Compound having heteroaromatic ring structure, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed in the present invention are a compound having a heteroaromatic ring structure, a pharmaceutical composition thereof and the use thereof. Provided in the present invention is a compound having a heteroaromatic ring structure as shown in formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof. The compound having the heteroaromatic ring structure is expected to be used for the treatment and / or prevention of a variety of diseases associated with poly(ADP-ribose) glycohydrolase (PARG).

Description

A heteroaromatic ring structure compound, its pharmaceutical composition and application

[0001] This application claims priority to Chinese patent application No. 202310718341.1, filed on June 16, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a heteroaromatic ring structure compound, a pharmaceutical composition and application thereof. Background Art

[0003] The division and proliferation of cancer cells are often uncontrolled, resulting in a higher incidence of DNA damage and DNA repair defects. Compared with normal cells, they are more dependent on DNA damage repair mechanisms.

[0004] Poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) hydrolase (PARG), and other proteins play a crucial role in DNA repair and have become important targets for anticancer drug development. PARP binds to single-strand DNA breaks, promoting the formation of poly(ADP-ribose) (PAR) chains, thereby initiating the repair process. PARG degrades the PAR attached to PARP, facilitating the completion of the repair cycle. Inhibition of either PARP or PARG impairs the entire repair process.

[0005] The research and development of PARP inhibitors has been a resounding success, with several approved drugs now demonstrating the feasibility of targeting DNA repair proteins. However, PARP inhibitors also present challenges, such as not being effective in all patients and drug resistance. Research on PARG inhibitors is still in its exploratory stages, and this target offers significant potential for research, potentially addressing unmet clinical needs.

[0006] Summary of the Invention

[0007] The technical problem to be solved by the present invention is the lack of effective drugs in the prior art as PARG inhibitors for clinical treatment. To this end, the present invention provides a heteroaromatic ring structure compound, a pharmaceutical composition and application thereof, which is expected to be used to treat and / or prevent various diseases related to PARG.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a heteroaromatic ring structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope thereof:

[0010] in, represents a single bond or a double bond;

[0011] Both rings in are aromatic;

[0012] A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen;

[0013] A3 is C or N;

[0014] A4 is N, CR 4 or NR 4 ;

[0015] A5 is NR 5 , N, CR 5 , S or O;

[0016] for

[0017] R a1 、R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxy or -OC 1-6 alkyl;

[0018] or, R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes, one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0019] R a2-1 and R a2-2are independently halogen, =O, hydroxy, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl;

[0020] R a-1 、R a-2 、R a-31 、R a-32 、R a-4 、R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0021] Ring Y is C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6- 20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, a fused heterocyclic group of "a 5-6 membered heteroaryl containing 1-4 heteroatoms which are independently selected from O, S and N" and "a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms which are independently selected from O, S and N", or "a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms which are independently selected from O, S and N";

[0022] n is 0, 1, 2, 3, 4, 5 or 6;

[0023] R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 2-2 Replaced -OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 、C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to form, independently together with the atoms in the ring to which they are connected, a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

[0024] R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ;

[0025] R 2a 、R 2b1 、R 2b2 、R 2c 、R 2d1 、R 2d2 、R 22a 、R 22b1 、R 22b2 、R 22c 、R 22d1 、R 22d2 、R 22e1 、R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0026] R 1 for

[0027] R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Independently C1-6 Alkyl, -OC 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-6 Substituted C 4- 8-membered cycloalkenyl, "a 4-8-membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0028] R 21 is hydrogen or C 1-6 alkyl;

[0029] R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 and R 1-7 Halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 1-1-1 Replaced -OC 1-6 Alkyl, one or more R 1-1-2 Substituted-SC 1-6 Alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f 、C 3-10 Cycloalkyl, one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0030] R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f 、C 3-10Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0031] R 1a 、R 1b1 、R 1b2 、R 1c 、R 1d1 、R 1d2 、R 1e1 、R 1e2 、R 1f 、R 11a 、R 11b1 、R 11b2 、R 11c 、R 11d1 、R 11d2 、R 11e1 、R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl;

[0032] R 3 "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N" or one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0033] R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0034] R 4 For hydrogen, halogen, C 1-6 Alkyl, or, with one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 Halogen, hydroxyl, C 3-12 Cycloalkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0035] R 5 for

[0036] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0037] Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced -OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", one or more R 5-7 Substituted "containing 1-3 heteroatoms, heteroatoms independently selected from O, S and N 4-8 membered heterocycloalkenyl", or, by one or more R 5-8 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0038] R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 and R 5-8 are independently halogen, hydroxy, oxo, cyano, C1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different;

[0039] R 5a 、R 5b1 、R 5b2 、R 5c 、R 5d1 、R 5d2 、R 51a 、R 51b1 、R 51b2 、R 51c 、R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0040] or, R 2 and R 5 connected to form, together with the atoms to which they are connected, a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N";

[0041] or, R a-31 and R a-32 、R a-51 and R a-52 、R 2b1 and R 2b2 、R 2d1 and R 2d2 、R 22b1 and R 22b2 、R 22d1 and R 22d2 、R 22e1 and R 22e2 、R 1b1 and R 1b2 、R 1d1 and R 1d2 、R 1e1 and R 1e2 、R 11b1 and R 11b2 、R 11d1 and R11d2 、R 11e1 and R 11e2 、R 5b1 and R 5b2 、R 5d1 and R 5d2 、R 51b1 and R 51b2 、R 51d1 and R 51d2 independently and separately form together with the connected N "containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N 3-8 membered heterocyclic ring", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

[0042] R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0043] The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds:

[0044] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide;

[0045] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide;

[0046] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide;

[0047] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide;

[0048] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide.

[0049] In a certain embodiment, in the heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any of the above embodiments (this paragraph is hereinafter referred to as "in a certain embodiment").

[0050] In one embodiment, the heteroaromatic ring structure compound shown in Formula I is shown in Formula II:

[0051] in, is a single bond or a double bond; B1 is N, C or CH, B2 is N or CH, and the definitions of other groups are the same as described above.

[0052] In one embodiment, the heteroaromatic ring structure compound shown in Formula I is shown in Formula III:

[0053] in, is a single bond or a double bond; B1 is N, C or CH; B2 is N or CH;

[0054] m is 0, 1 or 2;

[0055] R′ is R 11 NR 12 R 13 、R 14 or R 19 ;

[0056] R 11 、R 12 、R 13 、R 14 and R 19 and other groups are defined as above.

[0057] In a certain embodiment, the heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, the heteroaromatic ring structure compound as shown in Formula I is defined as Scheme 1, Scheme 2, Scheme 3 or Scheme 4:

[0058] Option 1:

[0059] represents a single bond or a double bond;

[0060] Both rings in are aromatic;

[0061] A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen;

[0062] A3 is C or N;

[0063] A4 is N, CR 4 or NR 4 ;

[0064] A5 is NR 5 , N, CR 5 , S or O;

[0065] for

[0066] R a1 、R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxy or -OC 1-6 alkyl;

[0067] or, R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes, one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0068] R a2-1 and R a2-2 are independently halogen, =O, hydroxy, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl;

[0069] R a-1 、R a-2 、Ra-31 、R a-32 、R a-4 、R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0070] Ring Y is C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6- 20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0071] n is 0, 1, 2, 3, 4, 5 or 6;

[0072] R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 2-2 Replaced -OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 、C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to form, independently together with the atoms in the ring to which they are connected, a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

[0073] R 2-1 and R2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ;

[0074] R 2a 、R 2b1 、R 2b2 、R 2c 、R 2d1 、R 2d2 、R 22a 、R 22b1 、R 22b2 、R 22c 、R 22d1 、R 22d2 、R 22e1 、R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0075] R 1 for

[0076] R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Independently C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-6 Substituted C 4- 8-membered cycloalkenyl, "a 4-8-membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0077] R 21 is hydrogen or C 1-6 alkyl;

[0078] R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 1-1-1 Replaced -OC 1-6 Alkyl, one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f 、C 3-10 Cycloalkyl, one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0079] R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f 、C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0080] R 1a 、R 1b1 、R 1b2 、R 1c 、R 1d1 、R 1d2 、R 1e1 、R 1e2 、R 1f 、R 11a 、R 11b1 、R 11b2 、R 11c 、R 11d1 、R11d2 、R 11e1 、R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl;

[0081] R 3 "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N" or one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0082] R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0083] R 4 For hydrogen, halogen, C 1-6 Alkyl, or, with one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 Halogen, hydroxyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0084] R 5 for

[0085] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0086] Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1Replaced -OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0087] R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 and R 5-7 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different;

[0088] R 5a 、R 5b1 、R 5b2 、R 5c 、R 5d1 、R5d2 、R 51a 、R 51b1 、R 51b2 、R 51c 、R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0089] or, R 2 and R 5 connected to form, together with the atoms to which they are connected, a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N";

[0090] or, R a-31 and R a-32 、R a-51 and R a-52 、R 2b1 and R 2b2 、R 2d1 and R 2d2 、R 22b1 and R 22b2 、R 22d1 and R 22d2 、R 22e1 and R 22e2 、R 1b1 and R 1b2 、R 1d1 and R 1d2 、R 1e1 and R 1e2 、R 11b1 and R 11b2 、R 11d1 and R 11d2 、R 11e1 and R 11e2 、R 5b1 and R 5b2 、R 5d1 and R 5d2 、R 51b1 and R 51b2 、R 51d1 and R 51d2 independently and separately form together with the connected N "containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N 3-8 membered heterocyclic ring", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

[0091] R 1-2-1 are independently hydrogen, C 1-6Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0092] The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds:

[0093] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide

[0094] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide

[0095] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide

[0096] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide

[0097] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide.

[0098] Option 2:

[0099] represents a single bond or a double bond;

[0100] A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen;

[0101] A3 is C or N;

[0102] for

[0103] R 4 is hydrogen or is replaced by one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 C 3-12Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0104] R 5 for

[0105] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0106] Q1 is hydrogen, deuterium, halogen, -OC 1-6 Alkyl, -NR 5b1 R 5b2 、-C(=O)NR 5d1 R 5d2 、C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, one or more R 5-8 Substituted C 1-6 Alkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0107] R 5b1 、R 5b2 、R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl;

[0108] R 5-8 are independently halogen;

[0109] R a1 、R a2 and R a3 are independently cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen;

[0110] or, R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkane; when there are multiple substituents, they may be the same or different;

[0111] R a-51 and R a-52 are independently hydrogen;

[0112] Ring Y is a "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, a fused heterocyclic group of "a 5-6 membered heteroaryl containing 1-4 heteroatoms which are independently selected from O, S and N" and "a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms which are independently selected from O, S and N", or "a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms which are independently selected from O, S and N";

[0113] n is 0, 1 or 2;

[0114] R 2 Halogen, hydroxyl, cyano, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)R 2a 、-C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ; or, when n is 2, two R 2 connected to form, independently together with the atoms in the ring to which they are connected, a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0115] R 2-1 Independently C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ;

[0116] R 2a 、R 2c 、R 2d1 、R 2d2 、R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl;

[0117] R 1 for

[0118] R 11 、R 12 、R 13 、R 14 、R 17 、R 18 、R 19 and R 20 Independently C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5- to 12-membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N";

[0119] R 21 is hydrogen or C 1-6 alkyl;

[0120] R 1-1 、R 1-2 and R 1-3 C 1-6 Alkyl or -OC 1-6 alkyl;

[0121] R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0122] R 3-1 Independently C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0123] The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds:

[0124] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide

[0125] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide

[0126] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide

[0127] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide

[0128] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide.

[0129] Option 3:

[0130] The heteroaromatic ring structure compound shown in Formula I has a structure as shown in Formula III-1 below:

[0131] R a1 、R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 Halogen, hydroxyl or -OC 1-6 alkyl;

[0132] or, R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes, one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0133] R a2-1 and R a2-2 are independently halogen, =O, hydroxy, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OC 1-6Alkyl, or -OC substituted by one or more halogens 1-6 alkyl;

[0134] R a-1 、R a-2 、R a-31 、R a-32 、R a-4 、R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0135] n is 0, 1, 2, 3, 4, 5 or 6;

[0136] R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, one or more R 2-2 Replaced -OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 、C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to form, independently together with the atoms in the ring to which they are connected, a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

[0137] R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ;

[0138] R 2a 、R 2b1 、R 2b2 、R 2c 、R 2d1 、R 2d2 、R 22a 、R 22b1 、R 22b2 、R 22c 、R 22d1 、R 22d2 、R 22e1 、R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0139] R 11 C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0140] R1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 1-1-1 Replaced -OC 1-6 Alkyl, one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f 、C 3-10 Cycloalkyl, one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0141] R 1-1-1 、R 1-1-2 、R 1-1-3 、R1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f 、C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0142] R 1a 、R 1b1 、R 1b2 、R 1c 、R 1d1 、R 1d2 、R 1e1 、R 1e2 、R 1f 、R 11a 、R 11b1 、R 11b2 、R 11c 、R 11d1 、R 11d2 、R 11e1 、R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl;

[0143] R 3 "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N" or one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0144] R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0145] R 5 for

[0146] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0147] Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced -OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N" or one or more R 5-8 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0148] R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 and R 5-8 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different;

[0149] R 5a 、R 5b1 、R 5b2 、R 5c 、R 5d1 、R 5d2 、R 51a 、R 51b1 、R 51b2 、R 51c 、R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0150] or, R 2 and R 5 connected to form, together with the atoms to which they are connected, a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N";

[0151] or, R a-31 and R a-32 、R a-51 and R a-52 、R 2b1 and R 2b2 、R 2d1 and R 2d2 、R 22b1 and R 22b2 、R 22d1 and R 22d2 、R 22e1 and R22e2 、R 1b1 and R 1b2 、R 1d1 and R 1d2 、R 1e1 and R 1e2 、R 11b1 and R 11b2 、R 11d1 and R 11d2 、R 11e1 and R 11e2 、R 5b1 and R 5b2 、R 5d1 and R 5d2 、R 51b1 and R 51b2 、R 51d1 and R 51d2 independently and separately form together with the connected N "containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N 3-8 membered heterocyclic ring", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

[0152] R 1-2-1 For hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl.

[0153] Option 4:

[0154] In the heteroaromatic ring structure compound shown in Formula I,

[0155] A1 and A2 are independently CR b1 , R b1 is hydrogen;

[0156] A3 is C or N;

[0157] A4 is N or CR 4 ; R 4 is hydrogen;

[0158] A5 is NR 5 , CR 5 or S;

[0159] R a1 For halogen, cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen;

[0160] R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes;

[0161] R a-51 and R a-52 are independently hydrogen;

[0162] Ring Y is a "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0163] n is 0, 1 or 2;

[0164] R 2 is hydroxyl, one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)OR 2c ; or, when n is 2, two R 2 connected to form, independently together with the atoms in the ring to which they are connected, a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0165] R 2-1 are independently hydroxyl groups;

[0166] R 2c is hydrogen;

[0167] R 1 for

[0168] R 11 、R 12 、R 13 、R 14 、R 17 、R 18 、R 19 and R 20 Independently C 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-3Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N";

[0169] R 21 is hydrogen or C 1-6 alkyl;

[0170] R 1-1 、R 1-2 and R 1-3 Independently C 1-6 Alkyl or -OC 1-6 alkyl;

[0171] R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0172] R 3-1 are independently C substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0173] R 5 for

[0174] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0175] Q1 is hydrogen, deuterium or -OC 1-6 alkyl.

[0176] In one embodiment, in the heteroaromatic ring structure compound shown in formula III-1,

[0177] R a1 、R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxy or -OC 1-6 alkyl;

[0178] or, Ra2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes, one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0179] R a2-1 and R a2-2 are independently halogen, =O, hydroxy, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl;

[0180] R a-1 、R a-2 、R a-31 、R a-32 、R a-4 、R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0181] n is 0, 1, 2, 3, 4, 5 or 6;

[0182] R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, one or more R 2-2 Replaced -OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 、C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to form, independently together with the atoms in the ring to which they are connected, a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

[0183] R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ;

[0184] R 2a 、R 2b1 、R 2b2 、R 2c 、R 2d1 、R 2d2 、R 22a 、R 22b1 、R 22b2 、R 22c 、R 22d1 、R 22d2 、R 22e1 、R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0185] R 11 C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0186] R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, one or more R 1-1-1 Replaced -OC 1-6 Alkyl, one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f 、C 3-10 Cycloalkyl, one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0187] R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f 、C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0188] R 1a 、R 1b1 、R 1b2 、R 1c 、R 1d1 、R 1d2 、R 1e1 、R 1e2 、R 1f 、R 11a 、R 11b1 、R 11b2 、R 11c 、R 11d1 、R11d2 、R 11e1 、 R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl;

[0189] R 3 "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N" or one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0190] R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0191] R 5 for

[0192] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0193] Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced -OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C3-12 Cycloalkyl, one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0194] R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 and R 5-7 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different;

[0195] R 5a 、R 5b1 、R 5b2 、R 5c 、R 5d1 、R 5d2 、R 51a 、R 51b1 、R 51b2 、R 51c 、R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0196] or, R 2 and R 5 connected to form, together with the atoms to which they are connected, a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N";

[0197] or, R a-31 and R a-32 、R a-51 and R a-52 、R 2b1 and R 2b2 、R 2d1 and R 2d2 、R 22b1 and R 22b2 、R 22d1 and R 22d2 、R 22e1 and R 22e2 、R 1b1 and R 1b2 、R 1d1 and R 1d2 、R 1e1 and R 1e2 、R 11b1 and R 11b2 、R 11d1 and R 11d2 、R 11e1 and R 11e2 、R 5b1 and R 5b2 、R 5d1 and R 5d2 、R 51b1 and R 51b2 、R 51d1 and R 51d2 independently and separately form together with the connected N "containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N 3-8 membered heterocyclic ring", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

[0198] R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl.

[0199] In one embodiment, in the heteroaromatic ring structure compound shown in formula III-1,

[0200] R a1 、R a2 and R a3 are independently cyano, C 1-6 Alkyl, -C(=O)NRa-51 R a-52 , or by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen;

[0201] or, R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkane; when there are multiple substituents, they may be the same or different;

[0202] R a-51 and R a-52 are independently hydrogen;

[0203] n is 0, 1 or 2;

[0204] R 2 are independently halogen, cyano, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)R 2a 、-C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ;

[0205] R 2-1 Independently C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ;

[0206] R 2a 、R 2c 、R 2d1 、R 2d2 、R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl;

[0207] R 11 C 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3- 10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20Aryl or "5- to 12-membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N";

[0208] R 1-1 、R 1-2 and R 1-3 Independently C 1-6 Alkyl or -OC 1-6 alkyl;

[0209] R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N";

[0210] R 3-1 Independently C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0211] R 5 for

[0212] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0213] Q1 is deuterium, -OC 1-6 Alkyl, -NR 5b1 R 5b2 、-C(=O)NR 5d1 R 5d2 、C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, one or more R 5-8 Substituted C 1-6 Alkyl or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0214] R 5b1 、R 5b2 、R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl;

[0215] R 5-8 are independently halogen;

[0216] The heteroaromatic ring structure compound shown in Formula III is not one of the following compounds:

[0217] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide

[0218] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide.

[0219] In group R b1 、R a1 、R a2 、R a3 、R a1-1 、R a2-1 、R a2-2 、R a-1 、R a-2 、R a-31 、R a-32 、R a-4 、R a-51 、R a-52 、R 2 、R 2-1 、R 2-2 、R 2a 、R 2b1 、R 2b2 、R 2c 、R 2d1 、R 2d2 、R 22a 、R 22b1 、R 22b2 、R 22c 、R 22d1 、R 22d2 、R 22e1 、R 22e2 、R 22f 、R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 、R 1-1-8 、R 3- 1 、R 4 、R 4-1,Q1,R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 5-8 、R 5a 、R 5b1 、R 5b2 、R 5c 、R 5d1 、R 5d2 、R 51a 、R 51b1 、R 51b2 、R 51c 、R 51d1 、R 51d2 and R 1-2-1 In the definition of , when halogen is mentioned, the halogen is fluorine, chlorine, bromine or iodine.

[0220] In group R a1 、R a2 、R a3 、R a2-1 、R a2-2 、R a-1 、R a-2 、R a-31 、R a-32 、R a-4 、R a-51 、R a-52 、R 2 、R 2-1 、R 2-2 、R 2a 、R 2b1 、R 2b2 、R 2c 、R 2d1 、R 2d2 、R 22a 、R 22b1 、R 22b2 、R 22c 、R 22d1 、R 22d2 、R 22e1 、R 22e2 、R 22f 、R 11 、R 12 、 R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 1-1、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-1-1 、R 1-1- 2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 、R 1-1-8 、R 1a 、R 1b1 、R 1b2 、R 1c 、R 1d1 、R 1d2 、R 1e1 、R 1e2 、R 1f 、R 11a 、R 11b1 、R 11b2 、R 11c 、R 11d1 、R 11d2 、R 11e1 、R 11e2 、R 11f 、R 3-1 、R 4 、R 4-1 ,Q1,R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 5-8 、R 5a 、R 5b1 、R 5b2 、R 5c 、R 5d1 、R 5d2 、R 51a 、R 51b1 、R 51b2 、R 51c 、R 51d1 、R 51d2 and R 1-2-1 In the definition of C 1-6 When alkyl, the C 1-6 Alkyl is C 1-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0221] In group R 4-1And in the definition of Q1, when it is mentioned that C 3-12 When cycloalkyl, the C 3-12 Cycloalkyl is C 3-6 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0222] When L1 is C 1-6 Alkylene or deuterated C 1-6 When alkylene, the C 1-6 The alkylene group can be -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, or -C(CH3)2CH2-.

[0223] When L1 is deuterated C 1-6 When alkylene, the deuterated 1-6 Two or three hydrogen atoms in the alkylene group are replaced by deuterium.

[0224] In the group ring Y, R 2 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 And in the definition of Q1, when it is mentioned that C 6-20 When the C 6-20 Aryl is phenyl or naphthyl.

[0225] In the group ring Y, R 2 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 1-1-7 and R 1-1-8 In the definition of C 3-10 When cycloalkyl, the C 3-10 The cycloalkyl group is a C3-C6 cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.

[0226] In one embodiment, A1 and A2 are independently CR b1 , R b1 is hydrogen or halogen.

[0227] In one solution, A4 is N or CR 4 ; R 4 is hydrogen or is replaced by one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 C 3-12 Cycloalkyl.

[0228] In one solution, A5 is N, NR 5 , CR 5 or S.

[0229] In one scenario, R 5 for

[0230] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 alkylene;

[0231] Q1 is hydrogen, deuterium, halogen, -OC 1-6 Alkyl, -NR 5b1 R 5b2 、-C(=O)NR 5d1 R 5d2 、C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, one or more R 5-8 Substituted C 1-6 Alkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0232] R 5b1 、R 5b2 、R5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl;

[0233] R 5-8 are independently halogen.

[0234] In one scenario, R a1 For cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 It is a halogen.

[0235] In one scenario, R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes.

[0236] In one scenario, R a1 For cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 is halogen; R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 Cycloalkanes.

[0237] In one scenario, R a-51 and R a-52 are independently hydrogen.

[0238] In one embodiment, ring Y is a "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 cycloalkenyl, a fused heterocyclic group of “a 5-6 membered heteroaryl containing 1-4 heteroatoms which are independently selected from O, S and N” and “a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms which are independently selected from O, S and N”, or “a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms which are independently selected from O, S and N”.

[0239] In one embodiment, n is 0, 1 or 2.

[0240] In one scenario, R 2 are independently halogen, hydroxy, cyano, C 1-6Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)R 2a 、-C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ; or, when n is 2, two R 2 are connected to each other and independently form together with the atoms in the ring to which they are connected a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N".

[0241] In one scenario, R 2-1 Independently C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 .

[0242] In one scenario, R 2a 、R 2c 、R 2d1 、R 2d2 、R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl.

[0243] In one scenario, R 1 for

[0244] In one scenario, R 11 、R 12 、R 13 、R 14 、R 17 、R 18 、R 19 and R 20 Independently C 1-6 Alkyl, -OC 1-6 Alkyl, one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", ... 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5- to 12-membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N".

[0245] In one scenario, R 21 is hydrogen or C1-6 alkyl.

[0246] In one scenario, R 1-1 、R 1-2 and R 1-3 Independently C 1-6 Alkyl or -OC 1-6 alkyl.

[0247] In a certain scheme, when R 1 for When R 11 C 1-6 Alkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 3-10 Cycloalkyl, one or more R 1-1 Substituted C 1-6 Alkyl, one or more R 1-2 Substituted C 3-10 Cycloalkyl, one or more R 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5- to 12-membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N"; R 1- 1 For-OC 1-6 Alkyl; R 1-2 and R 1-3 Independently C 1-6 alkyl.

[0248] In a certain scheme, when R 1 for When R 12 and R 13 Independently C 1-6 alkyl.

[0249] In a certain scheme, when R 1 for When R 14 and R 19 Independently C 1-6 alkyl.

[0250] In a certain scheme, when R 1 for When R 17 and R 18 Independently C 1-6 Alkyl or -OC 1-6 alkyl.

[0251] In a certain scheme, when R 1 for When R20 C 1-6 alkyl.

[0252] In one scenario, R 3 For one or more R 3-1 The substituted "5-6 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N".

[0253] In one scenario, R 3-1 Independently C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl; when there are multiple substituents, they may be the same or different.

[0254] In one embodiment, when Q1 is a "5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N", Q1 is a "5-6 membered heteroaryl group containing 1-2 heteroatoms N", for example, pyridyl.

[0255] In one embodiment, when Q1 is a "4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", the Q1 is a "4-6 membered heterocycloalkyl group containing 1-2 heteroatoms independently selected from O, S and N".

[0256] In a certain embodiment, when ring Y is a "4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", Y is a "4-8 membered heterocycloalkyl group containing 1-2 heteroatoms N", for example, a 6-membered heterocycloalkyl group containing two heteroatoms N.

[0257] In one embodiment, when ring Y is C 6-20 When Y is an aryl group, the Y is a phenyl group, a naphthyl group or an anthracenyl group.

[0258] In a certain embodiment, when ring Y is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N", Y is a "5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O and N", for example, pyridyl or pyrimidinyl.

[0259] In one embodiment, when ring Y is C 4-8 When cycloalkenyl, the Y is C 5-7 Cycloalkenyl, for example, cyclohexenyl.

[0260] In a certain embodiment, when ring Y is a heterocyclyl group consisting of a "5-6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N" fused to a "5-6-membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", Y is a heterocyclyl group consisting of a "5-6-membered heteroaryl group containing 1-2 heteroatoms N" fused to a "5-6-membered heterocycloalkyl group containing 1 heteroatom N".

[0261] In a certain embodiment, when ring Y is a "4-8 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O, S and N", the "4-8 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O, S and N" is a "5-7 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O and N", for example, a 6-membered heterocycloalkenyl group containing 1-3 heteroatoms N.

[0262] In one solution, when n is 2, two R 2 When the two atoms are connected to each other and independently form together with the atoms in the ring to which they are connected a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N", the "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N" is a "3-6 membered heterocyclic ring containing 1-2 heteroatoms, which are independently selected from O, S and N".

[0263] In a certain scheme, when R 11 、R 12 、R 13 、R 14 、R 17 、R 18 、R 19 and R 20 is independently "a 4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" or is replaced by one or more R 1-3 When the substituted “4-12-membered heterocycloalkyl group containing 1-3 heteroatoms which are independently selected from O, S and N” is used, the “4-12-membered heterocycloalkyl group containing 1-3 heteroatoms which are independently selected from O, S and N” is “4-6-membered heterocycloalkyl group containing 1-2 heteroatoms which are independently selected from O and N”.

[0264] In a certain scheme, when R 11 、R 12 、R 13 、R 14 、R 17 、R 18 、R 19 and R 20When it is independently “a 5- to 12-membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N”, the “a 5- to 12-membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N” is a “5- to 6-membered heteroaryl group containing 1-2 heteroatoms which are independently selected from O, S and N”, for example, pyridyl.

