in tertiary butanol (30 mL), and 2-cyanoacetamide (889 mg, 10.7 mmol) and sodium tertiary butoxide (1.13 g, 11.77) were added. React at 80°C for 12 hours, add 15 mL of water, adjust ph=5-6 with 10% hydrochloric acid, filter, and wash the filter cake (30 mL×2) with petroleum ether. After drying, 186B (2.2g, 100%) was obtained. LC-MS(ESI): m/z=184[M+H] ⁺ .

third step:

Compound 186B (2.2g, 10.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL), and a tetrahydrofuran solution of borane-dimethyl sulfide (2M, 42.8mmol, 22mL, 80°C) was added dropwise under the protection of nitrogen at 0°C and refluxed for 4 hours , Quenched by adding 30mL methanol under ice bath, and concentrated under reduced pressure to obtain crude product 186C (3.4g, 100%). LC-MS(ESI): m/z=188[M+H] ⁺ .

the fifth step:

Compound 186C (3.4g, 10.7mmol) was dissolved in tetrahydrofuran (50mL), triethylamine (3.2g, 32.1mmol) was added, and then di-tertiary butyl dicarbonate (3.5g, 16.05mmol) was added dropwise. Reaction at temperature for 12h. It was extracted with ethyl acetate and water, washed twice with saturated brine, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 186D (2.2g, 73%). LC-MS(ESI): m/z=288[M+H] ⁺ .

The sixth step:

Compound 186D (2.2g, 7.6mmol) was dissolved in hydrogen chloride in dioxane solution (50mL), reacted at room temperature for 2 hours, concentrated under reduced pressure, washed with dichloromethane twice, and dried to obtain 186E (1.6g, 94%). LC-MS(ESI): m/z=224[M+H] ⁺ .

The seventh step:

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4- ((Methyl-d3)sulfanyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 186 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyl-d3)thio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

At room temperature, to intermediate 104C (0.2g, 0.5mmol), compound 186E (0.23g, 1.03mmol) was added DMF (4mL), HATU (0.3g, 0.75mmol), N,N-diisopropyl Ethylamine (0.2g, 1.5mmol). Stir at room temperature for 2 hours, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify by column chromatography to obtain compound 186 (0.07 g, 21%).

¹ H NMR (400MHz, CDCl ₃ ) δ 12.49 (s, 1H), 7.82-7.80 (d, 1H), 7.43-7.41 (d, 1H), 7.30-7.28 (m, 1H), 7.09-7.00 (m, 2H), 5.99 (s, 1H), 4.80-4.62 (m, 2H), 4.04-4.00 (m, 1H), 3.33-3.31 (m, 1H), 2.80-2.69 (m, 5H), 2.42-2.30 ( m,3H),2.21(s,3H),2.16-1.99(m,3H),1.66-1.63(m,1H),1.58-1.56(d,3H),1.28-0.7(m,6H).LC- MS(ESI): m/z=560[M+H] ⁺ .

2-Methyl-N-(4-((R)-1-(2-methyl-3-((6-methyl-4-(methylthio)-2-oxo-1,2- Dihydropyridin-3-yl)methylformamide)-1H-indol-1-yl)ethyl)cyclohexyl)thiazole-4-formamide (compound 187 )

2-methyl-N-(4-((R)-1-(2-methyl-3-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl )-1H-indol-1-yl)ethyl)cyclohexyl)thiazole-4-carboxamide

first step:

Intermediate 1 (1.5 g, 4.8 mmol) was dissolved in dry methanol (20 mL), and ammonium acetate (400 mg, 10 mmol) and glacial acetic acid (2 mL) were added. After the addition is complete, add sodium triacetoxyborohydride after stirring for 3 hours. After stirring and reacting for 4 hours, the reaction solution is slowly poured into water. After potassium carbonate is adjusted to pH=9, it is extracted with ethyl acetate, washed with saturated brine, and anhydrous. It was dried over sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain 187A (1.4g, 92%). LC-MS(ESI): m/z=315.2[M+H] ⁺ .

The second step:

Add 187A (400mg, 1.28mmol) and 2-methylthiazole-4-carboxylic acid (186mg, 1.3mmol) to dichloromethane (10mL) at room temperature, add DIEA (400mg, 3mmol) dropwise, and stir for 30 minutes. , Add HATU (0.76g, 2mmol), after the addition, stir overnight at room temperature, pour the reaction solution into water, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 187B ( 260mg, 46.2%). LC-MS(ESI): m/z=440.2[M+H] ⁺ .

third step:

Dissolve 187B (210mg, 0.47mmol) in a mixed system of ethanol (2mL) and water (2mL) at room temperature, add sodium hydroxide (480mg, 12.0mmol), raise the temperature to 80°C, stir and react for 16 hours. The solution was concentrated, the residue was diluted with water, adjusted to PH=6-7 with dilute hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 187C (120mg, 60%).

LC-MS(ESI): m/z=426.2[M+H] ⁺ .

the fourth step:

Add 187C (120mg, 0.28mmol) and Intermediate 2 to dichloromethane (2mL), add DIEA (0.1mL) dropwise, add HATU (150mg, 0.4mmol), stir and react at room temperature for 2 hours, then use the reaction solution Dilute with dichloromethane, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain the mixture, which is further separated by preparative HPLC to obtain compound 187 , isomer 1 and compound 187, isomer 2 .

Preparative HPLC separation conditions: instrument Waters 2767 preparative liquid phase; preparative column SunFire C18 5μm, 19*250mm; mobile phase system: mobile phase A acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); 25%-70% gradient Elution; retention time of isomer 1 was 15.2 min, retention time of isomer 2 was 16.1 min.

LC-MS(ESI): m/z=592.2[M+H]+.

Isomer 1: ¹ H NMR (400MHz, d-DMSO) δ 11.62 (s, 1H), 8.06 (s, 1H), 7.96-7.90 (m, 1H), 7.75-7.70 (m, 1H), 7.65- 7.55(m,2H),7.08-7.02(m,2H),6.12(s,1H),4.45-4.39(m,3H),3.62-3.59(m,1H),2.73(s,3H),2.67( s, 3H), 2.49 (s, 3H) 2.18 (s, 3H), 1.85-1.75 (m, 3H), 1.67-1.50 (m, 6H), 1.40-1.30 (m, 1H), 1.2-0.9 (m ,2H).

Isomer 2: ¹ H NMR (400MHz, d-DMSO) δ 11.62 (s, 1H), 8.02 (s, 1H), 7.92-7.90 (m, 1H), 7.75-7.73 (m, 1H), 7.64 7.59(m,2H),7.08-7.02(m,2H),6.12(s,1H),4.41-4.39(m,2H),4.17-4.10(m,1H),3.75-3.65(m,1H), 2.67(s, 3H), 2.60(s, 3H), 2.48(s, 3H) 2.18(s, 3H), 2.10-1.85(m, 3H), 1.62-1.45(m, 5H), 1.10-0.78(m ,4H).

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-( 1-(( R ))-tetrahydrofuran-3-carbonyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (compound 188 )

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(1-(( R )-tetrahydrofuran- 3-carbonyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide

first step:

Compound 188A (15.0g, 66.08mmol) was dissolved in absolute ethanol (150mL), ammonium acetate (25.0g, 330.4mmol), glacial alcoholic acid (1mL), sodium acetate borohydride (28.0g, 132.16mmol) were added to the room Warm and stir overnight. Quench with water, concentrate under reduced pressure to remove organic solvents, extract once with ethyl acetate: petroleum ether=1:1, adjust the aqueous phase with saturated sodium carbonate aqueous solution to pH=7-8, then extract with dichloromethane 5 times, and combine The organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 188B (5.6 g, 38%). LC-MS(ESI): m/z=229[M+H] ⁺ .

The second step:

Compound 188B (5.6g, 24.56mmol) was dissolved in tertiary butanol (100mL), 2-(2-bromophenyl)-3-oxobutyric acid methyl ester (6.6g, 24.56mmol) was added, ice Acetic acid (4.4 g, 73.68 mmol). Stir at 100°C for 48h, concentrate under reduced pressure and separate and purify by silica gel column chromatography to obtain 188C (3.6g, 40%). LC-MS(ESI): m/z=481[M+H] ⁺ .

third step:

Compound 188C (3.5g, 7.3mmol) was dissolved in dioxane (50mL), and chlorine (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'- Biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (RUPHOS PD G2) (567mg, 0.73mmol), sodium methoxide (591mg, 10.95mmol), nitrogen protection, React at 100°C for 6h. It was quenched with water and extracted 3 times with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. After separation and purification by silica gel column chromatography, compound 188D (2.2g, 75%). LC-MS(ESI): m/z=401[M+H] ⁺ .

the fourth step:

Compound 188D (2.2 g, 5.5 mmol) was dissolved in methanol (20 mL) and sodium hydroxide solution water (sodium hydroxide 1.1 g, 27.5 mmol; 20 mL water) was added, and the reaction was carried out at 70° C. overnight. Concentrate under reduced pressure to remove the organic solvent, adjust ph=4~5 with dilute hydrochloric acid (2N), then extract 3 times with ethyl acetate, dry the combined organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 188E (1.8g ,84%). LC-MS(ESI): m/z=387[M+H] ⁺ .

the fifth step:

Compound 188E (1.8g, 4.7mmol) was dissolved in dimethylformamide (30mL), and HOBT (770mg, 5.7mmol), EDCI (1.1g, 5.7mmol), Intermediate 2 (1.03g, 4.7 mmol) and triethylamine (1.42g, 14.1mmol), stirred at room temperature for 4h. Quenched with water, extracted 3 times with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was separated and purified by silica gel column chromatography to obtain compound 188F (1.6g, 61%) . LC-MS(ESI): m/z=553[M+H] ⁺ .

The sixth step:

The dioxane solution (4N) of HCl was added to compound 188F (1.6 g, 2.9 mmol), and the mixture was stirred at room temperature for 2 h. Concentrate to obtain compound 188G (1.4 g, 100%). LC-MS(ESI): m/z=453[M+H]+.

The seventh step:

To ( R )-tetrahydrofuran-3-carboxylic acid (50 mg, 0.43 mmol) was added DMF (10 mL), HATU (190 mg, 0.5 mmol), compound 188G (160 mg, 0.33 mmol) and DIEA (194 mg, 1.5 mmol) in sequence, Stir at room temperature for 1 h. Quench with water, extract 3 times with ethyl acetate, wash the combined organic phase once with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude compound, which is separated and purified by silica gel column chromatography. Through the analysis of palm properties, compound 188 , isomer 1 (20mg, 11%) and compound 188 , isomer 2 (20mg, 11%) were obtained. The analysis conditions of Isomer 1 and Isomer 2 are as follows:

Apparatus: MG Ⅱ preparative SFC (SFC-1); column type: ChiralPak AS, 250×30mm ID, 10μm; mobile phase: A is CO ₂ , B is ethanol; gradient: B 40%; flow rate: 60 mL/min; Back pressure: 100bar; column temperature: 38°C; column length: 254nm; time period: ~7.7min; sample preparation: 90mg compound dissolved in 15mL mixed solvent of dichloromethane and methanol; injection: 2mL/time.

Isomer 1: LC-MS(ESI): m/z=551[M+H]+.

¹ H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),7.78-7.71(m,1H),7.66-7.59(m,2H),7.12-7.00(m,2H),6.12(s,1H) ), 4.44-4.36(m, 2H), 4.16(s, 1H), 3.84-3.61(m, 4H), 3.38-3.30(m, 2H), 3.29-2.99(m, 2H), 2.67(s, 1H) ), 2.51-2.60 (m, 3H), 2.48 (s, 3H), 2.33-2.20 (m, 1H), 2.19 (s, 3H), 2.05-1.87 (m, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.25-0.72 (m, 3H)

Isomer 2: LC-MS(ESI): m/z=551[M+H]+.

¹ H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),7.78-7.71(m,1H),7.66-7.59(m,2H),7.12-7.00(m,2H),6.12(s,1H) ), 4.44-4.36(m, 2H), 4.16(s, 1H), 3.83-3.58(m, 4H), 3.38-3.30(m, 2H), 3.29-2.99(m, 2H), 2.68(s, 1H) ), 2.51-2.60 (m, 3H), 2.48 (s, 3H), 2.33-2.20 (m, 1H), 2.19 (s, 3H), 2.05-1.87 (m, 3H), 1.55 (d, J=5.3 Hz, 3H), 1.23-0.75 (m, 3H).

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-( 1-(( S ))-tetrahydrofuran-3-carbonyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (compound 189 )

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(1-(( S )-tetrahydrofuran- 3-carbonyl)piperidin-4-yl)ethyl)-1H-ihdole-3-carboxamide

To ( S )-tetrahydrofuran-3-carboxylic acid (50mg, 0.43mmol) was added DMF (10mL), HATU (190mg, 0.5mmol), compound 188G (160mg, 0.33mmol) and DIEA (194mg, 1.5mmol) in sequence, Stir at room temperature for 1 h. Quench with water, extract 3 times with ethyl acetate, wash the combined organic phase once with water, once with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude compound, which is separated and purified by silica gel column chromatography. The palm properties were analyzed, and compound 189 , isomer 1 (20mg, 11%) and compound 189 , isomer 2 (20mg, 11%) were obtained. The analysis conditions of Isomer 1 and Isomer 2 are as follows:

Apparatus: MG Ⅱ preparative SFC (SFC-1); column type: ChiralPak AS, 250×30mm ID, 10μm; mobile phase: A is CO ₂ , B is ethanol; gradient: B 40%; flow rate: 60 mL/min; Back pressure: 100bar; column temperature: 38°C; column length: 254nm; time period: ~7.3min; sample preparation: 90mg compound dissolved in 15mL mixed solvent of dichloromethane and methanol; injection: 1mL/time.

Isomer 1: LC-MS(ESI): m/z=551[M+H]+.

¹ H NMR(400MHz,DMSO-d6)δ11.64(s,1H),7.77-7.68(m,1H),7.65-7.55(m,2H),7.14-6.99(m,2H),6.12(s, 1H), 4.44-4.35 (m, 2H), 4.17 (s, 1H), 3.82-3.57 (m, 4H), 3.30 (s, 2H), 3.29-3.04 (m, 2H), 2.75-2.64 (m, 1H), 2.62-2.52 (m, 3H), 2.48 (s, 3H), 2.36-2.21 (m, 1H), 2.19 (s, 3H), 2.01-1.89 (m, 3H), 1.55 (d, J= 5.3Hz, 3H), 1.27-0.66 (m, 3H).

Isomer 2: LC-MS(ESI): m/z=551[M+H]+.

¹ H NMR (400MHz, DMSO-d6) δ 11.64 (s, 1H), 7.84-7.69 (m, 1H), 7.69-7.54 (m, 2H), 7.16-6.86 (m, 2H), 6.12 (s, 1H) ), 4.44-4.35(m, 2H), 4.22-4.08(m, 1H), 3.81-3.58(m, 4H), 3.30(s, 2H), 3.28-2.96(m, 2H), 2.78-2.66(m ,1H),2.63-2.53(m,3H),2.48(s,3H),2.36-2.21(m,1H),2.19(s,3H),2.04-1.87(m,3H),1.55(d,J =6.8Hz,3H),1.26-0.85(m,3H).

1-(1-(1-(3-Fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-4-yl)ethyl)-2-methyl-N-((6-methyl -4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (compound 190 )

1-(1-(1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-4-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

To 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (56mg, 0.43mmol) were sequentially added DMF (10mL), HATU (190mg, 0.5mmol), compound 188G (160mg, 0.33mmol) and DIEA (194mg, 1.5mmol), stirred at room temperature for 1h. Quench with water, extract 3 times with ethyl acetate, wash the combined organic phase once with water and once with saturated brine, dry and concentrate the organic phase to obtain the crude compound, which is separated and purified by silica gel column chromatography, and then analyzed by contrast. Compound 190 , isomer 1 (20 mg, 11%) and compound 4 , isomer 2 (20 mg, 11%) were obtained. The analysis conditions of Isomer 1 and Isomer 2 are as follows:

Apparatus: MG Ⅱ preparative SFC (SFC-1); column type: ChiralPak AS, 250×30mm ID, 10μm; mobile phase: A is CO2, B is ethanol; gradient: B 40%; flow rate: 60 mL/min; back Pressure: 100bar; Column temperature: 38℃; Column length: 254nm; Time period: ~5min; Sample preparation: 100mg compound dissolved in 15mL mixed solvent of dichloromethane and methanol; Injection: 2mL/time.

Isomer 1: LC-MS (ESI): m/z=565[M+H]+.

¹ H NMR (400MHz, DMSO-d6) δ 11.65 (s, 1H), 7.81-7.68 (m, 1H), 7.68-7.53 (m, 2H), 7.13-6.98 (m, 2H), 6.13 (s, 1H) ), 4.40(s,2H),4.22-3.71(m,2H),3.15-2.91(m,1H),2.76-2.65(m,1H),2.65-2.54(m,3H),2.48(s,3H) ), 2.42 -2.33 (m, 3H), 2.28 (s, 4H), 2.19 (s, 3H), 1.96 (s, 1H), 1.54 (d, J=6.7Hz, 3H), 1.34-1.03 (m, 2H), 0.98-0.69 (m, 2H).

