Heteroaromatic ring structure compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a compound with a heteroaromatic ring structure as well as a pharmaceutical composition and application thereof. The invention provides a compound with a heteroaromatic ring structure as shown in a formula I, and pharmaceutically acceptable salts, stereoisomers, tautomers or isotope compounds thereof. The compound with the heteroaromatic ring structure is expected to be used for treating and / or preventing various diseases related to poly adenosine diphosphate ribose hydrolase (PARG). # imgabs0 #

Description

Technical Field

[0001] The invention relates to a heteroaromatic ring structure compound, a pharmaceutical composition and application thereof. Background Art

[0002] The division and proliferation of cancer cells are often uncontrolled, resulting in a higher incidence of DNA damage and DNA repair defects, and they are more dependent on DNA damage repair mechanisms than normal cells.

[0003] Poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) hydrolase (PARG) and some other proteins play an important role in DNA repair and have become important targets for the development of anticancer drugs. PARP can bind to the DNA single-strand break site and promote the generation of poly(ADP-ribose) (PAR) chains, thereby initiating the repair process. The role of PARG is to degrade PAR on PARP and promote the completion of the entire repair cycle. Whether it is the inhibition of PARP or PARG, it will affect the entire repair process.

[0004] At present, the research and development of PARP inhibitors has achieved great success, and many drugs have been approved for marketing, which also proves the feasibility of using DNA repair proteins as targets. At the same time, PARP inhibitors also have problems such as not being effective for all patients and drug resistance. The research on PARG inhibitors is still in the exploratory stage, and there is a lot of room for research in this target direction, which is expected to fill unmet clinical needs. Summary of the invention

[0005] The technical problem to be solved by the present invention is that there is a 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. The heteroaromatic ring structure compound is expected to be used to treat and / or prevent various diseases related to PARG.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] 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 compound thereof:

[0008]

[0009] in, represents a single bond or a double bond;

[0010] Both rings in are aromatic;

[0011] A1 and A2 are independently N or CRb1 , R b1 is hydrogen or halogen;

[0012] A3 is C or N;

[0013] A4 is N, CR 4 or NR 4 ;

[0014] A5 is NR 5 , N, CR 5 , S or O;

[0015] for

[0016] 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;

[0017] 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;

[0018] R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, 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 halogens1-6 alkyl;

[0019] 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;

[0020] 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 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";

[0021] n is 0, 1, 2, 3, 4, 5 or 6;

[0022] 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 4-8Cycloalkenyl, 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 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, which are independently selected from O, S and N;

[0023] 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 ;

[0024] 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;

[0025] R 1 for

[0026] 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 1-6Alkyl, 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", 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";

[0027] R 21 is hydrogen or C 1-6 alkyl;

[0028] R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 and R 1-7 For halogen, hydroxyl, 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 , C3-10 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", 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;

[0029] 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;

[0030] R 1a , R 1b1 , R1b2 , 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;

[0031] 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 independently selected from O, S and N";

[0032] 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;

[0033] 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;

[0034] R 5 for

[0035] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0036] 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;

[0037] 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 halogens1-6 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;

[0038] 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;

[0039] 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";

[0040] 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 51b1and R 51b2 , R 51d1 and R 51d2 independently and respectively together with the connected N 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";

[0041] R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0042] The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds:

[0043] N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide;

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

[0045] 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;

[0046] 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;

[0047] 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.

[0048] 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 (the content of this paragraph is hereinafter referred to as "in a certain embodiment").

[0049] In one embodiment, the heteroaromatic ring structure compound shown in formula I is shown in formula II:

[0050]

[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]

[0054] in, is a single bond or a double bond; B1 is N, C or CH; B2 is N or CH;

[0055] m is 0, 1 or 2;

[0056] R′ is R 11 NR 12 R 13 , R 14 or R 19 ;

[0057] R 11 , R 12 , R 13 , R 14 and R 19 The definitions of other groups are the same as above.