[0265] In a certain scheme, when R 3 For one or more R 3-1 When the substituted “5-6 membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N” is used, the “5-6 membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N” is “5-6 membered heteroaryl group containing 1-3 heteroatoms which are independently selected from O, S and N”.

[0266] In a certain scheme, when R 3-1 are independently C substituted by one or more halogens 1-6 When alkyl, the C 1-6 Alkyl is a C substituted by two or three halogens 1-2 Alkyl, for example, -CHF2 or -CF3.

[0267] When R a2 and R a3 Forms C with the carbon atom to which it is attached 3-7 In the case of cycloalkanes, the C 3-7 The cycloalkane is cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0268] In one plan, for

[0269] In one scenario, R 3 for

[0270] In one plan, for

[0271] In one embodiment, ring Y is Furthermore, the upper end and the are connected.

[0272] In one plan, for

[0273] In one embodiment, the heteroaromatic ring structure compound as shown in Formula I can be any of the following structures:

[0274] The present invention also provides a pharmaceutical composition comprising substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the above-mentioned heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound.

[0275] The present invention also provides a use of a substance A in the preparation of a PARG inhibitor, wherein the substance A is the heteroaromatic ring structure compound shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

[0276] The present invention also provides a method for inhibiting PARG using substance A, comprising administering to a subject an effective amount of substance A. The substance A is the heteroaromatic ring structure compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotope thereof.

[0277] The present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent PARG-mediated diseases; the substance A is the above-mentioned heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound.

[0278] The present invention also provides a method for treating or preventing PARG-mediated diseases using substance A, comprising administering to a subject an effective amount of substance A. The substance A is the heteroaromatic ring structure compound represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

[0279] The present invention also provides a use of a substance A in the preparation of a medicament, wherein the medicament is used to treat or prevent cancer; the substance A is the heteroaromatic ring structure compound represented by Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof. The cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0280] The present invention also provides a method for treating or preventing cancer using substance A, comprising administering an effective amount of substance A to a subject. The substance A is the heteroaromatic ring structure compound shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof. The cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0281] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0282] In the present invention, when there are multiple substituents, they may be the same or different.

[0283] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms or groups of atoms in a molecule in the same order of interconnection, such as cis-trans isomers, optical isomers, or atropisomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis or chiral separation methods (including but not limited to thin-layer chromatography, rotary chromatography, column chromatography, gas chromatography, and high-pressure liquid chromatography). They can also be obtained by chiral resolution through bonding (chemical bonding, etc.) or salification (physical bonding, etc.) with other chiral compounds.

[0284] The term "tautomer" refers to functional group isomers that result from the rapid shift of an atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can be interconverted by the rapid shift of a hydrogen atom between an oxygen and an α-carbon.

[0285] The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). The isotopic compounds of the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein.

[0286] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0287] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0288] The term "alkylene" refers to a connecting group between two other groups, which can also be straight or branched. Examples include but are not limited to -CH2-, -CH2CH2-, -CH2CH2CH2CH(CH3)-, -CH2CH(CH2CH3)CH2-.

[0289] The terms "cycloalkyl" and "carbocycle" refer to a saturated cyclic group consisting solely of carbon atoms, having a specified number of carbon atoms (e.g., C3-C6), and being monocyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0290] The term "aryl" refers to an aromatic group consisting of carbon atoms, with each ring having aromatic properties, such as phenyl or naphthyl.

[0291] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0292] The term "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic, bridged, or spirocyclic, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0293] The term "hydroxy" refers to an -OH group.

[0294] The term "cyano" refers to a -CN group.

[0295] The term "oxo" refers to a =0 group.

[0296] The term “a 3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N” means “a 3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and if there are other heteroatoms, the other heteroatoms are independently selected from O, S and N”, and the combinations of heteroatoms are (N, O and S), (N and S), (N and O) and N.

[0297] The "C" that determines the carbon number range x1 -C y1 " substituents (x1 and y1 are integers), such as "C x1 -C y1 "Alkyl, "C x1 -C y1 "Cycloalkyl", "C x1 -C y1 "Cycloalkenyl", "C x1 -C y1 "alkoxy", "C x1 -C y1 "Alkenyl, "C x1 -C y1 "Alkynyl, "C x1 -C y1 "Aryl, "C x1 -C y1 "heteroaryl or "Cx1 -C y1 "Heterocyclic group" refers to the number of carbon atoms not including substituents, for example, C1-C6 alkyl refers to C1-C6 alkyl not including substituents.

[0298] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0299] The reagents and raw materials used in the present invention are commercially available.

[0300] The positive progress of the present invention is that: the present invention provides a heteroaromatic ring structure compound, its pharmaceutical composition and application, the heteroaromatic ring compound has a good inhibitory effect on various disease cells involved in PARG, and is expected to treat and / or prevent various diseases involved in PARG. DETAILED DESCRIPTION

[0301] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0302] In the present invention, room temperature refers to ambient temperature, which is 10°C to 35°C. Overnight refers to 8 to 15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

[0303] The solvents used in the following examples are all analytically pure or chromatographically pure. When the solvents used in the following examples are mixed solvents, the ratios are by volume unless otherwise specified.

[0304] The following is a list of abbreviations used in the examples: DCM dichloromethane DMF N,N-dimethylformamide EA ethyl acetate DMSO dimethyl sulfoxide DMAP 4-dimethylaminopyridine DIPEA diisopropylethylamine TEA triethylamine TBSCl tert-butyldimethylchlorosilane TMS trimethylsilyl NCS N-chlorosuccinimide LHMDS lithium hexamethyldisilazide Oxone potassium peroxymonosulfonate Pd(dtbpf)Cl2 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium Pd(Amphos)Cl2 dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) Mn(TMHD)3 tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese Pd2(dba)3 trisdibenzylideneacetone dipalladium m-CPBA m-chloroperbenzoic acid Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl THF Tetrahydrofuran THP 2-Tetrahydropyran TFA Trifluoroacetic acid Ms Methanesulfonyl Tf Trifluoromethanesulfonyl DBDMH Dibromohydantoin SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride DHP 3,4-Dihydro-2H-pyran RuPhos Pd G3 Methanesulfonic acid (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) NMM N-Methylmorpholine [Ir(COD)OMe]2 (1,5-Cyclooctadiene)(methoxy)iridium(I) dimer

[0305] Synthesis route of intermediate I-1

[0306] Synthesis of compound I-1-f

[0307] Chlorosulfonic acid (30 mL) was added to the reaction flask. 1-Methyl-3-methoxycarbonyl indazole (10 g, 52.58 mmol) was added portionwise over 10 minutes under an ice bath. The reaction was allowed to react at room temperature for 5 minutes. The reaction mixture was stirred at 65°C for 18 hours (with an exhaust gas drying and absorption device). The reaction mixture was cooled to room temperature and added dropwise to 300 g of ice. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford I-1-f (13.5 g, 89%).

[0308] Synthesis of compound I-1-e

[0309] I-1-f (13.5 g, 46.76 mmol) and dichloromethane (135 mL) were added to a reaction flask. Dibromohydantoin (13.37 g, 46.76 mmol) was added under ice-cooling. Trifluoromethanesulfonic acid (5 mL) was added dropwise to the suspension. The reaction mixture was stirred in an ice-cooling bath for 10 minutes and then stirred at room temperature for 1.5 hours. Trifluoromethanesulfonic acid (5 mL) was added dropwise to the suspension. Dichloromethane (60 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Ice water was added to the reaction mixture, extracted twice with ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate 100:0 to 60:40) to obtain product I-1-e (10.1 g, 59%).

[0310] Synthesis of compound I-1-d

[0311] 1-Amino-1-cyclopropylcarbonitrile hydrochloride (7.05 g, 59.46 mmol), pyridine (35 mL), and a small amount of 3A molecular sieves were added to the reaction flask. Stir on ice for 5 minutes. Over 5 minutes, a solution of I-1-e (10.1 g, 27.48 mmol) in dichloromethane (70 mL) containing dry molecular sieves was added dropwise. React on ice for 10 minutes, then at room temperature for 2 hours. The solvent was removed by vortexing. Ice water and solid sodium bisulfate were added to a pH of 6-7. Petroleum ether was added, filtered, and the filter cake was washed with sodium bisulfate, water, and petroleum ether. The aqueous phase was extracted with ethyl acetate, the extract was washed with water, evaporated to dryness, and slurried with ethyl acetate and petroleum ether. The combined solids were dried under vacuum to give I-1-d (11.3 g, 100%). LC-MS (ESI): m / z 412.9 (M+H) + .

[0312] Synthesis of compound I-1-c

[0313] I-1-d (11.3 g, 27.34 mmol) and dichloromethane (150 mL) were added to the reaction flask. Triethylamine (12.5 mL, 89.93 mmol) was added under ice bath and stirred for 10 minutes. SEMCl (8.0 mL, 45.20 mmol) was added dropwise under ice bath and stirred for 10 minutes. Stir in a water bath at room temperature for 1.5 hours. The solvent was removed by vortexing at room temperature, water and ethyl acetate were added, stirred thoroughly and filtered, the filtrate was separated, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, and evaporated to dryness to obtain I-1-c (14.8 g, 100%). LC-MS (ESI): m / z 560.1 (M+NH4) + .

[0314] Synthesis of compound I-1-b

[0315] I-1-c (14.8 g, 27.23 mmol), anhydrous ethanol (150 mL) and hydrazine hydrate (10 mL, 206.15 mmol) were added to the reaction flask. The reaction solution was heated and stirred at 52°C for 7 hours. The reaction solution was cooled to room temperature. The solvent was removed by vortexing at room temperature, ice water was added, and the product was extracted twice with ethyl acetate. The product was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain I-1-b (14.5 g, 98%). LC-MS (ESI): m / z 1084.8 (2M+H) + .

[0316] Synthesis of compound I-1-a

[0317] I-1-b (14.5 g, 26.68 mmol) and dichloromethane (150 mL) were added to the reaction flask. Triethylamine (5.19 mL, 37.35 mmol) was added dropwise under ice bath. Stirred on ice bath for 5 minutes. Difluoroacetic anhydride (3.25 mL, 28.01 mmol) was added dropwise under ice bath. The reaction solution was stirred on ice bath for 1 hour. Methanol (2.5 mL) was added and stirred at room temperature after ice bath for 20 minutes. The solvent was removed by vortexing at room temperature. Water and ethyl acetate were added to the reaction flask, the phases were separated, the aqueous phase was extracted once, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 60 / 40) to obtain I-1-a (13.2 g, 80%). LC-MS (ESI): m / z 638.0 (M+NH4) + .

[0318] Synthesis of compound I-1

[0319] I-1-a (11.3 g, 18.18 mmol), Lawesson's reagent (17.75 g, 43.89 mmol), and THF (200 mL) were added to the reaction flask. The reaction mixture was heated and stirred at 80°C under argon for 10 hours. After cooling to room temperature, the solvent was removed by vortexing. The crude product was diluted with an ethyl acetate / petroleum ether mixture, washed three times with sodium bicarbonate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was added with ammonia methanol / methanol / dichloromethane (1:1:20) solution (200 mL) and stirred at room temperature for 2 hours. The product was evaporated to dryness and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain I-1 (5.8 g, 51%). LC-MS (ESI): m / z 619.0 (M+H) + .

[0320] Synthesis route of intermediate I-2

[0321] Synthesis of compound I-2-g

[0322] 3-Methoxycarbonyl indazole (12.4 g, 70.38 mmol) and dichloromethane (120 mL) were added to the reaction flask. Triethylamine (14.67 mL, 105.57 mmol) was added dropwise under an ice-water bath and stirred for 5 minutes. Methanesulfonyl chloride (6.81 mL, 87.98 mmol) was added dropwise under an ice-water bath. After the addition was completed, the reaction solution was stirred under an ice-water bath for 1 hour. The organic phase was evaporated to dryness, and water and petroleum ether were added to the residue, filtered, and the solid filter cake was washed with water and petroleum ether, dried on an oil pump, and then dried in a freeze dryer to obtain I-2-g (16.4 g, 92%). LC-MS (ESI): m / z 254.9 (M+H) + .

[0323] Synthesis of compound I-2-f

[0324] Chlorosulfonic acid (33 mL) was added to the reaction flask, and I-2-g (16.4 g, 64.50 mmol) was added in an ice-water bath. The reaction solution was reacted in an ice-water bath for 5 minutes and then stirred at 65°C for 5 hours. The reaction solution was cooled to room temperature and added dropwise to 400 g of ice. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain I-2-f (14.8 g, 84%).

[0325] Synthesis of compound I-2-e

[0326] I-2-f (14.8 g, 54.88 mmol) and dichloromethane (120 mL) were added to the reaction flask. TMSOTf (18 mL, 117.67 mmol) was added dropwise under an ice-water bath and stirred for 5 minutes. Dibromohydantoin (15.41 g, 53.88 mmol) and trifluoromethanesulfonic acid (7.5 mL, 84.76 mmol) were then added under an ice-water bath. The reaction solution was stirred at room temperature for 2 hours. Dichloromethane (150 mL) and trifluoromethanesulfonic acid (7.5 mL, 84.76 mmol) were added dropwise to the suspension. The reaction solution was stirred at room temperature for 5 hours. Ice water was added to the reaction solution, extracted twice with ethyl acetate, the organic phase was washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and dried at an oil pump to obtain I-2-e (19.05 g, 98%).

[0327] Synthesis of compound I-2-d

[0328] I-2-e (18.2 g, 51.47 mmol) and dichloromethane (200 mL) were added to a reaction flask. After stirring for 5 minutes in an ice-water bath, SEMCl (9.11 mL, 51.48 mmol) was added. After stirring for 5 minutes in an ice-water bath, triethylamine (7.16 mL, 51.48 mmol) was added dropwise over 15 minutes. The reaction solution was stirred for 30 minutes in an ice-water bath to obtain reaction solution A. 1-amino-1-cyclopropylnitrile hydrochloride (8.54 g, 72.07 mmol), pyridine (32 mL) and dichloromethane (60 mL) were added to a second reaction flask. After stirring for 5 minutes in an ice-water bath, reaction solution A was added by double needle transfer over 5 minutes in an ice-water bath. The reaction solution was reacted for 1 hour in an ice-water bath. Aqueous sodium bisulfate (10%) was added under an ice-water bath, the layers were separated, the aqueous phase was extracted once with dichloromethane, the organic phases were combined, washed with aqueous sodium bisulfate (5%), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain I-2-d (26 g, 95%). LC-MS (ESI): m / z 529.1 (M+H) + .

[0329] Synthesis of compound I-2-c

[0330] I-2-d (24.8 g, 46.84 mmol) and dichloromethane (200 mL) were added to the reaction flask. Triethylamine (13.0 mL, 93.53 mmol) was added under an ice-water bath and stirred for 5 minutes, and then SEMCl (9.6 mL, 54.24 mmol) was added dropwise under an ice-water bath. The mixture was stirred under an ice-water bath for 2 hours. Methanol (3 mL) was added to the reaction solution and stirred under an ice-water bath for 5 minutes. The solvent was removed by concentration under reduced pressure at room temperature, and the residue was diluted with ethyl acetate and petroleum ether. The organic phase was washed with 5% sodium bisulfate solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and dried at an oil pump to give I-2-c (30 g, 97%). LC-MS (ESI): m / z 659.1 (M+H) + .

[0331] Synthesis of compound I-2-b

[0332] I-2-c (30 g, 45.47 mmol) and anhydrous ethanol (180 mL) were added to the reaction flask. Hydrazine hydrate (13.5 mL, 278.31 mmol) was added to a room temperature water bath, and the reaction solution was heated and stirred at 55°C for 2 hours. Hydrazine hydrate (5.0 mL, 103.08 mmol) was added, and the reaction solution was heated and stirred at 55°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure at room temperature to remove the solvent, water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain I-2-b (26 g, 87%). LC-MS (ESI): m / z 659.2 (M+H) + .

[0333] Synthesis of compound I-2-a

[0334] I-2-b (26.0 g, 39.41 mmol) and dichloromethane (260 mL) were added to the reaction flask. Triethylamine (8.0 mL, 57.56 mmol) was added under ice-water bath. After the reaction solution was stirred under ice-water bath for 5 minutes, difluoroacetic anhydride (6.7 g, 38.50 mmol) was added dropwise over 15 minutes. The reaction solution was stirred under ice-water bath for 1 hour. A small amount of methanol was added to the reaction solution, and after stirring under ice-water bath for 5 minutes, an aqueous sodium bisulfate solution (5%) was added. The liquids were separated, and the aqueous phase was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 96.7 / 3.3) to obtain compound I-2-a (19.0 g, 65%). LC-MS (ESI): m / z 754.2 (M+NH4) + .

[0335] Synthesis of compound I-2

[0336] I-2-a (19 g, 25.75 mmol), anhydrous THF (190 mL) and Lawesson's reagent (35 g, 86.54 mmol) were added to the reaction flask. The reaction mixture was heated at 70°C for 12 hours. The reaction mixture was reacted at 75°C for 4 hours. The reaction solution was cooled to room temperature, and aqueous ammonia was added and stirred for 5 minutes in a water bath. The solvent was removed by concentration under reduced pressure, and the residue was diluted with ethyl acetate and petroleum ether. The organic phase was washed with water and aqueous ammonia (2%). The aqueous phase was back-extracted twice with ethyl acetate and petroleum ether (3:2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (mobile phase: (petroleum ether / dichloromethane 5:1) / ethyl acetate, 100 / 0 to 75 / 25) to obtain compound I-2 (6.3 g, 40%). LC-MS (ESI): m / z 605.0 (M+H) + .

[0337] Synthesis route of intermediate I-3

[0338] Synthesis of compound I-3

[0339] Compound 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (200 mg, 0.96 mmol) was dissolved in dichloromethane (20 mL), triethylamine (194 mg, 1.92 mmol) was added, and isopropylsulfonyl chloride (164 mg, 1.15 mmol) was added dropwise under ice-cooling. The reaction solution was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound I-3 (120 mg, 40%). LC-MS (ESI): m / z 316.2 (M+H) + .

[0340] Synthesis route of compound I-4

[0341] Synthesis of compound I-4

[0342] I-1 (80 mg, 0.13 mmol) and dichloromethane (5 mL) were added to the reaction flask. Trifluoroacetic acid (1 mL) was added dropwise at room temperature. After the addition, the reaction solution was allowed to react at room temperature for 4 hours. The reaction solution was concentrated at room temperature to remove the solvent, and the residue was diluted with dichloromethane. The residue was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / (petroleum ether / dichloromethane 4:1), 0% to 100%) to obtain compound I-4 (50 mg, 79%). LC-MS (ESI): m / z 488.9 [M+H] + .

[0343] Synthesis route of intermediate I-5

[0344] Synthesis of compound I-5-a

[0345] Under ice bath, thiosemicarbazide (3g, 32.9mmol) was added to difluoroacetic anhydride (8.6g, 49.4mol) in 4 batches. After the addition, the ice bath was removed and the reaction solution was stirred at 85°C for 36h. The reaction solution was cooled to room temperature and adjusted to pH 7-8 with saturated sodium bicarbonate solution under ice bath. Some solids precipitated and were filtered. The solids were washed with water (5mL). Acetonitrile (10mL) was added to the solids and the product was dried under reduced pressure. The filtrate was extracted 8 times with DCM:MeOH=10:1 (100mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH=10:1) to obtain the product. A total of compound I-5-a (1.6g, 32%) was obtained. LC-MS (ESI): m / z 152.1 (M+H) + ; 1 H NMR (400MHz, DMSO-d6): δ7.77 (s, 2H), 7.24 (t, J = 56.0Hz, 1H).

[0346] Synthesis of compound I-5

[0347] Compound I-5-a (400 mg, 2.65 mmol) was dissolved in anhydrous acetonitrile (20 mL), and copper bromide (620.1 mg, 2.78 mmol) was added. The mixture was cooled to 0°C, and isoamyl nitrite (1.183 g, 5.3 mmol) dissolved in 1 mL of acetonitrile was added dropwise. After the addition, the reaction solution was stirred at room temperature for 20 minutes and at 63°C for 12 hours. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was evaporated under reduced pressure to obtain a concentrate, which was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to obtain compound I-5 (370 mg, 65%).1 H NMR (400MHz, DMSO-d6): δ7.59 (t, J=52.0Hz, 1H).

[0348] Synthesis route of compound 1

[0349] Synthesis of compound 1-b

[0350] Compound I-2 (150 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (162 mg, 0.50 mmol) and 2-bromoethyl methyl ether (69 mg, 0.50 mmol) were added. The reaction mixture was heated to 70°C and stirred for 17 hours. 2-Bromoethyl methyl ether (69 mg, 0.50 mmol) was added, and stirring at 70°C was continued for 13 hours. The reaction mixture was cooled to room temperature, water (500 mL) was added, and extraction was performed with ethyl acetate (200 mL). The organic phase was separated, washed twice with water (500 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the desiccant was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, PE / EA 10 / 1) to obtain compound 1-b (80 mg, 48%).

[0351] Synthesis of compound 1-a

[0352] Compound 1-b (70 mg, 0.11 mmol), I-3 (67 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15 mg, 0.020 mmol), and potassium carbonate (44 mg, 0.32 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). The reaction solution was replaced with nitrogen three times, heated to 100°C, and stirred for 3 hours. The reaction solution was filtered through celite, water (100 mL) was added to the filtrate, and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 1-a (50 mg, 62%). LC-MS (ESI): m / z 772.2 (M+H) + .

[0353] Synthesis of compound 1

[0354] Compound 1-a (50 mg, 0.065 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added thereto in an ice-water bath, and the reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 1 (21 mg, 50%). LC-MS (ESI): m / z 642.1 (M+H) + .

[0355] Synthesis route of compound 2

[0356] Synthesis of compound 2-a

[0357] In a microwave tube, compound 1-b (75 mg, 0.11 mmol), 1-(isopropylsulfonyl)piperazine (43 mg, 0.22 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (10 mg, 0.012 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (5 mg, 0.011 mmol), and cesium carbonate (74 mg, 0.23 mmol) were added to 1,4-dioxane (4 mL). After bubbling with nitrogen for 3 minutes, the mixture was sealed and heated to 80°C with stirring for 14 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 2-a (40 mg, 45%). LC-MS (ESI): m / z 775.2 (M+H) + .

[0358] Synthesis of compound 2

[0359] Compound 2-a (40 mg, 0.052 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added thereto in an ice-water bath, and the reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 2 (14 mg, 42%). LC-MS (ESI): m / z 645.1 (M+H) + .

[0360] Synthesis route of compound 3

[0361] Synthesis of compound 3-a

[0362] In a microwave tube, compound I-1 (100 mg, 0.16 mmol), N,N-dimethyl-1-piperazinesulfonamide (47 mg, 0.24 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (14 mg, 0.017 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (8 mg, 0.017 mmol), and cesium carbonate (105 mg, 0.32 mmol) were added to 1,4-dioxane (4 mL). After bubbling with nitrogen for 3 minutes, the mixture was sealed and the reaction solution was heated and stirred at 80°C for 14 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 3-a (62 mg, 53%).

[0363] Synthesis of compound 3

[0364] Compound 3-a (60 mg, 0.082 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added thereto in an ice-water bath, and the reaction solution was stirred at room temperature for 1.5 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 3 (24 mg, 49%). LC-MS (ESI): m / z 602.1 (M+H) + .

[0365] Synthesis route of compound 4

[0366] Synthesis of compound 4-a

[0367] The compound 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (300 mg, 1.22 mmol) was dissolved in dichloromethane (15 mL). Triethylamine (124 mg, 1.23 mmol) was added. The mixture was stirred at room temperature for 10 minutes, followed by the addition of triethylamine (185 mg, 1.83 mmol). Isopropylsulfonyl chloride (209 mg, 1.47 mmol) was then added dropwise under ice-cooling. After the addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 4-a (177 mg, 46%). LC-MS (ESI): m / z 315.8 (M+H) + .

[0368] Synthesis of compound 4

[0369] Compound I-4 (100 mg, 0.20 mmol), 4-a (97 mg, 0.31 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (26 mg, 0.040 mmol), and cesium fluoride (93 mg, 0.61 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL). The reaction mixture was purged with nitrogen three times and then heated to 100°C with stirring for 12 hours. The reaction mixture was cooled to room temperature and filtered through celite. Water (50 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase: DCM / EA 3 / 1) and then by preparative HPLC (basic conditions) to obtain compound 4 (53 mg, 43%). LC-MS (ESI): m / z 598.2 (M+H) + .

[0370] Synthesis route of compound 5

[0371] Synthesis of compound 5-a

[0372] Compound 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (200 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL), triethylamine (194 mg, 1.92 mmol) was added thereto, and tetrahydropyran-4-sulfonyl chloride (184 mg, 1.15 mmol) was added dropwise under ice bath. After the addition, the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, water (100 mL) was added to the residue, and extracted with ethyl acetate (150 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 5-a (230 mg, 67%). LC-MS (ESI): m / z 358.1 (M+H) + .

[0373] Synthesis of compound 5

[0374] Compound I-4 (100 mg, 0.20 mmol), 5-a (109 mg, 0.31 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (26 mg, 0.040 mmol), and cesium fluoride (93 mg, 0.61 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 100°C for 12 hours. The reaction solution was filtered through celite, and water (50 mL) was added to the filtrate. The mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase: DCM / EA 1 / 1) and then by preparative HPLC (basic conditions) to obtain compound 5 (22 mg, 17%). LC-MS (ESI): m / z 640.2 (M+H) + .

[0375] Synthesis route of compound 6

[0376] Synthesis of compound 6-b

[0377] I-1-a (600 mg, 0.97 mmol), anhydrous tetrahydrofuran (10 mL), and Burgess reagent (345 mg, 1.45 mmol) were added to a microwave tube. After the addition, the microwave tube was sealed, heated to 80°C, and stirred overnight. The next day, the reaction solution was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 6-b (150 mg, 26%). LC-MS (ESI): m / z = 603.0 [M+H] + .

[0378] Synthesis of compound 6-a

[0379] To a reaction flask were added 6-b (120 mg, 0.20 mmol), I-3 (94 mg, 0.30 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1651823-59-4) (15 mg, 0.020 mmol), potassium phosphate (127 mg, 0.60 mmol), tetrahydrofuran (10 mL), and H2O (2 mL). After nitrogen substitution three times, the reaction solution was heated and stirred at 65°C for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product, which was then purified on a flash column (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to afford compound 6-a (100 mg, 71%). LC-MS (ESI): m / z 712.1 [M+H] + .

[0380] Synthesis of compound 6

[0381] To the reaction flask, 6-a (100 mg, 0.14 mmol) and dichloromethane (10 mL) were added. Trifluoroacetic acid (3 mL) was added dropwise at room temperature. After the addition was complete, the reaction solution was allowed to react at room temperature for 4 hours and then concentrated under reduced pressure to remove the solvent. Ethyl acetate was added to the residue and the organic phase was washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 6 (50 mg, 61%). LC-MS (ESI): m / z 582.1 [M+H] + .

[0382] Synthesis route of compound 7

[0383] Synthesis of compound 7-d

[0384] To a three-necked flask were added 6-bromo-4-chloro-1H-indazole (2.0 g, 8.64 mmol), Xantphos (500 mg, 0.86 mmol), 1,4-dioxane (50 mL), DIPEA (4.52 mL, 25.92 mmol), and methyl 3-mercaptopropionate (1.05 mL, 9.50 mmol). The atmosphere was purged with nitrogen twice, and Pd2(dba)3 (396 mg, 0.43 mmol) was added. The atmosphere was purged with nitrogen three times. The reaction mixture was heated at 90°C with stirring for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to afford compound 7-d (2.2 g, 94%). LC-MS (ESI): m / z = 271.1 [M+H] + .