Isomer 2: LC-MS (ESI): m/z=565[M+H]+.

¹ H NMR (400MHz, DMSO-d6) δ 11.65 (s, 1H), 7.77-7.69 (m, 1H), 7.66-7.57 (m, 2H), 7.23-6.89 (m, 2H), 6.13 (s, 1H) ), 4.46-4.37(m, 2H), 4.20-3.74(m, 2H), 3.15-2.94(m, 1H), 2.75-2.66(m, 1H), 2.63-2.53(m, 3H), 2.48(s ,3H),2.42-2.34(m,3H),2.28(s,4H),2.19(s,3H),1.96(s,1H),1.54(d,J=6.7Hz,3H),1.28-1.16( m, 2H), 0.96-0.72 (m, 2H).

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo- 1,2-Dihydropyridin-3-yl)methyl)-5-(methylamino)-1H-indole-3-carboxamide ( compound 191 )

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl )-5-(methylamino)-1H-indole-3-carboxamide

first step:

At minus 20 degrees Celsius, compound 191A (1 g, 4.37 mmol) was dissolved in concentrated sulfuric acid (5 mL), concentrated nitric acid (1 mL) was added thereto, and reacted at this temperature for half an hour. Pour the reaction system into a large amount of ice, extract the organic phase with ethyl acetate (50mL×2), combine the organic phases and neutralize the organic phase with sodium bicarbonate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 191B (1.1 g, 92%). LC-MS(ESI): m/z=275.08[M+H] ⁺ .

The second step:

Under nitrogen protection, compound 191B (1.1g, 4.01mmol) was dissolved in anhydrous tetrahydrofuran (10mL), cooled to -78℃ and then added LHMDS (6mL, 1M), half an hour later, then added 1-acetylimidazole (573.4mg , 5.21mmol), warm to room temperature and react for two hours, then add ice water (10mL) to quench the reaction, and extract twice with ethyl acetate (50mL×2). The combined organic phases are dried with anhydrous sodium sulfate and reduced under reduced pressure. After concentration, column chromatography (petroleum ether: ethyl acetate=5:1) was separated to obtain compound 191C (180 mg, 82%). LC-MS(ESI): m/z=316.1[M+H] ⁺ .

third step:

Compound 191C (1 g, 3.16 mmol) was dissolved in tertiary butanol (10 mL), and intermediate 1c (570 mg, 3.08 mmol) and acetic acid (1 mL) were sequentially added thereto, and reacted at 90° C. overnight. The crude product obtained by rotary drying the solvent was separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 191D (890 mg, 58%). LC-MS(ESI): m/z=484.4[M+H] ⁺ .

the fourth step:

Compound 191D (15.0g, 37.31mmol) was dissolved in dioxane (150mL), and Ru-Phos (3.5g, 7.46mmol), sodium methoxide (2.5g, 74.62mmol) and 2 ^nd Gen Ruphos precatalyst were added to it in sequence (2.9g, 3.73mmol), under the protection of nitrogen, the temperature was raised to 80°C and reacted overnight. After the reaction was cooled to room temperature, water (40mL) was added to it, and ethyl acetate (50mL×2) was extracted twice. The combined organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: Ethyl acetate=3:1) Compound 191E (11.0mg, 88%) was isolated. LC-MS(ESI): m/z=403.2[M+H] ⁺ .

the fifth step:

Compound 191E (1.0 g, 2.49 mmol) was dissolved in tetrahydrofuran (10 mL), hydrochloric acid solution (10 mL, 6M) was added thereto, and the reaction was carried out at room temperature overnight. The reaction solution was poured into water (40mL), ethyl acetate (50mL×2) was extracted twice, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate = 1:1) Compound 191F (700mg, 80%) was isolated. LC-MS(ESI): m/z=359.4[M+H] ⁺ .

The sixth step:

Compound 191F (850 mg, 2.37 mmol) was dissolved in methanol (8 mL), sodium borohydride (135 mg, 3.56 mmol) was added thereto, and the reaction was carried out at room temperature overnight. The reaction was quenched by adding water (40mL), the residue was extracted twice with ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate) =1: 2) Compound 191G (680mg, 80%) was isolated. LC-MS(ESI): m/z=361.4[M+H] ⁺ .

The seventh step:

Compound 191G (680 mg, 2.37 mmol) was dissolved in tetrahydrofuran (5 mL), NaH (948 mg, 23.70 mmol) and methyl iodide (3.4 g, 23.70 mmol) were added thereto, and the reaction was carried out at room temperature overnight. The reaction was quenched by adding water (40mL), the residue was extracted twice with ethyl acetate (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate=1: 1) Compound 191H (488mg, 81%) was isolated. LC-MS(ESI): m/z=375.4[M+H] ⁺ .

The eighth step:

Compound 191H (488mg, 1.30mmol) was dissolved in methanol (5mL), palladium on carbon (50mg, 10%) was added to it, and a balloon was used for hydrogenation at room temperature for two hours. The catalyst was removed by filtration, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1911 (418 mg, 93%). LC-MS(ESI): m/z=345.4[M+H] ⁺ .

Step 9:

Compound 1911 (418 mg, 1.21 mmol) was dissolved in dichloromethane (5 mL), triethylamine ( _{244 mg, 2.42 mmol) and (Boc) 2} O (690 mg, 1.82 mmol) were added thereto, and the reaction was carried out at room temperature for two hours. The reaction solution was poured into water (40mL), ethyl acetate (50mL×2) was extracted twice, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate = 1:1) Compound 191J (424mg, 80%) was isolated. LC-MS(ESI): m/z=445.5[M+H] ⁺ .

The tenth step:

Compound 191J (424mg, 0.96mmol ) was dissolved in tetrahydrofuran (5mL), sodium hydride (384mg, 9.6mmol) and methyl iodide (1.5g, 9.6mmol) were added to it at 0°C, and reacted at room temperature for two hours. The reaction was quenched by adding water, extracted twice with ethyl acetate (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate=1:1) was separated to obtain compound 191K ( 380mg, 86%). LC-MS(ESI): m/z=459.6[M+H] ⁺ .

The eleventh step:

Compound 191K (380 mg, 0.83 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL) and methanol (5 mL), potassium hydroxide (465 mg, 8.3 mmol) was added thereto, and the temperature was refluxed overnight. The reaction was quenched by adding water, extracted twice with ethyl acetate (50 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 191L (267 mg). LC-MS(ESI): m/z=445.6[M+H] ⁺ .

The twelfth step:

The crude compound 191L (267 mg) was dissolved in dichloromethane (5 mL), DIPEA (405 mg, 1.66 mmol) and HATU (410 mg, 1.08 mmol) were added thereto, and after reacting for ten minutes, intermediate 2 (418 mg, 1.21 mmol) was added to it. mmol), react at room temperature for one hour. The reaction was quenched by adding water, the residue was extracted with ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=1:1) Compound 191M (320 mg, two-step yield 63%) was obtained. LC-MS(ESI): m/z=611.8[M+H] ⁺ .

The thirteenth step:

Compound 191M (320 mg, 0.52 mmol) was dissolved in methanol (5 mL), and a methanol solution of hydrochloric acid (5 mL) was added thereto, and reacted at room temperature for one hour. After concentration under reduced pressure, the crude product was separated by column chromatography. The crude product was further separated by preparative HPLC to obtain compound 191 , isomer 1 (100mg, 37%) and compound 191 , isomer 2 (7mg, 2.6%)

Preparative HPLC separation conditions: preparative instrument W/J0407, preparative column Xbridge C18, mobile phase system: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1 : 3.427 min, isomer 2 : 3.488 min.

Isomer 1:

LC-MS(ESI): m/z=511.2[M+H] ⁺ .

¹ H NMR(400MHz, chloroform-d)δ 7.27(d,1H), 7.18(t,1H), 7.05(d,1H), 6.53(d,1H), 5.98(s,1H), 4.70(t, 2H), 3.99(d, 1H), 3.30(s, 3H), 3.13-2.94(m, 2H), 2.76(s, 3H), 2.66(s, 3H), 2.46(s, 3H), 2.19(s ,3H),2.11(d,3H),1.85(d,1H),1.55(d,3H),1.37-1.16(m,2H),1.08(t,2H),0.93(q,1H),0.90- 0.69(m,1H).

Isomer 2:

LC-MS(ESI): m/z=511.3[M+H] ⁺ .

¹ H NMR(400MHz, chloroform-d)δ 7.92(s,1H), 7.54(d,1H), 7.31(d,1H), 6.47(s,1H), 4.69(d,2H), 4.14(d, 1H), 3.41 (s, 1H), 3.27 (s, 3H), 3.09 (s, 3H), 2.68 (s, 2H), 2.55 (s, 3H), 2.47 (s, 3H), 2.14 (s, 1H) ),2.02(d,1H),1.75(dd,2H),1.56(d,3H),1.44(q,2H),1.26(d,2H),1.10(t,2H),0.88(t,1H) ,0.70(s,1H).

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6 -Methyl-4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 192 )

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-(methylthio) -2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

At 0° C., compound 192A (5 g, 17.06 mmol) was dissolved in methanol (50 mL), and dichloromethane (5 mL) was added thereto, and reacted at this temperature for half an hour. The reaction system was poured into a large amount of ice, the residue was extracted with ethyl acetate (50mL×2), the combined organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 192B (5.2g, 99%). LC-MS(ESI): m/z=308.9[M+H] ⁺ .

The second step:

Under nitrogen protection, dissolve compound 192B (5.2g, 16.93mmol) in anhydrous tetrahydrofuran (50mL), add LHMDS (20mL, 1M) at -78°C, stir for half an hour after the addition is complete, add compound 1-acetylimidazole (2.2g, 20mmol), the reaction was warmed to room temperature and stirred for 2h. The reaction was quenched by adding ice water (50mL), the residue was extracted twice with ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate) Ester=5:1) Compound 192C (4.5g, 72%) was isolated. LC-MS(ESI): m/z=350.9[M+H] ⁺ .

third step:

Compound 192C (560 mg, 3.16 mmol) was dissolved in tertiary butanol (10 mL), compound 1c (570 mg, 3.16 mmol) and acetic acid (1 mL) were sequentially added thereto, and reacted at 90° C. overnight. The reaction solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain compound 192D (720 mg, 50%). LC-MS(ESI): m/z=518.0[M+H] ⁺ .

the fourth step:

Compound 192D (3.2g, 6.19mmol) was dissolved in dioxane (15mL) and water (15mL), K ₃ PO ₄ (1.9g, 9.28mmol), 1-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5g, 6.8mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (560mg, 0.6mmol), under the protection of nitrogen, the temperature was raised to 100°C and reacted overnight. After the reaction was cooled to room temperature, the residue was extracted with ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate=2:1) Compound 192E (2.4g, 75%) was isolated. LC-MS(ESI): m/z=518.2[M+H] ⁺ .

the fifth step:

Compound 192E (2.4g, 1.8mmol) was dissolved in dioxane (30mL), and Ru-Phos (425g, 0.36mmol), sodium methoxide (169g, 2.7mmol) and 2 ^nd Gen Ruphos procatalyst (419g) were added to it in sequence. , 0.18mmol), under the protection of nitrogen, the temperature was raised to 80°C and reacted overnight. After the reaction was cooled to room temperature, 50 mL of water was added, and the residue was extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate) =2:1) Compound 192F (1.7g, 88%) was isolated. LC-MS(ESI): m/z=438.2[M+H] ⁺ .

The sixth step:

Compound 192F (1.7g, 1.6mmol) was dissolved in tetrahydrofuran (20mL), hydrochloric acid solution (20mL, 6M) was added thereto, and the reaction was carried out at room temperature overnight. The reaction solution was extracted with ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate=2:1) was separated to obtain compound 192G (1.4g) ,91%). LC-MS(ESI): m/z=394.2[M+H] ⁺ .

The seventh step:

Compound 192G (1.4 g, 1.5 mmol) was dissolved in methanol (15 mL), sodium borohydride (135 mg, 3 mmol) was added thereto, and the reaction was carried out at room temperature overnight. The reaction was quenched by adding 50 mL of water, the residue was extracted with ethyl acetate (50 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate = 1:2) ) The compound 192H (1.3g, 80%) was isolated. LC-MS(ESI): m/z=396.2[M+H] ⁺ .

The eighth step:

Compound 192H (1.3 g, 1.18 mmol) was dissolved in tetrahydrofuran (10 mL), NaH (472 mg, 11.8 mmol) and methyl iodide (1.8 g, 11.8 mmol) were added thereto, and the reaction was carried out at room temperature overnight. The reaction was quenched by adding 50mL water, the residue was extracted with ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatography (petroleum ether: ethyl acetate=1:1) ) The compound 1921 (1.1 g, 82%) was isolated. LC-MS(ESI): m/z=410.2[M+H] ⁺ .

Step 9:

Compound 1921 (1.1 g, 0.97 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL) and methanol (5 mL), potassium hydroxide (541 mg, 9.7 mmol) was added thereto, and the temperature was refluxed overnight. The reaction was quenched by adding water, extracted with ethyl acetate (50 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound 192J (1.3 g). LC-MS(ESI): m/z=395.2[M+H] ⁺ .

The tenth step:

The crude compound 192J (1.3g) was dissolved in dichloromethane (10mL), DIPEA (250mg, 1.94mmol) and HATU ( 480mg, 1.26mmol ) were added to it, and after reacting for ten minutes, intermediate 2 (418mg, 1.94mmol), react at room temperature for one hour. Ethyl acetate (50mL×2) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain the crude product, which was separated and purified by preparative HPLC Compound 192 , Isomer 1 (45mg, 19%) and Compound 192 , Isomer 2 (15mg, 7%).

Preparative HPLC separation conditions: preparative instrument W/J0407, preparative column Xbridge C18, mobile phase system: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1 : 4.176 min, isomer 2 : 4.172 min.

Isomer 1 : LC-MS (ESI): m/z=562.8[M+H] ⁺

¹ H NMR (400MHz, chloroform-d) δ 12.68 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.42 (d, 1H), 7.20 (d, 1H), 5.96 (s, 1H), 4.72 (s, 2H), 4.03 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H), 3.05 (t, 1H), 2.71 (s, 3H) ), 2.47(s, 3H), 2.18(s, 1H), 2.09(s, 4H), 1.85(d, 1H), 1.60(d, 3H), 1.25(q, 2H), 1.09(d, 2H) ,0.92(dd,1H),0.85-0.71(m,1H).

Isomer 2 : LC-MS (ESI): m/z=562.7[M+H] ⁺

¹ H NMR(400MHz, chloroform-d)δ 7.98(s,1H),7.78(s,1H),7.60(s,1H),7.50(s,1H),7.43(d,1H),7.21(d, 1H), 5.97(s, 1H), 4.72(s, 2H), 3.81(s, 3H), 3.30(s, 3H), 3.06(s, 1H), 2.71(s, 3H), 2.47(s, 3H) ), 2.14 (s, 4H), 1.86 (d, 2H), 1.71 (s, 3H), 1.37-1.17 (m, 4H), 1.09 (d, 4H), 0.91-0.79 (m, 4H).

1-(1-(3-Azabicyclo[3.1.1]heptane-6-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( compound 193 )

1-(1-(3-azabicyclo[3.1.1]heptan-6-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin -3-yl)methyl)-1H-indole-3-carboxamide

first step:

Add sodium hydride (1.0g, 26.0mmol) and THF (30mL) into a 250mL single-necked flask, and add triethyl 2-phosphinopropyl ester (6.2g, 26.0mmol) in THF (25mL) solution dropwise in an ice bath , Stirred for 1 h, added dropwise 3-benzyl-3-azabicyclo[3.1.1]heptane-6-one in THF (25 mL), stirred at room temperature overnight, washed with aqueous solution (100 mL), ethyl acetate Extraction (50mL×2), combine the organic phases, wash with saturated sodium chloride (50mL×1), dry with anhydrous sodium sulfate, concentrate under reduced pressure, column chromatography (PE:EA=10:1) to obtain compound 193B (4.4g, 89% yield). LC-MS(ESI): m/z=286.2[M+H] ⁺ .