[0058] 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:

[0059] Scenario 1:

[0060] represents a single bond or a double bond;

[0061] Both rings in are aromatic;

[0062] A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen;

[0063] A3 is C or N;

[0064] A4 is N, CR 4 or NR 4 ;

[0065] A5 is NR 5 , N, CR 5 , S or O;

[0066] for

[0067] 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;

[0068] 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;

[0069] R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, 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;

[0070] R a-1 , R a-2 , R a-31 , R a-32 , R a-4 , R a-51 and Ra-52 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0071] 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";

[0072] n is 0, 1, 2, 3, 4, 5 or 6;

[0073] 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, "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, which are independently selected from O, S and N;

[0074] R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ;

[0075] 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;

[0076] R 1 for

[0077] 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 6-20Aryl, "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 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";

[0078] R 21 is hydrogen or C 1-6 alkyl;

[0079] 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 6-20Aryl, "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 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;

[0080] 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;

[0081] 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 , R11e2 and R 11f are independently hydrogen or C 1-6 alkyl;

[0082] 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 independently selected from O, S and N";

[0083] 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;

[0084] 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;

[0085] R 5 for

[0086] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0087] 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, C6-20 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;

[0088] 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;

[0089] R 5a , R 5b1 , R 5b2 , R 5c , R 5d1 , R 5d2 , R 51a , R51b1 , 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;

[0090] 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";

[0091] 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 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";

[0092] R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0093] The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds:

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

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

[0097] 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

[0098] 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.

[0099] Scenario 2:

[0100] represents a single bond or a double bond;

[0101] A1 and A2 are independently N or CR b1 , R b1 is hydrogen or halogen;

[0102] A3 is C or N;

[0103] for

[0104] 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;

[0105] R 5 for

[0106] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0107] 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;

[0108] R 5b1 , R 5b2 , R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl;

[0109] R 5-8 are independently halogen;

[0110] 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;

[0111] 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;

[0112] R a-51 and R a-52 are independently hydrogen;

[0113] Ring Y is a "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, 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";

[0114] n is 0, 1 or 2;

[0115] R 2 For halogen, hydroxyl, 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";

[0116] R 2-1 Independently for C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ;

[0117] R 2a , R 2c , R 2d1 , R 2d2 , R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl;

[0118] R 1 for

[0119] 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 R1-2 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";

[0120] R 21 is hydrogen or C 1-6 alkyl;

[0121] R 1-1 , R 1-2 and R 1-3 C 1-6 Alkyl or -OC 1-6 alkyl;

[0122] 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";

[0123] 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;

[0124] The heteroaromatic ring structure compound shown in Formula I is not one of the following compounds:

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

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

[0128] 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

[0129] 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.

[0130] Solution 3:

[0131] The heteroaromatic ring structure compound shown in Formula I has a structure as shown in Formula III-1 below:

[0132]

[0133] 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 is halogen, hydroxyl or -OC 1-6 alkyl;

[0134] 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;

[0135] R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, C 1-6Alkyl, 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;

[0136] 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;

[0137] n is 0, 1, 2, 3, 4, 5 or 6;

[0138] 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, "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, which are independently selected from O, S and N;

[0139] R 2-1 and R 2-2 are independently halogen, cyano, C 1-6 Alkyl-O-, hydroxyl, -C(=O)R 22a 、-NR22b1 R 22b2 、-C(=O)OR 22c 、-C(=O)NR 22d1 R 22d2 、-S(O)2NR 22e1 R 22e2 or -S(O)2R 22f ;

[0140] 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;

[0141] 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", 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 1-7Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0142] 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", 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;

[0143] 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;

[0144] 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;

[0145] 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 independently selected from O, S and N";

[0146] R 3-1 are independently halogen, hydroxy, cyano, C 1-6 Alkyl, C substituted by one or more halogen 1-6Alkyl, 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;

[0147] R 5 for

[0148] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0149] 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 R5-8 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0150] 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;

[0151] 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;

[0152] 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";

[0153] 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 R22b2 , 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 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";

[0154] R 1-2-1 For hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl.