[0385] Synthesis of compound 7-c

[0386] To a solution of 7-d (2.2 g, 8.13 mmol) in DMF (15 mL) was added 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (1.92 g, 8.93 mmol) and cesium carbonate (3.18 g, 9.75 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, water was slowly added to quench the reaction. A white solid precipitated and was filtered. The filter cake was dissolved in ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 7-c (2.4 g, 73%). LC-MS (ESI): m / z = 404.9 [M+H] + .

[0387] Synthesis of compound 7-b

[0388] Under ice bath, m-CPBA (3.2 g, 18.53 mmol) was added to a solution of 7-c (2.4 g, 5.93 mmol) in dichloromethane (100 mL). After addition, the reaction mixture was kept at 0°C and stirred for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporation at room temperature, and the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 7-b (1.6 g, 62%). LC-MS (ESI): m / z = 437.0 [M+H] + .

[0389] Synthesis of compound 7-a

[0390] 7-b (800 mg, 1.83 mmol), methanol (10 mL), and dichloromethane (10 mL) were added to the reaction flask. The reaction mixture was cooled to 0°C in an ice bath, and sodium methoxide (297 mg, 5.49 mmol) was added. The reaction mixture was kept in an ice bath for 1 hour. 1-Amino-1-cyclopropylcarbonitrile hydrochloride (869 mg, 7.33 mmol) was added, and the mixture was stirred for 10 minutes. The solvent was removed by concentration at room temperature and dried under vacuum for 20 minutes. DMF (8 mL) and a small amount of 3A molecular sieves were added. After stirring in an ice bath for 3 minutes, triethylamine (0.51 mL, 3.66 mmol) and 1-amino-1-cyclopropylcarbonitrile hydrochloride (217 mg, 1.83 mmol) were added. NCS (489 mg, 3.66 mmol) was then added in an ice bath. The reaction mixture was stirred in an ice bath for 1 hour. The mixture was diluted with ethyl acetate, washed with sodium bisulfite solution, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to give 7-a (400 mg, 51%). LC-MS (ESI): m / z = 430.9 [M+H] + .

[0391] Synthesis of compound 7

[0392] To the reaction flask were added 7-a (50 mg, 0.12 mmol), I-3 (55 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol), potassium acetate (34 mg, 0.35 mmol), 1,4-dioxane (2 mL), and H2O (2 mL). After nitrogen displacement three times, the reaction solution was heated and stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Ethyl acetate was added to the residue and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Purification by Prep-HPLC gave compound 7 (18 mg, 27%). LC-MS (ESI): m / z 584.2 [M+H] + .

[0393] Synthesis route of compound 8

[0394] Synthesis of compound 8

[0395] To a microwave tube were added 7-a (50 mg, 0.12 mmol), 1-(isopropylsulfonyl)piperazine (34 mg, 0.18 mmol), Ruphos (5 mg, 0.012 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium (CAS: 1435347-24-2) (16 mg, 0.019 mmol), cesium carbonate (113 mg, 0.35 mmol), and 1,4-dioxane (3 mL). The atmosphere was replaced with nitrogen three times and the tube was sealed. The reaction mixture was heated at 75°C overnight. After the reaction, the mixture was cooled to room temperature, 1,4-dioxane was removed by vortexing, and the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 8 (30 mg, 44%). LC-MS (ESI): m / z 587.2 [M+H] + .

[0396] Synthesis route of compound 9

[0397] Synthesis of compound 9

[0398] To a reaction flask were added I-4 (50 mg, 0.10 mmol), 4-isopropylsulfonylphenylboronic acid (47 mg, 0.20 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (13 mg, 0.020 mmol), cesium fluoride (47 mg, 0.31 mmol), 1,4-dioxane (9 mL), and H2O (1 mL). After nitrogen substitution three times, the reaction solution was heated and stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Purification by Prep-HPLC afforded compound 9 (31 mg, 51%). LC-MS (ESI): m / z 593.1 [M+H] + .

[0399] Synthesis route of compound 10

[0400] Synthesis of compound 10-1

[0401] 3-Chloro-2-fluoro-benzoic acid (6.99 g, 40.04 mmol), dibromohydantoin (9.16 g, 32.04 mmol) and dichloromethane (80 mL) were added to the reaction flask. Trifluoromethanesulfonic acid (5 mL) was added under ice bath. The reaction was continued in ice bath until it reached room temperature in water bath for 3 hours. The reaction solution was poured into ice water, ethyl acetate (80 mL) was added, the liquid was separated, and the aqueous phase was extracted once with dichloromethane. The organic phase was washed twice with water, the organic phases were combined, washed once with sodium bisulfite aqueous solution, washed once with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 10-1 (8.6 g, 85%). LC-MS (ESI): m / z 250.9 (MH) - .

[0402] Synthesis of compound 10-k

[0403] To the reaction flask, 10-1 (8.6 g, 33.93 mmol) and methanol (70 mL) were added dropwise. Thionyl chloride (6.5 mL) was added dropwise with stirring in an ice bath. The reaction mixture was heated and stirred at 80°C for 4 hours. The solvent was removed by vortexing and the mixture was dried at an oil pump for 1 hour to yield 10-k (9.0 g, 99%).

[0404] Synthesis of compound 10-j

[0405] 10-k (9.0 g, 33.65 mmol), anhydrous DMF (45 mL), and methyl thioglycolate (3.61 mL, 40.38 mmol) were added to the reaction flask. Lithium hydroxide (2.82 g, 117.77 mmol) was added to the water bath under nitrogen protection. The reaction solution was stirred at room temperature for 2 hours, poured into ice water containing acetic acid (9 mL), stirred for 2 minutes, and filtered. The product was dried at room temperature to obtain 10-j (10 g, 92%). LC-MS (ESI): m / z 321.0 (M+H) + .

[0406] Synthesis of compound 10-i

[0407] 10-j (6 g, 18.66 mmol), DMSO (40 mL) and lithium hydroxide monohydrate (3.15 g, 75.07 mmol) were added to the reaction flask. The reaction solution was heated and stirred at 80°C for 2 hours. Lithium hydroxide monohydrate (0.95 g, 22.64 mmol) was added. The reaction solution was heated and stirred at 100°C for 15 hours. After cooling to room temperature, acetic acid (4.5 mL) was added dropwise (be careful of gas release). After stirring at room temperature for 1 hour, acetic acid (1.5 mL) was added dropwise and continued to stir at room temperature for 1 hour. The reaction solution was poured into ice water (gas release), extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 10-i (4.0 g, 81%). LC-MS (ESI): m / z 260.8 (MH) - .

[0408] Synthesis of compound 10-h

[0409] 10-i (4.25 g, 16.13 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol), Xantphos (0.93 g, 1.61 mmol), 1,4-dioxane (60 mL), DIPEA (8.6 mL, 48.57 mmol) and methyl 3-mercaptopropionate (1.89 mL, 16.93 mmol) were added to the reaction flask. The atmosphere was replaced with nitrogen three times. The reaction solution was heated and stirred at 90°C for 6 hours. It was cooled to room temperature. The reaction solution was vortexed to remove the solvent, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 75 / 25) to obtain compound 10-h (3.5 g, 72%). LC-MS (ESI): m / z 301.0 (MH) - .

[0410] Synthesis of compound 10-g

[0411] To a reaction flask, 10-h (3.5 g, 11.56 mmol), dichloromethane (25 mL), and triethylamine (4.82 mL, 34.68 mmol) were added dropwise. Trifluoromethanesulfonic anhydride (4.89 g, 17.34 mmol) was added dropwise under an ice-salt bath. The reaction mixture was stirred under an ice-salt bath for 1 hour (the ice was essentially melted). Aqueous sodium bicarbonate solution was added and stirred for 5 minutes. The mixture was separated, dried, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to afford compound 10-g (3.2 g, 64%).

[0412] Synthesis of compound 10-f

[0413] To a reaction flask, 10-g (3.0 g, 6.90 mmol), anhydrous DMF (15 mL), anhydrous ethanol (7.5 mL) (dried over molecular sieves), and triethylamine (2.8 mL, 20.14 mmol) were added. Palladium acetate (0.090 g, 0.40 mmol) and 1,3-bis(diphenylphosphino)propane (0.38 g, 0.92 mmol) were added. The reaction solution was purged with carbon monoxide three times. The reaction solution was heated and stirred at 70-78°C under a carbon monoxide atmosphere for 3 hours. Then, the reaction solution was heated and stirred at 75°C under a carbon monoxide atmosphere for 5 hours. The reaction solution was cooled to room temperature. The solvent was partially removed by vortexing, and ice water was added. The solution was extracted once with a mixture of ethyl acetate and petroleum ether. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to yield compound 10-f (1.05 g, 42%). LC-MS (ESI): m / z 359.0 (M+H) + .

[0414] Synthesis of compound 10-e

[0415] 10-f (1.05 g, 2.93 mmol) and dichloromethane (20 mL) were added to the reaction flask. m-CPBA (1.26 g, 7.30 mmol) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1.5 hours. The mixture was washed once with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 78 / 32) to obtain compound 10-e (1.1 g, 96%). LC-MS (ESI): m / z 391.1 (M+H) + .

[0416] Synthesis of compound 10-d

[0417] To the reaction flask, 10-e (166 mg, 0.43 mmol), methanol (10 mL), and dichloromethane (10 mL) were added. Sodium methoxide (71 mg, 1.32 mmol) was added under ice-water bath. The reaction mixture was stirred under ice-water bath for 1 hour. 1-Amino-1-cyclopropylcarbonitrile hydrochloride (209 mg, 1.76 mmol) was added under ice-water bath. The organic solvent was drained at room temperature and dried on an oil pump for 30 minutes. 1-Amino-1-cyclopropylcarbonitrile hydrochloride (52 mg, 0.44 mmol) and DMF (10 mL) were added. Triethylamine (0.12 mL, 0.88 mmol) and NCS (176 mg, 1.32 mmol) were added under ice-water bath. The reaction mixture was stirred under ice-water bath for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 3) to give 10-d (153 mg, 97%).

[0418] Synthesis of compound 10-c

[0419] To the reaction flask, 10-d (153 mg, 0.41 mmol), ethanol (20 mL), and hydrazine hydrate (6 mL, 80.40 mmol) were added. The reaction mixture was stirred at 90°C for 12 hours. The reaction mixture was concentrated to give 10-c (153 mg, 100%). LC-MS (ESI): m / z 370.9 (M+H) + .

[0420] Synthesis of compound 10-b

[0421] To the reaction flask, 10-c (150 mg, 0.40 mmol), dichloromethane (20 mL), and triethylamine (0.08 mL, 0.61 mmol) were added. Difluoroacetic anhydride (84 mg, 0.49 mmol) was added dropwise under an ice-water bath. The reaction solution was stirred under an ice-water bath for 1 hour. Methanol (1 mL) was added to the reaction solution. The organic solvent was concentrated at room temperature. Purification by column chromatography (mobile phase: dichloromethane / methanol, 100 / 1 to 10 / 1) gave 10-b (59 mg, 33%). LC-MS (ESI): m / z 446.9 (MH) - .

[0422] Synthesis of compound 10-a

[0423] To the reaction flask were added 10-b (56 mg, 0.13 mmol), Lawesson's reagent (126 mg, 0.31 mmol), and 1,4-dioxane (10 mL). The reaction mixture was heated and stirred at 75°C under nitrogen for 8 hours. The reaction mixture was concentrated, quenched with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 5 / 1 to 1 / 1) to obtain 10-a (19 mg, 34%). LC-MS (ESI): m / z 446.9 (M+H) + .

[0424] Synthesis of compound 10

[0425] To a microwave tube were added 10-a (16 mg, 0.04 mmol), 1,4-dioxane (5 mL), I-3 (16 mg, 0.05 mmol), water (1 mL), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (7 mg, 0.01 mmol), and potassium phosphate (20 mg, 0.09 mmol). The microwave tube was purged with nitrogen several times, sealed, and heated to 110°C with stirring for 11 hours. The reaction solution was concentrated and purified by preparative HPLC to give compound 10 (1 mg, 5%). LC-MS (ESI): m / z 600.1 (M+H) + .

[0426] Synthesis route of compound 11

[0427] Synthesis of compound 11-b

[0428] 1,2,3,6-Tetrahydropyridine-4-boronic acid pinacol ester (220 mg, 1.05 mmol), triethylamine (320 mg, 3.16 mmol) and cyclopropylsulfonyl chloride (260 mg, 1.85 mmol) were added to dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate (30 mL) was added for washing. The organic phase was concentrated to give compound 11-b (291 mg, 88%). LC-MS (ESI): m / z 314.0 (M+H) + .

[0429] Synthesis of compound 11-a

[0430] 11-b (114 mg, 0.36 mmol), I-1 (150 mg, 0.24 mmol), potassium carbonate (100 mg, 0.72 mmol), PdCl2(dppf).CH2Cl2 (20 mg, 0.02 mmol) were added to a reaction flask, followed by 1,4-dioxane (30 mL) and water (6 mL). Under nitrogen protection, the mixture was stirred at 90°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3 / 1, 1 / 1) to obtain compound 11-a (116 mg, 66%). LC-MS (ESI): m / z 726.0 (M+H) + .

[0431] Synthesis of compound 11

[0432] 11-a (116 mg, 0.16 mmol) was added to a reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours under nitrogen. The reaction solution was concentrated under reduced pressure, solid potassium carbonate (3 g) and water (10 mL) were added, and ethyl acetate (10 mL) was added to the reaction flask. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (10 mL*3) to obtain compound 11 (60.3 mg, 63%). LC-MS (ESI): m / z 596.2 (M+H) + .

[0433] Synthesis of compound 12

[0434] Referring to the synthesis method of compound 11, cyclobutylsulfonyl chloride was used instead of cyclopropylsulfonyl chloride to synthesize compound 12. LC-MS (ESI): m / z 610.5 (M+H) + .

[0435] Synthesis of compound 13

[0436] Referring to the synthesis method of compound 11, 2-methylpropanesulfonyl chloride was used instead of cyclopropylsulfonyl chloride to synthesize compound 13. LC-MS (ESI): m / z 612.1 (M+H) + .

[0437] Synthesis of compound 14

[0438] Referring to the synthesis method of compound 11, 1-methyl-cyclopropanesulfonyl chloride was used instead of cyclopropylsulfonyl chloride to synthesize compound 14. LC-MS (ESI): m / z 610.5 (M+H) + .

[0439] Synthesis route of compound 15

[0440] Synthesis of compound 15-g

[0441] To a solution of compound 5-bromo-7-chloro-1H-indazole (2.0 g, 8.64 mmol) in 3,4-dihydro-2H-pyran (25 mL) was carefully added trifluoroacetic acid (0.066 mL, 0.86 mmol). After the addition was complete, the reaction was heated to 90°C and stirred for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 15-g (2.5 g, 92%). LC-MS (ESI): m / z 314.9 (M+H) + .

[0442] Synthesis of compound 15-f

[0443] To a microwave tube, add iridium methoxy(cyclooctadiene) dimer (104 mg, 0.16 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (85 mg, 0.32 mmol), pinacol diboronate (603 mg, 2.38 mmol), and methyl tert-butyl ether (6 mL). After nitrogen purge twice, stir at room temperature for 5 minutes. Add a solution of 15-g (0.5 g, 1.58 mmol) in methyl tert-butyl ether (6 mL). Purge the tube with nitrogen three times, seal the tube, and stir at 85°C for 3.5 hours. Evaporate the reaction mixture to dryness to obtain the boronate intermediate.

[0444] The boronate intermediate was dissolved in toluene (20 mL), and 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (556 mg, 2.38 mmol), palladium acetate (36 mg, 0.16 mmol), Xantphos (183 mg, 0.32 mmol), NMM (0.52 mL, 4.75 mmol), and water (10 mL) were added. The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 40°C and stirred for 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 15-f (400 mg, 54%). LC-MS (ESI): m / z 466.9 (M+H) + .

[0445] Synthesis of compound 15-e

[0446] 15-f (350 mg, 0.75 mmol), 1,4-dioxane (20 mL), Xantphos (43 mg, 0.075 mmol), DIPEA (0.39 mL, 2.25 mmol) and methyl 3-mercaptopropionate (0.099 mL, 0.90 mmol) were added to the reaction flask, the atmosphere was purged with nitrogen twice, Pd2(dba)3 (34 mg, 0.037 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction solution was heated and stirred at 85°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, evaporated to dryness, and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 15-e (350 mg, 92%). LC-MS (ESI): m / z 507.0 (M+H) + .

[0447] Synthesis of compound 15-d

[0448] To a solution of 15-e (350 mg, 0.69 mmol) in dichloromethane (20 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed by rotary evaporation at room temperature, and the mixture was diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford compound 15-d (250 mg, 86%). LC-MS (ESI): m / z 423.0 (M+H). + .

[0449] Synthesis of compound 15-c

[0450] To a solution of 15-d (250 mg, 0.59 mmol) in DMF (5 mL) was added cesium carbonate (385 mg, 1.18 mmol) and iodomethane (0.096 mL, 1.18 mmol) at room temperature. After the addition, the reaction was stirred at room temperature overnight. After the reaction was completed, ethyl acetate was added to dilute the mixture, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was separated and purified by rapid separation column (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 15-c (200 mg, 77%). LC-MS (ESI): m / z 437.4 (M+H) + .

[0451] Synthesis of compound 15-b

[0452] Under an ice-water bath, m-CPBA (237 mg, 1.37 mmol) was added to a solution of 15-c (200 mg, 0.46 mmol) in dichloromethane (10 mL). After the addition was complete, the reactants were kept at 0°C and stirred for 1 hour. After the reaction was completed, the solvent was removed by rotary evaporation at room temperature, ethyl acetate was added to dilute, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated and purified by rapid separation column (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 15-b (200 mg, 93%). LC-MS (ESI): m / z 469.0 (M+H) + .

[0453] Synthesis of compound 15-a

[0454] To a reaction flask, 15-b (200 mg, 0.43 mmol), methanol (10 mL), and dichloromethane (10 mL) were added. Sodium methoxide (69 mg, 1.28 mmol) was added under ice-water bath. The reaction was stirred under ice-water bath for 1 hour. 1-Amino-1-cyclopropylcarbonitrile hydrochloride (202 mg, 1.70 mmol) was added under ice-water bath. The organic solvent was removed at room temperature and the mixture was dried at an oil pump for 30 minutes. 1-Amino-1-cyclopropylcarbonitrile hydrochloride (51 mg, 0.43 mmol) and DMF (10 mL) were added. Triethylamine (0.73 mL, 0.85 mmol) and NCS (171 mg, 1.28 mmol) were added under ice-water bath. The reaction mixture was stirred under ice-water bath for 1 hour. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography (PE / EA=3 / 1, 1 / 1) to obtain 15-a (103 mg, 52%). LC-MS (ESI): m / z 462.9 (M+H) + .

[0455] Synthesis of compound 15

[0456] 15-a (46 mg, 0.10 mmol), I-3 (16 mg, 0.05 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (18 mg, 0.03 mmol), and potassium phosphate (20 mg, 0.09 mmol) were added to a microwave tube, followed by 1,4-dioxane (5 mL) and water (1 mL). The tube was sealed with nitrogen and stirred at 110°C for 11 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 15 (15.9 mg, 76%). LC-MS (ESI): m / z 616.4 (M+H) + ; 1 H NMR(400MHz,DMSO-d6):d 8.86(1H,d,J=2.0Hz),7.70(1H,d,J=2.0Hz),6.00(1H,s),4.24(3H,s),4.07(2H,d,J=2.4Hz),3.63(2H,t ,J=5.2Hz),3.42-3.54(1H,m),2.57(2H,s),1.40-1.47(2H,m),1.30-1.35(2H,m),1.30(6H,d,J=6.8Hz).

[0457] Synthesis route of compound 16

[0458] Synthesis of compound 16-b

[0459] Add diethyl methylphosphonate (850 mg, 5.59 mmol) and dichloromethane (4 mL) to the reaction flask and stir at 0°C for 10 minutes. Dissolve oxalyl chloride (709.14 mg, 5.59 mmol) in dichloromethane (4 mL) and slowly add dropwise to the reaction mixture. After addition, stir at 0°C under nitrogen, slowly warm to room temperature, and stir for another 12 hours. The reaction mixture is then directly used in the next step.

[0460] Synthesis of compound 16-a

[0461] 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (80 mg, 0.38 mmol), triethylamine (728 mg, 7.19 mmol) and dichloromethane (20 mL) were added to the reaction flask and stirred at 0°C for 10 minutes. 16-b (164 mg) was slowly added dropwise to the reaction solution and stirred at 0°C for 3 hours under nitrogen protection. The reaction solution was washed with saturated sodium bisulfate (30 mL). The sodium bisulfate washings were extracted with dichloromethane (10 mL*3). The organic phases were combined and concentrated to give compound 16-a (110 mg, 91%). LC-MS (ESI): m / z 316.2 (M+H) + .

[0462] Synthesis of compound 16

[0463] 16-a (60 mg, 0.19 mmol), I-4 (40 mg, 0.08 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (17 mg, 0.02 mmol), and potassium phosphate (52 mg, 0.25 mmol) were added to a microwave tube, followed by 1,4-dioxane (8 mL) and water (2 mL). The tube was sealed with nitrogen and stirred at 110°C for 11 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 16 (3.6 mg, 7%). LC-MS (ESI): m / z 598.1 (M+H) + .

[0464] Synthesis route of compound 17

[0465] Synthesis of compound 17-b

[0466] Compound I-1 (50 mg, 0.081 mmol), I-3 (51 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12 mg, 0.016 mmol), and potassium carbonate (33 mg, 0.24 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 100°C for 6 hours. The reaction solution was filtered through celite, and water (100 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 17-b (50 mg, 85%). LC-MS (ESI): m / z 728.2 (M+H) + .

[0467] Synthesis of compound 17-a

[0468] Compound 17-b (50 mg, 0.069 mmol) was dissolved in dichloromethane (4.5 mL), trifluoroacetic acid (1.5 mL) was added thereto in an ice-water bath, and the reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 17-a (33 mg, 80%). LC-MS (ESI): m / z 598.4 (M+H) +.

[0469] Synthesis of compound 17

[0470] 17-a (50 mg, 0.08 mmol) and dichloromethane (8 mL) were added to the reaction flask and stirred for 10 minutes under ice-salt bath conditions. Concentrated sulfuric acid (1 mL) was slowly added to the mixture. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. The reaction solution was poured into ice water (20 mL) and extracted with dichloromethane (20 mL). The organic phase was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 17 (22.7 mg, 44%). LC-MS (ESI): m / z 616.1 (M+H) + .

[0471] Synthesis route of compound 18

[0472] Synthesis of compound 18-f

[0473] To a sealed tube, add pinacol diboronate (1.21 g, 4.75 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (208 mg, 0.32 mmol), and methyl tert-butyl ether (10 mL). Under nitrogen, add methoxy(cyclooctadiene)iridium dimer (170 mg, 0.63 mmol). After replacing the nitrogen atmosphere twice, stir at room temperature for 10 minutes. Add a solution of 15-g (1.0 g, 3.17 mmol) in methyl tert-butyl ether (10 mL). After replacing the nitrogen atmosphere three times, stir at 85°C for 3.5 hours. The reaction mixture is concentrated to obtain the crude borate ester.

[0474] The crude borate was dissolved in toluene (20 mL) and water (10 mL), and I-5 (886 mg, 4.12 mmol), palladium acetate (71 mg, 0.32 mmol), Xantphos (367 mg, 0.63 mmol), and N-methylmorpholine (1.05 mL, 9.51 mmol) were added. The atmosphere was purged with nitrogen twice. The reaction mixture was stirred at 40°C for 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 18-f (1.0 g, 70%). LC-MS (ESI): m / z = 449.0 (M+H) + .

[0475] Synthesis of compound 18-e

[0476] 18-f (200 mg, 0.44 mmol), XANT PHOS (16 mg, 0.028 mmol), Pd2(dba)3 (11 mg, 0.01 mmol), 1,4-dioxane (4 mL), DIPEA (180 mg, 1.39 mmol) and methyl 3-mercaptopropionate (57 mg, 0.47 mmol) were added to the reaction flask and the atmosphere was replaced with nitrogen three times. The reaction solution was heated at reflux at 85°C for 2 hours. Cooled to room temperature. The reaction solution was evaporated to dryness, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 18-e (217 mg, 100%). LC-MS (ESI): m / z 489.0 (M+H) + .

[0477] Synthesis of compound 18-d

[0478] 18-e (217 mg, 0.44 mmol) and dichloromethane (4.5 mL) were added to the reaction flask. Trifluoroacetic acid (1.5 mL) was added dropwise in an ice bath. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by vortexing, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 18-d (179 mg, 100%). LC-MS (ESI): m / z 405.0 (M+H) + .

[0479] Synthesis of compound 18-c

[0480] 18-d (171 mg, 0.42 mmol), DMF (4.2 mL), and cesium carbonate (360 mg, 1.10 mmol) were added to the reaction flask. Methyl iodide (0.042 mL, 0.68 mmol) was added dropwise in an ice bath. The reaction solution was reacted at room temperature for 2 hours. A small amount of methanol and ethyl acetate were added. Rotary evaporation was performed at room temperature for 5 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 100 / 0 to 96 / 4) to obtain 18-c (140 mg, 79%). LC-MS (ESI): m / z 419.0 (M+H) + .

[0481] Synthesis of compound 18-b

[0482] To a microwave tube were added 18-c (175 mg, 0.42 mmol), 1,4-dioxane (20 mL), I-3 (250 mg, 0.79 mmol), water (5 mL), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (44 mg, 0.06 mmol), and sodium carbonate (206 mg, 1.94 mmol). The microwave tube was purged with nitrogen, sealed, and heated to 100°C with stirring for 3 hours. The reaction mixture was concentrated and purified by column chromatography (PE / EA = 5 / 1, 3 / 1) to give compound 18-b (176 mg, 74%). LC-MS (ESI): m / z 572.1 (M+H) + .

[0483] Synthesis of compound 18-a

[0484] To the reaction flask, 18-b (179 mg, 0.31 mmol), dichloromethane (20 mL), and m-CPBA (159 mg, 0.78 mmol) were added, cooled in an ice-water bath, and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (30 mL x 2). The organic phase was concentrated and purified by column chromatography (PE / EA = 3 / 1, 1 / 3) to afford compound 18-a (170 mg, 90%). LC-MS (ESI): m / z 604.1 (M+H). + .

[0485] Synthesis of compound 18

[0486] To a reaction flask, 18-a (80 mg, 0.13 mmol), methanol (10 mL), and dichloromethane (10 mL) were added. Sodium methoxide (21 mg, 0.40 mmol) was added under ice-water bath. The reaction mixture was stirred under ice-water bath for 1 hour. 1-(Fluoromethyl)cyclopropylamine hydrochloride (67 mg, 0.53 mmol) was added under ice-water bath. The solvent was concentrated at room temperature and dried over oil pump for 30 minutes. 1-(Fluoromethyl)cyclopropylamine hydrochloride (17 mg, 0.13 mmol) and DMF (10 mL) were added. Triethylamine (0.04 mL, 0.27 mmol) and NCS (53 mg, 0.40 mmol) were added under ice-water bath. The mixture was stirred under ice-water bath for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated and purified by Prep-HPLC to yield 18 (19.3 mg, 24%). LC-MS (ESI): m / z 605.1 (M+H) + .

[0487] Synthesis route of compound 19

[0488] Synthesis of compound 19

[0489] To a reaction flask, 18-a (87 mg, 0.14 mmol), methanol (10 mL), and dichloromethane (10 mL) were added, followed by the addition of sodium methoxide (23 mg, 0.43 mmol) under ice-water bath conditions. The reaction mixture was stirred under ice-water bath conditions for 1 hour. 1-Methylcyclopropylamine hydrochloride (62 mg, 0.58 mmol) was added under ice-water bath conditions. The solvent was concentrated at room temperature and dried over an oil pump for 30 minutes. 1-Methylcyclopropylamine hydrochloride (16 mg, 0.14 mmol) and DMF (10 mL) were added, followed by the addition of triethylamine (0.04 mL, 0.29 mmol) and NCS (58 mg, 0.43 mmol) under ice-water bath conditions. The mixture was stirred under ice-water bath conditions for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated and purified by Prep-HPLC to yield 19 (16.9 mg, 20%). LC-MS (ESI): m / z 587.1 (M+H) + .