The second step:

Add 193B (4.4g, 15.0mmol) to a 100mL single-neck flask, dissolve in methanol (40mL), add 10% palladium on carbon (1g), replace with hydrogen three times, react at room temperature overnight, and concentrate to obtain a light yellow oil 193C (3.0 g, 99% yield). LC-MS(ESI): m/z=198.2[M+H] ⁺ .

third step:

Add 193C (3.0g, 15.0mmol) and DCM (20 mL) to a 100mL single-necked flask, add triethylamine (2.3g, 23.0mmol) and CBZOSu (4.2g, 17.0mmol), stir at room temperature overnight, use the aqueous solution (20mL) washed, dichloromethane extraction (50mL×2), combined organic phases, washed with saturated sodium chloride (50mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (PE:EA=4:1) ) To obtain 193D as a yellow oil (4.0 g, 79% yield). LC-MS(ESI): m/z=332.3[M+H] ⁺ .

the fourth step:

Add 193D (4.0g, 12.0mmol), THF (15mL), MeOH (15mL) and water (15mL) into a 100mL single-mouth flask, add lithium hydroxide (0.87g, 36.0mmol), stir at room temperature for 5h, and use HCl (2M) Adjust the pH to 3-4, extract with ethyl acetate (50 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a colorless oil 193E (3.5 g, 96% yield). LC-MS(ESI): m/z=304.1[M+H] ⁺ .

the fifth step:

Add 193E (3.5g, 12.0mmol) to a 100mL single-neck flask, dissolve tertiary butanol (30mL), add triethylamine (1.8g, 17.0mmol) and DPPA (4.8g, 17.0mmol), stir at 85°C overnight The reaction solution was concentrated, water (50mL) was added, EA (50mL×2) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=6:1) to obtain a yellow oil, DCM( 17mL) and TFA (5mL) were dissolved, stirred at room temperature for 2h, the reaction solution was concentrated, DCM (50mL) was dissolved, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a colorless oil 193F (1.7g, 54% yield) Rate). LC-MS(ESI): m/z=275.2[M+H] ⁺ .

The sixth step:

Add 193F (1.7g, 6.2mmol) to a 100mL single-necked flask, dissolve tertiary butanol (15mL), add 2-(2-bromophenyl)-3-oxobutyric acid methyl ester (2.5g, 9.3 ( PE:EA=5:1) to obtain yellow solid 193G (1.1g, yield 34%). LC-MS(ESI): m/z=527.2[M+H] ⁺ .

The seventh step:

Add 193G (1.1g, 2.1mmol) to a 100mL single-mouth flask, dissolve dioxane (10mL), add sodium methoxide (0.17g, 3.1mmol), Ruphos (0.19g, 0.42mmol), 2 ^nd Gen Ruphos pretreatment The catalyst (0.32g, 0.42mmol), under nitrogen protection, stirred at 100°C for 6h, filtered through Celite, diluted with water (30mL), extracted with EA (30mL×2), combined the organic phases, dried, and separated by column chromatography (PE : EA=3:1) to obtain yellow solid 193H (0.52g, yield 56%).

LC-MS(ESI): m/z=447.3[M+H] ⁺ .

The eighth step:

Add 193H (0.30g, 0.67mmol), THF (2mL), MeOH (2mL) and water (2mL) into a 100mL single-mouth flask, add potassium hydroxide (0.38g, 6.7mmol), stir at 70℃ for 16h, use HCl (2M) Adjust the pH to 3-4, extract with EA (20 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1931 (0.24 g, 83% yield) as a colorless oil. LC-MS(ESI): m/z=433.3[M+H] ⁺ .

Step 9:

Add 193I (0.24g, 0.55mmol) to a 100mL single-mouth flask, dissolve DCM (10mL), add triethylamine (0.17g, 1.7mmol) and HATU (0.25g, 0.67mmol), stir at room temperature for 0.5h, add Intermediate 2 (0.11g, 0.58mmol), stirred at room temperature for 16h, the reaction solution was added water (10mL), DCM (10mL×2) was extracted twice, the organic phase was dried with anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH=10:1) A yellow solid 193J (0.10g, 30% yield) was isolated. LC-MS(ESI): m/z=599.3[M+H] ⁺ .

The tenth step:

The starting material 193J (0.10g, 0.17mmol) was added to a 50mL single-necked flask, acetic acid (3mL) was dissolved, HBr (glacial acetic acid solution, 3mL) was added, and the mixture was stirred at room temperature for 1h. The reaction solution was diluted with water (10mL), EA( 10mL) Extraction to remove impurities. The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with (DCM:MeOH=6:1, 20mL×3), the organic phases were combined, concentrated, and separated by HPLC to obtain a white solid compound 193 (20mg, 30% yield) ). LC-MS(ESI): m/z=465.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.85-7.70 (m, 1H), 7.37-7.29 (m, 1H), 6.95 (tt, 2H), 6.06 (s, 1H), 5.01 (m, 1H), 4.64 (m, 1H), 4.48-4.34 (m, 2H), 3.59-3.38 (m, 2H), 3.06 (m, 1H), 2.85 (d, 1H), 2.74 (s, 3H), 2.50 (d, 3H) ), 2.38 (s, 2H), 2.33 (d, 2H), 2.00 (s, 3H), 1.72 (t, 1H), 1.54 (d, 2H), 1.32-1.23 (m, 1H).

1-(1-(3-Acetyl-3-azabicyclo[3.1.1]heptane-6-yl)ethyl)-2-methyl-N-((6-methyl-4- (Methylthio)-2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-amide ( compound 194 )

1-(1-(3-acetyl-3-azabicyclo[3.1.1]heptan-6-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

Compound 193 (0.04g, 0.086mmol) was added to a 100mL single-neck flask, DCM (5mL) was dissolved, triethylamine (0.017g, 0.17mmol) and acetyl chloride (8mg, 0.10mmol) were added, and stirred at room temperature for 2h, The reaction solution was added with water (10 mL) and extracted twice with DCM (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain compound 194 (5 mg, 10% yield). LC-MS(ESI): m/z=507.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.77-7.68 (m, 1H), 7.61-7.48 (m, 1H), 7.24-7.02 (m, 2H), 6.29 (s, 1H), 4.88 (dd, 1H) ), 4.68-4.54 (m, 2H), 3.89 (t, 1H), 3.82-3.43 (m, 3H), 2.78-2.66 (m, 4H), 2.53 (s, 5H), 2.30 (s, 3H), 2.11 (s, 2H), 1.98 (d, 1H), 1.71-1.56 (m, 4H), 1.46-1.28 (m, 1H).

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-( 3-(2,2,2-Trifluoroethyl)-3-azabicyclo[3.1.1]heptane-6-yl)ethyl)-1H-indole-3-methanamide ( Compound 195 )

2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(3-(2,2,2- trifluoroethyl)-3-azabicyclo[3.1.1]heptan-6-yl)ethyl)-1H-indole-3-carboxamide

first step:

Add 193H (0.22g, 0.49mmol) to a 50mL single-mouth flask, dissolve MeOH (5mL), add 10% palladium on carbon (0.1g), stir at room temperature for 2h, filter through Celite, and concentrate to obtain 195A (0.15g, 100% yield). LC-MS(ESI): m/z=313.2[M+H]+.

The second step:

Add 195A (0.15g, 0.48mmol) to a 50mL single-mouth flask, DME (5mL) is dissolved, add cesium carbonate (0.31g, 0.96mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate ( 0.17g, 0.72mmol), stirred at 80°C for 4h, the reaction solution was added with water (10mL), EA (10mL×2) was extracted twice, the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE:EA=3 :1) to obtain 195B (0.14g, 74% yield). LC-MS(ESI): m/z=395.3[M+H]+.

third step:

Add 195B (0.14g, 0.35mmol), THE (3mL), MeOH (3mL) and water (3mL) into a 50mL single-mouth flask, add potassium hydroxide (0.20g, 3.5mmol), stir at 70°C for 16h, use HCl (2 M) Adjust the pH to 3-4, extract with EA (20 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a pale yellow solid 195C (0.13 g, 96% yield). LC-MS(ESI): m/z=381.2[M+H] ⁺ .

the fourth step:

Add 195C (0.12g, 0.32mmol) to a 100mL single-mouth flask, dissolve DCM (5mL), add triethylamine (0.1g, 0.95mmol) and HATU (0.14g, 0.38mmol), stir at room temperature for 0.5h, add Intermediate 2 (0.076g, 0.41mmol), stirred at room temperature for 16h, the reaction solution was added with water (10mL), DCM (10mL×2) was extracted twice, the organic phase was dried with anhydrous sodium sulfate, concentrated, separated by HPLC and freeze-dried to obtain white Solid compound 195 (60 mg, 30% yield). LC-MS(ESI): m/z=547.3[M+H] ⁺ .

1H NMR (400MHz, CD ₃ OD) δ 7.71 (dd, 1H), 7.64-7.46 (m, 1H), 7.25-6.98 (m, 2H), 6.29 (s, 1H), 4.90-4.82 (m, 1H) ,4.61(d,2H),3.28-3.18(m,4H),3.02(dd,1H),2.79-2.67(m,5H),2.53(s,3H),2.43-2.32(m,2H),2.30 (d, 3H), 1.64 (d, 3H), 1.60-1.48 (m, 2H).

( R )-6-acetamido-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-(( 6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 196 )

( R )-6-acetamido-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2 -oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

Dissolve 196A (15g, 68.18mmol) in DMF (30mL), add ethyl acetate (8.87g, 68.18mmol), then add potassium carbonate (18.8g, 136.36mmol), and stir at room temperature for 4h. Aqueous solution (50 mL) was added, extracted with ethyl acetate (70 mL×3), the organic phases were combined, washed with water (100 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude light butter 196B (21 g). LC-MS(ESI): m/z=331.1[M+H] ⁺ .

The second step:

The crude product 196B (10g, 30.29mmol) was dissolved in tertiary butanol (30mL), 1c (5.61g, 30.29mmol) and glacial acetic acid (0.91g, 15.15mmol) were added, heated to reflux and stirred overnight. The column chromatography was concentrated to obtain 196C (5.1 g) as a light buttery solid. LC-MS(ESI): m/z=498.4[M+H] ⁺ .

third step:

Compound 196C (3.1g, 6.2mmol) was dissolved in 1,4-dioxane (20mL), and 2 ^nd Gen Ruphos precatalyst ( (2-dicyclohexylphosphino-2',6'-di-iso Propoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium(II) dichloride ) (0.97g, 1.2mmol), Ruphos(2 -Dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl) (0.58g, 1.2mmol), add sodium methoxide (0.67g, 12mmol), reflux and stir overnight. The column chromatography was concentrated to obtain 196D (1.2 g) as a pale yellow solid. LC-MS(ESI): m/z=417.5[M+H] ⁺ .

the fourth step:

Compound 196D (1 g, 2.40 mmol) was dissolved in methanol (15 mL), palladium on carbon (1.5 g) was added, and the reaction was carried out at room temperature overnight. After suction filtration, the filtrate was spin-dried to obtain a yellow solid 196E (0.96 g). LC-MS(ESI): m/z=387.2[M+H] ⁺ .

the fifth step:

Compound 196E (700 mg, 1.81 mmol) was dissolved in dichloromethane (10 mL), acetyl chloride (156 mg, 1.99 mmol) and triethylamine (367 mg, 3.62 mmol) were added, and the reaction was carried out at room temperature overnight. Wash with water (30 mL), extract with ethyl acetate (50 mL×2), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude yellow solid 196F (800 mg). LC-MS(ESI): m/z=429.2[M+H] ⁺ .

Sixth step

The crude product 196F was analyzed on the palm to obtain the desired configuration 196G (400mg).

The crude product 1d (750mg) was prepared in the opposite direction. The preparation conditions were as follows: instrument: MG Ⅱ preparative SFC (SFC-1); chromatography column: ChiralPAK AD-H, 250×20mm ID, 5μm. Preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: CO2 mobile phase B: ethanol. Gradient elution, mobile phase B content 10%; flow rate 25ml/min. The elution time is 22min. The component with a residence time of 18min is 196G (400mg). LC-MS(ESI): m/z=429.2[M+H] ⁺ .

The seventh step:

Compound 196G (350mg, 0.82mmol) was dissolved in THF/HCl (6mol/L)=1/1 mixed solvent (10mL), and reacted at room temperature overnight. Wash with water (30 mL), extract with ethyl acetate (50 mL×2), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude yellow solid 196H (300 mg). LC-MS(ESI): m/z=385.2[M+H]+.

The eighth step:

Dissolve compound 196H (160mg, 0.42mmol) in DCM (6mL), add difluorocyclobutylamine hydrochloride (54mg, 0.50mmol), glacial acetic acid 3d, react at room temperature for 3h, add sodium triacetylborohydride (176mg, 0.83mmol), react at room temperature for 3h, wash with water (30mL), extract with ethyl acetate (50mL×2), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude yellow solid 1961 (230mg). LC-MS(ESI): m/z=476.2[M+H] ⁺ .

Step 9:

Compound 1961 (230mg, 0.48mmol) was dissolved in THF/MeOH/H ₂ O=1/1/1 mixed solvent (6mL), lithium hydroxide (232mg, 9.67mmol) was added, and the reaction was refluxed for two days, and diluted acid was added. To pH=4, dilute with water (10mL), extract with ethyl acetate (50mL×2), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain brown crude product 196J (260mg). LC-MS(ESI): m/z=448.2[M+H] ⁺ .

The tenth step:

Dissolve compound 196J (230mg, 0.51mmol), intermediate 2 , HATU (181mg, 0.77mmol), DIEA (133mg, 1.03mmol), DCM (10mL), react at room temperature for 4h, add water (10mL) to wash, ethyl acetate (50mL×2) extraction, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a brown crude product, which was further purified by preparative HPLC to obtain compound 196 , isomer 1 and compound 196 , isomer 2 .

The preparative HPLC conditions are: instrument: Waters 2767 preparative liquid phase; chromatographic column: XBridge C18 5 μm , 19*250mm. The sample was dissolved in acetonitrile and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (containing 1% TFA). Gradient elution, mobile phase A content from 10%-46%, time 12min; flow rate 12ml/min. The elution time is 16min.

The component with a residence time of 12.20 min is compound 196 , isomer 1 (5.2 mg).

LC-MS(ESI): m/z=614.3[M+H] ⁺ .

¹ H NMR(400MHz,CD3OD)δ 8.20(s,1H), 7.65(d,J=8.0Hz,1H), 7.00(d,J=8.0Hz,1H), 6.31(s,1H), 4.60(s ,2H),4.32-4.28(m,1H),3.90-3.85(m,1H),3.13-3.02(m,3H),2.91-2.81(m,3H),2.70-2.64(m,3H),2.54 (s,3H),2.31(s,3H),2.14(s,3H),1.99-1.93(m,3H),1.66-1.57(m,5H),1.31-1.29(m,1H),1.12-0.97 (m,3H).

The component with a residence time of 12.62 min is 196 , and the isomer 2 (5.0 mg).

LC-MS(ESI): m/z=614.3[M+H] ⁺ .

¹ H NMR(400MHz,CDCl3)δ 8.25(s,1H), 7.65(d,J=8.0Hz,1H), 6.94(d,J=8.0Hz,1H), 6.31(s,1H), 4.60(s ,2H),4.19-4.14(m,1H),3.89-3.83(m,1H),3.13-3.06(m,3H),2.82-2.76(m,3H),2.59(s,3H),2.54(s ,3H),2.31-2.15(m,8H),1.91-1.84(m,1H),1.63-1.61(m,3H),1.49-1.40(m,1H),1.33-0.97(m,6H).

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-5-fluoro-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (compound 197 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-5-fluoro-2-methyl-N-((6-methyl-4-(methylthio)-2 -oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

The feedstock 197A (5g, 21.46mmol) was dissolved in MeOH (30mL) was added dichloro sulfoxide (3.83g, 32.19mmol), The reaction was refluxed for 4h. Concentrate to remove methanol, add aqueous solution (50mL), extract with ethyl acetate (70mL×3), combine the organic phases, wash with water (100mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude yellow 197B (5g) ). LC-MS(ESI): m/z=247.0[M+H] ⁺ .

The second step:

Dissolve the crude 197B (5g, 20.24mmol) in THF (30mL), add LDA (30mL, 30mmol) at -78℃, react for 1h at -78℃, add 1-imidazole-1-acetone (2.45g, 22.26mmol) , Automatically warm to room temperature and react overnight. Aqueous solution (50 mL) was added, extracted with ethyl acetate (70 mL×3), and the combined organic phases were washed with water (100 mL). After drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure, a yellow crude product 197C (6g) was obtained. LC-MS(ESI): m/z=290.0[M+H] ⁺ .

third step:

The crude product 197C (3g, 10.38mmol) was dissolved in tertiary butanol (30mL), 1c (2g, 10.80mmol) and glacial acetic acid (1mL) were added, heated to reflux and stirred overnight. The column chromatography was concentrated to obtain 197D (5.1 g) as a light buttery solid. LC-MS(ESI): m/z=456.1[M+H] ⁺ .

the fourth step:

Dissolve compound 197D (3g, 6.58mmol) in 1,4-dioxane (20mL), add 2 ^nd Gen Ruphos precatalyst (1.02g, 1.32mmol), Ruphos (0.61g, 1.32mmol), and add methanol Sodium (0.71g, 13.15mmol), reflux and stir overnight. The column chromatography was concentrated to obtain 197E (850 mg) as a pale yellow solid. LC-MS(ESI): m/z=376.1[M+H]+.

the fifth step:

The crude product 197E (1.9g) was prepared in parallel, and the preparation conditions were as follows: instrument: MG Ⅱ preparative SFC (SFC-1); chromatography column: ChiralCel OJ, 250×30mm ID, 5μm. Preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: CO2 mobile phase B: ethanol. Gradient elution, mobile phase B content 30%; flow rate 60mL/min. The elution time is 7.7 min. The component with a residence time of 5.7 minutes is 197F (1.3g). LC-MS(ESI): m/z=376.1[M+H] ⁺ .