[0155] Solution 4:

[0156] In the heteroaromatic ring structure compound shown in Formula I,

[0157] A1 and A2 are CR independently b1 , R b1 is hydrogen;

[0158] A3 is C or N;

[0159] A4 is N or CR 4 ; R 4 is hydrogen;

[0160] A5 is NR 5 , CR 5 or S;

[0161] R a1 For halogen, cyano, C 1-6 Alkyl, -C(=O)NR a-51 R a-52 , or, by one or more Ra1-1 Substituted C 1-6 Alkyl, R a1-1 are independently halogen;

[0162] R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes;

[0163] R a-51 and R a-52 are independently hydrogen;

[0164] 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 independently selected from O, S and N";

[0165] n is 0, 1 or 2;

[0166] R 2 is a hydroxyl group, is occupied 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";

[0167] R 2-1 are independently hydroxyl groups;

[0168] R 2c is hydrogen;

[0169] R 1 for

[0170] 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 3-10Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, with one or more R 1-3 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N";

[0171] R 21 is hydrogen or C 1-6 alkyl;

[0172] R 1-1 , R 1-2 and R 1-3 Independently for C 1-6 Alkyl or -OC 1-6 alkyl;

[0173] 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";

[0174] R 3-1 is independently C substituted by one or more halogens 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0175] R 5 for

[0176] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0177] Q1 is hydrogen, deuterium or -OC 1-6 alkyl.

[0178] In one embodiment, in the heteroaromatic ring structure compound shown in formula III-1,

[0179] 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, Ra1-1 are independently halogen, hydroxyl or -OC 1-6 alkyl;

[0180] 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;

[0181] R a2-1 and R a2-2 are independently halogen, =O, hydroxyl, 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;

[0182] 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;

[0183] n is 0, 1, 2, 3, 4, 5 or 6;

[0184] 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 3-10Cycloalkyl, "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 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, which are independently selected from O, S and N;

[0185] 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 ;

[0186] 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;

[0187] 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 3-10Cycloalkyl, "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 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";

[0188] 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", 1-1-4Substituted "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 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;

[0189] 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;

[0190] 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;

[0191] 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 independently selected from O, S and N";

[0192] 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;

[0193] R 5 for

[0194] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0195] 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 6-20Aryl, "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;

[0196] 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;

[0197] R 5a , R 5b1 , R 5b2 , R 5c , R 5d1 , R 5d2 , R 51a , R 51b1 , R 51b2 , R 51c , R51d1 and R 51d2 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl;

[0198] 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";

[0199] 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 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";

[0200] R 1-2-1 are independently hydrogen, C 1-6 Alkyl, or C substituted by one or more halogen 1-6 alkyl.

[0201] In one embodiment, in the heteroaromatic ring structure compound shown in formula III-1,

[0202] 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;

[0203] 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;

[0204] R a-51 and R a-52 are independently hydrogen;

[0205] n is 0, 1 or 2;

[0206] 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 ;

[0207] R 2-1 Independently for C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 ;

[0208] R 2a , R 2c , R 2d1 , R 2d2 , R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl;

[0209] 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 3-10Cycloalkyl, "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";

[0210] R 1-1 , R 1-2 and R 1-3 Independently for C 1-6 Alkyl or -OC 1-6 alkyl;

[0211] 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";

[0212] 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;

[0213] R 5 for

[0214] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0215] 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 "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;

[0216] R 5b1 , R 5b2 , R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl;

[0217] R5-8 are independently halogen;

[0218] The heteroaromatic ring structure compound shown in formula III is not one of the following compounds:

[0219] 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

[0220] 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.

[0221] 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 , R1-1-5 , 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.

[0222] 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 , R16 , 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 the C 1-6Alkyl is C 1-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0223] In group R 4-1 and 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.

[0224] When L1 is C 1-6 Alkylene or deuterated C 1-6 When the alkylene group is 1-6 The alkylene group may be -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, or -C(CH3)2CH2-.

[0225] When L1 is deuterated C 1-6 When the alkylene group is 1-6 Two or three hydrogen atoms in the alkylene group are substituted with deuterium.

[0226] 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.