[0490] Synthesis route of compound 20

[0491] Synthesis of compound 20-b

[0492] At room temperature, 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (105 mg, 0.50 mmol), triethylamine (203 mg, 2.01 mmol) and dichloromethane (10 mL) were added to the reaction flask, and N-BOC-azetidine-3-sulfonyl chloride (193 mg, 0.75 mmol) was slowly added dropwise. After the addition, the reaction solution was stirred at room temperature under nitrogen for 1 hour. The reaction solution was washed with saturated sodium bisulfate (30 mL) and the reaction solution was concentrated to give compound 20-b (186 mg, 87%). LC-MS (ESI): m / z 446.1 (M+NH4) + .

[0493] Synthesis of compound 20-a

[0494] 20-b (180 mg, 0.42 mmol), I-4 (100 mg, 0.20 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.06 mmol), and cesium fluoride (93 mg, 0.61 mmol) were added to a microwave tube, followed by 1,4-dioxane (9 mL) and water (1 mL), protected by nitrogen, and sealed. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EA=3 / 2, 1 / 3) to give compound 20-a (110 mg, 76%). LC-MS (ESI): m / z 711.1 (M+H) + .

[0495] Synthesis of compound 20

[0496] Compound 20-a (110 mg, 0.16 mmol), dichloromethane (10 mL), and trifluoroacetic acid (3 mL) were stirred at room temperature under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give compound 20 (66.3 mg, 70%). LC-MS (ESI): m / z 611.1 (M+H) + .

[0497] Synthesis route of compound 21

[0498] Synthesis of compound 21

[0499] To the reaction flask were added 20 (49 mg, 0.08 mmol), paraformaldehyde (49 mg), sodium cyanoborohydride (15 mg, 0.24 mmol), and methanol (20 mL), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated and purified by preparative HPLC to afford compound 21 (9.3 mg, 19%). LC-MS (ESI): m / z 625.5 (M+H) + .

[0500] Synthesis route of compound 22

[0501] Synthesis of compound 22-b

[0502] At room temperature, the compound toluene-4-sulfonic acid oxetane-3-yl ester (5 g, 21.90 mmol) was dissolved in 50 mL of DMF and potassium thioacetate (7.57 g, 65.72 mmol) was added. The reaction mixture was stirred at 100 ° C under nitrogen for 2 hours. The reaction solution was cooled to room temperature, 200 mL of water was added to the reaction solution, and extracted with ethyl acetate (300 mL). The organic phase was washed with saturated brine (200 mL * 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. The crude product 22-b (2.9 g, 100%) was obtained. The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 133.0 [M+H] + .

[0503] Synthesis of compound 22-a

[0504] At room temperature, compound NCS (4.04 g, 30.26 mmol) was dissolved in 30 mL of acetonitrile, and 2 M hydrochloric acid (5.67 mL, 11.35 mmol) was added. Compound 22-b (1.00 g, 7.57 mmol) was then dissolved in acetonitrile (10 mL) and slowly added dropwise to the above mixture. After approximately 15 minutes of dropwise addition, the reaction mixture was concentrated under reduced pressure at room temperature, and the residue was dissolved in 100 mL of diethyl ether. The organic phase was washed sequentially with saturated sodium bicarbonate solution (100 mL*2), saturated sodium thiosulfate solution (100 mL*2), and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at room temperature, and the residue was dissolved in 5 mL of DCM to obtain Solution A. Compound 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester hydrochloride (1.52 g, 6.19 mmol) was dissolved in 50 mL of DCM and TEA (5.26 mL, 37.83 mmol) was added under ice-water bath. The reaction mixture was stirred under ice-water bath for 10 minutes, and then solution A was added dropwise to the above mixture. After the addition was completed, the reaction mixture was stirred at room temperature for 30 minutes. 100 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (100 mL). The organic phase was washed with 10% sodium bisulfate solution (100 mL) and saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 22-a (1.2 g). LC-MS (ESI): m / z = 330.1 [M+H] + .

[0505] Synthesis of compound 22

[0506] At room temperature, compound I-4 (100 mg, 0.20 mmol) was dissolved in 18 mL of 1,4-dioxane, and compound 22-a (101 mg, 0.31 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (27 mg, 0.041 mmol), cesium fluoride (93 mg, 0.61 mmol), and water (2 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of water was added to the residue, and the mixture was extracted with DCM (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3) to obtain compound 22 (92 mg, 75%). LC-MS (ESI): m / z = 612.2 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ8.79 (1H, d, J = 2.0Hz), 7.70 (1H, t, J = 53.2Hz), 7.63 (1H, d, J = 1.6Hz), 6.08 (1H, brs), 5.96-5.91 (1H, m), 4.96-4.83 ( 3H,m),4.78(2H,t,J=5.6Hz),4.20(3H,s),4.02-3.96(2H,m),3.55(2H ,t,J=5.2Hz),2.60-2.53(2H,m),1.28-1.21(2H,m),1.16-1.10(2H,m).

[0507] Synthesis route of compound 23

[0508] Synthesis of compound 23-c

[0509] At room temperature, compound 1-methoxy-2-propanol (5 g, 55.48 mmol) was dissolved in 50 mL of DCM, and p-toluenesulfonyl chloride (11.63 g, 61.03 mmol) was added. DMAP (0.68 g, 5.55 mmol) was added under an ice-water bath, and TEA (11.57 mL, 83.22 mmol) was added dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. 200 mL of water was added to the reaction solution, and the mixture was extracted with DCM (200 mL). The organic phase was washed sequentially with 10% sodium bisulfate solution (200 mL) and saturated sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 23-c (13.5 g, 100%). The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 262.1 [M+NH4] + .

[0510] Synthesis of compound 23-b

[0511] At room temperature, compound 23-c (5 g, 20.47 mmol) was dissolved in 50 mL of DMF and potassium thioacetate (7.07 g, 61.40 mmol) was added. The reaction mixture was stirred at 100 ° C under nitrogen for 2 hours. The reaction solution was cooled to room temperature, 200 mL of water was added to the reaction solution, and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (200 mL * 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. The crude product 23-b (3.4 g) was obtained. The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 149.1 [M+H] + .

[0512] Synthesis of compound 23-a

[0513] At room temperature, compound NCS (3.60 g, 26.99 mmol) was dissolved in 30 mL of acetonitrile, and 2 M hydrochloric acid (5.06 mL, 10.12 mmol) was added. Compound 23-b (1.00 g, 6.75 mmol) was then dissolved in acetonitrile (10 mL) and slowly added dropwise to the above mixture. After approximately 15 minutes, the reaction mixture was concentrated under reduced pressure at room temperature, and the residue was dissolved in 100 mL of diethyl ether. The organic phase was washed sequentially with saturated sodium bicarbonate solution (100 mL*2), saturated sodium thiosulfate solution (100 mL*2), and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. The residue was dissolved in 5 mL of DCM to obtain Solution A. Compound 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester hydrochloride (1.33 g, 5.40 mmol) was dissolved in 30 mL of DCM. TEA (4.69 mL, 33.73 mmol) was added under ice-water bath. The reaction mixture was stirred under ice-water bath for 10 minutes, and then solution A was added dropwise to the mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. 100 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (100 mL). The organic phase was washed sequentially with 10% sodium bisulfate solution (100 mL x 2) and saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 23-a (1.7 g). LC-MS (ESI): m / z = 345.8 [M+H] + .

[0514] Synthesis of compound 23

[0515] At room temperature, compound I-4 (200 mg, 0.41 mmol) was dissolved in 36 mL of 1,4-dioxane, and compound 23-a (212 mg, 0.61 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (53 mg, 0.082 mmol), cesium fluoride (186 mg, 1.23 mmol), and water (4 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of water was added to the residue, and the mixture was extracted with DCM (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3) to obtain compound 23 (150 mg, 58%). LC-MS (ESI): m / z = 628.2 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ9.05 (1H, brs), 8.87 (1H, d, J = 2.0Hz), 7.71 (1H, t, J = 53.2Hz), 7.69 (1H, d, J = 1.6Hz), 6.02-5.96 (1H, m), 4.23 (3 H,s),4.05(2H,d,J=2.0Hz),3.70-3.56(4H,m),3.54-3.47(1H,m),3.32(3H,s),2.61-2.53(2H,m),1.47-1.39(2H,m),1.35-1.27(5H,m).

[0516] Synthesis route of compound 24

[0517] Synthesis of compound 24-b

[0518] At room temperature, the compound 2-isopropylthio-5-bromopyridine (500 mg, 2.15 mmol) was dissolved in 10 mL of DCM, and m-CPBA (1.09 g, 5.39 mmol) was added in batches. The mixture was stirred at room temperature under nitrogen for 30 minutes. 100 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with DCM (100 mL). The organic phase was washed with saturated sodium bicarbonate solution (100 mL) and water (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 24-b (665 mg). The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z=264.0 [M+H] + .

[0519] Synthesis of compound 24-a

[0520] At room temperature, compound 24-b (120 mg, 0.45 mmol) was dissolved in 10 mL of 1,4-dioxane. Diboronic acid pinacol ester (346 mg, 1.36 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (37 mg, 0.045 mmol), and potassium acetate (223 mg, 2.27 mmol) were added sequentially. The reaction mixture was stirred at 80°C under argon for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 10 mL of DCM and filtered through a short silica gel column (~10 cm). The filtrate was discarded and the column was further eluted with methanol (50 mL). The methanol filtrate was concentrated under reduced pressure, and the residue was dried under vacuum for 30 minutes to obtain crude product 24-a (100 mg). The crude product was used directly in the next step without further purification. LC-MS (ESI): m / z = 230.0 [M+H] + .

[0521] Synthesis of compound 24

[0522] At room temperature, compound I-4 (50 mg, 0.10 mmol) was dissolved in 18 mL of 1,4-dioxane, and compound 24-a (47 mg, 0.20 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (13 mg, 0.020 mmol), cesium fluoride (47 mg, 0.31 mmol), and water (2 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 50 mL of water was added to the residue, and the mixture was extracted with DCM (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3) to obtain compound 24 (15.4 mg, 25%). LC-MS (ESI): m / z = 594.1 [M+H] + .

[0523] Synthesis route of compound 25

[0524] Synthesis of compound 25-b

[0525] Isopropyl disulfide (606 mg, 4.03 mmol) and acetic acid (0.461 mL, 8.06 mmol) were added to the reaction flask. The mixture was stirred in an ice-salt bath for 5 minutes, and then sulfonyl chloride (1632 mg, 12.10 mmol) was added dropwise over 10 minutes. The reaction mixture was reacted at -20°C to room temperature for 3 hours, followed by 1 hour at 35°C. The solvent was removed by rotary evaporation at room temperature to yield 25-b (900 mg, 88%).

[0526] Synthesis of compound 25-a

[0527] 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (105 mg, 0.50 mmol), dichloromethane (5 mL) and triethylamine (0.275 mL, 1.98 mmol) were added to the reaction flask. 25-b (102 mg, 0.81 mmol) was added dropwise under ice bath. The reaction solution was stirred in ice bath for 1 hour. The reaction mixture was placed in the lower layer of the refrigerator overnight. The solvent was removed by rotary evaporation, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 25-a (120 mg, 80%). LC-MS (ESI): m / z 300.1 (M+H) + .

[0528] Synthesis of compound 25

[0529] 25-a (120 mg, 0.40 mmol), I-4 (106 mg, 0.22 mmol), Pd(Amphos)Cl2 (12 mg, 0.017 mmol), anhydrous potassium phosphate (136 mg, 0.64 mmol), 1,4-dioxane (2.5 mL) and water (0.5 mL) were added to a microwave tube. The atmosphere was replaced with nitrogen five times. The reaction mixture was heated and stirred for 18 hours. The upper organic phase of the reaction mixture was dried by spin drying, dissolved in DMF and purified by preparative HPLC (ammonium bicarbonate) to obtain 25 (36.5 mg, 29%). LC-MS (ESI): m / z 582.1 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ9.13(1H,bs),8.86(1H,d,J=1.2Hz),7.87–7.54(2H,m),6.00(1H,s),4.23(3H,s),3.95–3.78(2H,m),3.55–3.3 9(2H,m),3.11(1H,p,J=6.8Hz),2.69–2.53(2H,m),1.46–1.38(2H,m),1.35–1.26(2H,m),1.24(3H,d,J=6.8Hz),1.14(3H,d,J=6.8Hz).

[0530] Synthesis route of compound 26

[0531] Synthesis of compound 26-b

[0532] I-2 (150 mg, 0.25 mmol), N,N-dimethylaminoethyl bromide hydrobromide (86 mg, 0.37 mmol), cesium carbonate (323 mg, 0.99 mmol) and DMF (2.5 mL) were added to a microwave tube. The mixture was sealed and heated with stirring at 70°C for 18 hours. The reaction solution was heated and stirred at 70°C for 4 hours. The reaction solution was cooled to room temperature, ice water was added, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 26-b (125 mg, 74%). LC-MS (ESI): m / z 675.9 (M+H) + .

[0533] Synthesis of compound 26-a

[0534] 26-b (125 mg, 0.18 mmol), I-3 (80 mg, 0.25 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), potassium carbonate (76 mg, 0.55 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were added to a microwave tube. The microwave tube was purged with nitrogen four times and sealed. The reaction mixture was heated and stirred at 100°C for 3 hours. Additional Pd(dppf)Cl2 (18 mg, 0.025 mmol) was added, and the microwave tube was purged with nitrogen four times and sealed. The reaction mixture was heated and stirred at 100°C for 18 hours. The reaction mixture was cooled, ethyl acetate was added, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 0 / 100) to yield 26-a (120 mg, 85%). LC-MS (ESI): m / z 785.1 (M+H) + .

[0535] Synthesis of compound 26

[0536] 26-a (120 mg, 0.15 mmol) and dichloromethane (2 mL) were added to the reaction flask. Trifluoroacetic acid (0.7 mL) was added dropwise under ice bath. After the addition, the reaction solution was naturally warmed to room temperature and reacted for 2 hours. The reaction solution was spin-dried. Saturated sodium bicarbonate aqueous solution and anhydrous potassium carbonate solid were added to the residue, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (DCM / MeOH, 100 / 0 to 85 / 15) to obtain the crude product, which was then purified (ammonium bicarbonate) to obtain 26 (22.2 mg, 23%). LC-MS (ESI): m / z 655.2 (M+H) + ; 1H NMR (DMSO-d6, 400MHz): δ8.95 (1H, bs), 8.89 (1H, d, J = 1.6Hz), 7.85–7.56 (2 H,m),6.13–6.05(1H,m),4.63(2H,t,J=6.8Hz),4.11–4.00(2H,m),3.63(2H, t,J=5.2Hz),3.49(1H,p,J=6.8Hz),2.73(2H,t,J=6.4Hz),2.65–2.55(2H,m ),2.13(6H,s),1.47–1.40(2H,m),1.38–1.30(2H,m),1.30(6H,d,J=6.8Hz).

[0537] Synthesis routes of compounds 27 and 28

[0538] Synthesis of compounds 27 and 28

[0539] To a two-necked flask, 17-a (100 mg, 0.17 mmol) and Mn(TMHD)3 (18 mg, 0.030 mmol) were added. Isopropyl alcohol (2 mL) and dichloromethane (1 mL) were slowly added along the side of the flask under the protection of an air balloon in an ice bath. Phenylsilane (46 mg, 0.43 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution (2 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate and saturated brine were added, the layers were separated, and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative HPLC (ammonium bicarbonate) to afford 27 (14.8 mg, 14%) and 28 (21.8 mg, 21%).

[0540] Compound 27, LC-MS (ESI): m / z 602.1 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ8.73(1H,s),8.59(2H,bs),7.80–7.49(2H,m),6.19(1H,s),3.72–3.62(2H,m),3.45–3.4 1(3H,m),2.38–2.27(2H,m),1.94(2H,d,J=12.8Hz),1.43–1.34(2H,m),1.28(6H,d,J=6.8Hz),1.26–1.22(2H,m).

[0541] Compound 28, LC-MS (ESI): m / z 616.1 (M+H) + ; 1H NMR (DMSO-d6, 400MHz): δ8.97(1H,d,J=1.6Hz),8.86(1H,bs),7.87(1H,d,J=1.6Hz),7.71(1H,t,J=53.2Hz),6.17(1H,s),4.67(3H,s),3.68( 2H,d,J=11.6Hz),3.52–3.40(3H,m),2.22(2H,d,J=12.8Hz),2.15–2.01(2H,m),1.46–1.40(2H,m),1.35–1.30(2H,m),1.27(6H,d,J=6.8Hz).

[0542] Synthesis route of compound 29

[0543] Synthesis of compound 29-f

[0544] To a reaction flask, add 4-hydroxycyclohexanone glycol acetal (3.16 g, 19.97 mmol), DCM (50 mL), and triethylamine (8.33 mL, 59.92 mmol). Add TsCl (5.71 g, 29.95 mmol) and DMAP (0.24 g, 2.00 mmol) under ice-cooling. Stir the reaction mixture in an ice-cooling bath for 10 minutes and then at room temperature for 18 hours. The solvent was removed by vortexing, and the residue was diluted with ethyl acetate and petroleum ether, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford 29-f (6.2 g, 99%).

[0545] Synthesis of compound 29-e

[0546] 29-f (1.2 g, 3.84 mmol), potassium thioacetate (0.71 g, 6.15 mmol), and DMF (10 mL) were added to the reaction flask. The reaction solution was heated and stirred at 80°C for 7 hours. Ice water was added to the reaction solution and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 29-e (800 mg, 96%). LC-MS (ESI): m / z 217.0 (M+H) + .

[0547] Synthesis of compound 29-d

[0548] To a reaction flask, 29-e (800 mg, 3.70 mmol), 2-iodopropane (0.94 mL, 9.41 mmol), and anhydrous ethanol (15 mL) were added. Potassium tert-butoxide (1060 mg, 9.45 mmol) was added under ice-cooling. The reaction mixture was stirred on ice for 10 minutes and then at room temperature overnight. The solvent was removed by vortexing, and ethyl acetate and ice water were added. The layers were separated, and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 75 / 25) to afford 29-d (600 mg, 75%).

[0549] Synthesis of compound 29-c

[0550] To a reaction flask, add 29-d (600 mg, 2.77 mmol), tetrahydrofuran (10 mL), and aqueous hydrochloric acid (4 mL, 4 M). Stir the reaction mixture at room temperature overnight. Remove the tetrahydrofuran by vortexing at room temperature, add purified water, and extract twice with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to yield 29-c (470 mg, 98%).

[0551] Synthesis of compound 29-b

[0552] Add 29-c (470 mg, 2.73 mmol) and anhydrous tetrahydrofuran (5 mL) to a reaction flask. Slowly add a 1 M solution of LHMDS in tetrahydrofuran (4.0 mL, 4.00 mmol) dropwise at -78°C. Incubate the reaction mixture at -78°C for 1 hour. Slowly add a solution of N-phenylbis(trifluoromethanesulfonyl)imide (1300 mg, 3.64 mmol) in anhydrous tetrahydrofuran (5 mL) dropwise at -78°C. Incubate the reaction mixture at -78°C to room temperature for 2 hours. Refrigerate overnight. Add ethyl acetate and petroleum ether, wash twice with water, then with 5% sodium bicarbonate solution and saturated brine. Dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 29-b (830 mg, 100%).

[0553] Synthesis of compound 29-a

[0554] To a microwave tube, add pinacol diboronate (860 mg, 3.39 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (100 mg, 0.12 mmol), potassium acetate (800 mg, 8.15 mmol), and a solution of 29-b (830 mg, 2.73 mmol) in 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen three times, the tube was sealed, and the reaction mixture was heated and stirred at 90°C for 5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and petroleum ether were added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to afford 29-a (440 mg, 57%).

[0555] Synthesis of compound 29

[0556] To a microwave tube, add 29-a (153 mg, 0.54 mmol), I-4 (200 mg, 0.41 mmol), Pd(dtbpf)Cl2 (28 mg, 0.043 mmol), cesium fluoride (180 mg, 1.19 mmol), 1,4-dioxane (8 mL), and water (2 mL). The reaction mixture was purged with nitrogen three times, sealed, and heated at 100°C with stirring for 3.5 hours. The reaction mixture was cooled to room temperature. Additional Pd(dtbpf)Cl2 (50 mg, 0.077 mmol), cesium fluoride (60 mg, 0.40 mmol), and 1,4-dioxane (2 mL) were added. The reaction mixture was purged with nitrogen three times, sealed, and heated at 100°C with stirring for 4 hours. The reaction mixture was cooled to room temperature. The reaction mixture was added to ice water and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 50 / 50) to give a crude product (130 mg). The crude product (40 mg) was purified by preparative HPLC (ammonium bicarbonate) to give 29 (18.5 mg, 8.0%). LC-MS (ESI): m / z 565.3 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ9.22(1H,brs),8.84(1H,d,J=1.6Hz),7.87–7.52(2H,m),5.57–5.53(1H,m),4.24(3H,s),3.27–3.18(1H,m),3.13(1H,h) ,J=6.8Hz),2.76–2.61(1H,m),2.50–2.47(2H,m),2.29–2.09(2H,m),1.8 9–1.75(1H,m),1.50–1.39(2H,m),1.33–1.29(2H,m),1.29–1.25(6H,m).

[0557] Synthesis routes of compounds 30 and 31

[0558] Synthesis of compounds 30 and 31

[0559] To a reaction flask, 29 (85 mg, 0.15 mmol) and acetone (4 mL) were added. A solution of Oxone (60 mg, 0.098 mmol) in water (2 mL) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred on ice for 1 hour and then at room temperature for 1 hour. An additional amount of Oxone (5 mg, 0.008 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by preparative HPLC (ammonium bicarbonate) to afford 30 (25 mg, 29%) as a white solid and 31 (16 mg, 18%) as a white solid.

[0560] Compound 30, LC-MS (ESI): m / z 581.1 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ9.22(1H,bs),8.85(1H,d,J=1.2Hz),7.88–7.51(2H,m),6.01–5.86(1H,m),4.23(3H,s),3.20–3.03( 2H,m),2.98(1H,p,J=6.8Hz),2.70–2.54(2H,m),2.38–2.07(2H,m),2.01–1.83(1H,m),1.48–1.38(2H,m),1.34–1.18(8H,m).

[0561] Compound 31, LC-MS (ESI): m / z 597.1 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ9.16(1H,bs),8.86(1H,d,J=1.2Hz),7.89–7.53(2H,m),5.99–5.85(1H,m),4.23(3H,s),3.79–3.65( 1H,m),3.48(1H,h,J=6.8Hz),2.72–2.53(4H,m),2.37–2.27(1H,m),2.00–1.83(1H,m),1.50–1.38(2H,m),1.35–1.25(8H,m).

[0562] Synthesis route of compound 32

[0563] Synthesis of compound 32-b

[0564] 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (80 mg, 0.38 mmol), triethylamine (728 mg, 7.19 mmol) and dimethylaminosulfonyl chloride (110 mg, 0.77 mmol) were added to dichloromethane (20 mL) and stirred at room temperature for 3 hours. The mixture was washed with saturated sodium bicarbonate (30 mL) and the organic phase was concentrated to obtain compound 32-b (98 mg, 81%). LC-MS (ESI): m / z 317.0 (M+H) + .

[0565] Synthesis of compound 32-a

[0566] 32-b (80 mg, 0.25 mmol), I-1 (46 mg, 0.07 mmol), potassium carbonate (124 mg, 0.90 mmol), PdCl2(dppf).CH2Cl2 (18 mg, 0.02 mmol) were added to a microwave tube, followed by 1,4-dioxane (4 mL) and water (1 mL). The tube was sealed with nitrogen and stirred at 90°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3 / 1, 1 / 1) to obtain compound 32-a (41 mg, 76%). LC-MS (ESI): m / z 729.1 (M+H) + .

[0567] Synthesis of compound 32

[0568] 32-a (41 mg, 0.06 mmol) was added to a reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, solid potassium carbonate (3 g) and water (10 mL) were added, and ethyl acetate (10 mL) was added to the reaction flask and stirred at room temperature for 2 hours. Extraction with ethyl acetate (10 mL*3) and purification by preparative HPLC gave compound 32 (18.3 mg, 54%). LC-MS (ESI): m / z 599.1 (M+H) + .

[0569] Synthesis route of compound 33

[0570] Synthesis of compound 33-b

[0571] At room temperature, compound isopropylsulfonamide (1.0 g, 8.12 mmol) was dissolved in 15 mL of chloroform, and tert-butyldimethylsilyl chloride (1.84 g, 12.18 mmol) was added. The mixture was cooled in an ice-water bath, and triethylamine (1.69 mL, 12.18 mmol) was slowly added dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate, washed with water (100 mL) and saturated brine (100 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 33-b (1.68 g, 87%). LC-MS (ESI): m / z = 238.1 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz) δ6.75 (1H, s), 3.03-2.96 (1H, m), 1.21 (6H, d, J = 6.8Hz), 0.89 (9H, s), 0.14 (6H, s).

[0572] Synthesis of compound 33-a

[0573] At room temperature, triphenylphosphine dichloride (814 mg, 2.44 mmol) was dissolved in 10 mL of chloroform. Triethylamine (0.46 mL, 3.30 mmol) was added dropwise under an ice-water bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction solution was cooled under an ice-water bath, and a solution of compound 33-b (600 mg, 2.53 mmol) in chloroform (5 mL) was added to the reaction solution and stirred under an ice-water bath for 20 minutes. Under an ice-water bath, a solution of 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester hydrochloride (200 mg, 0.81 mmol) in chloroform (5 mL) and triethylamine (0.17 mL, 1.22 mmol) was added to the reaction solution. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain crude compound 33-a (256 mg). The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 315.1 [M+H] + .

[0574] Synthesis of compound 33

[0575] At room temperature, compound I-4 (100 mg, 0.20 mmol) was dissolved in 36 mL of 1,4-dioxane, and compound 33-a (96 mg, 0.31 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (27 mg, 0.041 mmol), cesium fluoride (93 mg, 0.61 mmol), and water (4 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3) to obtain compound 33 (15 mg, 13%). LC-MS (ESI): m / z = 597.2 [M+H] + ; 1 H NMR (CDCl3, 400MHz) δ9.05 (1H, d, J = 2.0Hz), 7.75 (1H, d, J = 1.6Hz), 7.10 (1H, t, J = 54.0Hz), 6.34 (1H, s), 5.99-5.93 (1H, m), 4. 21(3H,s),4.18-4.12(2H,m),3.78-3.66(2H,m),3.42-3.31(1H,m),2.67-2.54(2H,m),1.67-1.60(2H,m),1.48-1.37(8H,m).

[0576] Synthesis route of compound 34

[0577] Synthesis of compound 34-c

[0578] To the reaction flask, add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester-3-carboxylic acid ethyl ester (300 mg, 0.79 mmol) and dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at room temperature. After the addition was complete, the reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure at room temperature. The crude product, compound 34-c (300 mg, 96%), was obtained. LC-MS (ESI): m / z 281.8 [M+H] + .

[0579] Synthesis of compound 34-b

[0580] Under an ice-water bath, 34-c (300 mg, 0.76 mmol), dichloromethane (10 mL), and triethylamine (0.53 mL, 3.80 mmol) were added to the reaction flask, followed by the dropwise addition of isopropylsulfonyl chloride (0.17 mL, 1.52 mmol). After completion of the addition, the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: methanol / dichloromethane: 0% to 10%) to obtain compound 34-b (250 mg, 85%). LC-MS (ESI): m / z = 388.4 [M+H] + .