The sixth step:

Compound 197F (600mg, 1.60mmol) was dissolved in THF/HCl (6mol/L)=1/1 mixed solvent (10mL), and reacted at room temperature overnight. Wash with water (30 mL), extract with ethyl acetate (50 mL×2), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude yellow solid 197G (520 mg). LC-MS(ESI): m/z=332.2[M+H] ⁺ .

The seventh step:

Dissolve compound 197G (520mg, 1.57mmol ) in DCM (6mL), add difluorocyclobutylamine hydrochloride (226mg, 1.57mmol), glacial acetic acid (48mg, 0.78mmol), react at room temperature for 3h, add triethyl Sodium borohydride (665mg, 3.14mmol), react at room temperature for 3h, wash with water (30mL), extract with ethyl acetate (50mL×2), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude yellow solid 197H ( 500mg). LC-MS(ESI): m/z=423.3[M+H] ⁺ .

The eighth step:

Compound 197H (500mg, 1.18mmol) was dissolved in THF/MeOH/H ₂ O=1/1/1 mixed solvent (6mL), potassium hydroxide (664mg, 11.83mmol) was added, the reaction was refluxed overnight, and diluted acid was added to pH=4, dilute with water (10 mL), extract with ethyl acetate (50 mL×2), wash the combined organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain brown crude product 1971 (400 mg). LC-MS(ESI): m/z=409.2[M+H] ⁺ .

Step 9:

Dissolve compound 1971 (100mg, 0.24mmol), intermediate 2 (90mg, 0.49mmol), HATU (140mg, 0.37mmol), DIEA (95mg, 0.73mmol), DCM (10mL), react at room temperature for 4h, add water (10mL ) Was washed, extracted with ethyl acetate (50mL×2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The brown crude product obtained was separated by preparative HPLC to obtain compound 197 , isomer 1 and compound 197 . Isomer 2.

The HPLC preparation conditions are: instrument: Waters 2767 preparative liquid phase; chromatographic column: XBridge C18 5 μm , 19*250mm. The sample was dissolved in acetonitrile and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (containing 1% TFA). Gradient elution, mobile phase A content from 5%-50%, time 15min; flow rate 12ml/min. The elution time is 20min.

The component with a residence time of 16.80 min is 197 , and the isomer 1 (30.0 mg).

LC-MS(ESI): m/z=575.3[M+H] ⁺ .

¹ H NMR(400MHz, CD3OD)δ 7.56-7.52(m,1H),7.44-7.41(m,1H),6.91-6.86(m,1H),6.34-6.32(m,1H), 4.60(s,2H) ),4.35-4.31(m,1H),3.92-3.84(m,1H),3.13-3.01(m,3H),2.93-2.80(m,2H),2.71-2.64(m,3H),2.55-2.46 (m, 4H), 2.32 (s, 3H), 2.01-1.92 (m, 3H), 1.63-1.61 (m, 6H), 1.12-1.00 (m, 2H).

The component with a residence time of 17.2 min is 197 , and the isomer 2 (32.0 mg).

LC-MS(ESI): m/z=575.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl3) δ 7.56-7.53 (m, 1H), 7.44-7.42 (m, 1H), 6.90-6.86 (m, 1H), 6.33-6.32 (m, 1H), 4.60 (s, 2H) ), 4.21-4.15 (m, 1H), 3.88-3.83 (m, 1H), 3.13-3.05 (m, 3H), 2.86-2.72 (m, 3H), 2.59-2.55 (m, 5H), 2.32-2.19 (m, 6H), 1.91-1.88 (m, 1H), 1.63-1.61 (m, 3H), 1.51-1.42 (m, 1H), 1.29-0.97 (m, 4H).

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-5-fluoro-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide (compound 198 )

( R )-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-5-fluoro-2-methyl-N-((6-methyl-4-(methylthio)-2 -oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide

Dissolve compound 1971 (100mg, 0.24mmol ), 185G (90mg, 0.49mmol), HATU (140mg, 0.37mmol), DIEA (95mg, 0.73mmol), DCM (10mL), react at room temperature for 4h, add water (10mL) to wash After extraction with ethyl acetate (50mL×2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain brown crude compound 198 (120mg), which was further separated by preparative HPLC to obtain compound 198 , isomer 1 And compound 198 , isomer 2.

The HPLC preparation conditions are: instrument: Waters 2767 preparative liquid phase; chromatographic column: XBridge C18 5 μm , 19*250mm. The sample was dissolved in acetonitrile and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (containing 1% TFA). Gradient elution, mobile phase A content from 5%-50%, time 15min; flow rate 12ml/min. The elution time is 20min.

The component with a residence time of 16.80 min is compound 198 , isomer 1 (31 mg).

LC-MS(ESI): m/z=577.3[M+H]+.

¹ H NMR (400MHz, CD3OD) δ 7.55-7.51 (m, 1H), 7.43-7.41 (m, 1H), 6.89-6.85 (m, 1H), 6.30 (s, 1H), 4.16-4.11 (m, 1H) ), 3.39-3.36 (m, 1H), 2.82-2.71 (m, 3H), 2.58-2.48 (m, 6H), 2.45-2.38 (m, 2H), 2.31 (s, 3H), 2.19-1.95 (m ,3H),1.77-1.73(m,1H),1.61-1.59(m,3H),1.29-1.17(m,2H),0.97-0.88(m,3H).

The component with a residence time of 17.2 min is compound 198 and isomer 2 (62 mg).

LC-MS(ESI): m/z=577.3[M+H]+.

¹ H NMR (400MHz, CDCl3) δ 7.61-7.40 (m, 2H), 6.88-6.84 (m, 1H), 6.30 (s, 1H), 4.32-4.28 (m, 1H), 3.30-3.24 (m, 1H) ), 2.79-2.74 (m, 3H), 2.63 (s, 2H), 2.54 (s, 3H), 2.45-2.30 (m, 6H), 1.94-1.57 (m, 8H), 1.44-1.35 (m, 2H) ), 1.13-1.08 (m, 1H), 0.84-0.80 (m, 1H).

( R )-5-acetamido-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-(( 6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 199 )

( R )-5-acetamido-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2 -oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

Add 191E (1.0g, 2.5mmol), THF (5mL), MeOH (5mL) and water (5mL) into a 50mL single-necked flask, add sodium hydroxide (1.0g, 25.0mmol), reflux at 70°C and stir for 16h. Adjust the pH to 3-4 with HCl (2M), extract with ethyl acetate (50 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a colorless oil 199A (0.9 g, 90% yield). LC-MS(ESI): m/z=389.3[M+H] ⁺ .

The second step:

Add 199A (0.9g, 2.3mmol) to a 50mL single-mouth flask, dissolve DCM (10mL), add triethylamine (0.7g, 7.0mmol) and HATU (1.1g, 2.8mmol), stir at room temperature for 0.5h, add Intermediate 2 (0.45g, 2.4mmol), stirred at room temperature for 16h, the reaction solution was added water (10mL), DCM (10mL×2) was extracted twice, the organic phase was dried with anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH=10:1) isolated yellow solid 199B (0.60g, 47% yield). LC-MS(ESI): m/z=555.3[M+H] ⁺ .

third step:

Add 199B (0.6g, 1.0mmol) to a 50mL single-necked flask, dissolve methanol (10mL), add iron powder (0.3g, 5.0mmol) and ammonium chloride (0.6g, 10.0mmol), react at 70°C for 3h, Filter through diatomaceous earth and concentrate to obtain yellow solid 199C (0.5g, 90% yield). LC-MS(ESI): m/z=525.3[M+H] ⁺ .

the fourth step:

Add 199C (0.5g, 0.95mmol) to a 50mL single-neck flask, dissolve DCM (10mL), add triethylamine (0.14g, 1.4mmol) and acetic anhydride (0.11g, 1.0mmol), stir at room temperature for 4h, and react The solution was added with water (10mL), DCM (10mL×2) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM:MeOH=15:1) to obtain a yellow solid 199D (0.26g, 48%) Yield). LC-MS(ESI): m/z=567.2[M+H] ⁺ .

the fifth step:

The starting material 199D (0.26g, 0.46mmol) was added to a 50mL single-necked flask, dissolved in THF (5mL), HCl (6M, 5mL) was added, and stirred at room temperature for 6h. The reaction solution was adjusted to pH 8- with saturated sodium bicarbonate. 9. Extract with DCM (10 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain yellow solid 199E (0.17 g, yield 71%). LC-MS(ESI): m/z=523.3[M+H] ⁺ .

The sixth step:

Add starting material 199E (0.17g, 0.33mmol) in a 50mL single-necked flask, dissolve dichloromethane (10mL), add 3,3-difluorocyclobutyl-1-amine (0.1g, 0.98mmol), acetic acid (20mg, 0.33mmol), stirred at room temperature for 1.0h, added NaBH(OAc) ₃ (0.21g, 0.98mmol), stirred at room temperature for 2h, quenched by adding water, saturated sodium bicarbonate adjusted pH to 8-9, DCM (2 ×100mL) extraction, combined organic phases, dried over anhydrous sodium sulfate, concentrated, the crude product was separated by HPLC to obtain white solid compound 199 , isomer 1 (60mg, yield 30%) and white solid compound 199 , isomer 1 ( 42mg, yield 21%). LC-MS(ESI): m/z=614.3[M+H] ⁺ .

HPLC separation conditions:

1. Instrument: Waters 2767 preparative liquid phase; chromatography column: SunFire C18 5μm, 19*250mm.

2. The sample is dissolved in water and filtered with a 0.45μm filter to make a sample solution.

3. Preparative chromatography conditions:

a. Composition of mobile phase A and B:

Mobile phase A: Acetonitrile

Mobile phase B: water (containing 5mM ammonium acetate)

b. Gradient elution, the content of mobile phase A ranges from 15% to 70%

c. Flow 12ml/min.

d. The elution time is 20min.

Isomer 1: ¹ H NMR (400MHz, CDCl ₃ ) δ 8.58 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 5.98(s,1H),4.91-4.49(m,2H),4.03(s,1H),3.30(d,1H),2.83-2.71(m,5H),2.51-2.17(m,6H),2.10- 1.93 (d, 6H), 1.79 (s, 3H), 1.71-1.47 (m, 4H), 1.38-0.62 (m, 5H).

Isomer 2: ¹ H NMR (400MHz, CDCl ₃ ) δ 8.56 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.50-7.30 (m, 2H), 5.95 (s, 1H) ), 4.92-4.55 (m, 2H), 4.20 (s, 1H), 3.26 (d, 1H), 2.85-2.76 (m, 5H), 2.47-2.00 (m, 12H), 1.75 (s, 3H), 1.56 (d, 3H), 1.42 (d, 1H), 1.31-0.83 (m, 5H).

( R )-1-(1-(4-(((3,3-Difluorocyclobutyl)amino)methyl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide (compound 200 )

( R )-1-(1-(4-(((3,3-difluorocyclobutyl)amino)methyl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2- oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

118C was separated by preparative HPLC to obtain cis-trans isomers 118C-1 and 118C-2 . The separation conditions were as follows: instrument Waters 2767 preparative liquid phase; preparative column SunFire C18 5μm, 19*250mm; mobile phase system: mobile phase A acetonitrile, Mobile phase B: water (containing 5mM ammonium acetate); elution gradient: mobile phase A from 50% to 80%; 118C-1 retention time 12.2min, 118C-2 retention time 12.4min.

The second step:

Compound 200 and isomer 1 were obtained by referring to compound 104B using intermediate 118C-1 and 3,3-difluorocyclobutylamine hydrochloride as starting materials.

LC-MS(ESI): m/z=571.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 12.51 (br s, 1H), 7.82-7.78 (m, 1H), 7.44-7.42 (m, 1H), 7.29-7.26 (m, 1H), 7.09-7.01 (m , 2H), 6.00 (s, 1H), 4.79-4.65 (m, 2H), 4.04-4.03 (m, 1H), 3.20-3.16 (m, 1H), 2.82-2.70 (m, 4H), 2.48 (s ,3H),2.35-2.33(m,3H),2.21(s,3H),1.60-1.55(m,4H),1.32-1.25(m,4H),1.30-1.19(m,4H),0.90-0.84 (m,4H).

third step:

Compound 200 and isomer 2 were obtained by referring to compound 104B using intermediate 118C-2 and 3,3-difluorocyclobutylamine hydrochloride as starting materials.

LC-MS(ESI): m/z=571.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 12.04 (br s, 1H), 7.82-7.80 (m, 1H), 7.44-7.42 (m, 1H), 7.27-7.25 (m, 2H), 7.07-7.03 (m ,1H),6.00(s,1H),4.75-4.67(m,2H),4.04-4.03(m,1H),3.21-3.20(m,1H),2.82-2.69(m,4H),2.48(s ,3H),2.36-2.34(m,3H),2.23(s,3H),1.60-1.55(m,4H),1.32-1.25(m,4H),1.30-1.19(m,4H),0.90-0.84 (m,4H).

1-((1 R )-1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo -1,2-Dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide ( Compound 204 )

1-((1 R )-1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl) methyl-d2)-1H-indole-3-carboxamide

first step:

Intermediate 1 (1.5 g, 4.79 mmol) was dissolved in THF (20 mL), sodium borohydride (362 mg, 9.58 mmol) was added in portions, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction monitored by TLC, an aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and EA (30 mL) was extracted three times. The combined organic phases were dried with anhydrous sodium sulfate, concentrated under reduced pressure and column chromatography to obtain compound 204A (1.2g) ,79.5%).

The second step:

204A (1.2 g, 3.8 mmol), NaH (760 mg, 31.67 mmol) and methyl iodide (2 mL) were added to anhydrous tetrahydrofuran (20 mL), and stirred at room temperature for 16 hours. The reaction was quenched by adding ammonium chloride aqueous solution (20 mL), EA (30 mL) was extracted three times, the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 204B (1.2 g, 96%).

LC-MS(ESI): m/z=330.2[M+H] ⁺ .

third step:

204B (1.2 g, 3.65 mmol) and KOH (2.04 g, 36.5 mmol) were added to a mixed system of EtOH (10 mL) and water (6 mL), and stirred at 80°C for 6 hours. After the reaction was cooled to room temperature, the 6mol/L hydrochloric acid solution was adjusted to pH=4-5, EA (30mL) was extracted three times, the combined organic phases were dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 204C (1g, 87%). LC-MS(ESI): m/z=316.2[M+H] ⁺ . Fourth step:

204C (300mg, 0.95mmol) and 185G (421mg, 1.9mmol ) were dissolved in DCM (10mL), HATU (722mg, 1.9mmol) and DIPEA (490mg, 3.8mmol) were added and stirred at room temperature for 1 hour. The reaction was quenched by adding water (20 mL), and extracted twice with DCM (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain compound 204 (110 mg, 24%).

¹ H NMR (400MHz, CDCl ₃ ) δ 12.80 (s, 1H), 7.81 (d, 1H), 7.46 (d, 1H), 7.22 (s, 1H), 7.14-7.02 (m, 2H), 6.04 (s ,1H),4.12-3.99(m,1H), 3.30(s,3H), 3.10-2.99(m,1H), 2.71(s,3H), 2.48(s,3H), 2.23(s,3H), 2.19-2.05(m,3H),1.86-1.84(m,1H),1.59(d,3H),1.31-1.18(m,1H),1.15-1.01(m,2H),0.98-0.89(m,1H) ), 0.83-0.73 (m, 1H).

LC-MS(ESI): m/z=484.3[M+H] ⁺ .

1-((1 R )-1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyld-3)sulfanyl) -2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 206 )

1-((1 R )-1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyl-d3)thio)-2-oxo-1,2-dihydropyridin -3-yl)methyl)-1H-indole-3-carboxamide

204C (300mg, 0.95mmol) and 186E (423mg, 1.9mmol ) were dissolved in DCM (10mL), HATU (722mg, 1.9mmol) and DIPEA (490mg, 3.8mmol) were added and stirred at room temperature for 1 hour. The reaction was quenched by adding water (20 mL), and extracted twice with DCM (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain compound 206 (110 mg, 24%).

¹ H NMR (400MHz, CDCl ₃ ) δ 12.83 (s, 1H), 7.81 (d, 1H), 7.46 (d, 1H), 7.30 (s, 1H), 7.13-7.01 (m, 2H), 6.02 (s ,1H),4.73-4.71(m,2H),4.34-3.98(m,1H),3.30(s,3H),3.10-3.00(m,1H),2.71(s,3H),2.21(s,3H) ), 2.19-2.06(m,3H),1.86-1.84(m,1H),1.59(d,3H),1.32-1.19(m,1H),1.16-1.02(m,2H),0.95-0.89(m ,1H),0.85-0.71(m,1H).

LC-MS(ESI): m/z=485.3[M+H] ⁺ .