[0227] In the group ring Y, R 2 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R19 , 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 Cycloalkyl is C3-C6 cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0228] In one embodiment, A1 and A2 are independently CR b1 , R b1 is hydrogen or halogen.

[0229] 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.

[0230] In one solution, A5 is N, NR 5 , CR 5 or S.

[0231] In one scenario, R 5 for

[0232] L1 is the connecting key, C 1-6 Alkylene or deuterated C 1-6 Alkylene;

[0233] 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 1-6Alkyl, 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;

[0234] R 5b1 , R 5b2 , R 5d1 and R 5d2 are independently hydrogen or C 1-6 alkyl;

[0235] R 5-8 are independently halogen.

[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 It is a halogen.

[0237] In one scenario, R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes.

[0238] In one scenario, R a1 For 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 halogen; R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 Cycloalkanes.

[0239] In one scenario, R a-51 and R a-52 are independently hydrogen.

[0240] 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 The present invention also comprises a cycloalkenyl group, a fused heterocyclic group of “a 5-6-membered heteroaryl group containing 1-4 heteroatoms which are independently selected from O, S and N” and “a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms which are independently selected from O, S and N”, or a 4-8-membered heterocycloalkenyl group containing 1-3 heteroatoms which are independently selected from O, S and N”.

[0241] In one embodiment, n is 0, 1 or 2.

[0242] In one scenario, 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 The atoms in the ring to which they are connected independently form a "3-8 membered heterocyclic ring containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N".

[0243] In one scenario, R 2-1 Independently for C 1-6 Alkyl-O-, hydroxyl or -NR 22b1 R 22b2 .

[0244] In one scenario, R 2a , R 2c , R 2d1 , R 2d2 , R 22b1 and R 22b2 are independently hydrogen or C 1-6 alkyl.

[0245] In one scenario, R 1 for

[0246] In one scenario, 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", 1-3Substituted "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".

[0247] In one scenario, R 21 is hydrogen or C 1-6 alkyl.

[0248] In one scenario, R 1-1 , R 1-2 and R 1-3 Independently for C 1-6 Alkyl or -OC 1-6 alkyl.

[0249] In one 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, 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.

[0250] In one scheme, when R 1 for When R 12 and R 13 Independently for C 1-6 alkyl.

[0251] In one scheme, when R 1 for When R 14 and R 19 Independently for C 1-6 alkyl.

[0252] In one scheme, when R 1 for When R 17and R 18 Independently for C 1-6 Alkyl or -OC 1-6 alkyl.

[0253] In one scheme, when R 1 for When R 20 C 1-6 alkyl.

[0254] In one scenario, R 3 For one or more R 3-1 The substituted "5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, S and N".

[0255] In one scenario, 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.

[0256] 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.

[0257] In one embodiment, when Q1 is a "4-12 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N", Q1 is a "4-6 membered heterocycloalkyl group containing 1-2 heteroatoms independently selected from O, S and N".

[0258] 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.

[0259] 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.

[0260] 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.

[0261] In one embodiment, when ring Y is C 4-8 When cycloalkenyl, Y is C 5-7 Cycloalkenyl, for example, cyclohexenyl.

[0262] 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".

[0263] 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 "a 4-8 membered heterocycloalkenyl group containing 1-3 heteroatoms independently selected from O, S and N" is a "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.

[0264] In one scheme, 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 which are 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 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".

[0265] In one 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”.

[0266] In one 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 “a 5- to 6-membered heteroaryl group containing 1-2 heteroatoms which are independently selected from O, S and N”, for example, pyridyl.

[0267] In one 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”.

[0268] In one scheme, when R 3-1 is 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, for example, -CHF2 or -CF3.

[0269] When R a2 and R a3 The carbon atom to which it is attached forms a C 3-7 In the case of cycloalkanes, the C 3-7 The cycloalkane is cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0270] In one plan, for

[0271] In one scenario, R 3 for

[0272]

[0273] In one plan, for In one embodiment, ring Y is Further, the upper end and the are connected.