[0581] Synthesis of compound 34-a

[0582] To a reaction flask were added I-4 (250 mg, 0.51 mmol), 34-b (238 mg, 0.61 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (66 mg, 0.10 mmol), cesium fluoride (233 mg, 1.53 mmol), 1,4-dioxane (18 mL), and H2O (2 mL). After nitrogen displacement three times, the reaction solution was heated and stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 34-a (250 mg, 73%). LC-MS (ESI): m / z = 670.5 [M+H] + .

[0583] Synthesis of compound 34

[0584] 34-a (100 mg, 0.15 mmol) was dissolved in THF (5 mL) and water (5 mL), and LiOH.H2O (25 mg, 0.60 mmol) was added. After the addition, the reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was neutralized with dilute hydrochloric acid to neutrality, concentrated under reduced pressure to remove the organic solvent, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 34 (35 mg, 37%). LC-MS (ESI): m / z 642.2 [M+H] + ; 1H NMR (DMSO-d6,400MHz): δ8.78(1H,s),7.71(1H,t,J=53.2Hz),7.50(1H,s),4.17(3H,s),4.08-4.34(2H,m),3.58-3.6 9(1H,m),3.43-3.56(2H,m),2.49-2.59(2H,m),1.34-1.41(2H,m),1.30(6H,dd,J=6.8,1.2Hz),1.13-1.20(2H,m).

[0585] Synthesis route of compound 35

[0586] Synthesis of compound 35-b

[0587] Referring to the synthetic route of intermediate I-1, using I-1-b as the starting material and using trifluoroacetic anhydride instead of difluoroacetic anhydride, compound 35-b was obtained.

[0588] Synthesis of compound 35-a

[0589] To a microwave tube were added 35-b (50 mg, 0.08 mmol), 1-(isopropylsulfonyl)piperazine (30 mg, 0.16 mmol), Ruphos (4 mg, 0.008 mmol), cesium carbonate (77 mg, 0.24 mmol), and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium (14 mg, 0.02 mmol). The mixture was purged with nitrogen three times. 1,4-Dioxane (1.5 mL) was added to the microwave tube, which was then purged with nitrogen three times and sealed. The reaction mixture was heated to 88°C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (5 mL*2), filtered, and the dichloromethane phase was concentrated under reduced pressure. Column chromatography (methanol / dichloromethane = 0 / 100; 1 / 10) gave compound 35-a (28 mg, 48%). LC-MS (ESI): m / z 749.3 (M+H) + .

[0590] Synthesis of compound 35

[0591] To the reaction flask were added 35-a (28 mg, 0.04 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 2 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and potassium carbonate (3 g), water (20 mL), and ethyl acetate (20 mL) were added to the residue. The mixture was stirred at room temperature for 2 hours. Extraction was performed with ethyl acetate (20 mL*2), and the organic phase was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 35 (6.1 mg, 26%). LC-MS (ESI): m / z 619.2 (M+H) + .

[0592] Synthesis route of compound 36

[0593] Synthesis of compound 36

[0594] Under an ice-water bath, LiCl (63 mg, 1.49 mmol) and NaBH4 (56 mg, 1.49 mmol) were added sequentially to a solution of 34-a (100 mg, 0.16 mmol) in THF (10 mL) and ethanol (5 mL). After the addition, the reaction solution was warmed to room temperature and stirred for 10 minutes, then heated to 50°C and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and carefully quenched by adding water. The residue was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to give compound 36 (15 mg, 15%). LC-MS (ESI): m / z 628.2 [M+H] + .

[0595] Synthesis route of compound 37

[0596] Synthesis of compound 37-b

[0597] At room temperature, compound I-2 (950 mg, 1.57 mmol) was dissolved in 20 mL of DMF and potassium carbonate (650 mg, 4.70 mmol) was added. The mixture was cooled in an ice-water bath, and then deuterated iodomethane (146 uL, 2.35 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred for 3 hours in an ice-water bath. 100 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL * 2), the organic phase was washed with saturated brine (100 mL * 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by rapid separation column (PE / EA = 2: 1) to obtain compound 37-b (538 mg, 55%). LC-MS (ESI): m / z = 622.0 [M + H] + .

[0598] Synthesis of compound 37-a

[0599] At room temperature, compound 37-b (76 mg, 0.12 mmol) was dissolved in 20 mL of 1,4-dioxane. Water (2 mL), compound I-3 (50 mg, 0.16 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (18 mg, 0.024 mmol), and potassium carbonate (51 mg, 0.37 mmol) were added sequentially. The reaction mixture was stirred at 100°C under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA = 1:1) to obtain compound 37-a (75 mg, 85%). LC-MS (ESI): m / z = 731.1 [M+H] + .

[0600] Synthesis of compound 37

[0601] At room temperature, compound 37-a (75 mg, 0.10 mmol) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was suspended in 5 mL of saturated sodium bicarbonate, potassium carbonate (500 mg) and ethyl acetate (50 mL) were added. After the reaction mixture was stirred at room temperature for 30 minutes, 50 mL of water was added to the reaction solution, extracted with ethyl acetate (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (NH4HCO3) to obtain a crude product. The crude product was further purified by prep-TLC (DCM / MeOH=40:1, 2 times) to obtain compound 37 (23.8 mg, 40%). LC-MS (ESI): m / z=601.1[M+H] + ; 1 H NMR(CDCl3,400MHz): δ9.07(1H,s),7.75(1H,s),7.10(1H,t,J=53.6Hz),6.04(1H,s),5.96(1H,s),4.12(2H,s),3.7 4-3.63(2H,m),3.33-3.26(1H,m),2.66-2.56(2H,m),1.68-1.61(4H,m),1.42(6H,d,J=6.8Hz).

[0602] Synthesis route of compound 38

[0603] Synthesis of compound 38

[0604] 17-a (50 mg, 0.084 mmol) and dichloromethane (5 mL) were added to the reaction flask. m-CPBA (18 mg, 0.10 mmol) was added under ice bath. The reaction solution was reacted at room temperature for 18 hours. m-CPBA (50 mg, 0.29 mmol) was added and the reaction was continued at room temperature for 48 hours. The solvent was removed by vortexing, and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate aqueous solution and anhydrous sodium sulfate solid were added, and the layers were separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified (ammonium bicarbonate) to obtain 38 (12 mg, 23%). LC-MS (ESI): m / z 614.1 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ8.92(1H,bs),8.91(1H,s),7.98(1H,s),7.71(1H,t,J=53.2Hz),4.42(3H,s),4.16–4.01(1H,m),3.88 (1H,s),3.79(1H,d,J=14.4Hz),3.52–3.43(2H,m),3.33–3.26(1H,m),2.44–2.12(2H,m),1.47–1.38(2H,m),1.33–1.20(8H,m).

[0605] Synthesis route of compound 39

[0606] Synthesis of compound 39-b

[0607] Under an ice-water bath, 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (250 mg, 1.20 mmol), dichloromethane (10 mL) and triethylamine (0.83 mL, 5.98 mmol) were added to the reaction flask, followed by the dropwise addition of tert-butyl 4-chlorosulfonylpiperidine-1-carboxylate (0.39 mL, 1.79 mmol). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 39-b (500 mg, 92%). LC-MS (ESI): m / z = 457.2 [M+H] + .

[0608] Synthesis of compound 39-a

[0609] To a reaction flask were added I-4 (50 mg, 0.10 mmol), 39-b (93 mg, 0.20 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (13 mg, 0.020 mmol), cesium fluoride (47 mg, 0.31 mmol), 1,4-dioxane (9 mL), and H2O (1 mL). After nitrogen displacement three times, the reaction solution was heated and stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Ethyl acetate was added to the residue and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 39-a (50 mg, 66%). LC-MS (ESI): m / z = 739.3 [M+H] + .

[0610] Synthesis of compound 39

[0611] To the reaction flask, 39-a (50 mg, 0.068 mmol) and dichloromethane (10 mL) were added, and trifluoroacetic acid (3 mL) was added dropwise at room temperature. After the addition was complete, the reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure at room temperature. Ethyl acetate was added to dilute the residue, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. Compound 39 (25 mg, 58%) was purified by Prep-HPLC. LC-MS (ESI): m / z 639.2 [M+H] + .

[0612] Synthesis route of compound 40

[0613] Synthesis of compound 40-b

[0614] Under ice-water bath, compound isopropylsulfonyl chloride (1.0 g, 7.01 mmol) was dissolved in 30 mL of dichloromethane, and methylamine hydrochloride (947 mg, 14.03 mmol) was added. The mixture was stirred under ice-water bath for 10 minutes, and then triethylamine (4.87 mL, 35.06 mmol) was slowly added dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. 100 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL). The organic phase was washed with 10% sodium bisulfate solution (100 mL) and saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature to obtain compound 40-b (208 mg, 22%). LC-MS (ESI): m / z = 138.0 [M+H] + .

[0615] Synthesis of compound 40-a

[0616] At room temperature, triphenylphosphine dichloride (488 mg, 1.47 mmol) was dissolved in 10 mL of chloroform. Triethylamine (275 uL, 1.98 mmol) was added dropwise under an ice-water bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction solution was cooled under an ice-water bath, and a solution of compound 40-b (208 mg, 1.52 mmol) in chloroform (2 mL) was added to the reaction solution and stirred under an ice-water bath for 20 minutes. Under an ice-water bath, a solution of 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester hydrochloride (120 mg, 0.49 mmol) in chloroform (5 mL) and triethylamine (102 uL, 0.73 mmol) was added to the reaction solution. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain crude compound 40-a (160 mg). The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 329.2 [M+H] + .

[0617] Synthesis of compound 40

[0618] At room temperature, compound I-4 (100 mg, 0.20 mmol) was dissolved in 36 mL of 1,4-dioxane, and compound 40-a (100 mg, 0.31 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (27 mg, 0.041 mmol), cesium fluoride (93 mg, 0.61 mmol), and water (4 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3) to obtain compound 40 (3 mg, 2.4%). LC-MS (ESI): m / z = 611.1 [M+H] + .

[0619] Synthesis of comparative compound 1′

[0620] Synthesized according to WO2021055744A1 method.

[0621] Synthesis route of compound 41

[0622] Synthesis of compound 41-b

[0623] The compound 5-bromo-2-chloropyrimidine (1 g, 5.17 mmol) and sodium 2-propanethiolate (760 mg, 7.74 mmol) were dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (1.43 g, 10.36 mmol) was added thereto. After the reaction solution was stirred at 50°C for 2 hours, water (200 mL) was added thereto, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and the desiccant was removed by filtration. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 10 / 1) to obtain 41-b (1.12 g, 93%).

[0624] Synthesis of compound 41-a

[0625] Compound 41-b (100 mg, 0.43 mmol) was dissolved in 1,4-dioxane (10 mL), and diboronic acid pinacol bis(pyrazolium chloride) (163 mg, 0.64 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (31 mg, 0.042 mmol), and potassium acetate (126 mg, 1.28 mmol) were added. The reaction mixture was stirred at 85°C under nitrogen for 12 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain compound 41-a (80 mg, 94%). LC-MS (ESI): m / z 199.1 (M+H) + .

[0626] Synthesis of compound 41

[0627] Compound I-4 (200 mg, 0.41 mmol), 41-a (162 mg, 0.82 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (53 mg, 0.082 mmol), and cesium fluoride (186 mg, 1.22 mmol) were added to 1,4-dioxane (27 mL) and water (3 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 100°C for 6 hours. The reaction solution was filtered through celite, and water (100 mL) was added to the filtrate. The mixture was extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, PE / EA 1 / 1). A portion of the product was further purified by preparative HPLC (basic conditions) to obtain compound 41 (25 mg, 11%). LC-MS (ESI): m / z 563.2 (M+H) + .

[0628] Synthesis route of compound 42

[0629] Synthesis of compound 42

[0630] Compound 41 (50 mg, 0.089 mmol) was dissolved in dichloromethane (6 mL), and m-chloroperoxybenzoic acid (20 mg, 0.12 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and then saturated sodium bicarbonate solution (10 mL) was added. The mixture was extracted with dichloromethane (50 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (basic conditions) to obtain compound 42 (13 mg, 25%). LC-MS (ESI): m / z 579.1 (M+H) + .

[0631] Synthesis route of compound 43

[0632] Synthesis of compound 43

[0633] Compound 41 (100 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (90 mg, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (50 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (basic conditions) to obtain compound 43 (32 mg, 30%). LC-MS (ESI): m / z 595.1 (M+H) + .

[0634] Synthetic routes of compounds 44 and 45

[0635] Synthesis of compound 44-f-2

[0636] At room temperature, compound I-2-d (5.0 g, 9.44 mmol) was dissolved in 20 mL of DMF, potassium carbonate (3.26 g, 23.59 mmol) was added, the mixture was cooled in an ice-water bath, and 4-methoxybenzyl chloride (1.93 mL, 14.17 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature overnight. 100 mL of water was added to the reaction solution, and then extracted with ethyl acetate (100 mL * 2). The organic phase was washed with saturated brine (100 mL * 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by a rapid separation column (PE / EA = 1:1 ~ EA) to obtain compound 44-f-1 (2.0 g, 33%), LC-MS (ESI): m / z = 649.1 [M + H] + Compound 44-f-2 (3.0 g, 61%). LC-MS (ESI): m / z = 519.1 [M+H]+ .

[0637] Synthesis of compound 44-e

[0638] At room temperature, compound 44-f-2 (3.0 g, 5.78 mmol) was dissolved in 30 mL of ethanol, and hydrazine hydrate (3.0 mL, 59.93 mmol) was added. The reaction mixture was stirred at 60°C under nitrogen for 3 hours, then cooled to room temperature, concentrated under reduced pressure, and the residue was dried under vacuum for 1 hour to obtain compound 44-e (3.0 g, 100%). LC-MS (ESI): m / z = 519.0 [M+H] + .

[0639] Synthesis of compound 44-d

[0640] Compound 44-e (1.0 g, 1.93 mmol) was dissolved in 15 mL of DCM at room temperature. Triethylamine (0.80 mL, 5.78 mmol) was added under ice-water bath, and the reaction mixture was stirred under ice-water bath for 10 minutes. Difluoroacetic anhydride (0.55 mL, 4.43 mmol) was added dropwise under ice-water bath until the reaction solution became clear. After the addition was complete, the reaction mixture was stirred under ice-water bath for 30 minutes, after which 5 mL of methanol was added and stirring continued for 10 minutes at the same temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate. The organic phase was washed sequentially with 10% NaHSO4 solution (100 mL), saturated sodium bicarbonate solution (100 mL), and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 44-d (1.15 g, 100%). LC-MS (ESI): m / z = 597.1 [M+H] + .

[0641] Synthesis of compound 44-c

[0642] At room temperature, compound 44-d (1.15 g, 1.93 mmol) was dissolved in 20 mL of anhydrous THF, and Lawesson's reagent (1.95 g, 4.81 mmol) was added. The reaction mixture was stirred at 80°C under nitrogen for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate. The organic phase was washed sequentially with saturated sodium bicarbonate solution (100 mL), 10% NaHSO4 solution (100 mL), and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA = 1:1) to obtain the crude product. The crude product was suspended in methyl tert-butyl ether (15 mL) and ultrasonically dispersed for 5 minutes. The mixture was filtered, and the filter cake was rinsed with methyl tert-butyl ether (5 mL). The filter cake was collected and dried under vacuum for 1 hour to obtain compound 44-c (330 mg, 29%). LC-MS (ESI): m / z = 595.1 [M+H] +

[0643] Synthesis of compound 44-b

[0644] At room temperature, compound 44-c (110 mg, 0.18 mmol) was dissolved in 36 mL of 1,4-dioxane, and compound I-3 (87 mg, 0.28 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (24 mg, 0.037 mmol), cesium fluoride (84 mg, 0.55 mmol), and water (4 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of water was added to the residue, and the mixture was extracted with DCM (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash column chromatography (PE / EA = 1:1) to obtain compound 44-b (110 mg, 87%). LC-MS (ESI): m / z = 704.3 [M+H] + .

[0645] Synthesis of compound 44-a

[0646] At room temperature, compound 44-b (58 mg, 0.082 mmol) was dissolved in 2 mL of DMF in a microwave tube. Potassium carbonate (36 mg, 0.26 mmol), potassium iodide (2.7 mg, 0.016 mmol), and bromomethylcyclopropane (24 uL, 0.25 mmol) were added sequentially. The reaction mixture was stirred at 50°C overnight. The reaction solution was cooled to room temperature and quenched with 50 mL of water. The mixture was then extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash column chromatography (PE / EA=1:1) to obtain compound 44-a (39 mg, 63%, a mixture of two isomers). LC-MS (ESI): m / z=758.3 [M+H] + .

[0647] Synthesis of compounds 44 and 45

[0648] At room temperature, compound 44-a (35 mg, 0.046 mmol) was dissolved in 2 mL of DCM, and methanesulfonic acid (150 uL, 2.31 mmol) was added under an ice-water bath. The reaction mixture was warmed to room temperature and stirred for 3 hours. 50 mL of DCM was added to the reaction solution, washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3 system) to obtain compound 44 (1.5 mg, 5%), LC-MS (ESI): m / z = 638.2 [M+H] + Compound 45 (9.1 mg, 31%). LC-MS (ESI): m / z = 638.2 [M+H] + .

[0649] Synthesis route of compound 46

[0650] Synthesis of compound I-6

[0651] 35-b (88 mg, 0.14 mmol) and dichloromethane (5 mL) were added to the reaction flask. Trifluoroacetic acid (1 mL) and water (0.1 mL) were added dropwise at room temperature. After the addition, the reaction solution was reacted at room temperature for 3 hours. The reaction solution was concentrated at room temperature to remove the solvent, and dichloromethane was added to the residue to dilute it, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The product was separated and purified by a rapid separation column (mobile phase: petroleum ether / ethyl acetate, 0% to 100%) to obtain compound I-6 (56 mg, 80%). LC-MS (ESI): m / z 506.9 [M+H] + .

[0652] Synthesis of compound 46-b

[0653] The compound 5-bromo-2-(isopropylthio)pyridine (200 mg, 0.86 mmol) was dissolved in 1,4-dioxane (20 mL). Diboronic acid pinacol ester (328 mg, 1.29 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (63 mg, 0.086 mmol), and potassium acetate (254 mg, 2.59 mmol) were added. The reaction solution was stirred at 95°C under nitrogen for 6 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give compound 46-b (169 mg, 99%). LC-MS (ESI): m / z 198.1 (M+H). + .

[0654] Synthesis of compound 46-a

[0655] Compound I-6 (200 mg, 0.39 mmol), 46-b (155 mg, 0.79 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (51 mg, 0.079 mmol), and cesium fluoride (180 mg, 1.18 mmol) were added to 1,4-dioxane (27 mL) and water (3 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 100°C for 6 hours. The reaction solution was filtered through celite, water (100 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 46-a (170 mg, 74%).

[0656] Synthesis of compound 46

[0657] Compound 46-a (86 mg, 0.15 mmol) was dissolved in dichloromethane (8 mL), and m-chloroperoxybenzoic acid (30 mg, 0.17 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (50 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (basic conditions) to obtain compound 46 (57 mg, 65%). LC-MS (ESI): m / z 596.2 (M+H) + .

[0658] Synthesis route of compound 47

[0659] Synthesis of compound 47

[0660] Compound 46-a (86 mg, 0.15 mmol) was dissolved in dichloromethane (8 mL), and m-chloroperoxybenzoic acid (90 mg, 0.52 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (50 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (basic conditions) to obtain compound 47 (60 mg, 66%). LC-MS (ESI): m / z 612.2 (M+H) + .

[0661] Synthesis route of compound 48

[0662] Synthesis of compound 48-d

[0663] Compound 35-b (200 mg, 0.31 mmol) was dissolved in toluene (6 mL), and bis(pinacol) borate (199 mg, 0.78 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (25 mg, 0.32 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.063 mmol), and potassium acetate (92 mg, 0.94 mmol) were added thereto. The reaction solution was purged with nitrogen three times and then stirred at 65°C for 8 hours. The reaction mixture was filtered through celite, and water (50 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give compound 48-d (200 mg, 93%).

[0664] Synthesis of compound 48-c

[0665] Under nitrogen at room temperature, 5-bromo-2-chloropyridine (3000 mg, 15.59 mmol) was dissolved in 30 mL of anhydrous THF. The mixture was cooled at -78°C and n-BuLi (7.5 mL, 18.71 mmol, 2.5 M) was added dropwise. After the addition, the mixture was stirred at -78°C under nitrogen for 30 minutes, followed by the dropwise addition of isopropyl disulfide (2.98 mL, 18.71 mmol). After the addition, the reaction mixture was stirred at room temperature under nitrogen for 1 hour. At room temperature, 100 mL of saturated ammonium chloride solution was slowly added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EA = 10:1) to afford compound 48-c (750 mg, 26%). LC-MS (ESI): m / z = 188.1 [M+H] + .

[0666] Synthesis of compound 48-b

[0667] Compound 48-c (446 mg, 2.38 mmol) was dissolved in dichloromethane (15 mL), and m-chloroperoxybenzoic acid (473 mg, 2.74 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 48-b (299 mg, 62%). LC-MS (ESI): m / z 204.1 (M+H) + .

[0668] Synthesis of compound 48-a

[0669] Compound 48-b (60 mg, 0.29 mmol), 48-d (200 mg, 0.29 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (38 mg, 0.059 mmol), and cesium fluoride (133 mg, 0.88 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 75°C for 3 hours. The reaction solution was filtered through celite, and water (50 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 2) to obtain compound 48-a (40 mg, 19%). LC-MS (ESI): m / z 726.2 (M+H) + .

[0670] Synthesis of compound 48

[0671] Compound 48-a (40 mg, 0.055 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 48 (12 mg, 36%). LC-MS (ESI): m / z 596.2 (M+H) + .

[0672] Synthesis route of compound 49

[0673] Synthesis of compound 49-b

[0674] Compound 48-b (200 mg, 0.98 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (498 mg, 2.89 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 3 / 1) to obtain compound 49-b (200 mg, 93%). LC-MS (ESI): m / z 220.1 (M+H) + .

[0675] Synthesis of compound 49-a

[0676] Compound 49-b (64 mg, 0.29 mmol), 48-d (200 mg, 0.29 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (38 mg, 0.059 mmol), and cesium fluoride (133 mg, 0.88 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 73°C for 3 hours. The reaction solution was filtered through celite, and water (50 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 49-a (55 mg, 25%). LC-MS (ESI): m / z 742.3 (M+H) + .

[0677] Synthesis of compound 49

[0678] Compound 49-a (55 mg, 0.074 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 49 (18 mg, 39%). LC-MS (ESI): m / z 612.2 (M+H) + .

[0679] Synthesis route of compound 50

[0680] Synthesis of compound 50-a

[0681] Under an ice-water bath, 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (209 mg, 1.00 mmol), dichloromethane (10 mL), and triethylamine (0.70 mL, 5.00 mmol) were added to the reaction flask, followed by the dropwise addition of benzenesulfonyl chloride (0.19 mL, 1.50 mmol). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 50-a (200 mg, 57%). LC-MS (ESI): m / z = 350.0 [M+H]+ .

[0682] Synthesis of compound 50

[0683] To the reaction flask were added I-6 (50 mg, 0.099 mmol), 50-a (52 mg, 0.15 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (13 mg, 0.020 mmol), cesium fluoride (45 mg, 0.30 mmol), 1,4-dioxane (9 mL), and H2O (1 mL). After nitrogen displacement three times, the reaction solution was heated and stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 50 (30 mg, 47%). LC-MS (ESI): m / z = 650.0 [M+H] + .

[0684] Synthesis route of compound 51

[0685] Synthesis of compound 51-a

[0686] Under an ice-water bath, 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (209 mg, 1.00 mmol), dichloromethane (10 mL), and triethylamine (0.70 mL, 5.00 mmol) were added to the reaction flask, followed by the dropwise addition of 3-pyridinesulfonyl chloride (0.18 mL, 1.50 mmol). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 51-a (100 mg, 29%). LC-MS (ESI): m / z = 351.2 [M+H] + .

[0687] Synthesis of compound 51

[0688] To the reaction flask were added I-6 (50 mg, 0.099 mmol), 51-a (52 mg, 0.15 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (13 mg, 0.020 mmol), cesium fluoride (45 mg, 0.30 mmol), 1,4-dioxane (9 mL), and H2O (1 mL). After nitrogen substitution three times, the reaction solution was heated and stirred at 100°C for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 51 (25 mg, 39%) was purified by Prep-HPLC. LC-MS (ESI): m / z = 651.2 [M+H] + .

[0689] Synthesis route of compound 52

[0690] Synthesis of compound 52-b

[0691] To a microwave tube were added I-1 (200 mg, 0.32 mmol), tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (135 mg, 0.65 mmol), t-BuXPhosPd-G3 (26 mg, 0.032 mmol), t-BuXphos (27 mg, 0.065 mmol), cesium carbonate (263 mg, 0.81 mmol), and 1,4-dioxane (8 mL). After nitrogen substitution three times, the reaction mixture was heated and stirred at 75°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to afford compound 52-b (50 mg, 21%). LC-MS (ESI): m / z = 748.3 [M+H] + .

[0692] Synthesis of compound 52-a

[0693] 52-b (50 mg, 0.067 mmol) and dichloromethane (10 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added dropwise at room temperature. After the addition was completed, the reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure at room temperature. Ethyl acetate was added to dilute the residue, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. Compound 52-a (22 mg, 64%) was purified by Prep-HPLC. LC-MS (ESI): m / z 518.1 [M+H] + .

[0694] Synthesis of compound 52

[0695] Under an ice-water bath, 52-a (15 mg, 0.029 mmol), dichloromethane (10 mL), and triethylamine (20 μL, 0.15 mmol) were added to the reaction flask, followed by the dropwise addition of isopropylsulfonyl chloride (4 μL, 0.035 mmol). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Compound 52 (5 mg, 28%) was purified by Prep-HPLC. LC-MS (ESI): m / z 624.1 [M+H] + .

[0696] Synthesis route of compound 53

[0697] Synthesis of compound 53-d

[0698] 1-Methyl-1H-indazole-3-carbonitrile (1.00 g, 6.36 mmol), hydroxylamine hydrochloride (0.88 g, 12.72 mmol), anhydrous potassium carbonate (1.76 g, 12.72 mmol), and anhydrous ethanol (30 mL) were added to a reaction flask. The reaction solution was stirred at 80°C for 15 hours. The reaction solution was cooled to room temperature, the solvent was removed by vortexing, and the solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 53-d (1.2 g, 99%). LC-MS (ESI): m / z 191.2 (M+H) + .

[0699] Synthesis of compound 53-c

[0700] 53-d (1.2 g, 6.31 mmol) and anhydrous tetrahydrofuran (20 mL) were added to the reaction flask. Pyridine (1.53 mL, 18.93 mmol) and trifluoroacetic anhydride (1.32 mL, 9.46 mmol) were added dropwise under ice bath. The reaction solution was stirred under ice bath for 30 minutes and then stirred at room temperature for 2 hours. Pyridine (0.5 mL, 6.18 mmol) and trifluoroacetic anhydride (0.5 mL, 3.60 mmol) were added, and the reaction solution was stirred at room temperature for 1 hour. The solvent of the reaction solution was removed by vortexing, and the crude product was diluted with ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 53-c (1.61 g, 95%). LC-MS (ESI): m / z 269.1 (M+H) + .