1-((1 R )-1-(4-((3,3-Difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-6-(1-methyl-1H- Pyrazol-4-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-ind Dole-3-carboxamide ( Compound 221 )

1-((1 R )-1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N- ((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

Compound 249F (150mg, 0.22mmol), N-methylpyrazole-4-boronic acid pinacol ester (46mg, 0.22mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (16mg, 0.22mmol), potassium phosphate (140mg, 0.66mmol), add 1,4-dioxane (6mL) sequentially. Under the protection of nitrogen, the reaction was refluxed overnight. Dilute with water (20mL), extract with ethyl acetate (50mL×2), wash the combined organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and column chromatography to obtain crude yellow compound (200mg), which is further separated by preparative HPLC .

Preparative HPLC separation conditions are: instrument: Waters 2767 preparative liquid phase; chromatography column: Atlantis@ Prep T3 (19mm×250mm). The sample was dissolved in water and filtered with a 0.45μm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (containing 1% TFA). Gradient elution, the content of mobile phase A ranges from 30%-65%, the flow rate is 12mL/min, and the elution time is 20min.

Compound 221 , Isomer 1: Retention time is 13.00min (20mg).

LC-MS(ESI): m/z=636.3[[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 6.88 (s, 1H), 6.27 (s, 1H), 4.49 (s, 2H), 3.28-3.25 (m, 1H), 2.81-2.71 (m, 2H), 2.52(s,3H),2.46-2.27(m,6H),2.18(s,3H),1.98-1.83(m,5H),1.60(s,3H),1.33-1.23(m,2H),1.16- 1.07(m,2H).

Compound 221 , Isomer 2: Retention time is 13.4 min (20 mg).

LC-MS(ESI): m/z=636.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 6.88 (s, 1H), 6.27 (s, 1H), 4.49 (s, 2H), 3.23-3.20 (m, 1H), 2.87-2.74 (m, 3H), 2.52 (s, 3H), 2.42-2.29 (m, 5H), 2.20 (s, 3H), 1.93-1.87 (m, 1H), 1.81-1.79 (m, 2H), 1.69-1.48 (m, 9H).

1-(1-(1-(3,3-Difluorocyclobutane-1-carbonyl)piperidin-4-yl)ethyl)-2-methyl-N-((6-methyl-4- (Methylthio)-2-Pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 248 )

1-(1-(1-(3,3-difluorocyclobutane-1-carbonyl)piperidin-4-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

To 3,3-difluorocyclobutane-1-carboxylic acid (58mg, 0.43mmol) was added DMF (10 mL), HATU (190mg, 0.5mmol), compound 188G (160mg, 0.33mmol) and DIEA (194mg , 1.5mmol), stirred at room temperature for 1h. It was quenched with water and extracted three times with ethyl acetate. The combined organic phase was washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 248 , isomer 1 (20 mg, 21%) and compound 248 , isomer 2 (20 mg, 21%) were obtained.

Hand-held preparative HPLC separation conditions: instrument: MG Ⅱ preparative SFC (SFC-14); column type: ChiralPak AS, 250×30mm ID, 10μm; mobile phase: A is CO ₂ , B is ethanol (0.1% ammonia) ; Gradient: B 40%; Flow rate: 80mL/min; Back pressure: 100bar; Column temperature: 38°C; Column length: 220nm; Time period: ~6.5min; Sample preparation: 90mg compound dissolved in a mixture of 15mL dichloride and methanol In solvent; injection: 2mL/time.

The retention time of 3.58 min is compound 248 , isomer 1.

LC-MS(ESI): m/z=571.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.64 (s, 1H), 7.77-7.69 (m, 1H), 7.68-7.51 (m, 2H), 7.29-6.95 (m, 2H), 6.12 (s, 1H),4.54-4.32(m,3H),4.23-4.08(m,1H),3.91-3.46(m,1H),3.24-2.97(m,2H),2.78-2.64(m,6H),2.61- 2.56 (m, 3H), 2.48 (s, 3H), 2.19 (s, 3H), 1.99-1.87 (m, 1H), 1.54 (s, 3H), 1.24 (s, 1H), 1.02-1.00 (m, 2H).

The retention time of 4.74 min is compound 248 , isomer 2.

LC-MS(ESI): m/z=571.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.62 (s, 1H), 7.81-7.71 (m, 1H), 7.69-7.57 (m, 2H), 7.29-6.80 (m, 2H), 6.12 (s, 1H),4.57-4.41(m,1H),4.41-4.37(m,2H),4.23-4.10(m,1H),3.92-3.46(m,1H),3.27-2.95(m,2H),2.84- 2.62 (m, 6H), 2.62-2.56 (m, 3H), 2.48 (s, 3H), 2.19 (s, 3H), 1.98-1.89 (m, 1H), 1.58-1.50 (m, 3H), 1.28- 1.16 (m, 1H), 0.95-0.67 (m, 2H).

6-cyano-1-((1 R )-1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl- N-((6 -Methyl-4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( compound 249 )

6-cyano-1-((1 R )-1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

first step:

The 196D (5g) was analyzed for palm properties, and the preparation conditions were: instrument: MG Ⅱ preparative SFC (SFC-1); chromatography column: ChiralCel OJ, 250×30mm ID, 5μm. Preparative chromatography conditions: a. Mobile phase A, B composition: mobile phase A: CO ₂ mobile phase B: ethanol. Gradient elution, mobile phase B content 30%; flow rate 60mL/min. The elution time is 7.7 min. Retention time 5.7min component is the desired configuration 249A (3.3g). LC-MS (ESI): m/z=417.2 [M+H] ⁺ .

The second step:

Compound 249A (1 g, 2.40 mmol) was dissolved in methanol (15 mL), palladium carbon (1.5 g) was added, and the reaction was carried out at room temperature overnight. After suction filtration, the filtrate was spin-dried to obtain yellow solid 249B (0.92 g). LC-MS(ESI): m/z=387.2[M+H] ⁺ .

third step:

Compound 249B (500mg, 1.29mmol) was dissolved in THF: H ₂ O: 3mol/L HCl=3/2/1.5 mixed solvent (13mL), sodium nitrite (196mg, 2.85mmol) was added, and the reaction was carried out under ice bath. 1h. Add urea (171 mg, 2.85 mmol), stir under ice bath for 30 min, add potassium iodide (537 mg, 3.23 mmol), react on ice bath for 30 min, warm to room temperature and react for 3 h. Add HCl (6mol/L) aqueous solution, react overnight at room temperature, dilute with water (50mL), extract with ethyl acetate (50mL×3), wash the combined organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Chromatographic separation gave 249C (450 mg) as a yellow solid. LC-MS(ESI): m/z=454.1[M+H] ⁺ .

the fourth step:

Using compound 249C (350mg, 0.82mmol) as raw material, referring to the synthesis method of compound 196 in the eighth step, a crude yellow solid 249D (400mg) was obtained. LC-MS(ESI): m/z=545.1[M+H] ⁺ .

the fifth step:

Using compound 249D (500 mg, 0.92 mmol) as a raw material, referring to the ninth step synthesis method of compound 196 , a crude yellow solid product 249E (450 mg) was obtained. LC-MS(ESI): m/z=517.1[M+H] ⁺ .

The sixth step:

Using compound 249E (450 mg, 0.87 mmol) as a raw material, referring to the tenth step synthesis method of compound 196 , a brown crude product 249F (550 mg) was obtained. LC-MS(ESI): m/z=683.2[M+H] ⁺ .

The seventh step:

Compound 249F (400mg, 0.59mmol) was dissolved in 1,4-dioxane (15mL), potassium ferrocyanide trihydrate (496mg, 1.17mmol), palladium acetate (66mg, 0.29mmol) were added to it in turn, React at 100°C for 4h. After the reaction was cooled to room temperature, it was filtered with suction, washed with water (10 mL), and the filtrate was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the brown crude product The compound (300 mg) was further separated by preparative HPLC.

Preparative HPLC separation conditions are: instrument: Waters 2767 preparative liquid phase; chromatography column: SunFire ^@ Prep C18 (19mm×250mm). The sample was dissolved in water and filtered with a 0.45μm filter to prepare a sample solution. Preparation chromatographic conditions: mobile phase A, B composition: mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate). Gradient elution, mobile phase A content from 25%-70%, flow rate 12mL/min, elution time 24min.

Compound 249 , Isomer 1: Retention time is 20.32 min (5.2 mg).

LC-MS(ESI): m/z=582.3[M+H] ⁺ .

¹ H NMR(400MHz,CD ₃ OD)δ 8.00(s,1H), 7.87(d, J =8.0Hz,1H), 7.35(d, J =8.0Hz,1H), 6.29(s,1H), 4.60 (s,2H),4.22-4.18(m,1H),3.52(m,1H),3.17(m,1H),2.82-2.75(m,3H),2.62(s,2H),2.52-2.47(m ,3H),2.40-2.30(m,4H),2.22-2.14(m,1H),2.04-2.01(m,1H),1.93(s,1H),1.72-1.62(m,4H),1.29-1.19 (m,3H),0.91-0.90(m,3H).

Compound 249 , Isomer 2: Retention time is 21.83 min (2.0 mg).

LC-MS(ESI): m/z=582.3[M+H] ⁺ .

¹ H NMR(400MHz, CDCl ₃ )δ 8.02(s,1H), 7.88(d, J =8.0Hz,1H), 7.37(d, J =8.0Hz,1H), 6.31(s,1H), 4.60( s, 2H), 4.40-4.35 (m, 1H), 3.90-3.86 (m, 1H), 3.13-3.07 (m, 2H), 2.86-2.67 (m, 6H), 2.54 (s, 3H), 2.31 ( s, 3H), 2.04-1.96 (m, 3H), 1.66-1.56 (m, 6H), 1.29 (s, 1H), 1.06-1.02 (m, 2H).

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6 -Methyl-4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide ( compound 259 )

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-(methylthio) -2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide

Compound 192J (0.1g) was dissolved in DMF (5mL), DIPEA (32mg, 0.75mmol ) and HATU (124mg, 0.33mmol) were added to it, after reacting for ten minutes, compound 185G (44mg, 0.28mmol) was added to it, React at room temperature for one hour. The reaction solution was diluted with water, extracted twice with ethyl acetate (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by preparative HPLC to obtain compound 259 (single cis-trans isomer, cis-trans uncertain) ( 50mg, 35%).

Preparation method: instrument: Waters 2767 preparative liquid phase; chromatography column: SunFire@ Prep C18 (19mm×250mm); preparation chromatography conditions: mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; Gradient elution, mobile phase A content from 20%-75%; flow rate 12mL/min. The elution time is 20min. Peak time: 15.15min.

LC-MS(ESI): m/z=564.3[M+H] ⁺

¹ H NMR (400MHz, chloroform-d) δ 12.68 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.42 (d, 1H), 7.20 (d, 1H), 5.96(s, 1H), 4.03(s, 1H), 3.77(s, 3H), 3.30(s, 3H), 3.05(t, 1H), 2.71(s, 3H), 2.47(s, 3H) ), 2.18(s, 1H), 2.09(s, 4H), 1.85(d, 1H), 1.60(d, 3H), 1.25(q, 2H), 1.09(d, 2H), 0.92(dd, 1H) ,0.85-0.71(m,1H).

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6 -Methyl-4-((methyl-d3)sulfanyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-methanamide( Compound 262 )

( R )-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-((methyl -d3)thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

Compound 192J was dissolved in DMF (5mL), DIPEA (32mg, 0.75mmol ) and HATU (124mg, 0.33mmol) were added to it, after ten minutes of reaction, compound 186E (44mg, 0.28mmol) was added to it, and reacted at room temperature. Hour. The reaction solution was diluted with water, extracted twice with ethyl acetate (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative HPLC to obtain compound 262 (single cis-trans isomer, cis-trans uncertain) ( 40mg, 28%).

Preparation method: instrument: Waters 2767 preparative liquid phase; chromatography column: SunFire@ Prep C18 (19mm×250mm); preparation chromatography conditions: mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; Gradient elution, mobile phase A content from 20%-75%; flow rate 12mL/min. The elution time is 20min. Peak time: 14.75min.

LC-MS(ESI): m/z=565.3[M+H] ⁺

¹ H NMR (400MHz, chloroform-d) δ 12.68 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.42 (d, 1H), 7.20 (d, 1H), 5.96 (s, 1H), 4.72 (s, 2H), 4.03 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H), 3.05 (t, 1H), 2.70 (s, 3H) ), 2.18(s, 1H), 2.09(s, 4H), 1.85(d, 1H), 1.60(d, 3H), 1.25(q, 2H), 1.09(d, 2H), 0.92(dd, 1H) ,0.85-0.71(m,1H).

( R )-1-(1-(4-((3,3-Difluorocyclobutyl)(methyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl 4-(methylthio)-2-pendant oxy-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide ( Compound 265 )

(R)-1-(1-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2- oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide

The raw material compound 104, isomer 2 (40mg, 0.07mmol) and 37% aqueous formaldehyde solution (0.3mL) were dissolved in methanol (5mL) at room temperature, then acetic acid (0.3mL) was added, and stirring was continued at room temperature 1 Hour. Sodium triacetoxyborohydride (45mg, 0.21mmol) was added and reacted at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust pH=8, extract with dichloromethane (5mL×3), wash the organic phase with saturated sodium chloride (5mL×1), dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography (DCM: MeOH =50:1 to 15:1) to obtain compound 265 (22mg, yield 55%) as a white solid.

LC-MS: m/z=571.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 12.29 (s, 1H), 7.85-7.83 (m, 1H), 7.44-7.42 (m, 1H), 7.29-7.26 (m, 1H), 7.10-7.03 (m, 2H),6.00(s,1H),4.78-4.66(m,2H),4.08-4.03(m,1H),3.16-3.14(m,1H),2.83-2.65(m,6H),2.45(s, 3H), 2.13-2.16(m, 7H), 2.02-2.01(m, 1H), 1.70-1.58(m, 5H), 1.43-1.37(m, 1H), 1.29-1.26(m, 2H), 1.14 1.11(m,3H), 0.88-0.79(m,1H).

2-(Difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]-N-[(6-methyl-4-methylthio-2-oxo -1H-pyridin-3-yl)methyl)indole-3-carboxamide ( compound 266 )

2-(difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]indole -3-carboxamide

The first step: ( R )-1-(1-(1,4-dioxaspiro[4.5]decane-8-yl)ethyl)-2-(bromomethyl)-1H-indole-3 -Methyl formate (266A)

(R)-methyl-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(bromomethyl)-1H-indole-3-carboxylate

Add Intermediate 1 (0.50g, 1.4mmol) and NBS (0.25g, 1.4mmol) to carbon tetrachloride (10mL) at room temperature, then add AIBN (0.07g, 0.4mmol), and reflux 1 after addition. Hours; cooled to room temperature, concentrated under reduced pressure and directly separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v)=, 10:1~5:1) to obtain compound 266A (0.50g, yield 82%). LC-MS m/z=436.0[M(Br79)+1],438.0[M(Br81)+1]

¹ H NMR (400MHz, CD ₃ OD) δ 8.16-8.14 (m, 1H), 7.71 (d, 1H), 7.30-7.20 (m, 2H), 5.63-5.60 (m, 1H), 4.99 (d, 1H) ), 4.39-4.31(m, 1H), 3.97(s, 3H), 3.95-3.89(m, 4H), 2.42-2.37(m, 1H), 2.15-2.11(m, 1H), 1.90-1.85(m ,1H),1.73(d,3H),1.70-1.48(m,4H),1.32-1.30(m,1H),0.90-0.88(m,1H).

The second step: (R)-1-(1-(1,4-dioxaspiro[4.5]decane-8-yl)ethyl)-2-(acetoxymethyl)-1H-indole Methyl-3-carboxylate ( 266B )

methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(acetoxymethyl)-1H-indole-3-carboxylate

Add 266A (450mg, 1.0mmol) and potassium acetate (200mg, 2.0mmol) to acetonitrile (20mL) at room temperature, then add benzyltrimethylammonium bromide (230mg, 1.0mmol), continue stirring at room temperature 3 hours; the reaction solution was spin-dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1~5:1) to obtain 266B (390mg, yield 91%). LC-MS m/z=356.2[M-HOAc+1]

The third step: (R)-1-(1-(1,4-dioxaspiro[4.5]decane-8-yl)ethyl)-2-(hydroxymethyl)-1H-indole-3 -Methyl formate (266C)

methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(hydroxymethyl)-1H-indole-3-carboxylate

Add 266B (360mg, 0.87mmol) to methanol (20mL) at room temperature, and then add potassium carbonate (500mg, 3.6mmol). After the addition, continue stirring at room temperature for 2 hours; spin dry the reaction solution and go directly to silica gel column chromatography Purified (petroleum ether: ethyl acetate=8:1~2:1) to obtain 266C (310mg, yield 93%). LC-MS m/z=356.2[MH ₂ O+1]

The fourth step: (R)-1-(1-(1,4-oxaspiro[4.5]decane-8-yl)ethyl)-2-methanyl-1H-indole-3-carboxylic acid methyl Ester ( 266D )

methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-formyl-1H-indole-3-carboxylate

Dissolve 266C (300mg, 0.80mmol) in anhydrous dichloromethane (10mL) at room temperature, and then add Dess-Martin oxidant (680mg, 1.6mmol) dropwise. After dropping, continue the reaction at room temperature for 2 hours; add the reaction solution It was quenched into sodium thiosulfate (10%, 10mL), extracted with dichloromethane (10mL×3), combined the organic phases, washed with saturated sodium bicarbonate aqueous solution (10mL×1), washed with water (50mL×2), saturated chlorine Wash with sodium chloride (20mL×1), dry with anhydrous sodium sulfate, concentrate and purify by silica gel column chromatography (petroleum ether: ethyl acetate=20:1~10:1) to obtain 266D (300mg, yield 100%).