[0274] In one plan, for

[0275]

[0276] In one embodiment, the heteroaromatic ring structure compound as shown in Formula I can be any of the following structures:

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283] The present invention also provides a pharmaceutical composition, which comprises 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.

[0284] The present invention also provides an application 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 compound thereof.

[0285] The present invention also provides a method for inhibiting PARG using substance A, which comprises administering to a subject an effective amount of substance A. The substance A is the heteroaromatic ring structure compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound.

[0286] The present invention also provides an application 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 heteroaromatic ring structure compound shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

[0287] The present invention also provides a method for treating or preventing PARG-mediated diseases using substance A, which comprises administering to a subject an effective amount of substance A. The substance A is the heteroaromatic ring structure compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound.

[0288] 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 cancer; 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. 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.

[0289] The present invention also provides a method for treating or preventing cancer with substance A, which comprises administering an effective amount of substance A to a subject. 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. 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.

[0290] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and 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 a 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 a 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 an inorganic acid, and the inorganic acid includes, but is 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).

[0291] In the present invention, when there are plural substituents, they may be the same or different.

[0292] The term "stereoisomer" refers to isomers caused by the same order of interconnection of atoms or atomic groups in a molecule but different spatial arrangements, such as cis-trans isomers, optical isomers or atropisomers, etc. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral separation by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

[0293] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. For example, acetone and 1-propene-2-ol can be interconverted by the rapid movement of hydrogen atoms on oxygen and α-carbon.

[0294] 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 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 invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein.

[0295] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0296] The term "alkyl" refers to a straight or branched chain alkyl group having a 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.

[0297] 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-.

[0298] The term "cycloalkyl" or "carbocycle" refers to a saturated cyclic group consisting of only carbon atoms, having a specified number of carbon atoms (e.g., C3 to C6), which is a monocyclic, bridged or spirocyclic ring. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0299] The term "aryl" refers to an aromatic group consisting of carbon atoms, each ring having aromatic properties, such as phenyl or naphthyl.

[0300] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (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, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0301] 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), a specified heteroatom type (one or more of N, O and S), which is a monocyclic, bridged or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

[0302] The term "hydroxy" refers to an -OH group.

[0303] The term "cyano" refers to a -CN group.

[0304] The term "oxo" refers to a =0 group.

[0305] The term "a 3-8 membered heterocycle 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 heterocycle 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.

[0306] The "C" that determines the carbon number range x1 -C y1 " (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" means the number of carbon atoms not including the substituents, for example, C1-C6 alkyl means C1-C6 alkyl not including the substituents.

[0307] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0308] The reagents and raw materials used in the present invention are commercially available.

[0309] The positive progressive effect of the present invention is that the present invention provides a heteroaromatic ring structure compound, a pharmaceutical composition and application thereof, and 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

[0310] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0311] 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.

[0312] The solvents involved in the following examples are all analytically pure or chromatographically pure. When the solvents involved in the following examples are mixed solvents, unless otherwise specified, they are all volume ratios.

[0313] The following is a list of abbreviations used in the examples:

[0314] DCM Dichloromethane

[0315] DMF N,N-Dimethylformamide

[0316] EA Ethyl acetate

[0317] DMSO Dimethyl sulfoxide

[0318] DMAP 4-dimethylaminopyridine

[0319] DIPEA Diisopropylethylamine

[0320] TEA Triethylamine

[0321] TBSCl tert-Butyldimethylsilyl chloride

[0322] TMS Trimethylsilyl

[0323] NCS N-Chlorosuccinimide

[0324] LHMDS Lithium Hexamethyldisilazide

[0325] Oxone Potassium Peroxymonosulfonate

[0326] Pd(dtbpf)Cl2 1,1'-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride

[0327] Pd(Amphos)Cl2 Dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II)

[0328] Mn(TMHD)3 Tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese

[0329] Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium

[0330] m-CPBA m-Chloroperbenzoic acid

[0331] Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

[0332] RuPhos 2-Bicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0333] THF Tetrahydrofuran