[0701] Synthesis of compound 53-b

[0702] 53-c (101 mg, 0.38 mmol) was added to a reaction flask, and chlorosulfonic acid (1 mL) was added dropwise under a water bath. The reaction mixture was heated and stirred at 65°C for 6 hours. The reaction mixture was cooled to room temperature, added to ice water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude solid. The crude product was added to a reaction flask, and anhydrous dichloromethane (5 mL) and dibromohydantoin (118 mg, 0.41 mmol) were added under an ice bath. After stirring under an ice bath for 5 minutes, trifluoromethanesulfonic acid (0.1 mL, 1.13 mmol) (8 drops) was added dropwise. After the addition, the reaction mixture was stirred under an ice bath for 3 hours. Ice water was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product, which was dissolved in dichloromethane to obtain Solution A. 1-Amino-1-cyclopropyl cyanide hydrochloride (89 mg, 0.75 mmol) was added to the reaction flask, and pyridine (0.5 mL) and anhydrous dichloromethane (5 mL) were added under ice bath. After stirring under ice bath for 5 minutes, solution A was added dropwise. After the addition was completed, the reaction solution was stirred under ice bath for 5 minutes and then stirred at room temperature for 2 hours. The solvent was removed by vortexing and dried. The crude product was diluted with ethyl acetate, saturated brine and a small amount of sodium bisulfate were added, the layers were separated, and the aqueous phase was extracted twice with ethyl acetate / tetrahydrofuran. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 53-b (185 mg, 100%). LC-MS (ESI): m / z 491.0 (M+H) + .

[0703] Synthesis of compound 53-a

[0704] To a reaction flask, 53-b (185 mg, 0.38 mmol), I-3 (180 mg, 0.57 mmol), Pd(dtbpf)Cl2 (20 mg, 0.031 mmol), 1,4-dioxane (20 mL), and a solution of cesium fluoride (720 mg, 4.74 mmol) in water (4 mL) were added. The reaction mixture was heated and stirred at 100°C under nitrogen for 2 hours. Pd(dtbpf)Cl2 (20 mg, 0.031 mmol) was added, and heating and stirring at 100°C under nitrogen for another 2 hours. I-3 (90 mg, 0.29 mmol) and anhydrous potassium phosphate (60 mg, 0.28 mmol) were added. The reaction mixture was heated and stirred at 100°C under nitrogen for another 4 hours. The mixture was cooled to room temperature. Pd(dtbpf)Cl2 (20 mg, 0.031 mmol) was added. The reaction solution was heated and stirred at 100°C for 5 hours under nitrogen protection. The reaction solution was cooled to room temperature, the aqueous phase was separated, a small amount of saturated brine was added to the residue where 1,4-dioxane was located, and the aqueous phase was separated again. The aqueous phases were combined and extracted twice with ethyl acetate. The 1,4-dioxane phase and the ethyl acetate extract were combined, evaporated to dryness, and the crude product was purified by reverse phase column (C8, 10mM aqueous ammonium bicarbonate solution, acetonitrile) to obtain 53-a (90mg, 46%). LC-MS (ESI): m / z 522.2 (M+H) + .

[0705] Synthesis of compound 53

[0706] 53-a (90 mg, 0.17 mmol) and tetrahydrofuran (5 mL) were added to the reaction flask. Pyridine (0.18 mL, 2.21 mmol) was added under ice-cooling, and trifluoroacetic anhydride (0.15 mL, 0.52 mmol) was added dropwise. The reaction mixture was stirred in an ice-cooling bath for 15 minutes and then stirred at room temperature for 4 hours. The solvent was removed by vortexing, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by preparative HPLC (ammonium bicarbonate) to give 53 (10.1 mg, yield 9.7%). LC-MS (ESI): m / z 600.2 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ8.61(1H,d,J=1.6Hz),7.67(1H,d,J=1.2Hz),6.02–5.96(1H,m),4.25(3H,s),4.10–4.03(2H,m),3 .63(2H,t,J=5.6Hz), 3.47(1H,p,J=6.8Hz), 2.60–2.54(2H,m), 1.40–1.34(2H,m), 1.30(6H,d,J=6.8Hz), 1.27–1.22(2H,m).

[0707] Synthesis route of compound 54

[0708] Synthesis of compound 54-c

[0709] To the reaction flask, add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester-3-carboxylic acid ethyl ester (300 mg, 0.79 mmol) and dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at room temperature. After the addition was complete, the reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure at room temperature. This afforded the crude product, Compound 54-c (300 mg).

[0710] Synthesis of compound 54-b

[0711] Under an ice-water bath, 54-c (300 mg, 0.76 mmol), dichloromethane (10 mL), and triethylamine (0.53 mL, 3.80 mmol) were added to the reaction flask, followed by the dropwise addition of isopropylsulfonyl chloride (0.17 mL, 1.52 mmol). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: methanol / dichloromethane: 0% to 10%) to obtain compound 54-b (250 mg, 85%). LC-MS (ESI): m / z = 388.4 [M+H] + .

[0712] Synthesis of compound 54-a

[0713] To a reaction flask were added I-6 (200 mg, 0.39 mmol), 54-b (183 mg, 0.47 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (51 mg, 0.079 mmol), cesium fluoride (180 mg, 1.18 mmol), 1,4-dioxane (18 mL), and H2O (2 mL). After nitrogen substitution three times, the reaction solution was heated and stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 54-a (200 mg, 74%). LC-MS (ESI): m / z = 688.2 [M+H] + .

[0714] Synthesis of compound 54

[0715] 54-a (200 mg, 0.29 mmol) was dissolved in THF (30 mL) and water (8 mL), and LiOH.H2O (122 mg, 2.91 mmol) was added. After the addition, the reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was neutralized with dilute hydrochloric acid until neutral, and the organic solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 54 (100 mg, 52%). LC-MS (ESI): m / z 660.1 [M+H] + .

[0716] Synthesis route of compound 55

[0717] Synthesis of compound 55

[0718] To the reaction flask were added 54 (50 mg, 0.076 mmol), ammonium chloride (41 mg, 0.76 mmol), DMF (5 mL) and DIPEA (0.066 mL, 0.38 mmol), followed by the slow addition of HATU (58 mg, 0.015 mmol) under an ice-water bath. After the addition, the reaction solution was warmed to room temperature and stirred overnight. The next day, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford compound 55 (10 mg, 20%). LC-MS (ESI): m / z 659.1 [M+H] + .

[0719] Synthesis route of compound 56

[0720] Synthesis of compound 56-a

[0721] To a solution of 35-a (150 mg, 0.20 mmol) in acetonitrile (10 mL) were added SelectFluor II (1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate) (256 mg, 0.80 mmol) and AcOH (0.2 mL). The reaction solution was heated and stirred at 50°C overnight. The next day, the reaction solution was cooled to room temperature and the organic solvent was removed under reduced pressure and low temperature. The crude product was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product, which was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 56-a (30 mg, 20%). LC-MS (ESI): m / z 767.1 [M+H] + .

[0722] Synthesis of compound 56

[0723] To the reaction flask, 56-a (30 mg, 0.039 mmol) and dichloromethane (5 mL) were added. Trifluoroacetic acid (1 mL) was added dropwise at room temperature. After the addition was complete, the reaction solution was allowed to react at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure at room temperature. The residue was diluted with dichloromethane. The organic phase was washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Prep-HPLC separation and purification afforded compound 56 (15 mg, 60%). LC-MS (ESI): m / z 637.2 [M+H] + .

[0724] Synthesis route of compound 57

[0725] Synthesis of Compound 57

[0726] To the reaction flask, 35 (50 mg, 0.08 mmol) and dichloromethane (8 mL) were added, and concentrated sulfuric acid (1 mL) was slowly added to the mixture. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water (20 mL), extracted with dichloromethane (20 mL), and the organic phase was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 57 (23.3 mg, 45%). LC-MS (ESI): m / z 634.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6):d 9.01(1H,s),8.86(1H,s),7.90(1H,s),5.71(1H,s),4.26(3H,s),4.02(2H,d,J=2.0Hz),3.54(2H,t,J =5.2Hz),3.40-3.51(1H,m),2.46(2H,s),1.39-1.47(2H,m),1.30(6H,d,J=6.8Hz),1.15-1.21(2H,m).

[0727] Synthesis route of compound 58

[0728] Synthesis of compound 58-d

[0729] 44-e (980 mg, 1.89 mmol), triethylamine (477 mg, 4.72 mmol) and dichloromethane (60 mL) were added to the reaction flask and stirred in an ice-water bath for 10 minutes. Trifluoroacetic anhydride (475 mg, 2.26 mmol) was slowly added dropwise to the reaction solution. After the addition, the reaction solution was stirred in an ice-water bath under nitrogen protection for 3 hours. The reaction solution was washed with saturated sodium bisulfate (40 mL*2) and water (30 mL) once, and the organic phase was concentrated to obtain compound 58-d (1100 mg, 95%). LC-MS (ESI): m / z 632.1 (M+NH4) + .

[0730] Synthesis of compound 58-c

[0731] To the reaction flask, 58-d (1100 mg, 1.79 mmol), Lawesson's reagent (1807 mg, 4.47 mmol) and tetrahydrofuran (100 mL) were added. Under nitrogen protection, the mixture was stirred at 85°C for 5 hours. The reaction solution was concentrated. Toluene (70 mL), sodium carbonate (7.5 g) and water (75 mL) were added to the concentrated crude product. The mixture was stirred at room temperature for 2 hours. The liquid was separated, the organic phase was concentrated, and compound 58-c (241 mg, 22%) was obtained by column chromatography (petroleum ether / ethyl acetate = 100 / 0; 100 / 70). LC-MS (ESI): m / z 613.1 (M+H) + .

[0732] Synthesis of compound 58-b

[0733] I-3 (280 mg, 0.89 mmol), 58-c (241 mg, 0.39 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (63 mg, 0.10 mmol), cesium fluoride (179 mg, 1.18 mmol), 1,4-dioxane (90 mL) and water (10 mL) were added to the reaction flask, and the atmosphere was replaced with nitrogen three times. The reaction solution was heated to 100°C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate (10 mL*3). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0, 10 / 20) to give compound 58-b (240 mg, 84%). LC-MS (ESI): m / z 722.3 (M+H) + .

[0734] Synthesis of compound 58-a

[0735] To the reaction flask were added 58-b (45 mg, 0.06 mmol), trifluoroethyl trifluoromethanesulfonate (43 mg, 0.19 mmol), cesium carbonate (220 mg, 0.68 mmol), and N,N-dimethylformamide (4 mL), and stirred at room temperature for 8 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (15 mL*2). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 58-a (12 mg, 24%). LC-MS (ESI): m / z 804.3 (M+H) + .

[0736] Synthesis of compound 58

[0737] To the reaction flask were added 58-a (12 mg, 0.015 mmol), methanesulfonic acid (120 mg, 1.25 mmol), and dichloromethane (8 mL), and stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL), extracted with dichloromethane (10 mL x 2), and the organic phase was concentrated under reduced pressure and purified by preparative HPLC to afford compound 58 (2.9 mg, 28%). LC-MS (ESI): m / z 684.1 (M+H). + .

[0738] Synthesis of compound 59

[0739] Referring to the synthesis method of compound 58, 4-(bromomethyl)pyridine hydrochloride was used instead of trifluoroethyl trifluoromethanesulfonate to synthesize compound 59. LC-MS (ESI): m / z 693.2 (M+H) + .

[0740] Synthesis of compound 60

[0741] Referring to the synthesis method of compound 58, 3-iodomethyloxetane was used instead of trifluoroethyl trifluoromethanesulfonate to synthesize compound 60. LC-MS (ESI): m / z 672.2 (M+H) + .

[0742] Synthesis route of compound 61

[0743] Synthesis of compound 61-a

[0744] To the reaction flask were added 58-b (50 mg, 0.07 mmol), 1-BOC-(3-iodomethyl)azetidine (83 mg, 0.28 mmol), potassium carbonate (10 mg, 0.07 mmol), and N,N-dimethylformamide (4 mL), and stirred at room temperature for 48 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL*3), and the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 61-a (31 mg, 50%). LC-MS (ESI): m / z 891.3 (M+H) + .

[0745] Synthesis of compound 61

[0746] To the reaction flask were added 61-a (31 mg, 0.035 mmol), methanesulfonic acid (120 mg, 1.25 mmol), and dichloromethane (8 mL), and the mixture was stirred at room temperature for 3 hours. Ammonia methanol (0.12 mL) was added to the reaction solution to quench the reaction. The organic phase was concentrated under reduced pressure and purified by preparative HPLC to afford compound 61 (6.2 mg, 26%). LC-MS (ESI): m / z 671.3 (M+H) + .

[0747] Synthesis of compound 62

[0748] Referring to the synthesis method of compound 58, benzyl bromide was used instead of trifluoroethyl trifluoromethanesulfonate to synthesize compound 62. LC-MS (ESI): m / z 692.1 (M+H) + .

[0749] Synthesis route of compound 63

[0750] Synthesis of compound 63-d

[0751] At room temperature, compound I-1 (100 mg, 0.16 mmol) was dissolved in 10 mL of toluene, and pinacol diboron (123 mg, 0.48 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (13 mg, 0.016 mmol), potassium acetate (48 mg, 0.48 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (13 mg, 0.016 mmol), potassium acetate (48 mg, 0.48 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl Hexylphosphino-2,4,6-triisopropylbiphenyl (15 mg, 0.032 mmol). The reaction mixture was stirred at 65°C under argon for 8 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 63-d (107 mg). The crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 667.2 [M+H] + .

[0752] Synthesis of compound 63-c

[0753] Under nitrogen at room temperature, 5-bromo-2-chloropyridine (3000 mg, 15.59 mmol) was dissolved in 30 mL of anhydrous THF. The mixture was cooled at -78°C and n-BuLi (7.5 mL, 18.71 mmol, 2.5 M) was added dropwise. After the addition, the mixture was stirred at -78°C under nitrogen for 30 minutes, followed by the dropwise addition of isopropyl disulfide (2.98 mL, 18.71 mmol). After the addition, the reaction mixture was stirred at room temperature under nitrogen for 1 hour. At room temperature, 100 mL of saturated ammonium chloride solution was slowly added to the reaction solution, followed by extraction with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EA = 10 / 1) to yield compound 63-c (750 mg, 26%). LC-MS (ESI): m / z = 188.1 [M+H] + .

[0754] Synthesis of compound 63-b

[0755] At room temperature, compound 63-c (200 mg, 1.07 mmol) was dissolved in 10 mL of DCM, and m-CPBA (541 mg, 2.66 mmol) was added in batches. The mixture was stirred at room temperature under nitrogen for 30 minutes. 100 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with DCM (100 mL). The organic phase was washed with saturated sodium bicarbonate solution (100 mL) and water (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by rapid separation column (PE / EA=3:1) to obtain compound 63-b (188 mg, 80%). LC-MS (ESI): m / z=220.1[M+H] + .

[0756] Synthesis of compound 63-a

[0757] At room temperature, compound 63-d (107 mg, 0.16 mmol) was dissolved in 18 mL of 1,4-dioxane, and compound 63-b (176 mg, 0.80 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (21 mg, 0.032 mmol), cesium fluoride (73 mg, 0.48 mmol), and water (2 mL) were added. The reaction mixture was stirred at 80°C under nitrogen for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-TLC (PE / EA = 2:1) to obtain crude compound 63-a (80 mg, 69%). The crude product was used directly in the next step without further purification. LC-MS (ESI): m / z = 724.3 [M+H] + .

[0758] Synthesis of compound 63

[0759] At room temperature, compound 63-a (80 mg, 0.11 mmol) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was suspended in 5 mL of saturated sodium bicarbonate, potassium carbonate (200 mg) and ethyl acetate (20 mL) were added. After the reaction mixture was stirred at room temperature for 30 minutes, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (NH4HCO3) to obtain compound 63 (8.2 mg, 13%). LC-MS (ESI): m / z=594.1[M+H] + .

[0760] Synthesis route of compound 64

[0761] Synthesis of compound 64-c

[0762] The compound N-BOC-3-cyano-4-piperidone (1 g, 4.46 mmol) was dissolved in dichloromethane (10 mL), and dimethylaminopyridine (110 mg, 0.90 mmol) and triethylamine (590 mg, 5.83 mmol) were added thereto. Trifluoromethanesulfonic anhydride (1.64 g, 5.81 mmol) was then added dropwise under ice bath. The reaction solution was stirred at room temperature for 4 hours, and then water (100 mL) was added thereto. The mixture was extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, PE / EA 3 / 1) to obtain 64-c (1.16 g, 73%). 1 H NMR (400MHz, DMSO-d6): δ4.28-4.24(2H,m),3.62-3.55(2H,m),2.70-2.64(2H,m),1.42(9H,s).

[0763] Synthesis of compound 64-b

[0764] Compound 64-c (500 mg, 1.40 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and the pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate solution. The solution was extracted with a dichloromethane solution containing 10% methanol (100 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in dichloromethane (10 mL), triethylamine (284 mg, 2.81 mmol) was added, and isopropylsulfonyl chloride (300 mg, 2.10 mmol) was added dropwise under ice-water bath. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain 64-b (166 mg, 33%).

[0765] Synthesis of compound 64-a

[0766] Compound 64-b (74 mg, 0.20 mmol), 48-d (200 mg, 0.29 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (40 mg, 0.062 mmol), and cesium fluoride (133 mg, 0.88 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 90°C for 3 hours. The reaction solution was filtered through celite, and water (50 mL) was added to the filtrate. The mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL) and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain 64-a (44 mg, 28%). LC-MS (ESI): m / z 769.2 (MH) - .

[0767] Synthesis of compound 64

[0768] Compound 64-a (44 mg, 0.057 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added thereto in an ice-water bath, and the reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 64 (19 mg, 52%). LC-MS (ESI): m / z 639.1 (MH) - .

[0769] Synthesis route of compound 65

[0770] Synthesis of compound 65-g

[0771] To the reaction flask were added 6-bromo-4-chloroindole (660 mg, 2.86 mmol), N,N-diisopropylethylamine (1110 mg, 8.59 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol), di-tert-butyl dicarbonate (1250 mg, 5.73 mmol), and dichloromethane (100 mL). After the addition, the reaction mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was washed with saturated sodium bisulfate (20 mL), and the organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 65-g (610 mg, 64%).

[0772] Synthesis of compound 65-f

[0773] 65-g (610 mg, 1.85 mmol), Pd2(dba)3 (84 mg, 0.09 mmol), Xantphos (107 mg, 0.19 mmol), 1,4-dioxane (10 mL), N,N-diisopropylethylamine (715 mg, 5.54 mmol) and methyl 3-mercaptopropionate (266 mg, 2.21 mmol) were added to the reaction flask. Nitrogen was replaced three times. The reaction solution was heated and stirred at 90°C for 3 hours. The reaction solution was cooled to room temperature, the solvent was concentrated, and compound 65-f (620 mg, 91%) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1, 3 / 1). LC-MS (ESI): m / z 387.2 (M+NH4) + .

[0774] Synthesis of compound 65-e

[0775] To the reaction flask, 65-f (620 mg, 1.68 mmol), dichloromethane (6 mL), and trifluoroacetic acid (2 mL) were added and stirred at room temperature under nitrogen for 3 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate (20 mL) was added to the residue, followed by extraction with dichloromethane (20 mL x 2). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 3) to afford compound 65-e (409 mg, 90%).

[0776] Synthesis of compound 65-d

[0777] To the reaction flask were added 65-e (410 mg, 1.52 mmol), 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (710 mg, 3.05 mmol), cesium carbonate (990 mg, 3.04 mmol), and N,N-dimethylformamide (10 mL). Under nitrogen protection, the mixture was stirred at room temperature for 4 hours. Saturated brine (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 1) to give compound 65-d (390 mg, 61%). LC-MS (ESI): m / z 422.1 (M+H) + .

[0778] Synthesis of compound 65-c

[0779] To the reaction flask were added 65-d (390 mg, 0.93 mmol), m-chloroperbenzoic acid (469 mg, 2.31 mmol), and ethyl acetate (40 mL). The mixture was stirred in an ice-water bath for 10 minutes, then the temperature was raised to room temperature and stirred for 3 hours. Saturated aqueous sodium bicarbonate solution (40 mL) was added to the reaction solution, the layers were separated, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 100 / 0, 10 / 1) to obtain compound 65-c (292 mg, 70%). LC-MS (ESI): m / z 454.0 (M+H) + .

[0780] Synthesis of compound 65-b

[0781] To the reaction flask, 65-c (120 mg, 0.26 mmol), methanol (10 mL), and dichloromethane (10 mL) were added. Sodium methoxide (43 mg, 0.79 mmol) was added under ice-water bath. The reaction mixture was stirred under ice-water bath for 1 hour. 1-Cyanocyclopropylamine hydrochloride (125 mg, 1.06 mmol) was added under ice-water bath and stirred for 15 minutes. The solvent was concentrated at room temperature and dried over oil pump for 1 hour. 1-Cyanocyclopropylamine hydrochloride (31 mg, 0.26 mmol) and N,N-dimethylformamide (10 mL) were then added. N,N-dimethylaminopyridine (65 mg, 0.53 mmol) and EDCI (152 mg, 0.79 mmol) were added under ice-water bath and stirred under ice-water bath. The mixture was then warmed to room temperature and stirred for 2 hours. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 3) to give 65-b (73 mg, 63%). LC-MS (ESI): m / z 432.1 (M+H) + .

[0782] Synthesis of compound 65-a

[0783] To the reaction flask were added 65-b (73 mg, 0.17 mmol), m-chloroperbenzoic acid (44 mg, 0.25 mmol), and dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (40 mL) was added to quench the mixture, and the layers were separated. The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1 to 1 / 1) to give compound 65-a (63 mg, 83%). LC-MS (ESI): m / z 448.0 (M+H) + .

[0784] Synthesis of compound 65

[0785] To the reaction flask were added 65-a (30 mg, 0.07 mmol), I-3 (32 mg, 0.10 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (II) (11 mg, 0.02 mmol), cesium fluoride (31 mg, 0.20 mmol), 1,4-dioxane (9 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 100°C and stirred for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate (10 mL*3). The organic phase was concentrated under reduced pressure and purified by preparative HPLC to give compound 65 (6.2 mg, 15%). LC-MS (ESI): m / z 601.0 (M+H) + .

[0786] Synthesis route of compound 66

[0787] Synthesis of compound 66-a

[0788] At room temperature, compound 44-b (50 mg, 0.071 mmol) was dissolved in 5 mL of DMF. Potassium carbonate (31 mg, 0.22 mmol), potassium iodide (2.4 mg, 0.014 mmol), and 2-bromoacetamide (49 mg, 0.36 mmol) were added sequentially. The reaction mixture was stirred at room temperature under nitrogen for 36 hours. 50 mL of saturated brine was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (50 mL*5), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain compound 66-a (crude product, 48 mg, 89%), which was used directly in the next reaction. LC-MS (ESI): m / z = 761.3 [M+H] + .

[0789] Synthesis of compound 66

[0790] At room temperature, compound 66-a (48 mg, 0.063 mmol) was dissolved in 2.5 mL of DCM, and methanesulfonic acid (180 uL, 2.77 mmol) was added under an ice-water bath. The reaction mixture was warmed to room temperature and stirred for 1 hour. 50 mL of DCM was added to the reaction solution, washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3 system) to obtain compound 66 (12.8 mg, 32%). LC-MS (ESI): m / z = 641.2 [M+H] + .

[0791] Synthesis route of compound 67

[0792] Synthesis of compound 67-d

[0793] To a reaction flask, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5.60 g, 23.81 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (17.01 g, 47.61 mmol), DMAP (0.29 g, 2.37 mmol), and anhydrous dichloromethane (100 mL) were added dropwise. Triethylamine (20.0 mL, 143.89 mmol) was added dropwise. The reaction mixture was allowed to react at room temperature for 18 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The organic phase was separated and washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to afford 67-d (8.1 g, 93%).

[0794] Synthesis of compound 67-c

[0795] To the reaction flask, 67-d (1.15 g, 3.13 mmol) and dichloromethane (8 mL) were added. Trifluoroacetic acid (3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by vortexing and the mixture was dried at an oil pump. Petroleum ether and methyl tert-butyl ether were added to the residue, and the mixture was slurried. The residue was filtered, and the solid was washed with petroleum ether and dried at an oil pump to obtain 67-c (1.19 g, 100%). LC-MS (ESI): m / z 267.9 (M+H) + .

[0796] Synthesis of compound 67-b

[0797] To a reaction flask, add 67-c (1.19 g, 3.13 mmol) and dichloromethane (10 mL). Add triethylamine (2.0 mL, 14.3 mmol) under ice-cooling, followed by the dropwise addition of isopropylsulfonyl chloride (0.60 g, 4.21 mmol) under ice-cooling. After addition, the reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for 3 hours. The reaction mixture was quenched by the addition of saturated sodium bicarbonate. The layers were separated, and the aqueous phase was extracted once with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to afford 67-b (700 mg, 60%).

[0798] Synthesis of compound 67-a

[0799] To a reaction flask, 67-b (260 mg, 0.70 mmol), 63-d (110 mg, 0.17 mmol), Pd(dtbpf)Cl2 (22 mg, 0.034 mmol), and 1,4-dioxane (10 mL) were added. The atmosphere was replaced with nitrogen three times, and a solution of cesium fluoride (210 mg, 1.38 mmol) in water (1 mL) was added dropwise with stirring. The reaction mixture was heated and stirred at 50°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30) to obtain 67-a (80 mg, 63%). LC-MS (ESI): m / z 764.3 (M+H). + .

[0800] Synthesis of compound 67

[0801] 67-a (80 mg, 0.11 mmol) and dichloromethane (3 mL) were added to the reaction flask. Trifluoroacetic acid (0.7 mL) was added at room temperature. The reaction solution was stirred at room temperature for 2 hours. The solvent was removed by vortexing, and the residue was diluted with ethyl acetate. Saturated sodium bicarbonate and anhydrous potassium carbonate were added and stirred at room temperature for 20 minutes. The liquids were separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified (ammonium bicarbonate) to obtain 67 (18 mg, 27%). LC-MS (ESI): m / z 634.2 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ9.10(1H,bs),8.98(1H,d,J=1.6Hz),7.92–7.50(2H,m),6.70(1H,s),4.31–4.25(2H,m),4 .16(3H,s),4.15–4.05(2H,m),3.56(1H,p,J=6.8Hz),1.45–1.38(2H,m),1.33(6H,d,J=6.8Hz),1.28–1.22(2H,m).

[0802] Synthesis route of compound 68

[0803] Synthesis of compound 68-b

[0804] A 1M solution of LHMDS in tetrahydrofuran (17 mL, 17.00 mmol) was added to the reaction flask. Under nitrogen at -78°C, a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (2.9 g, 13.35 mmol) in anhydrous THF (20 mL) was slowly added dropwise over 30 minutes. The reaction mixture was allowed to react at -78°C for 30 minutes. A solution of N-phenylbis(trifluoromethanesulfonyl)imide (5.72 g, 16.02 mmol) in anhydrous THF (20 mL) was slowly added dropwise at -78°C. Following addition, the reaction mixture was allowed to react at -78°C to room temperature for 1 hour. The solvent was removed by vortexing, and ethyl acetate and petroleum ether were added to the residue. The residue was washed with ice water, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 85 / 15) to yield compound 68-b (200 mg, 4.3%).

[0805] Synthesis of compound 68-a

[0806] To a reaction flask, 68-b (200 mg, 0.57 mmol) and dichloromethane (2 mL) were added dropwise. Trifluoroacetic acid (0.7 mL) was added dropwise in a water bath at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by vortexing and the mixture was dried at an oil pump to obtain a crude solid. The crude product and dichloromethane (20 mL) were added to a reaction flask, and triethylamine (0.32 mL, 2.30 mmol) and 2-propylsulfonyl chloride (120 mg, 0.84 mmol) were added in an ice bath. The reaction mixture was stirred from the ice bath to room temperature for 2 hours. Triethylamine (0.32 mL, 2.30 mmol) and 2-propylsulfonyl chloride (120 mg, 0.84 mmol) were then added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by vortexing. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain compound 68-a (200 mg, 98%).