LC-MS m/z=372.2[M+1]

The fifth step: (R)-1-(1-(1,4-oxaspiro[4.5]decane-8-yl)ethyl)-2-difluoromethyl-1H-indole-3-carboxylic acid Methyl ester ( 266E )

methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(difluoromethyl)-1H-indole-3-carboxylate

Dissolve 266D (300mg, 0.80mmol) in anhydrous dichloromethane (10mL) under the protection of nitrogen at 0°C, then add DAST (260mg, 1.6mmol) dropwise, after the dripping, it will naturally rise to room temperature and continue the reaction for 1 hour; The solution was added to methanol (5.0 mL) for quenching, spin-dried and purified directly by silica gel column chromatography (petroleum ether: ethyl acetate=15:1~5:1) to obtain 266E (300mg, yield 95%).

LC-MS m/z=394.1[M+1]

The sixth step: (R)-2-(difluoromethyl)-1-(1-(4-methoxycyclohexyl)ethyl)-1H-indole-3-carboxylic acid ( 266F )

(R)-2-(difluoromethyl)-1-(1-(4-methoxycyclohexyl)ethyl)-1H-indole-3-carboxylic acid

Using carboxylic acid 266E as a raw material, according to the synthesis method of compound 204C , 266F was obtained. LC-MS m/z=352.3[M+1]

The seventh step: 2-(Difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]-N-[(6-methyl-4-methylthio- 2-Pendant oxy-1H-pyridin-3-yl)methyl)indole-3-carboxamide ( compound 266 )

2-(difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]indole -3-carboxamide

Using 266F and Intermediate 2 as raw materials, according to the synthesis method of compound 47, compound 266 was obtained.

LC-MS m/z=518.3[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 12.55 (s, 1H), 8.02-7.76 (m, 2H), 7.60 (d, 1H), 7.44-7.42 (m, 1H), 7.29-7.25 (m, 1H) , 7.20-7.16 (m, 1H), 6.16 (s, 1H), 4.76-4.67 (m, 2H), 4.55-4.47 (m, 1H), 3.30 (s, 3H), 3.11-3.04 (m, 1H) ,2.52(s,3H),2.29(s,3H),2.28-2.08(m,3H),1.86-1.84(m,1H),1.63(d,3H),1.30-1.11(m,2H),1.04 -0.88(m,3H).

N-[Di-deuterated-(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]-2-(difluoromethyl)-1-[( 1R)-1-(4-Methoxycyclohexyl)ethyl)indole-3-carboxamide (Compound 267)

N-[dideuterio-(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]-2-(difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl ]indole-3-carboxamide

Using carboxylic acid 266F and di-deuterated-(6-methyl-4-methylthio-2-side oxy-1H-pyridin-3-yl)methylamine hydrochloride ( 185G ) as raw materials, according to compound 204 Synthetic method, compound 267 is obtained.

LC-MS m/z=520.3[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 12.91 (s, 1H), 8.04-7.77 (m, 2H), 7.60-7.56 (m, 2H), 7.27-7.23 (m, 1H), 7.15-7.11 (m, 1H), 6.06 (s, 1H), 4.55-4.47 (m, 1H), 3.30 (s, 3H), 3.11-3.04 (m, 1H), 2.50 (s, 3H), 2.20-2.15 (m, 4H) ,2.12-2.07(m,2H),1.87-1.83(m,1H),1.64(d,3H),1.27-1.11(m,2H),1.04-0.90(m,3H).

Biological test case

Test example 1 EZH2 enzyme activity test method

The compound was dissolved in DMSO, prepared as a 10mM solution, and gradually diluted with DMSO to 100 times the final concentration. Use Echo550 to transfer 200 nL of the compound solution to a 384-well plate (Perkin Elmer, Cat. No. 6007299). Dilute EZH2 (BPS, Cat. No. 51004) with 1X detection buffer (50mM Tris-HCl9.0, 0.01% Tween-20, 1mM DTT) to 2 times the final concentration (EZH2: 3nM), and prepare H3K27 (21 -44) A mixture of [3H]-SAM (PerkinElmer, Lot. No. 2146246) (H3K27(21-44): 200 nM, [3H]-SAM: 100 nM). Add 10μL/well of EZH2 dilution into a 384-well plate (add 10μL of 1X detection buffer to the control group), seal the plate and incubate at room temperature for 15 minutes. Add 10 μL of a mixture of H3K27(21-44) and [3H]-SAM to each well, seal the plate and incubate at room temperature for 60 minutes. Prepare 50μM SAM (Sigma, Cat.No.A7007) at low temperature, add 10μL/well to a 384-well plate, take 25μL/well and transfer to the flashplate, and incubate at room temperature for more than 1 hour. Wash the flashplate 3 times with plate washing solution (dH2O+0.1% Tween-20), and use Microbeta to read the plate. Calculate the inhibition rate in Excel: inhibition rate (%) = (maximum _{positive control} -detection signal value) / (maximum _{positive control} -minimum _{negative control} ) * 100, use XL-Fit to fit the IC ₅₀ value.

Test result: The IC50 value of the example compound on EZH2 is in the range of 0.1-10 nM, indicating that the compound of the present invention has inhibitory activity on EZH2. Among them, the test results of representative examples are shown in Table 1:

Table 1 The inhibitory activity of the compounds of the present invention on EZH2

Test Example 2 DHL-6 cell proliferation activity

SU-DHL-6 cells are human B-cell lymphoma cell lines, purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured in 37℃, 5% CO ₂ incubator. Cells are plated in a 12-well plate, cell concentration: 1×10 ⁵ cells/mL. After plating, add different concentrations of compounds, _{incubate in a 37°C, 5% CO 2} incubator, count cells every 3-4 days (Countstar automatic cell counter), centrifuge to remove the supernatant, and re-dilute the cells to 1× After 10 ⁵ cells/mL and plated, add different concentrations of compounds again, until after 14 days of culture for cell counting, the experiment ends, and the Origen9.2 software is used to calculate the IC ₅₀ value.

Test result: The IC50 value of the example compound on DHL-6 cells is in the range of 1-300nM Inside, it shows that the compound of the present invention can inhibit the proliferation of DHL-6 cells. Among them, the test results of representative examples are shown in Table 2:

Table 2 The inhibitory activity of the compounds of the present invention on the proliferation of DHL-6 cells

Test Example 3 Pharmacokinetic test in mice

Experimental purpose: to administer the test substance to ICR mice by single-dose gavage, determine the concentration of the test substance in the mouse plasma, and evaluate the pharmacokinetic characteristics of the test substance in the mice.

Subject: Known compound I-1 and example compounds.

Experimental animals: male ICR mice, about 20-25g, 6-8 weeks old, 3 mice/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Test method: On the day of the test, 3 ICR mice were randomly grouped according to their body weight. Fasting for 12-14 hours without water for 1 day before the administration, and 4 hours after the administration. Vote according to Table 3.

The concentration of the compound in the _{EDTA-K 2} anticoagulated plasma was determined by LC-MS/MS method. Linear standard curve of compound 2 ~ 2000ng / mL, for LC-MS after protein precipitation protein / MS analysis, calculated using standard curve regression weighted least squares ^{(W = 1 / X 2)} , to the test compound was The ratio of the peak area to the peak area of the internal standard is quantified.

Table 3 Investment information

*Dose is based on free base.

Biological sample collection

Before and after the administration, 0.03ml of blood was taken from the orbit with isoflurane anesthesia and placed in EDTAK2 Centrifuge tube. Centrifuge at 5000 rpm, 4°C for 10 min, and collect plasma.

Sample collection time points of G1 group: 0,15,30min,1,2,4,6,8,24h.

Before analysis and testing, all samples were stored at -80°C.

Sample preparation

(1) In addition to the blank sample, add 400μL of internal standard working solution (Verapamil internal standard concentration in precipitant acetonitrile is 10.0ng/mL) to a 1.5mL centrifuge tube containing 30μL of standard curve samples and quality control samples; Add 200μL of internal standard working solution to the 1.5mL centrifuge tube of the unknown sample (the concentration of Verapamil internal standard in the precipitant acetonitrile is 10.0ng/mL); add 400μL of acetonitrile to the blank sample;

(2) Vortex and mix for about 1 min;

(3) Centrifuge at 10000rpm for 10min at 4℃;

(4) Transfer 175 μL of supernatant to a new 96-well polypropylene plate, seal the plate and place it in a 10°C sample tray for sample injection.

The experimental results are shown in Table 4 and Table 5.

Table 4

table 5

Compound I-1 is patent WO2019094552 compound example 18, isomer 1.

Conclusion: The compound of the present invention has good pharmacokinetics.

Claims (42)

A compound represented by formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product,

Wherein, R _{1 is} selected from H, C _1-4 alkyl, halogenated C _1-4 alkyl and halogen; R _{2 is} selected from C _1-4 alkyl; The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;} W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)-, -C(=S)- and bond; Each R _La and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R _La and R _Lb on the carbon atom are formed together with the carbon atom to which they are attached C _3-6 carbon ring; Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl; m, n, p, q are independently selected from an integer of 0-4; Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom; Each R _{X1 is} independently selected from H, C _1-4 alkyl and C _3-6 cycloalkyl; Each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1-3 halogens; Ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Non-aromatic heterocyclic ring, or non-existent; Each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, CN, halogen, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the alkyl group, Cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy and NH ₂ ; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 ring Alkyl groups and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic rings are optionally selected from 1-3 C _1-4 alkyl groups, Halogen and -C(O)C _1-4 alkyl group substitution; Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and The heterocycle is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl; t is an integer of 0-3; Each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or forms with R ₄ and R ₅ on the carbon atom together with the carbon atom to which they are attached C _3-6 carbocyclic ring; the C _1-4 alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen; s is an integer of 0-3; A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl group, amino group, -C(O)C _1-4 alkyl group, hydroxyl group and halogen group substitution; alternatively, the two substituents on the same carbon atom and the connected carbon atom of the carbocyclic or heterocyclic ring Together to form a C _3-6 carbon ring; L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, =NO-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond; R _L2 is H or C _1-4 alkyl; r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time; Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen; R ₇ is C _1-4 alkyl, -Si(R ₆₃ ) ₃ , halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, halogenated C _{1 -4} alkoxy, phenyl or 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, wherein the C _1-4 alkyl group is optionally substituted by 1-2 -Si (R ₆₄ ) ₃ substitution, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkane Oxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _{1- 4} Alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted; Each of R ₆₃ and R _{64 is} independently H, C _1-4 alkyl or halogen; The condition is that when A is substituted or unsubstituted

or

When, L ₂ and R ₇ does not exist; when A is a substituted or unsubstituted piperidinyl group, satisfies L ₂ is -C (O) -, or -C (O) NH-, R ₇ is satisfied or -Si ( R ₆₃ ) ₃ or R _{7 is C 1-4} alkyl substituted with 1-2 -Si(R ₆₄ ) ₃ ; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(5): (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl; or A is

, L ₂ is -N(CH ₃ )-, R ₇ is substituted or unsubstituted

, Or C _1-4 alkyl, and

The substituents of are 1-3 C _1-4 alkyl groups; (2) A is

, When L ₂ is a bond, R ₇ is a halogenated C _1-4 alkoxy group, or substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxy, cyano, -S(O) ₂ -C _1-4 alkyl group is substituted; or R ₇ is substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl; (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

； (4) -AL ₂ -R ₇ is

； (5) When A is

, When L ₂ is -NH-, R ₇ is

. A compound represented by formula (I), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product,

Wherein, R _{1 is} selected from H, C _1-4 alkyl, halogenated C _1-4 alkyl and halogen; R _{2 is} selected from C _1-4 alkyl; The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;} W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)- and bond; Each R _La and R _{Lb is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or R _La and R _Lb on the carbon atom are formed together with the carbon atom to which they are attached C _3-6 carbon ring; Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl; m, n, p, q are independently selected from an integer of 0-4; Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom; Each R _{X1 is} independently selected from H, C _1-4 alkyl and C _3-6 cycloalkyl; Each R _{X2 is} independently selected from H, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1-3 halogens; Ring B is

,

,

,

,

, A five-membered carbocyclic or five-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or six-membered heterocyclic ring containing 0-3 heteroatoms selected from N, S, O Non-aromatic heterocyclic ring, or non-existent; Each R _{B is} independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 ,- C(O)OR _B3 , -OR _B3 , -C(O)R _B3 and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, The heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, cyano, OH and NH _2; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 ring Alkyl groups and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic rings are optionally selected from 1-3 C _1-4 alkyl groups, Halogen and -C(O)C _1-4 alkyl group substitution; Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and The heterocycle is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl; t is an integer of 0-3; Each of R ₄ and R _{5 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen, or forms with R ₄ and R ₅ on the carbon atom together with the carbon atom to which they are attached C _3-6 carbon ring; s is an integer of 0-3; A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic ring is not a benzene ring or

, The heterocyclic ring is not a pyrimidine ring, the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 Alkyl group, amino group, -C(O)C _1-4 alkyl group, hydroxyl group and halogen group substitution; alternatively, the two substituents on the same carbon atom and the connected carbon atom of the carbocyclic or heterocyclic ring Together to form a C _3-6 carbon ring; L ₂ is -C(O)-(NH) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond; r is 0 or 1, y is an integer from 0 to 3, and r and y are not 0 at the same time; Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen; R ₇ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, halogenated C _1-4 alkoxy, phenyl, or contains 1-2 selected from N, S 4-10 membered heterocyclic ring of O heteroatom, the cycloalkyl, phenyl and heterocyclic ring are optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy , Mono-C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halo C _1-4 alkyl, -C _1-4 alkyl -OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted; The condition is that when A is substituted or unsubstituted

or

When L ₂ and R _{7 are} not present; when A is a substituted or unsubstituted piperidinyl group, L ₂ is -C(O)-; and, when the compound of formula (I) is

When it does not meet any of the following (1)-(4): (1) A is

, L ₂ is -NH-, R ₇ is substituted or unsubstituted

, Substituted or unsubstituted

,and

The substituents of are 1-3 groups selected from C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl;

The substituent of is C _1-4 alkyl; (2) A is

, When L ₂ is a bond, R ₇ is substituted or unsubstituted

, The substitution is by 1-3 selected from C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, halogen, hydroxyl, cyano, -S(O) ₂ -C _{1- 4} alkyl groups; or R ₇ is a substituted or unsubstituted

,

, The substitution is by 1-3 groups selected from =0 and halogen; or R ₇ is

,

, C _1-4 alkyl; (3) A is

, L ₂ is -O-, R ₇ is C _1-4 alkyl, cyclopropyl, halogenated C _1-4 alkyl or

； (4) -AL ₂ -R ₇ is

. The compound according to claim 2, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: R _{1 is} selected from C _1-4 alkyl; The L ₁ is -(CR _La R _Lb ) _m -(NR _Lc ) _n -W-(NR _Lc ) _p -(CR _La R _Lb ) _q -, or contains 1-3 selected from N, S, O Heteroatomic 3-6 membered heterocyclic ring optionally substituted _{by 1-3 R Lc;} W is selected from -C(O)-, -S(O) ₂ -, -C=N(CN)- and bond; Each of R _La and R _Lb is H, or the R _La and R _Lb on the carbon atom together with the carbon atom to which they are connected form a C _3-6 carbocyclic ring; Each R _{Lc is} independently selected from H, C _1-4 alkyl and halo C _1-4 alkyl; m, n, p, q are independently selected from an integer of 0-4; Each X is independently C, N, NR _X1 or CR _X2 and has at least one N atom; Each R _{X1 is} independently selected from H and C _1-4 alkyl; Each R _{X2 is} independently selected from H, halogen and C _1-4 alkyl; Ring B is