[0334] THP 2-Tetrahydropyran

[0335] TFA Trifluoroacetic acid

[0336] Ms Methanesulfonyl

[0337] Tf trifluoromethanesulfonyl

[0338] DBDMH Dibromohydantoin

[0339] SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride

[0340] DHP 3,4-Dihydro-2H-pyran

[0341] RuPhos Pd G3 Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0342] NMM N-Methylmorpholine

[0343] [Ir(COD)OMe]2 (1,5-cyclooctadiene)(methoxy)iridium(I) dimer

[0344] Synthetic route of intermediate I-1

[0345]

[0346] Synthesis of Compound I-1-f

[0347] Add chlorosulfonic acid (30 mL) to the reaction flask, and add 1-methyl-3-methoxycarbonyl indazole (10 g, 52.58 mmol) in batches within 10 minutes under ice bath. React at room temperature for 5 minutes. Stir the reaction solution at 65°C for 18 hours (add tail gas drying absorption device). Cool the reaction solution to room temperature. Add dropwise to 300 g of ice, extract with ethyl acetate, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain I-1-f (13.5 g, 89%).

[0348] Synthesis of compound I-1-e

[0349] I-1-f (13.5 g, 46.76 mmol) and dichloromethane (135 mL) were added to the reaction flask. Dibromohydantoin (13.37 g, 46.76 mmol) was added under ice bath. Trifluoromethanesulfonic acid (5 mL) was added dropwise to the suspension. The reaction solution was stirred in ice 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 solution was stirred at room temperature for 1.5 hours. Ice water was added to the reaction solution, 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 (mobile phase: petroleum ether / ethyl acetate 100:0 to 60:40) to obtain the product I-1-e (10.1 g, 59%).

[0350] Synthesis of compound I-1-d

[0351] Add 1-amino-1-cyclopropylnitrile hydrochloride (7.05 g, 59.46 mmol), pyridine (35 mL) and a small amount of 3A molecular sieves to the reaction flask. Stir in an ice bath for 5 minutes. Add a dry solution of I-1-e (10.1 g, 27.48 mmol) in dichloromethane (70 mL) containing molecular sieves dropwise within 5 minutes of the ice bath. React in an ice bath for 10 minutes and then react at room temperature for 2 hours. Rotate to remove the solvent. Add ice water and solid sodium bisulfate to pH = 6-7, add petroleum ether, filter, wash the filter cake with sodium bisulfate, water, and petroleum ether. Extract the aqueous phase with ethyl acetate, wash the extract with water, evaporate to dryness, slurry with ethyl acetate and petroleum ether, combine the solids, and dry in vacuo to obtain I-1-d (11.3 g, 100%). LC-MS (ESI): m / z 412.9 (M+H) + .

[0352] Synthesis of compound I-1-c

[0353] Add I-1-d (11.3 g, 27.34 mmol) and dichloromethane (150 mL) to the reaction flask. Add triethylamine (12.5 mL, 89.93 mmol) under ice bath and stir for 10 minutes. Add SEMCl (8.0 mL, 45.20 mmol) dropwise under ice bath and stir for 10 minutes. Stir in water bath at room temperature for 1.5 hours. Remove the solvent at room temperature, add water and ethyl acetate, stir thoroughly and filter, separate the filtrate, extract the aqueous phase once with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, and evaporate to dryness to obtain I-1-c (14.8 g, 100%). LC-MS (ESI): m / z 560.1 (M+NH4) + .

[0355] Synthesis of compound I-1-b

[0356] 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, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, filtered and evaporated to obtain I-1-b (14.5 g, 98%). LC-MS (ESI): m / z 1084.8 (2M+H) + .

[0357] Synthesis of Compound I-1-a

[0358] Add I-1-b (14.5 g, 26.68 mmol) and dichloromethane (150 mL) to the reaction flask. Add triethylamine (5.19 mL, 37.35 mmol) dropwise under ice bath. Stir in ice bath for 5 minutes. Add difluoroacetic anhydride (3.25 mL, 28.01 mmol) dropwise under ice bath. Stir the reaction solution in ice bath for 1 hour. Add methanol (2.5 mL) and stir from ice bath to room temperature for 20 minutes. Rotate to remove the solvent at room temperature. Add water and ethyl acetate to the reaction flask, separate the liquids, extract the aqueous phase once, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness and purify by column (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) + .