[0807] Synthesis of compound 68

[0808] To a microwave tube, add 68-a (100 mg, 0.28 mmol), pinacol diboronate (86 mg, 0.34 mmol), XPhos (10 mg, 0.021 mmol), XPhos Pd G2 (10 mg, 0.013 mmol), and potassium acetate (100 mg, 1.02 mmol). The atmosphere was purged with nitrogen, and anhydrous toluene (10 mL) was added. The atmosphere was purged with nitrogen three times. The tube was sealed, and the reaction mixture was heated and stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vortexing. The crude product was dissolved in 1,4-dioxane (4 mL) and added to a microwave tube. I-4 (120 mg, 0.25 mmol), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), cesium fluoride (170 mg, 1.12 mmol), and water (1 mL) were added. The atmosphere was purged with nitrogen three times, and the tube was sealed. The reaction mixture was heated and stirred at 100°C for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in 1,4-dioxane (4 mL) again and added to a microwave tube. Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), cesium fluoride (170 mg, 1.12 mmol), and water (1 mL) were added. The atmosphere was replaced with nitrogen three times and the tube was sealed. The reaction solution was heated and stirred at 100°C for 5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30) to obtain the crude product. The crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 68 (27 mg, 16%). LC-MS (ESI): m / z 616.4 (M+H) + ; 1 H NMR(DMSO-d6,400MHz): δ9.21(1H,bs),8.91(1H,d,J=1.6Hz),7.88–7.56(2H,m),4.30–4.22(4H,m),4.13(1H,d ,J=16.8Hz),3.64(2H,t,J=5.5Hz),3.59–3.52(1H,m),2.70–2.62(2H,m),1.45–1.39(2H,m),1.33–1.26(8H,m).

[0809] Synthesis route of compound 69

[0810] Synthesis of compound 69-b

[0811] To a reaction flask, add tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (1.5 g, 6.91 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (2.96 g, 8.29 mmol), and anhydrous dichloromethane (20 mL). Under nitrogen, add DBU (3.15 g, 20.72 mmol) dropwise at 60°C. Warm the reaction mixture to 70°C for 4 hours. Remove the solvent by vortexing, and add ethyl acetate / petroleum ether (1:1) to the residue. Wash the mixture twice with water and saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain the crude product. Add dichloromethane (10 mL) and trifluoroacetic acid (3.5 mL) to the crude product, and stir the reaction mixture at room temperature for 3 hours. Remove the solvent by vortexing, and dry the mixture at an oil pump to obtain the crude product. To the crude product was added dichloromethane (20 mL), followed by triethylamine (4.5 mL, 32.38 mmol) under ice-cooling, and 2-propylsulfonyl chloride (1.5 mL) was added dropwise. After addition, the reaction mixture was cooled to room temperature and stirred for 4 hours. The solvent was removed by vortexing, and the residue was added with ethyl acetate / petroleum ether (1:1). The mixture was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to afford 69-b (480 mg, 20%). 1 H NMR (CHCl3, 400MHz): δ6.25(1H,dt,J=4.8,2.4Hz), 4.99(1H,d,J=49.6Hz), 4.30(1H,ddd,J=18.8,7.8,4.8Hz), 4.20–4.11(1 H,m),3.97(1H,dd,J=18.8,10.8Hz),3.52–3.37(1H,m),3.29(1H,p,J=6.8Hz),1.40(3H,d,J=6.8Hz),1.34(3H,d,J=6.8Hz).

[0812] Synthesis of compound 69-a

[0813] To the reaction flask, 69-b (150 mg, 0.42 mmol), 63-d (110 mg, 0.17 mmol), and Pd(dtbpf)Cl2 (15 mg, 0.023 mmol) were added. The atmosphere was replaced with nitrogen three times, and a solution of cesium fluoride (130 mg, 0.86 mmol) in water (1 mL) was added dropwise with stirring. The reaction mixture was heated and stirred at 55°C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30) to obtain 69-a (50 mg, 41%). LC-MS (ESI): m / z 746.3 (M+H) + .

[0814] Synthesis of compound 69

[0815] 69-a (50 mg, 0.067 mmol) and dichloromethane (2 mL) were added to the reaction flask. Trifluoroacetic acid (0.7 mL) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. The solvent was removed by vortexing and dried at an oil pump. Saturated aqueous sodium bicarbonate solution, ethyl acetate and anhydrous potassium carbonate were added to the residue. The reaction mixture was stirred at room temperature for 3 minutes. The liquids were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30) and purified by preparative HPLC (ammonium bicarbonate) to give 69 (2.6 mg, 6.3%). LC-MS (ESI): m / z 616.2 (M+H) + .

[0816] Synthesis route of compound 70

[0817] Synthesis of compound 70-c

[0818] To a reaction flask, add 4-oxopiperidone hydrochloride (2.72 g, 20.06 mmol), acetone (30 mL), and water (15 mL). Add anhydrous potassium carbonate (7.21 g, 52.16 mmol) in an ice bath, followed by the dropwise addition of 2-propylsulfonyl chloride (3.38 mL, 30.09 mmol). The reaction mixture was cooled to room temperature and stirred for 18 hours. Saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate and anhydrous magnesium sulfate, filtered, and evaporated to dryness. The crude product was washed twice with petroleum ether to obtain compound 70-c (2.7 g, 66%).

[0819] Synthesis of compound 70-b

[0820] Add N,N-dimethylformamide (3.18 mL, 39.46 mmol) and dichloromethane (60 mL) to the reaction flask. Slowly add a solution of phosphorus tribromide (2.97 mL, 31.57 mmol) in dichloromethane (10 mL) dropwise under ice-cooling. After addition, stir the reaction mixture in an ice-cooling bath for 1 hour. Add a solution of 70-c (2.7 g, 13.15 mmol) in dichloromethane (20 mL) dropwise under ice-cooling. After addition, stir the reaction mixture at room temperature overnight. Cool the reaction mixture in an ice-cooling bath and stir for 5 minutes. Saturated sodium bicarbonate solution is slowly added dropwise until no bubbles form. Separate the mixture, extract the aqueous phase twice with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain compound 70-b (1.6 g, 41%). LC-MS (ESI): m / z 313.1 (M+NH4) + .

[0821] Synthesis of compound 70-a

[0822] Add 70-b (400 mg, 1.35 mmol), bis-pinacol borate (403 mg, 1.59 mmol), Pd(dppf)Cl2.CH2Cl2 (80 mg, 0.098 mmol) and potassium acetate (396 mg, 4.04 mmol) to a microwave tube. Replace the atmosphere with nitrogen and add 1,4-dioxane (10 mL). Replace the atmosphere with nitrogen three times and seal. Heat the reaction mixture at 80°C with stirring for 6 hours. Cool the reaction mixture to room temperature and remove the reaction mixture (2 mL) for direct reaction. Dilute the remaining reaction mixture with ethyl acetate, wash once with saturated brine, extract the aqueous phase with ethyl acetate three times, combine the organic phases, evaporate to dryness, and dry at an oil pump to obtain the crude product 70-a (463 mg, 100%). LC-MS (ESI): m / z 344.2 (M+H) + .

[0823] Synthesis of compound 70

[0824] A crude solution of 70-a (115 mg, 0.34 mmol) in 1,4-dioxane (2 mL), Pd(dtbpf)Cl2 (14 mg, 0.022 mmol), I-4 (107 mg, 0.21 mmol) and cesium fluoride (110 mg, 0.72 mmol) in water (0.5 mL) were added to the reaction flask. The atmosphere was replaced with nitrogen three times and the mixture was sealed. The reaction solution was heated and stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, evaporated to dryness, and the crude product (1 / 5) was purified by preparative HPLC (ammonium bicarbonate) to obtain 70 (7.6 mg, 28%). LC-MS (ESI): m / z 626.2 (M+H) + . 1 H NMR(DMSO-d6,400MHz)δ9.33(1H,s),8.98(1H,d,J=1.6Hz),7.89–7.55(2H,m),4.27–4.12(5H,m),3.7 5–3.68(1H,m),3.64–3.51(2H,m),2.96–2.73(2H,m),1.48–1.34(4H,m),1.30(6H,dd,J=6.8,2.4Hz).

[0825] Synthesis route of compound 71

[0826] Synthesis of compound 71

[0827] 70 (108 mg, 0.17 mmol), dimethylamine hydrochloride (64 mg, 0.79 mmol), anhydrous ethanol (5 mL) and potassium acetate (62 mg, 0.63 mmol) were added to the reaction flask. The reaction mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (200 mg, 0.95 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (72 mg, 0.34 mmol) was added. After stirring at room temperature for 1 hour, the solution was placed in the refrigerator and refrigerated overnight. Ice water was added to the reaction solution to quench the reaction, and the solution was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain 71 (9.2 mg, 8.2%). LC-MS (ESI): m / z 655.3 (M+H) + ; 1 H NMR(DMSO-d6,400MHz)δ9.24(1H,bs),8.89(1H,d,J=1.6Hz),7.86–7.55(2H,m),4.26–4.12(4H,m),3.94(1H,d,J=18.0Hz),3 .71–3.65(1H,m),3.59–3.30(3H,m),2.87(1H,d,J=13.2Hz),2.52(2H,s),1.99(6H,s),1.53–1.35(2H,m),1.36–1.26(8H,m).

[0828] Synthesis route of compound 72

[0829] Synthesis of compound 72-b

[0830] To a reaction flask, 70-b (630 mg, 2.13 mmol), tetrahydrofuran (20 mL), and anhydrous methanol (10 mL) were added. After stirring on ice for 5 minutes, anhydrous cerium (III) chloride (786 mg, 3.19 mmol) and sodium borohydride (90 mg, 2.38 mmol) were added, with a large amount of bubbling forming. The reaction mixture was stirred on ice for 1 hour. Water (10 mL) was added to the reaction mixture to quench the mixture. The solvent was removed by vortexing at room temperature, and a small amount of solid anhydrous sodium sulfate was added. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was added to a reaction flask, and anhydrous tetrahydrofuran (10 mL) was added. Sodium borohydride (170 mg, 4.25 mmol) was added on ice. The reaction mixture was stirred on ice for 1 hour, then warmed to room temperature and stirred for 15 minutes. Methyl iodide (0.45 mL, 5.55 mmol) was then added. The reaction solution was stirred at room temperature for 2 hours, dried by rotary evaporation, ethyl acetate was added, ice water was slowly added, the liquids were separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to give compound 72-b (350 mg, 53%).

[0831] Synthesis of compound 72-a

[0832] To a microwave tube, 72-b (350 mg, 1.12 mmol), bis-pinacol boronate (342 mg, 1.35 mmol), Pd(dppf)Cl2·CH2Cl2 (46 mg, 0.056 mmol), and potassium acetate (330 mg, 3.36 mmol) were added. The atmosphere was purged with nitrogen, and 1,4-dioxane (10 mL) was added. The atmosphere was purged with nitrogen three times and the tube was sealed. The reaction mixture was heated and stirred at 80°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to obtain compound 72-a (110 mg, 27%). LC-MS (ESI): m / z 359.9 (M+H) + .

[0833] Synthesis of compound 72

[0834] A solution of 72-a (55 mg, 0.15 mmol), Pd(dtbpf)Cl2 (9 mg, 0.014 mmol), I-6 (86 mg, 0.17 mmol), 1,4-dioxane (2 mL), and cesium fluoride (80 mg, 0.53 mmol) in water (0.5 mL) was added to a reaction flask. The atmosphere was replaced with nitrogen three times. The reaction solution was heated and stirred at 100°C for 3 hours. The mixture was cooled to room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and evaporated to dryness. The crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain 72 (30 mg, 30%). LC-MS (ESI): m / z 660.6 (M+H) + . 1 H NMR (DMSO-d6, 400MHz): δ9.28 (1H, bs), 8.90 (1H, d, J = 2.0Hz), 7.65 (1H, d, J = 1.6Hz), 4.20 (3H, s), 4.07 (2H, s), 3.73 (1H, d, J = 11.6Hz), 3.71–3.52(3H,m),3.50(1H,q,J=6.8Hz),3.05(3H,s),2.59–2.52(2H,m),1.47–1.38(2H,m),1.37–1.32(2H,m),1.30(6H,d,J=6.8Hz).

[0835] Synthetic routes of compounds 73 and 74

[0836] Synthesis of compound 73-a

[0837] A solution of 70-a (345 mg, 1.01 mmol), Pd(dtbpf)Cl2 (41 mg, 0.063 mmol), I-6 (335 mg, 0.66 mmol), and cesium fluoride (340 mg, 2.24 mmol) in water (2 mL) was added to a reaction flask. The atmosphere was replaced with nitrogen three times. The reaction solution was heated and stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, evaporated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30) to obtain compound 73-a (290 mg, 68%). LC-MS (ESI): m / z 644.1 (M+H) + .

[0838] Synthesis of compounds 73 and 74

[0839] To a reaction flask were added 73-a (130 mg, 0.20 mmol), dimethylamine hydrochloride (180 mg, 2.21 mmol), potassium acetate (220 mg, 2.24 mmol), and anhydrous ethanol (10 mL). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (50 mg, 0.80 mmol). Stirring was continued for 30 minutes, followed by the addition of sodium cyanoborohydride (50 mg, 0.80 mmol). The reaction mixture was stirred at room temperature for another 30 minutes. The majority of the solvent was removed by vortexing at room temperature, and saturated brine was added. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and dried under nitrogen. The crude product was purified by preparative HPLC (ammonium bicarbonate) to afford 73 (28 mg, 21%). The remaining fraction was further purified by preparative TLC (8% MeOH / DCM) to afford 74 (22 mg, 16%).

[0840] 73, LC-MS(ESI):m / z 646.1(M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ9.23 (1H, bs), 8.87 (1H, d, J = 2.0Hz), 7.65 (1H, d, J = 1.6Hz), 4.93 (1H, t, J = 5.2Hz), 4.23 (3H, s), 4.19–4.0 5(2H,m),3.73(2H,d,J=5.2Hz),3.66–3.54(2H,m),3.48(1H,q,J=6.8Hz),2.58–2.50(2H,m),1.50–1.38(2H,m),1.36–1.23(8H,m).

[0841] 74, LC-MS(ESI):m / z 673.4(M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ9.34 (1H, bs), 8.88 (1H, d, J = 1.6Hz), 7.61 (1H, d, J = 1.6Hz), 4.24–4.12 (4H, m), 3.95 (1H, d, J = 18.0Hz), 3.73–3.64 ( 1H,m),3.58–3.44(2H,m),3.39–3.31(1H,m),2.88(1H,d,J=12.8Hz), 2.54–2.50(2H,m),1.99(6H,s),1.48–1.37(2H,m),1.37–1.24(8H,m).

[0842] Synthesis route of compound 75

[0843] Synthesis of compound 75-a

[0844] Add 70-b (330 mg, 1.11 mmol) and anhydrous methanol (10 mL) to a reaction flask. Stir on ice for 5 minutes, then add sodium borohydride (22 mg, 0.58 mmol). Stir on ice for 5 minutes, then add sodium borohydride (30 mg, 0.79 mmol). Stir the reaction mixture on ice for 1 hour. Add saturated aqueous ammonium chloride dropwise to the reaction mixture, remove the methanol by vortexing, and extract twice with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Add anhydrous dichloromethane (10 mL) to the crude product, and add triethylamine (0.55 mL, 3.96 mmol) and methanesulfonyl chloride (0.2 mL, 2.58 mmol) dropwise on ice. After the addition, stir the reaction mixture on ice for 1 hour. Remove the solvent by vortexing, dry the mixture using an oil pump, and add anhydrous tetrahydrofuran (10 mL) to the residue. Lithium aluminum hydride tetrahydrofuran solution (1M, 2.5 mL, 2.50 mmol) was slowly added dropwise over 20 minutes in an ice-salt bath. After addition, the reaction solution was stirred in an ice-salt bath for 1 hour. Solid sodium sulfate decahydrate was slowly added to the reaction solution to quench the reaction. The reaction solution was stirred for 15 minutes, and ethyl acetate was added to dilute the reaction solution. The solution was stirred at room temperature for 15 minutes. Filter, evaporate to dryness, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to obtain compound 75-a (95 mg, 30%). LC-MS (ESI): m / z 281.9 (M+H) + .

[0845] Synthesis of compound 75

[0846] To a microwave tube, add 75-a (95 mg, 0.34 mmol), bis-pinacol boronate (128 mg, 0.50 mmol), Pd(dppf)Cl2.CH2Cl2 (15 mg, 0.018 mmol), and potassium acetate (100 mg, 1.02 mmol). The atmosphere was purged with nitrogen, and 1,4-dioxane (4 mL) was added. The atmosphere was purged with nitrogen three times and the tube was sealed. The reaction mixture was heated and stirred at 80°C for 20 hours. The reaction mixture was cooled to room temperature, and I-6 (100 mg, 0.20 mmol), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), cesium fluoride (200 mg, 1.32 mmol), and water (1 mL) were added. The atmosphere was purged with nitrogen three times and the tube was sealed. The reaction mixture was heated and stirred at 100°C for 2 hours. I-6 (100 mg, 0.20 mmol), Pd(dtbpf)Cl2 (20 mg, 0.031 mmol) and cesium fluoride (120 mg, 0.79 mmol) were added. The atmosphere was replaced with nitrogen and the reaction mixture was heated and stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 97 / 3) to obtain a crude product, which was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 75 (32 mg, 15%). LC-MS (ESI): m / z 630.1 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ9.26 (1H, bs), 8.87 (1H, d, J = 2.0Hz), 7.64 (1H, d, J = 1.6Hz), 4.19 (3H, s), 4.01– 3.88(2H,m),3.68–3.51(2H,m),3.49(1H,q,J=6.8Hz),1.47(3H,s),2.50– 2.42(2H,m),1.45–1.39(2H,m),1.38–1.32(2H,m),1.30(6H,d,J=6.7Hz).

[0847] Synthesis route of compound 76

[0848] Synthesis of compound 76

[0849] To a microwave tube, add 68-a (100 mg, 0.28 mmol), pinacol diboronate (86 g, 0.34 mmol), XPhos (10 mg, 0.021 mmol), XPhos Pd G2 (10 mg, 0.013 mmol), and potassium acetate (100 mg, 1.02 mmol). Replace the atmosphere with nitrogen. Add anhydrous toluene (10 mL). Replace the atmosphere with nitrogen three times and seal the tube. Heat and stir the reaction mixture at 80°C for 4 hours. Cool the reaction mixture to room temperature, and add I-6 (143 mg, 0.28 mmol), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), cesium fluoride (170 mg, 1.12 mmol), and water (1 mL). Replace the atmosphere with nitrogen three times and seal the tube. Heat and stir the reaction mixture at 100°C for 6 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30) to obtain a crude product. The crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 76 (38 mg, 21%). LC-MS (ESI): m / z 634.5 (M+H) + ; 1 H NMR (DMSO-d6, 400MHz): δ9.28 (1H, bs), 8.90 (1H, d, J = 1.6Hz), 7.81 (1H, d, J = 1.6Hz), 4.32–4.20 (4H, m), 4.18–4. 09(1H,m),3.65(2H,t,J=5.2Hz),3.55(1H,p,J=6.8Hz),2.73–2.62(2H,m),1.50–1.38(2H,m),1.37–1.25(8H,m).

[0850] Synthesis route of compound 77

[0851] Synthesis of compound 77-i

[0852] 5-Bromo-7-chloro-1H-indole (3.0 g, 13.02 mmol) was dissolved in 20 mL of dichloromethane at room temperature. Trichloroacetyl chloride (5.84 mL, 52.06 mmol) was added, followed by the dropwise addition of pyridine (4.21 mL, 52.06 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was stirred at 48°C under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and poured into 50 mL of ice-water. The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dried under vacuum for 2 hours to yield approximately 10 g (theoretical 4.89 g) of crude product (77-i, 100%), which was used directly in the next step.

[0853] Synthesis of compound 77-h

[0854] 77-i (4.89 g, 13.01 mmol) was suspended in 50 mL of methanol at room temperature. KOH (1.88 g, 33.50 mmol) was added portionwise, and the reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was concentrated under reduced pressure to approximately 20 mL, and then 50 mL of water was added. The pH was adjusted to 6 with 1 M hydrochloric acid and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with 20 mL of DCM, filtered, and the filter cake was washed with DCM (5 mL). The solid was collected and dried under vacuum for 2 hours to obtain 2.8 g of the product. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (PE / EA = 1:1) to obtain 380 mg of the product. The two products were combined to obtain compound 77-h (3.18 g, 85%). LC-MS (ESI): m / z = 286.1 [MH] - .

[0855] Synthesis of compound 77-g

[0856] Compound 77-h (3.15 g, 10.92 mmol) was dissolved in 20 mL of DMF at room temperature. NaH (655 mg, 16.38 mmol, 60%) was added portionwise in an ice-water bath under nitrogen. The mixture was stirred at room temperature under nitrogen for 30 minutes, and then iodomethane (1.02 mL, 16.38 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL) in an ice-water bath and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in methanol (10 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with methanol (10 mL). The collected solid was dried under vacuum for 2 hours to yield compound 77-g (2.8 g, 85%). 1 H NMR (DMSO-d6, 400MHz): δ3.81(3H,s), 4.11(3H,s), 7.45(1H,d,J=1.2Hz), 8.07(1H,d,J=1.2Hz), 8.20(1H,s).

[0857] Synthesis of compound 77-f

[0858] Compound 77-g (700 mg, 2.31 mmol) was suspended in 20 mL of ethanol at room temperature, and hydrazine hydrate (4 mL, 67.92 mmol, 85%) was added. The reaction mixture was stirred at 85°C under nitrogen for 72 hours. The reaction mixture was cooled in an ice-water bath and filtered. The filter cake was washed with ethanol (10 mL). The collected solid was dried under vacuum for 2 hours to give compound 77-f (305 mg, 44%). LC-MS (ESI): m / z = 302.0 [M+H] + .

[0859] Synthesis of compound 77-e

[0860] 77-f (290 mg, 0.96 mmol) was dissolved in 20 mL of DCM at room temperature, and TEA (400 uL, 2.88 mmol) was added. Difluoroacetic anhydride (131 uL, 1.05 mmol) was added dropwise in an ice-water bath. After addition, the reaction mixture was stirred in an ice-water bath for 6 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (5 mL). The solid was collected and dried under vacuum for 2 hours to obtain compound 77-e (238 mg, 65%). LC-MS (ESI): m / z = 379.9 [MS+H] + .

[0861] Synthesis of compound 77-d

[0862] At room temperature, 77-e (238 mg, 0.62 mmol) was dissolved in 10 mL of 1,4-dioxane, and Lawesson's reagent (379 mg, 0.94 mmol) was added. The reaction mixture was stirred at 80°C under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of dichloromethane and washed sequentially with saturated sodium bicarbonate (100 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA = 1:1) to obtain compound 77-d (172 mg, 73%). LC-MS (ESI): m / z = 378.0 [M+H] + .

[0863] Synthesis of compound 77-c

[0864] 77-d (172 mg, 0.45 mmol) was dissolved in 10 mL of 1,4-dioxane at room temperature. Tris(dibenzylideneacetone)dipalladium (42 mg, 0.045 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg, 0.091 mmol), DIPEA (225 uL, 1.36 mmol), and methyl 3-mercaptopropionate (56 uL, 0.50 mmol) were added sequentially. The reaction mixture was reacted at 80°C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA = 1:1) to obtain compound 77-c (170 mg, 90%). LC-MS (ESI): m / z = 418.5 [M+H] + .

[0865] Synthesis of compound 77-b

[0866] 77-c (170 mg, 0.41 mmol) was dissolved in 10 mL of DCM at room temperature, and m-CPBA (248 mg, 1.22 mmol) was added in an ice-water bath under nitrogen. After the addition, the mixture was reacted for 2 hours under an ice-water bath under nitrogen. Saturated sodium bicarbonate (50 mL) was added to the reaction mixture, and the mixture was extracted with DCM (100 mL). The organic phase was washed with saturated sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 20:1) to obtain compound 77-b (205 mg, crude product). LC-MS (ESI): m / z = 450.1 [M+H] + .

[0867] Synthesis of compound 77-a

[0868] 77-b (120 mg, 0.27 mmol) was dissolved in a mixture of 10 mL of methanol and 15 mL of DCM at room temperature. Sodium methoxide (43 mg, 0.80 mmol) was added under an ice-water bath, and the reaction mixture was stirred at room temperature under nitrogen for 60 minutes. 1-Aminocyclopropylcarbonitrile hydrochloride (127 mg, 1.07 mmol) was added under an ice-water bath, and the reaction mixture was stirred under an ice-water bath for 15 minutes. The mixture was concentrated under reduced pressure and dried under vacuum for 2 hours. The residue was dissolved in dry DMF (5 mL), and 1-aminocyclopropylcarbonitrile hydrochloride (32 mg, 0.27 mmol), triethylamine (74 uL, 0.53 mmol), and NCS (107 mg, 0.80 mmol) were added sequentially under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed sequentially with water (100 mL) and saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain compound 77-a (90 mg, 76%). LC-MS (ESI): m / z = 444.1 [M+H] + .

[0869] Synthesis of compound 77

[0870] At room temperature, compound 77-a (30 mg, 0.068 mmol) was dissolved in 18 mL of 1,4-dioxane, and compound I-3 (32 mg, 0.10 mmol), 1,1′-di-tert-butylphosphinoferrocenepalladium dichloride (8.8 mg, 0.014 mmol), cesium fluoride (31 mg, 0.20 mmol), and water (2 mL) were added. The reaction mixture was stirred at 100°C under nitrogen for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA = 1:3) to obtain a crude product. The crude product was separated and purified by Prep-HPLC (alkaline method, NH4HCO3 system) to obtain compound 77 (13.5 mg, 33%). LC-MS (ESI): m / z = 597.2 [M+H] + .

[0871] Synthesis route of compound 78

[0872] Synthesis of compound 78-g

[0873] Under ice-cooling, diethylaminosulfur trifluoride (DAST) (1.06 mL, 8.06 mmol) was added to a solution of 6-bromopyridazine-3-carboxaldehyde (1.0 g, 5.35 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature overnight. After the reaction was complete, saturated sodium bicarbonate solution (10 mL) was added and stirred for 30 minutes. The liquids were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 78-g (900 mg, 81%). 1 H NMR (DMSO-d6, 400MHz): δ7.28 (1H, t, J = 54.0Hz), 8.02 (1H, t, J = 8.8Hz), 8.29 (1H, d, J = 8.8Hz).

[0874] Synthesis of compound 78-f

[0875] To a sealed tube, add pinacol diboronate (724 mg, 2.85 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (125 mg, 0.19 mmol), and methyl tert-butyl ether (10 mL). Under nitrogen, add methoxy(cyclooctadiene)iridium dimer (102 mg, 0.38 mmol). After nitrogen purge twice, stir at room temperature for 10 minutes. Add a solution of 15-g (600 mg, 1.90 mmol) in methyl tert-butyl ether (10 mL). After nitrogen purge three times, stir at 85°C for 3.5 hours. The reaction mixture is concentrated to obtain the crude borate ester.

[0876] Toluene (20 mL) and water (10 mL) were added to the crude borate ester, along with 78-g (397 mg, 1.90 mmol), palladium acetate (43 mg, 0.19 mmol), Xantphos (220 mg, 0.38 mmol), and N-methylmorpholine (0.63 mL, 5.70 mmol). The atmosphere was purged with nitrogen twice. The reaction mixture was stirred at 40°C for 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to afford compound 78-f (300 mg, 36%). LC-MS (ESI): m / z = 443.0 (M+H) + .

[0877] Synthesis of compound 78-e

[0878] To a three-necked flask were added 78-f (300 mg, 0.68 mmol), Xantphos (39 mg, 0.068 mmol), 1,4-dioxane (20 mL), DIPEA (0.35 mL, 2.03 mmol), and methyl 3-mercaptopropionate (0.09 mL, 0.81 mmol). The atmosphere was purged with nitrogen twice, and Pd2(dba)3 (31 mg, 0.034 mmol) was added. The atmosphere was purged with nitrogen three times. The reaction mixture was heated under reflux at 85°C for 2 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 78-e (300 mg, 92%). LC-MS (ESI): m / z = 483.5 [M+H] + .