,

,

,

, Or does not exist; Each R _{B is} independently selected from H, -NR _B1 R _B2 and -OR _B3 ; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl, -S(O) ₂ C _1-4 alkyl; Each R _{B3 is} independently a C _3-6 cycloalkyl group or a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, and the heterocyclic ring is optionally substituted by 1 -C(O)C _{1 -4} alkyl substitution; t is 0 or 1; Each R ₄ and R _{5 is} independently selected from H and C _1-4 alkyl; s is 1 or 2; A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S, and the carbocyclic or heterocyclic ring is optionally selected from =0, C _1-4 alkane Substitution of the group, hydroxyl and halogen; alternatively, or the two substituents on the carbon atom and the two substituents on the carbon atom together with the connected carbon atom form a C _3-6 carbocycle; L ₂ is -C(O)-(NH) _r -, -NH-C(O)-, -O-, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -or bond, when L ₂ is =NO-, L ₂ and A are connected by a double bond; Each R ₆₁ and R _{62 is} independently selected from H and C _1-4 alkyl; R ₇ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, halogenated C _1-4 alkoxy or contains 1-2 selected from N, S, O hetero A 4-10 membered heterocyclic ring, the cycloalkyl and heterocyclic ring are optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 Alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, hydroxy, halogen, halogenated C _1-4 alkoxy, -C(O)-C _{1 -4} alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl, -O-halogenated C _1-4 alkyl, -C _1-4 alkyl -OC(O) -C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted. The compound according to claim 2 or 3, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has a structure of formula (IIa) or (IIb) :

The compound according to claim 4, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein at least one of _{R 1} , R ₂ , L ₁ and R _{X is} The cluster contains deuterium atoms. The compound according to claim 4, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein ring B is

,

,

, Or does not exist. The compound according to claim 4, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein:

for

,

,

,

or

, The R _X is H or C _1-4 alkyl; or

for

, R _X is halogen. The compound according to claim 2 or 3, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₁ is not -CH ₂ -NH-C(O)- . The compound according to claim 8, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated substance, wherein the compound has the structure of formula (IIIa) or (IIIb):

The compound according to claim 9, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: L ₁ is a 3-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the heterocyclic ring is optionally _{substituted by 1-3 R Lc} , R _Lc is H or C _1-4 Alkyl; or L ₁ is -(NH) ₂ -C(O)-, -CH ₂ -NR _Lc -C(O)-, -CH ₂ -C(O)-NR _Lc -, -CH ₂ -NR _Lc -S( O) ₂ -、

,

Or -C(O)-NR _Lc -CH ₂ -. The compound according to claim 10, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₁ is

, Wherein R _Lc is H or C _1-4 alkyl. The compound according to claim 2 or 3, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has a structure of formula (IVa) or (IVb) :

The compound according to claim 12, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: t is 1, R _B is -NR _B1 R _B2 or -OR _B3 , R _B1 and R _{B2 are} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl, and -S (O) ₂ C _1-4 alkyl; R _B3 is a C _3-6 cycloalkyl group or a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, the heterocyclic ring is optionally substituted by 1 -C(O)C _1-4 alkyl replace. The compound according to claim 13, its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterated products, wherein the compound contains 1 heteroatom selected from N and O 4-8 The membered heterocycle is

,

or

, The heterocyclic ring is optionally substituted with 1 -C(O)C _1-4 alkyl. The compound according to claim 12, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein s is 1, R ₄ and R ₅ are H; or s is 2 , R ₄ and R _{5 are} independently selected from H and methyl. The compound according to claim 2 or 3, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has the structure of formula (V):

The compound according to claim 16, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: A is

,

,

,

,

,

or

;or A is

,

or

;or A is

, And the two substituents on the same carbon atom on ring A form a C _3-6 carbocyclic ring together with the connected carbon atom; or A is a 7-10 membered spiro ring or bridged ring containing 0-2 N atoms; or A is a 7-10 membered ring containing 0-2 N atoms. The compound according to claim 17, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein A is

,

,

,

,or

, These groups are optionally substituted by =0. The compound of claim 16, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₂ is -NH-C(O)-, -C(O )-(NH) _r -, =NO-, -(NH) _r -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -(NH) _r -, when L ₂ =NO- , L ₂ and A are connected by a double bond; r is 0 or 1, and y is an integer of 1-3; Both R ₆₁ and R ₆₂ are H. The compound of claim 16, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: R ₇ is a C _3-6 cycloalkyl group or a 4-6 membered monocyclic heterocyclic ring or 4-6 membered bridged ring heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group, Monocyclic heterocycles and bridged heterocycles are substituted with 1-3 C _1-4 alkyl groups selected from cyano groups, cyano groups, halogens, halogenated C _1-4 alkoxy groups, -C _1-4 alkyl groups- O-halogenated C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C _1-4 alkyl-OC(O) -C _1-4 alkyl, hydroxy, C _2-4 alkenyl and C _2-4 alkynyl group substitution; or R ₇ is a 7-10 membered spiro heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from =0, C _1-4 Alkoxy, mono C _1-4 alkylamino and C _1-4 alkyl groups are substituted. The compound according to claim 20, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the bridged heterocyclic ring is

, The spirocyclic heterocycle is

,

,

,

,

. The compound of claim 2 or 3, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuterated compound, wherein the compound has a structure of formula (VI),

The compound according to claim 1, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein the compound has the structure of formula (Ia),

Wherein, L ₁ is -CH ₂ NHW-; W is selected from -C(O)-, -S(O) ₂ -and -C(=S)-; R _X2 is C _1-4 alkyl or halogenated C _1-4 alkyl; R _{B is} selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C(O) OR _B3 , -OR _B3 , -C(O)R _B3 and 4-6 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl, and heterocycles are optional Is substituted with 1-3 groups selected from halogen, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, NH ₂ ; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C (O) C _1-4 alkyl, -S (O) ₂ C _1-4 alkyl, C _3-6 ring Alkyl groups and 4-10 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl and heterocyclic rings are optionally selected from 1-3 C _1-4 alkyl groups, Halogen and -C(O)C _1-4 alkyl group substitution; Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group and The heterocycle is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl; R ₄ and R _{5 are} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl and halogen; or R ₄ and R ₅ together with the carbon atom to which they are attached form a C _3-6 carbocyclic ring; The alkyl group is optionally substituted with 1-3 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen; A is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N and S; L ₂ is -C(O)-(NR _L2 ) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -; R ₇ is C _3-6 cycloalkyl, -Si(R ₆₃ ) _{3 , C 1-4} alkyl substituted with 0-2 -Si(R ₆₄ ) ₃ , C _5-8 bicyclic bridged cycloalkyl , Or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally selected from 1-3 = O, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano, Hydroxy, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl-O -Group substitution of halogenated C _1-4 alkyl, -C _1-4 alkyl-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl; each The R ₆₃ and R _{64 are} independently H, C _1-4 alkyl or halogen. The compound according to claim 1 or 23, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein A contains 0-1 heteroatoms selected from N and S的4-membered carbocyclic or heterocyclic ring. The compound according to claim 24, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated substance, Wherein, R _X2 is C _1-4 alkyl or halogenated C _1-4 alkyl; R ₄ and R _{5 are} independently selected from H and C _1-4 alkyl; R _{B is} selected from H, -NR _B1 R _B2 , -OR _B3 and a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the heterocyclic ring is optionally composed of 1-3 Substitution by a group selected from C _1-4 alkyl and C _{1-4 alkoxy;} Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl; R _B3 is C _1-4 alkyl, C _3-6 cycloalkyl; L ₂ is -C(O)-(NH) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NR _L2 ) _r -; r is 0 or 1, y is 0 or 1; R _L2 is H or C _1-2 alkyl; R ₇ is a C _3-6 cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring are optionally selected from 1-3 From =O, C _1-4 alkyl, C _1-4 alkoxy, mono C _1-4 alkylamino, halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, cyano Group, hydroxy, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkyl -O-halogenated C _1-4 alkyl, -C _1-4 alkyl, -OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups are substituted. The compound according to claim 25, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated substance, Wherein, R _X2 is C _1-2 alkyl or halogenated C _1-2 alkyl; R ₄ and R _{5 are} independently selected from H and C _1-2 alkyl; A is cyclobutylene or azetidine; L ₂ is -C(O)-(NH) _r -, -NR _L2 -C(O)-, -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, or -(CR ₆₁ R ₆₂ ) _y -(NH) _r -; R ₇ is a C _3-6 cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the cycloalkyl group and the heterocyclic ring are optionally selected from 1-3 From C _1-4 alkyl, cyano, hydroxyl, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl and -S (O) ₂ -C _1-4 alkane The group of the group is substituted. The compound according to claim 26, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein R _{7 is} selected from substituted or unsubstituted groups:

,

,

,

with

, The substitution refers to being selected from C _1-2 alkyl, cyano, hydroxyl, halogen, halogenated C _1-2 alkoxy, -C(O)-C _1-2 alkyl And -S(O) ₂ -C _1-2 alkyl group. The compound according to claim 23, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein L ₁ is -CH ₂ NHC(O)-, R ₄ and R _{5 is} independently selected from H and C _1-2 alkyl, A is cyclohexyl, L ₂ is -NH-, R ₇ is C _5-8 bicyclic bridged cycloalkyl, said bicyclic bridged cycloalkyl optionally Ground is replaced by 1-2 halogens. The compound according to claim 1 or 23, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein At least one of R ₄ and R _{5 is C 1-4} alkyl substituted with 1-2 -Si(Rs) ₃ , and each Rs is independently H, C _1-4 alkyl or halogen; or, R ₇ is -Si(R ₆₃ ) ₃ or C _1-4 alkyl substituted by 1-2 -Si(R ₆₄ ) ₃ , each of R ₆₃ and R _{64 is} independently H, C _1-4 alkyl Or halogen. The compound according to claim 29, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: L ₁ is -CH ₂ NHW-, W is selected from -C(O)-, -S(O) ₂ -and -C(=S)-, R ₄ and R _{5 are independently H, C 1-2} alkyl substituted or unsubstituted by 1-2 -Si(Rs) ₃ , and each Rs is independently C _1-2 alkyl or halogen; A is a 6-membered carbocyclic or heterocyclic ring containing 0-2 heteroatoms selected from N and S, L ₂ is -O-, -(NR _L2 ) _r -(CR ₆₁ R ₆₂ ) _y -, -NR _L2 -C(O)-, or -C(O)-(NR _L2 ) _r -, r is 0 or 1, y is 0 or 1, R _L2 is H or C _1-2 alkyl, R ₆₁ and R _{62 are} independently H or C _1-2 alkyl. A compound represented by formula (VII), its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product,

Wherein, R _{1 is} selected from H, D, C _1-4 alkyl, deuterated C _1-4 alkyl, halo C _1-4 alkyl and halogen; R _{2 is} selected from C _1-4 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, halogenated C _1-4 alkyl and Deuterated C _1-4 alkyl; R _La and R _{Lb are} independently selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterated C _1-4 alkyl and halogen, or R _La and R _Lb are connected to them The carbon atoms together form a C _3-6 carbocyclic ring, or R _La and R _Lb together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O; M is -CR' _{La R'Lb} -, -C(=S)-, -C(=N-CN)-, -C(=O)-, -S(O)- or -S(O) ₂ -; _R'La and _{R'Lb are} independently selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterated C _1-4 alkyl and halogen, or _R'La and _R'Lb Together with the carbon atoms to which they are connected, they form a C _3-6 carbocyclic ring, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O; R _{X2 is} selected from H, D, halogen, C _1-4 alkyl and C _3-6 cycloalkyl, the alkyl and cycloalkyl are optionally substituted with 1-3 halogens or D; Each R _{B is} independently selected from OH, halogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkoxy, CN, C _3-9 cycloalkyl, phenyl, -NR _B1 R _B2 , -C(O)NR _B1 R _B2 , -C(O)OR _B3 , -OR _B3 , -C _1-4 alkylene-R _B3 , -C(O)R _B3 and containing 1 -4 4-10 membered heterocycles selected from N, S, O heteroatoms, the alkyl, cycloalkyl, phenyl, and heterocycles are optionally selected from 1-3 halogen, =0, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, CN, OH, C _3-6 cycloalkyl, containing 1-3 4-7 membered heterocyclic ring selected from N, S, O heteroatoms, NH ₂ and -C(O)C _1-4 alkyl group substitution; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl, -C (O) C _1-4 alkyl, -C (O) C _3-6 Cycloalkyl, -S (O) ₂ C _1-4 alkyl, -S (O) C _1-4 alkyl, C _3-6 cycloalkyl and containing 1-3 selected from N, S, O hetero A 4-10 membered heterocyclic ring, the cycloalkyl and heterocyclic ring are optionally substituted by 1-3 _{groups selected from the group consisting of C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl replace; Each R _{B3 is} independently a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the alkyl group, ring The alkyl group and the heterocyclic ring are optionally selected from the group consisting of C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogen , CN, OH, NH ₂ and -C(O)C _1-4 alkyl group substitution; t is an integer of 0-3; R _{5 is} independently selected from H, D, C _1-4 alkyl, deuterated C _1-4 alkyl, halo C _1-4 alkyl and halogen; s is an integer of 1-3; z is an integer of 0-2, when z is 0, the key represented by ----- does not exist; R _A and R _A 'are independently selected from H, halogen, CN, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, NH ₂ , -C(O)C _1-4 alkyl and OH; Y is CH or N, Y is CH, H atoms may be optionally substituted with RA or R _A 'substituents; L ₂ is QT; Q is a bond, -C(O)-, -NR _L2 -, -O-, =N-, -(CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, or contains 1- 3 4-7 membered heterocycles selected from N, S, O heteroatoms, when Q is =N-, Q and Y are connected through a double bond; T is a bond, -C(O)-, -NR _L2 -, -C(O)NR _L2 -, -NR _L2 C(O)-, -O-, -(CR ₆₁ R ₆₂ ) _y -, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, -(CR ₆₁ R ₆₂ ) _y -O-, -O-(CR ₆₁ R ₆₂ ) _y -, or contain 1- 3 4-7 membered heterocycles selected from N, S, O heteroatoms;

Represents a single bond or a double bond; R _L2 is H, C _1-4 alkyl or halogenated C _1-4 alkyl; Each of R ₆₁ and R _{62 is} independently selected from H, C _1-4 alkyl and halogen; y is an integer of 0-3; R ₇ is H, C _1-4 alkyl, halogen, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _3-6 monocycloalkyl, C _5-8 bicyclic bridged cycloalkyl , Halogenated C _1-4 alkoxy, C _2-4 alkenyl, -NHC(O)C _1-4 alkyl, phenyl or 4-containing 1-3 heteroatoms selected from N, S, O A 12-membered heterocyclic ring, when R7 is an alkyl group, optionally 1-3 selected from C _1-4 alkoxy, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, CN, OH , -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, or 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O When R ₇ is a monocyclic alkyl group, a phenyl group, a bicyclic bridged cycloalkyl group and a heterocyclic ring, it is optionally substituted by 1-3 selected from =0, C _1-4 alkyl, -C _1-4 alkyl -OH, C _1-4 alkoxy, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _1-4 Alkylene -NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C (O) -C _1-4 alkyl, -S( O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkane Group, C _2-4 alkenyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group. The compound according to claim 31, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated substance, wherein: i. At least one hydrogen atom in the compound is replaced by a deuterium atom; or ii, z is 1 or 2; or s is 1, and R ₅ is H; or s is an integer of 2-3; or iii. M is -CR' _{La R'Lb} -, -C(=N-CN)-, C(=S), -S(O)- or -S(O) ₂ -; R _'La and R' and the carbon atom to which they are attached together _Lb C _3-6 carbocyclic ring or contains 1-3 heteroatoms selected from N, S, 4-7 membered heterocycle O heteroatom; or iv, t is an integer of 1-3; Each R _{B is} independently selected from C _3-9 cycloalkyl, -NR _B1 R _B2 , -C (O) NR _B1 R _B2 , -C (O) OR _B3 , -OR _B3 , -C _1-4 sub Alkyl -R _B3 , -C(O)R _B3 and 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring are optionally substituted by 1- 3 selected from halogen, =O, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, CN, OH, C _{3- 6} cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, NH ₂ and -C(O)C _1-4 alkyl group substitution; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, halo C _1-4 alkyl, -C (O) C _1-4 alkyl, -C (O) C _3-6 Cycloalkyl, -S (O) ₂ C _1-4 alkyl, -S (O) C _1-4 alkyl, C _3-6 cycloalkyl and containing 1-3 selected from N, S, O hetero A 4-10 membered heterocyclic ring, the cycloalkyl and heterocyclic ring are optionally substituted by 1-3 _{groups selected from the group consisting of C 1-4} alkyl, halogen and -C(O)C _1-4 alkyl replace; Each R _{B3 is} independently a C _3-6 cycloalkyl group or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the cycloalkyl group and the heterocyclic ring are optionally substituted by 1 -3 selected from C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogen, CN, OH, NH ₂ and -C (O) _{Substitution of C 1-4} alkyl group; or v, L ₂ =NO-, -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, -(CR ₆₁ R ₆₂ ) _y C(O )NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 C(O)-, -C(O)NR _L2 (CR ₆₁ R ₆₂ ) _y -, containing 1-3 selected from N, S, O Atomic 4-7 membered heterocyclic ring-C(O)-, containing 1-3 heteroatoms selected from N, S, O, 4-7 membered heterocyclic ring-C(O)NR _L2 -, containing 1-3 4-7 membered heterocyclic ring selected from N, S, O heteroatoms-NR _L2 C(O)-, 4-7 membered heterocyclic ring containing 1-3 selected N, S, O heteroatoms-(CR ₆₁ R ₆₂ ) _y -O-, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S and O-(CR ₆₁ R ₆₂ ) _y -NR _L2 -, y is not 0, R ₇ C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, halogenated C _1-4 Alkoxy, phenyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, _{when R 7} is alkyl, optionally 1-3 selected from C _{1- 4} alkoxy, halo C _1-4 alkyl, C _3-6 cycloalkyl, CN, OH, -C (O ) -C 1-4 alkyl, -S (O) ₂ -C _1-4 Alkyl group, or a 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, phenyl, bicyclic bridged cycloalkyl and hetero The ring is optionally substituted by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _1-4 alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-haloC _{1 -4} alkyl, -C _1-4 alkylene, -OC(O)-C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, containing 1-3 selected from N, S, O heteroatoms 4-7 membered heterocyclic ring and C _2-4 alkynyl group substitution; or L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, -(CR ₆₁ R ₆₂ ) _y -, 4-7 containing 1-3 heteroatoms selected from N, S, O -Membered heterocyclic ring -NR _L2 -, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O -NR _L2 (CR ₆₁ R ₆₂ ) _y -, containing 1-3 heteroatoms selected from N, S, O heteroatoms 4-7 membered heterocyclic ring -(CR ₆₁ R ₆₂ ) _y -, or containing 1-3 selected from N, S, O heteroatoms 4-7 membered heterocyclic ring -O-(CR ₆₁ R ₆₂ ) _y -, y is not 0, R ₇ is C _2-4 alkenyl, -NHC(O)C _1-4 alkyl, C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged ring Alkyl group, or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group, bicyclic bridged cycloalkyl group and heterocyclic ring are optionally further selected from 1-3 From halogen, =O, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, mono C _1-4 alkylamino, -N (C _1-4 alkyl ) ₂ , halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, CN, OH, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _{1 -4} alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group Group replacement; or L ₂ is -NR _L2 -, or a 4-7 membered heterocyclic ring -O- containing 1-3 heteroatoms selected from N, S, O, R ₇ is C _2-4 alkenyl, C _3-6 monocyclic ring Alkyl group, C _5-8 bicyclic cycloalkyl group or 4-12 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl group, bicyclic bridged cycloalkyl group And non-aromatic heterocyclic ring substituted by 1-3 selected from halogen, mono-C _1-4 alkylamino, -N(C _1-4 alkyl) _{2 , C 1-4} alkyl substituted with cyano group, CN, OH , Halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halo Substituted C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl and C _2-4 alkynyl groups, and optionally Is 1-3 selected from C _1-4 alkyl, =O, C _1-4 alkoxy, -C _1-4 alkyl-OH, C _3-6 cycloalkyl, containing 1-3 selected from N, S, O heteroatoms of 4-7 membered heterocyclic ring and halogenated C _1-4 alkyl group substitution; or L ₂ is -NR _L2 -, R ₇ is a 4-7 membered heteroaromatic ring or phenyl containing 1-3 heteroatoms selected from N, S, O, and the heteroaromatic ring and phenyl are optionally substituted by 1 -3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -NHC _1-4 alkyl, -N (C _1-4 alkyl ) _2. Halogenated C _1-4 alkyl, -C _1-4 alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy , -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene, -O-halo C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 4 containing 1-3 heteroatoms selected from N, S, O Substitution of -7 membered heterocyclic ring and C _2-4 alkynyl group; or L ₂ is -O-, R ₇ is C _3-6 cycloalkyl, C _5-8 bicyclic bridged cycloalkyl, phenyl or 4-12 containing 1-3 heteroatoms selected from N, S, O -Membered heterocyclic ring, the cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring are substituted by 1-3 halogens, =O, C _1-4 alkoxy, mono C _1-4 alkylamino, Halogenated C _1-4 alkyl, cyano substituted C _1-4 alkyl, CN, OH, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S( O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkane Group, C _2-4 alkenyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group; or L ₂ is -O-(CR ₆₁ R ₆₂ ) _y -, y is not 0, R ₇ is C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, C _{2 -4} alkenyl, -NHC(O)C _1-4 alkyl, C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl, phenyl or containing 1-3 selected from N, S , O heteroatom of 4-12 membered heterocycle, when R ₇ is C _1-4 alkyl, 1-3 are selected from C _3-6 cycloalkyl, CN, OH, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, or a 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, said R ₇ is a monocyclic alkyl group, a phenyl group, a bicyclic bridged cycloalkyl group and a heterocyclic ring, optionally by 1-3 selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -C _1-4 alkyl-OH, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _{1 -4} alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl,- S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _{1- 4} alkyl group, C _2-4 alkenyl group, C _3-6 cycloalkyl group, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and C _2-4 alkynyl group Replace; or L ₂ is a bond, R ₇ is a C _3-6 cycloalkyl group or a C _5-8 bicyclic bridged cycloalkyl group, and the cycloalkyl group and the bicyclic bridged cycloalkyl group are 1-3 selected from -NHC _{1- 4} alkyl, -N (C _1-4 alkyl) ₂ , halo C _1-4 alkyl, -C _1-4 alkylene -NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-O- Halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl, containing 1-3 selected from N, S, O hetero A 4-7 membered heterocyclic ring of atoms and a C _2-4 alkynyl group; or L ₂ is a bond, R ₇ is a 4-12 membered monocyclic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the monocyclic heterocyclic ring is connected to Y through a ring carbon atom, the monocyclic The heterocyclic ring is selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂ , halogenated C _1-4 alkyl, -C _1-4 alkylene-NH ₂ , cyano substituted C _1-4 alkyl, CN, OH, halogen, halogenated C _1-4 alkoxy, -C(O) -C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene, -O-halogenated C _1-4 alkyl, -C _1-4 alkylene -OC(O)-C _1-4 alkyl, C _2-4 alkenyl, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O and C _2-4 alkynyl group Group replacement; or L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocycle, bridged heterocycle or conjugated heterocycle containing 1-3 heteroatoms selected from N, S, O, the spiro heterocycle, bridge The cyclic heterocyclic ring and the bicyclic heterocyclic ring are optionally selected from =0, C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl-OH, -NHC _{1 -4} alkyl, -N(C _1-4 alkyl) ₂ , halo C _1-4 alkyl, -C _1-4 alkylene -NH ₂ , cyano substituted C _1-4 alkyl, CN , OH, halogen, halogenated C _1-4 alkoxy, -C(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene -O-halogenated C _1-4 alkyl, -C _1-4 alkylene-OC(O)-C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, containing 1 -3 substitutions of 4-7 membered heterocycles selected from N, S, O heteroatoms and C _2-4 alkynyl groups; or L ₂ is -O-, R ₇ is C _1-4 alkyl, and R _X2 is halogenated C _1-4 alkyl. The compound according to claim 32, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, said compound having the structure of formula (VIII),

(VIII). The compound of claim 33, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: Y is CH; t is selected from 0 or 1; R _{B is} independently selected from halogen, -NR _B1 R _B2 , CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, and the heterocyclic ring is optionally composed of 1-3 Substitution with a group selected from halogen, C _1-4 alkyl, and halogenated C _{1-4 alkyl;} Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl; L ₂ is -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, y is selected from 1 or 2, R ₇ is C _3-6 cycloalkyl , C _5-8 bicyclic bridged cycloalkyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, bicyclic bridged cycloalkyl and The heterocyclic ring is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl and halogen; or L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, y is selected from 1 or 2, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkane Group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally further selected from 1-3 halogens , C _1-4 alkyl group substitution; or L ₂ is -NR _L2 -, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl or 4-12 member containing 1-3 heteroatoms selected from N, S, O Non-aromatic heterocycle, the cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle are substituted by 1-3 groups selected from halogen, OH, -S(O) ₂ -C _1-4 alkyl ;or L ₂ is a bond, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, the bicyclic bridged cycloalkyl group is substituted with 1-3 halogenated C _1-4 alkyl groups, -C(O)-C _{1- 4} alkyl group substitution; or L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from C _{1 -4} Alkyl, halogen group substitution; R _L2 is H, C _1-2 alkyl or halogenated C _1-2 alkyl. The compound of claim 34, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: R _{B is} independently selected from F, Cl, -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , CN, 5-6 membered heteroatoms containing 1-4 heteroatoms selected from N, S, O Aryl, the heteroaryl group is optionally selected from 1-3 selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ Group substitution L ₂ is -NHC(O)-, -C(O) _{NH-, -CH 2} NH-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or L ₂ is -C(O)-, -NHCH ₂ -, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or

When the R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, 1-3 are selected from F, Cl, OH, -S(O) ₂ -CH ₃ , -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -CH ₂ CH ₂ CH ₃ , -S(O) ₂ -CH(CH ₃ )CH ₃ group substitution; or L ₂ is the bond, R ₇ is

The R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, and isopropyl. The compound according to claim 32, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated product, wherein: R _{1 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl; R _{2 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl; R _La and R _{Lb are} independently selected from H and D; M is -C(=O)-; R _{X2 is} selected from H, D, C _1-4 alkyl, halo C _1-4 alkyl, deuterium halo C _1-4 alkyl; R _A and R _A 'are independently selected from H;

Represents a single key; i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and, t is 0 or 1; s is 1; Y is CH or N; z is selected from 0, 1, 2; R _{5 is} selected from H, D, C _1-4 alkyl, and deuterated C _1-4 alkyl; R _{B is} independently selected from halogen, CN, -NR _B1 R _B2 and a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, the heterocyclic ring is optionally composed of 1-3 Substitution by a group selected from halogen and C _{1-4 alkyl;} Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl; L ₂ is -NR _L2 -, -O-; R _L2 is H or C _1-4 alkyl; R ₇ is a C _1-4 alkyl group, a C _3-6 monocyclic alkyl group, and when R ₇ is a monocyclic alkyl group, optionally 1-3 _{groups selected from C 1-4} alkyl group and halogen Replace; or ii, z is 1 or 2; s is 1; Y is N; t is 0 or 1; R _{B is} selected from halogen, CN, -NR _B1 R _B2 and 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally composed of 1-3 Substitution by a group selected from halogen and C _{1-2 alkyl;} Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl; R _{5 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl; L ₂ is a bond, -C(O)-, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, R ₇ is H, halogen, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl; or iii, s is 1, R _{5 is} selected from H; z is selected from 0; t is 0 or 1; Y is CH; R _{B is} selected from halogen, CN, -NR _B1 R _B2 and 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring is optionally composed of 1-3 Substitution by a group selected from halogen and C _{1-2 alkyl;} Each of R _B1 and R _{B2 is} independently selected from H, C _1-2 alkyl, -C(O)C _1-2 alkyl; L ₂ is -NR _L2 -; R _L2 is H or C _1-4 alkyl; R ₇ is a C _3-6 monocyclic alkyl group, a 4-12 membered non-aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, said R ₇ is a monocyclic alkyl group, a non-aromatic heterocyclic ring When optionally substituted by 1-3 _{groups selected from halogen and C 1-4} alkyl; or iv and t are 1 or 2, Y is CH or N; s is 1; z is 0; R _{5 is} selected from C _1-4 alkyl and deuterated C _1-4 alkyl; R _{B is} independently selected from -NR _B1 R _B2 and a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, the heterocyclic ring is optionally selected from 1-3 halogen, Substitution of C _1-4 alkyl groups; Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl; L _{2 is} selected from -O-; R _{7 is} selected from C _1-4 alkyl; or v and z are 0, Y is selected from CH or N, t is selected from 0 or 1; s is 1; R _{5 is} selected from H, D, C _1-4 alkyl, and deuterated C _1-4 alkyl; R _{B is} selected from halogen, -NR _B1 R _B2 , CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, the heterocyclic ring is optionally selected from 1-3 Substitution of halogen, C _1-4 alkyl, and halogenated C _{1-4 alkyl;} Each R _B1 and R _{B2 is} independently selected from H, C _1-4 alkyl, -C(O)C _1-4 alkyl; L ₂ is -NR _L2 C(O)-, -C(O)NR _L2 -, -(CR ₆₁ R ₆₂ ) _y NR _L2 -, y is selected from 1 or 2, R ₇ is C _3-6 cycloalkyl , C _5-8 bicyclic bridged cycloalkyl or 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R ₇ is cycloalkyl, bicyclic bridged cycloalkyl and The heterocyclic ring is optionally substituted with 1-3 _{groups selected from C 1-4} alkyl and halogen; or L ₂ is -C(O)-, -NR _L2 (CR ₆₁ R ₆₂ ) _y -, y is selected from 1 or 2, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkane Group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring are optionally further selected from 1-3 halogens , C _1-4 alkyl group substitution; or L ₂ is -NR _L2 -, R ₇ is C _3-6 monocyclic alkyl, C _5-8 bicyclic bridged cycloalkyl or 4-12 member containing 1-3 heteroatoms selected from N, S, O Non-aromatic heterocycle, the cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle are substituted by 1-3 groups selected from halogen, OH, -S(O) ₂ -C _1-4 alkyl ;or L ₂ is a bond, R ₇ is a C _5-8 bicyclic bridged cycloalkyl group, the bicyclic bridged cycloalkyl group is substituted with 1-3 halogenated C _1-4 alkyl groups, -C(O)-C _{1- 4} alkyl group substitution; or L ₂ is a bond, R ₇ is an 8-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the spiro heterocyclic ring is optionally selected from C _{1 -4} Alkyl, halogen group substitution; or L ₂ is -O-, R ₇ is C _1-4 alkyl, and R _X2 is halogenated C _1-4 alkyl. The compound according to claim 36, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated substance, wherein: R _{1 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; R _{2 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; R _{X2 is} selected from methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ; i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and, t is 0 or 1; s is 1; Y is CH or N; z is selected from 0 or 1; R _{5 is} selected from H, methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; R _{B is} independently selected from F, Cl, CN, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ and 5 containing 1-4 heteroatoms selected from N, S, O -6-membered heteroaryl, said heteroaryl is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; L ₂ is -NH-, -N(CH ₃ )-, -O-; R ₇ is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said R ₇ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl When optionally substituted by 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or ii. z is 1; s is 1; Y is N; t is 0 or 1; R _{B is} independently selected from F, Cl, CN, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ and 5 containing 1-4 heteroatoms selected from N, S, O -6-membered heteroaryl, said heteroaryl is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; R _{5 is} selected from H, methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; L ₂ is a bond, -C(O)-, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , R ₇ is H, F, Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ;or iii, s is 1, R _{5 is} selected from H; z is selected from 0; t is 0 or 1; Y is CH; R _{B is} independently selected from F, Cl, CN, -NHCH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ and 5 containing 1-4 heteroatoms selected from N, S, O -6-membered heteroaryl, said heteroaryl is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F and Cl; or iv and t are 1 or 2, Y is CH or N; s is 1; z is 0; R _{5 is} selected from methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; R _{B is} selected from -NH-C _1-4 alkyl, -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , 5-6 containing 1-2 heteroatoms selected from N, S, O -Membered heteroaromatic ring, said heteroaromatic ring is optionally substituted by 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; L _{2 is} selected from -O-; R _{7 is} selected from methyl, ethyl, propyl, isopropyl; or v and z are 0, Y is selected from CH or N, t is selected from 0 or 1, and s is 1; R _{5 is} selected from H, D, methyl, ethyl, propyl, isopropyl, CD ₃ , CHD ₂ , CH ₂ D, CH ₂ CD ₃ ; R _{B is} selected from F, Cl, -NH-CH ₃ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , CN, 5 containing 1-4 heteroatoms selected from N, S, O -6 membered heterocyclic ring, the heterocyclic ring is optionally selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ group substitution; L ₂ is -NHC(O)-, -C(O) _{NH-, -CH 2} NH-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or L ₂ is -C(O)-, -NHCH ₂ -, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

or

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or L ₂ is -NH-, -N(CH ₃ )-, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or

When R ₇ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 1-3 are selected from F, Cl, OH, -S(O) ₂ -CH ₃ , -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -CH ₂ CH ₂ CH ₃ , -S(O) ₂ -CH(CH ₃ )CH ₃ group substitution; or L ₂ is the bond, R ₇ is

, Said R _{7 is} optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ ;or L ₂ is -O-, R ₇ is methyl, ethyl, propyl, isopropyl, and R _X2 is CF ₃ , CHF ₂ , CH ₂ F, and CH ₂ CF ₃ . The compound according to claim 1, 2 or 31, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated compound, wherein the compound is selected from one of the following structures:

The deuterated substance is selected from one of the following structures:

A pharmaceutical composition, characterized in that it contains the compound according to any one of claims 1-38, its stereoisomers, pharmaceutically acceptable salts, solvates or co-crystals, and pharmaceutically acceptable Excipients and/or carriers. The compound according to any one of claims 1-38, its stereoisomers, pharmaceutically acceptable salts, solvates or co-crystals, or the composition according to claim 39 is used for the treatment of EZH2. Use in medicines for mediated diseases. The compound according to any one of claims 1-38, its stereoisomers, pharmaceutically acceptable salts, solvates or co-crystals, or the composition according to claim 39 in the treatment of EZH2-mediated Use in disease. The use according to claim 40 or 41, wherein the EZH2-mediated disease is a tumor or an autoimmune disease.