[0879] Synthesis of compound 78-d

[0880] To a solution of 78-e (300 mg, 0.62 mmol) in dichloromethane (10 mL) was added TFA (3 mL) at room temperature. The reaction was stirred at room temperature overnight. After completion of the reaction, the solvent was removed by rotary evaporation at room temperature, and the mixture was diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford compound 78-d (200 mg, 81%). LC-MS (ESI): m / z = 398.8 [M+H] + .

[0881] Synthesis of compound 78-c

[0882] To a solution of 78-d (200 mg, 0.50 mmol) in DMF (10 mL) was added cesium carbonate (327 mg, 1.00 mmol) and iodomethane (0.081 mL, 1.00 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 78-c (200 mg, 96%). LC-MS (ESI): m / z = 413.1 [M+H] + .

[0883] Synthesis of compound 78-b

[0884] Under ice bath, m-CPBA (251 mg, 1.45 mmol) was added to a solution of 78-c (200 mg, 0.48 mmol) in dichloromethane (10 mL). After addition, the reaction mixture was kept at 0°C and stirred for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporation at room temperature, and the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 78-b (160 mg, 74%). LC-MS (ESI): m / z = 445.1 [M+H] + .

[0885] Synthesis of compound 78-a

[0886] 78-b (160 mg, 0.36 mmol), methanol (10 mL) and dichloromethane (10 mL) were added to the reaction flask. The reaction was cooled to 0°C in an ice bath, sodium methoxide (58 mg, 1.08 mmol) was added, and the reaction solution was kept in an ice bath for 1 hour. 1-Amino-1-cyclopropylcyanide hydrochloride (171 mg, 1.44 mmol) was added, the solvent was removed by concentration at room temperature, and then vacuum dried for 20 minutes. DMF (8 mL) and a small amount of 3A molecular sieves were added. After stirring in an ice bath for 3 minutes, triethylamine (0.10 mL, 0.72 mmol) and 1-amino-1-cyclopropylcyanide hydrochloride (43 mg, 0.36 mmol) were added. NCS (96 mg, 0.72 mmol) was then added in an ice bath. The reaction solution was stirred in an ice bath for 1 hour. Diluted with ethyl acetate, washed with sodium bisulfite solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain 78-a (120 mg, 76%). LC-MS (ESI): m / z = 439.0 [M+H] + .

[0887] Synthesis of compound 78

[0888] To the reaction flask were added 78-a (50 mg, 0.11 mmol), I-3 (54 mg, 0.17 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (15 mg, 0.023 mmol), cesium fluoride (52 mg, 0.34 mmol), 1,4-dioxane (9 mL), and H2O (1 mL). After nitrogen displacement three times, the reaction solution was heated and stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was diluted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 78 (20 mg, 30%). LC-MS (ESI): m / z = 592.0 [M+H] + .

[0889] Synthesis route of compound 79

[0890] Synthesis of compound 79-b

[0891] Compound I-1-d (200 mg, 0.48 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (102 mg, 2.43 mmol) dissolved in 1 mL of water was added. The reaction solution was stirred at room temperature for 1.5 hours, then concentrated, and water (3 mL) was added. 6 M hydrochloric acid solution was added dropwise to adjust the pH to 3-4. The precipitated solid was filtered and washed with a small amount of water. The solid was dried to obtain 79-b (188 mg, 97%).

[0892] Synthesis of compound 79-a

[0893] Compound 79-b (230 mg, 0.58 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), and (1Z)-2,2,2-trifluoro-N'-hydroxyacetamidine (81 mg, 0.63 mmol), dimethylaminopyridine (70 mg, 0.57 mmol), 1-hydroxybenzotriazole (117 mg, 0.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (166 mg, 0.87 mmol) were added thereto under an ice-water bath, and the reaction solution was stirred at room temperature for 12 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (mobile phase, DCM / EA 10 / 1) to give 79-a (84 mg, 30%).

[0894] Synthesis of compound 79

[0895] Compound 79-a (84 mg, 0.17 mmol), I-3 (81 mg, 0.26 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (22 mg, 0.034 mmol), and cesium fluoride (78 mg, 0.51 mmol) were added to 1,4-dioxane (18 mL) and water (2 mL). The reaction solution was purged with nitrogen three times and then heated and stirred at 90°C for 6 hours. The reaction solution was filtered through celite, and water (50 mL) was added to the filtrate. The mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, PE / EA 1 / 1) and then by preparative HPLC (basic conditions) to obtain compound 79 (41 mg, 40%). LC-MS (ESI): m / z 598.2 (MH) - ; 1 H NMR (400MHz, DMSO-d6): δ9.30(1H,s),8.64(1H,s),7.73(1H,s),6.01(1H,s),4.31(3H,s),4.12-4.04( 2H,m),3.70-3.58(2H,m),3.55-3.43(1H,m),2.63-2.53(2H,m),1.48-1.40(2H,m),1.36-1.24(8H,m).

[0896] Synthesis route of compound 80

[0897] Synthesis of compound 80-f

[0898] Compound 5-bromo-3-chloro-o-phenylenediamine (1 g, 4.52 mmol) was dissolved in acetonitrile (10 mL), and isoamyl nitrite (2.6 g, 22.19 mmol) was added. The reaction solution was stirred at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, EA) to obtain compound 80-f (900 mg, 86%).

[0899] Synthesis of compound 80-e

[0900] Compound 80-f (300 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (630 mg, 1.93 mmol) and 2-bromo-5-trifluoromethyl-1,3,4-thiazole (451 mg, 1.94 mmol) were added. The reaction solution was stirred at 50°C for 12 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 10 / 1) to obtain compound 80-e (350 mg, 71%).

[0901] Synthesis of compound 80-d

[0902] Compound 80-e (210 mg, 0.55 mmol), methyl 3-mercaptopropionate (75 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.055 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and diisopropylethylamine (212 mg, 1.64 mmol) were added to 1,4-dioxane (15 mL). The reaction solution was purged with nitrogen three times and stirred in an 80°C oil bath for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 10 / 1) to obtain compound 80-d (187 mg, 81%).

[0903] Synthesis of compound 80-c

[0904] Compound 80-d (187 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL) and m-chloroperoxybenzoic acid (269 mg, 1.56 mmol) was added under an ice-water bath. The reaction solution was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 80-c (200 mg, 99%).

[0905] Synthesis of compound 80-b

[0906] Compound 80-c (200 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL). Sodium methoxi...

Claims

1. A heteroaromatic ring structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof: in, represents a single bond or a double bond; Both rings in are aromatic; A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen; A3 is C or N; A4 is N, CR 4 or NR 4 ; A5 is NR 5 , N, CR 5 , S or O; for R a1 , R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxyl or -OC 1-6 alkyl; or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes, with one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl; R a-1 , R a-2 , R a-31 , R a-32 , R a-4 , R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; Ring Y is C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6- 20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, "5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N" and "5-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" fused heterocyclic group, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; n is 0, 1, 2, 3, 4, 5 or 6; R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 2-2 Replaced-OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 , C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 cycloalkenyl, or "a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to each other, independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N; R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ; R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2d2 , R 22a , R 22b1 , R 22b2 , R 22c , R 22d1 , R 22d2 , R 22e1 , R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; R 1 for R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-6 Substituted C 4- 8-membered cycloalkenyl, "a 4-8-membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; R 21 is hydrogen or C 1-6 alkyl; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 1-1-1 Replaced-OC 1-6 Alkyl, with one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f , C 3-10 Cycloalkyl, with one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they are the same or different; R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f , C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1a , R 1b1 , R 1b2 , R 1c , R 1d1 , R 1d2 , R 1e1 , R 1e2 , R 1f , R 11a , R 11b1 , R 11b2 , R 11c , R 11d1 , R 11d2 , R 11e1 , R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl; R 3 is "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N", or, is replaced by one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 4 For hydrogen, halogen, C 1-6 Alkyl, or, with one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 For halogen, hydroxyl, C 3-12 Cycloalkyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced-OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", one or more R 5-7 Substituted "containing 1-3 heteroatoms, the heteroatoms are independently selected from O, S and N 4-8 membered heterocycloalkenyl" or, by one or more R 5-8 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 and R 5-8 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different; R 5a , R 5b1 , R 5b2 , R 5c , R 5d1 , R 5d2 , R 51a , R 51b1 , R 51b2 , R 51c , R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; or, R 2 and R 5 connected to each other, and together with the atoms to which they are connected, they form a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N"; or, R a-31 and R a-32 , R a-51 and R a-52 , R 2b1 and R 2b2 , R 2d1 and R 2d2 , R 22b1 and R 22b2 , R 22d1 and R 22d2 , R 22e1 and R 22e2 , R 1b1 and R 1b2 , R 1d1 and R 1d2 , R 1e1 and R 1e2 , R 11b1 and R 11b2 , R 11d1 and R 11d2 , R 11e1 and R 11e2 , R 5b1 and R 5b2 , R 5d1 and R 5d2 , R 51b1 and R 51b2 , R 51d1 and R 51d2 independently and respectively together with the connected N to form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds: N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide.

2. The heteroaromatic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that: The heteroaromatic ring structure compound shown in formula I is shown in formula II: in, is a single bond or a double bond; B1 is N, C or CH, B2 is N or CH, and the definitions of other groups are as described in claim 1.

3. The heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound as claimed in claim 1 or 2, characterized in that: The heteroaromatic ring structure compound shown in formula I is shown in formula III: in, is a single bond or a double bond; B1 is N, C or CH; B2 is N or CH; m is 0, 1 or 2; R′ is R 11 NR 12 R 13 , R 14 or R 19 ; R 11 , R 12 , R 13 , R 14 and R 19 and other groups are as defined in claim 1 or 2.

4. The heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound as claimed in claim 1 or 2, characterized in that: In the heteroaromatic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, the heteroaromatic ring structure compound as shown in Formula I is defined as Scheme 1, Scheme 2, Scheme 3 or Scheme 4: Scenario 1: represents a single bond or a double bond; Both rings in are aromatic; A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen; A3 is C or N; A4 is N, CR 4 or NR 4 ; A5 is NR 5 , N, CR 5 , S or O; for R a1 , R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxyl or -OC 1-6 alkyl; or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes, with one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl; R a-1 , R a-2 , R a-31 , R a-32 , R a-4 , R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; Ring Y is C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6- 20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; n is 0, 1, 2, 3, 4, 5 or 6; R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 2-2 Replaced-OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 , C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 cycloalkenyl, or "a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to each other, independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N; R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ; R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2d2 , R 22a , R 22b1 , R 22b2 , R 22c , R 22d1 , R 22d2 , R 22e1 , R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; R 1 for R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "contains 1-3 heteroatoms, heteroatoms The 4-12 membered heterocycloalkyl group is independently selected from O, S and N, C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-6 Substituted C 4- 8-membered cycloalkenyl, "a 4-8-membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; R 21 is hydrogen or C 1-6 alkyl; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 1-1-1 Replaced-OC 1-6 Alkyl, with one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f , C 3-10 Cycloalkyl, with one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they are the same or different; R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f , C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1a , R 1b1 , R 1b2 , R 1c , R 1d1 , R 1d2 , R 1e1 , R 1e2 , R 1f , R 11a , R 11b1 , R 11b2 , R 11c , R 11d1 , R 11d2 , R 11e1 , R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl; R 3 is "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N", or, is replaced by one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 4 For hydrogen, halogen, C 1-6 Alkyl, or, with one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 Halogen, hydroxyl, -OC 1-6 Alkyl or -SC 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced-OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", R 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they are the same or different; R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 and R 5-7 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different; R 5a , R 5b1 , R 5b2 , R 5c , R 5d1 , R 5d2 , R 51a , R 51b1 , R 51b2 , R 51c , R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; or, R 2 and R 5 connected to each other, and together with the atoms to which they are connected, they form a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N"; or, R a-31 and R a-32 , R a-51 and R a-52 , R 2b1 and R 2b2 , R 2d1 and R 2d2 , R 22b1 and R 22b2 , R 22d1 and R 22d2 , R 22e1 and R 22e2 , R 1b1 and R 1b2 , R 1d1 and R 1d2 , R 1e1 and R 1e2 , R 11b1 and R 11b2 , R 11d1 and R 11d2 , R 11e1 and R 11e2 , R 5b1 and R 5b2 , R 5d1 and R 5d2 , R 51b1 and R 51b2 , R 51d1 and R 51d2 independently and respectively together with the connected N to form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 1-2-1 For hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds: N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide; Scenario 2: represents a single bond or a double bond; A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen; A3 is C or N; for R 4 is hydrogen or is replaced by one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 C 3-12 Cycloalkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium, halogen, -OC 1-6 Alkyl, -NR 5b1 R 5b2 、-C(=O)NR 5d1 R 5d2 , C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-8 Substituted C 1-6 Alkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 5b1 , R 5b2 , R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl; R 5-8 are independently halogen; R a1 , R a2 and R a3 are independently cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 is a halogen; or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkane; when there are multiple substituents, they may be the same or different; R a-51 and R a-52 are independently hydrogen; Ring Y is a "4-12 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, "5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N" and "5-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" fused heterocyclic group, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; n is 0, 1 or 2; R 2 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)R 2a 、-C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ; or, when n is 2, two R 2 connected to each other, independently together with the atoms in the ring to which they are connected, form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N"; R 2-1 Independently for C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ; R 2a , R 2c , R 2d1 , R 2d2 , R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl; R 1 for R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 and R 20 Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N"; R 21 is hydrogen or C 1-6 alkyl; R 1-1 , R 1-2 and R 1-3 C 1-6 Alkyl or -OC 1-6 alkyl; R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 Independently for C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl; when there are multiple substituents, they may be the same or different; The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds: N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide; Solution 3: The heteroaromatic ring structure compound shown in Formula I has a structure of Formula III-1 or III-2 as shown below: R a1 , R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxyl or -OC 1-6 alkyl; or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes, with one or more R a2-1 Substituted C 3-7 Cycloalkanes, "containing 1- 3 heteroatoms, the heteroatoms are independently selected from O, S and N 3-8 membered heterocyclic ring ", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl; R a-1 , R a-2 , R a-31 , R a-32 , R a-4 , R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, with one or more R 2-2 Replaced-OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 , C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 cycloalkenyl, or "a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to each other, independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N; R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ; R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2d2 , R 22a , R 22b1 , R 22b2 , R 22c , R 22d1 , R 22d2 , R 22e1 , R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; R 11 C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 1-1-1 Replaced-OC 1-6 Alkyl, with one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f , C 3-10 Cycloalkyl, with one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 1-1-8 "substituted" contains 1 to 3 heteroatoms, "4-8 membered heterocycloalkenyl group wherein the heteroatoms are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f , C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1a , R 1b1 , R 1b2 , R 1c , R 1d1 , R 1d2 , R 1e1 , R 1e2 , R 1f , R 11a , R 11b1 , R 11b2 , R 11c , R 11d1 , R 11d2 , R 11e1 , R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl; R 3 is "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N", or, is replaced by one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced-OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N" or one or more R 5-8 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 and R 5-8 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different; R 5a , R 5b1 , R 5b2 , R 5c , R 5d1 , R 5d2 , R 51a , R 51b1 , R 51b2 , R 51c , R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; or, R 2 and R 5 connected to each other, and together with the atoms to which they are connected, they form a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N"; or, R a-31 and R a-32 , R a-51 and R a-52 , R 2b1 and R 2b2 , R 2d1 and R 2d2 , R 22b1 and R 22b2 , R 22d1 and R 22d2 , R 22e1 and R 22e2 , R 1b1 and R 1b2 , R 1d1 and R 1d2 , R 1e1 and R 1e2 , R 11b1 and R 11b2 , R 11d1 and R 11d2 , R 11e1 and R 11e2 , R 5b1 and R 5b2 , R 5d1 and R 5d2 , R 51b1 and R 51b2 , R 51d1 and R 51d2 independently and together with the connected N form "containing 1-3 heteroatoms, wherein A 3-8 membered heterocyclic ring with one heteroatom being N and other heteroatoms being independently selected from O, S and N, or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; Solution 4: In the heteroaromatic ring structure compound shown in Formula I, A1 and A2 are CR independently b1 , R b1 is hydrogen; A3 is C or N; A4 is N or CR 4 ; R 4 is hydrogen; A5 is NR 5 , CR 5 or S; R a1 For halogen, cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen; R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes; R a-51 and R a-52 are independently hydrogen; Ring Y is a "4-12 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, or "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; n is 0, 1 or 2; R 2 are independently hydroxyl groups, and are represented by one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)OR 2c ; or, when n is 2, two R 2 connected to each other, independently together with the atoms in the ring to which they are connected, form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N"; R 2-1 are independently hydroxyl groups; R 2c is hydrogen; R 1 for R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 and R 20 Independently for C 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R 21 is hydrogen or C 1-6 alkyl; R 1-1 , R 1-2 and R 1-3 Independently for C 1-6 Alkyl or -OC 1-6 alkyl; R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 are independently C substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium or -OC 1-6 alkyl.

5. The heteroaromatic ring structure compound as shown in Formula I according to claim 4, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that: The heteroaromatic ring structure compound shown in Formula III-1 is defined as Scheme 1 or Scheme 2: Scenario 1: R a1 , R a2 and R a3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OR a-1 、C(=O)R a-2 、-NR a-31 R a-32 、-C(=O)OR a-4 、-C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen, hydroxyl or -OC 1-6 alkyl; or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes, with one or more R a2-1 Substituted C 3-7 Cycloalkane, "3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R a2-2 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, -OC 1-6 Alkyl, or -OC substituted by one or more halogens 1-6 alkyl; R a-1 , R a-2 , R a-31 , R a-32 , R a-4 , R a-51 and R a-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; R 2 are independently halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, with one or more R 2-2 Replaced-OC 1-6 Alkyl, -C(=O)R 2a 、-NR 2b1 R 2b2 、-C(=O)OR 2c 、-C(=O)NR 2d1 R 2d2 , C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 cycloalkenyl, or "a 4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N"; or, when n is 2, 3, 4, 5 or 6, any two R 2 connected to each other, independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N; R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR 22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ; R 2a , R 2b1 , R 2b2 , R 2c , R 2d1 , R 2d2 , R 22a , R 22b1 , R 22b2 , R 22c , R 22d1 , R 22d2 , R 22e1 , R 22e2 and R 22f are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; R 11 C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-4 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-5 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-6 Substituted C 4-8 Cycloalkenyl, "containing 1-3 heteroatoms, the heteroatoms are independently selected from O, S and N 4-8 membered heterocycloalkenyl" or, 1-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, with one or more R 1-1-1 Replaced-OC 1-6 Alkyl, with one or more R 1-1-2 Substituted-SC 1- 6-alkyl, -C(=O)R 1a 、-NR 1b1 R 1b2 、-C(=O)OR 1c 、-C(=O)NR 1d1 R 1d2 、-S(O)2NR 1e1 R 1e2 、-S(O)2R 1f , C 3-10 Cycloalkyl, with one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-1-4 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, one or more R 1-1-5 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1-6 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 1-1-7 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 1-1-8 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they are the same or different; R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 1-1-7 and R 1-1-8 are independently azido, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(=O)R 11a 、-NR 11b1 R 11b2 、-C(=O)OR 11c 、-C(=O)NR 11d1 R 11d2 、-S(O)2NR 11e1 R 11e2 、-S(O)2R 11f , C 3-10 Cycloalkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1a , R 1b1 , R 1b2 , R 1c , R 1d1 , R 1d2 , R 1e1 , R 1e2 , R 1f , R 11a , R 11b1 , R 11b2 , R 11c , R 11d1 , R 11d2 , R 11e1 , R 11e2 and R 11f are independently hydrogen or C 1-6 alkyl; R 3 is "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N", or, is replaced by one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, with one or more -OC 1-6 Alkyl substituted C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, or -SC substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, -OC 1-6 Alkyl, -C(=O)R 5a 、-NR 5b1 R 5b2 、-C(=O)OR 5c 、-C(=O)NR 5d1 R 5d2 , by one or more R 5-1 Replaced-OC 1-6 Alkyl, C 6-20 Aryl, one or more R 5-2 Substituted C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 5-3 Substituted "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-4 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 5-5 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, with one or more R 5-6 Substituted C 4-8 Cycloalkenyl, "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they are the same or different; R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 and R 5-7 are independently halogen, hydroxy, oxo, cyano, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC substituted by one or more halogens 1-6 Alkyl, -C(=O)R 51a 、-NR 51b1 R 51b2 、-C(=O)OR 51c , or, -C(=O)NR 51d1 R 51d2 ; When there are multiple substituents, they are the same or different; R 5a , R 5b1 , R 5b2 , R 5c , R 5d1 , R 5d2 , R 51a , R 51b1 , R 51b2 , R 51c , R 51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; or, R 2 and R 5 connected to each other, and together with the atoms to which they are connected, they form a "5-12 membered heterocyclic olefin containing 1-3 heteroatoms independently selected from O, S and N"; or, R a-31 and R a-32 , R a-51 and R a-52 , R 2b1 and R 2b2 , R 2d1 and R 2d2 , R 22b1 and R 22b2 , R 22d1 and R 22d2 , R 22e1 and R 22e2 , R 1b1 and R 1b2 , R 1d1 and R 1d2 , R 1e1 and R 1e2 , R 11b1 and R 11b2 , R 11d1 and R 11d2 , R 11e1 and R 11e2 , R 5b1 and R 5b2 , R 5d1 and R 5d2 , R 51b1 and R 51b2 , R 51d1 and R 51d2 independently and respectively together with the connected N to form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 1-2-1 Substituted "3-8 membered heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl; Scenario 2: R a1 , R a2 and R a3 are independently cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen; or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkane; when there are multiple substituents, they may be the same or different; R a-51 and R a-52 are independently hydrogen; n is 0, 1 or 2; R 2 are independently halogen, cyano, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)R 2a 、-C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ; R 2-1 Independently for C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ; R 2a , R 2c , R 2d1 , R 2d2 , R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl; R 11 C 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3- 10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N"; R 1-1 , R 1-2 and R 1-3 Independently for C 1-6 Alkyl or -OC 1-6 alkyl; R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, S and N"; R 3-1 Independently for C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is deuterium, -OC 1-6 Alkyl, -NR 5b1 R 5b2 、-C(=O)NR 5d1 R 5d2 , C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-8 Substituted C 1-6 Alkyl or "containing 1-3 "4-12 membered heterocycloalkyl" wherein the heteroatom is independently selected from O, S and N; when there are multiple substituents, they may be the same or different; R 5b1 , R 5b2 , R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl; R 5-8 are independently halogen; The heteroaromatic ring structure compound shown in formula III is not one of the following compounds: N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide.

6. The heteroaromatic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that: A1 and A2 are CR independently b1 , R b1 is hydrogen or halogen; And / or, A4 is N or CR 4 ; R 4 is hydrogen or is replaced by one or more R 4-1 Substituted C 1-6 Alkyl; R 4-1 Independently for C 3-12 Cycloalkyl; and / or, A5 is N, NR 5 , CR 5 or S; and / or, R 5 for L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene; Q1 is hydrogen, deuterium, halogen, -OC 1-6 Alkyl, -NR 5b1 R 5b2 、-C(=O)NR 5d1 R 5d2 , C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 3-12 Cycloalkyl, with one or more R 5-8 Substituted C 1-6 Alkyl, or "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 5b1 , R 5b2 , R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl; R 5-8 are independently halogen; and / or, R a1 For cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen. and / or, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes. and / or, R a-51 and R a-52 are independently hydrogen. and / or, Ring Y is "a 4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", C 4-8 Cycloalkenyl, a fused heterocyclic group of "a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N" and "a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", or "a 4-8 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O, S and N"; and / or, n is 0, 1 or 2; and / or, R 2 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, with one or more R 2-1 Substituted C 1-6 Alkyl, -C(=O)R 2a 、-C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ; or, when n is 2, two R 2 connected, independently of the atoms in the ring to which they are connected Together they form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N"; and / or, R 2-1 Independently for C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ; and / or, R 2a , R 2c , R 2d1 , R 2d2 , R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl; and / or, R 1 for and / or, R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 and R 20 Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N"; and / or, R 21 is hydrogen or C 1-6 alkyl; and / or, R 1-1 , R 1-2 and R 1-3 Independently for C 1-6 Alkyl or -OC 1-6 alkyl; and / or, R 3 For one or more R 3-1 Substituted "5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N". and / or, R 3-1 Independently for C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl; when there are multiple substituents, they may be the same or different.

7. The heteroaromatic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that: R a1 For cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or, by one or more R a1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen; R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes; and / or, when R 1 for When R 11 C 1-6 Alkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms, which are independently selected from O, S and N", C 3-10 Cycloalkyl, with one or more R 1-1 Substituted C 1-6 Alkyl, with one or more R 1-2 Substituted C 3-10 Cycloalkyl, with one or more R 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 6-20 Aryl or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N"; R 1-1 For-OC 1-6 Alkyl; R 1-2 and R 1-3 Independently for C 1-6 alkyl; and / or, when R 1 for When R 12 and R 13 Independently for C 1-6 alkyl; and / or, when R 1 for When R 14 and R 19 Independently for C 1-6 alkyl; and / or, when R 1 for When R 17 and R 18 Independently for C 1-6 Alkyl or -OC 1-6 alkyl; and / or, when R 1 for When R 20 C 1-6 alkyl; And / or, when Q1 is "a 5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N", said Q1 is "a 5-6 membered heteroaryl group containing 1-2 heteroatoms N"; And / or, when Q1 is "a 4-12-membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", said Q1 is "a 4-6-membered heterocycloalkyl group containing 1-2 heteroatoms independently selected from O, S and N"; and / or, when ring Y is "a 4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", said Y is "a 4-8 membered heterocycloalkyl group containing 1-2 heteroatoms N"; and / or, when ring Y is C 6-20 When Y is aryl, it is phenyl, naphthyl or anthracenyl; and / or, when ring Y is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N", said Y is "a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O and N"; and / or, when ring Y is C 4-8 When cycloalkenyl, Y is C 5-7 Cycloalkenyl; and / or, when ring Y is a heterocyclic group of "a 5-6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" fused to a 5-6-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N", said Y is a heterocyclic group of "a 5-6-membered heteroaryl group containing 1 to 2 heteroatoms N" fused to a 5-6-membered heterocycloalkyl group containing 1 heteroatom N"; and / or, when Ring Y is a "4-8 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O, S and N", the "4-8 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O, S and N" is a "5-7 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O and N"; And / or, when n is 2, two R 2 When the two atoms are connected to each other and independently form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N" together with the atoms in the ring to which they are connected, the "3-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N" is a "3-6 membered heterocyclic ring containing 1-2 heteroatoms independently selected from O, S and N"; and / or, when R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 and R 20 is independently "a 4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" or is replaced by one or more R 1-3 When the substituted "4-12-membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" is used, the "4-12-membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" is "4-6-membered heterocycloalkyl containing 1-2 heteroatoms independently selected from O and N"; and / or, when R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 and R 20 When the term "heteroaryl group" is independently "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms which are independently selected from O, S and N", the "heteroaryl group containing 1 to 4 heteroatoms which are independently selected from O, S and N" is "a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms which are independently selected from O, S and N"; and / or, when R 3 For one or more R 3-1 When the substituted "5-6 membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N" is "5-6 membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N"; and / or, when R 3-1 are independently C substituted by one or more halogens 1-6 When the C 1- 6-alkyl is a C substituted with two or three halogens 1-2 alkyl.

8. The heteroaromatic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that: for and / or, R 3 for and / or, for and / or, ring Y is and / or, for 9. The heteroaromatic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that: The heteroaromatic ring structure compound shown in Formula I can be any of the following structures:

10. A pharmaceutical composition comprising substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of a heteroaromatic ring structure compound as shown in formula I as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

11. Use of a substance A in the preparation of a PARG inhibitor, wherein the substance A is a heteroaromatic ring structure compound as shown in formula I as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

12. Use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent PARG-mediated diseases; the substance A is a heteroaromatic ring structure compound as shown in formula I as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

13. Use of a substance A in preparing a drug, wherein the drug is used to treat or prevent cancer; the substance A is a heteroaromatic ring structure compound as shown in formula I as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof; the cancer is one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

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