[0359] Synthesis of Compound I-1

[0360] 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 solution was heated and stirred at 80 ° C under argon protection for 10 hours. Cool to room temperature and spin off the solvent. The crude product was diluted with a mixture of ethyl acetate / petroleum ether, washed with sodium bicarbonate aqueous solution 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, and ammonia methanol / methanol / dichloromethane (1:1:20) solution (200 mL) was added and stirred at room temperature for 2 hours. Evaporate and column purification (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) + .

[0361] Synthetic route of intermediate I-2

[0362]

[0363] Synthesis of compound I-2-g

[0364] Add 3-methoxycarbonyl indazole (12.4 g, 70.38 mmol) and dichloromethane (120 mL) to the reaction flask. Add triethylamine (14.67 mL, 105.57 mmol) dropwise under an ice-water bath and stir for 5 minutes. Add methanesulfonyl chloride (6.81 mL, 87.98 mmol) dropwise under an ice-water bath. After the addition is completed, the reaction solution is stirred under an ice-water bath for 1 hour. The organic phase is evaporated to dryness, water and petroleum ether are added to the residue, filtered, the solid filter cake is washed with water, washed with petroleum ether, dried by oil pump, and then dried by freeze dryer to obtain I-2-g (16.4 g, 92%). LC-MS (ESI): m / z 254.9 (M+H) + .

[0365] Synthesis of Compound I-2-f

[0366] 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, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain I-2-f (14.8 g, 84%).

[0367] Synthesis of compound I-2-e

[0368] Add I-2-f (14.8 g, 54.88 mmol) and dichloromethane (120 mL) to the reaction flask. Add TMSOTf (18 mL, 117.67 mmol) dropwise under an ice-water bath and stir for 5 minutes. Then add dibromohydantoin (15.41 g, 53.88 mmol) and trifluoromethanesulfonic acid (7.5 mL, 84.76 mmol) under an ice-water bath. The reaction solution is stirred at room temperature for 2 hours. Dichloromethane (150 mL) and trifluoromethanesulfonic acid (7.5 mL, 84.76 mmol) are added dropwise to the suspension. The reaction solution is stirred at room temperature for 5 hours. Ice water is added to the reaction solution, extracted twice with ethyl acetate, the organic phase is washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate is evaporated to dryness, and dried at an oil pump to obtain I-2-e (19.05 g, 98%).

[0369] Synthesis of compound I-2-d

[0370] I-2-e (18.2 g, 51.47 mmol) and dichloromethane (200 mL) were added to the reaction bottle. 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 within 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 the second reaction bottle. After stirring for 5 minutes in an ice-water bath, reaction solution A was added by double needle transfer within 5 minutes in an ice-water bath. The reaction solution was reacted for 1 hour in an ice-water bath. Add sodium bisulfate aqueous solution (10%) under ice water bath, separate the liquids, extract the aqueous phase with dichloromethane once, combine the organic phases, wash with sodium bisulfate aqueous solution (5%), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to obtain I-2-d (26 g, 95%). LC-MS (ESI): m / z 529.1 (M+H) + .

[0371] Synthesis of compound I-2-c

[0372] 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, water, 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-c (30 g, 97%). LC-MS (ESI): m / z 659.1 (M+H) + .

[0373] Synthesis of compound I-2-b

[0374] Add I-2-c (30 g, 45.47 mmol) and anhydrous ethanol (180 mL) to the reaction flask. Add hydrazine hydrate (13.5 mL, 278.31 mmol) in a room temperature water bath, and heat the reaction solution at 55°C with stirring for 2 hours. Add additional hydrazine hydrate (5.0 mL, 103.08 mmol), and heat the reaction solution at 55°C with stirring for 2 hours. The reaction solution is cooled to room temperature, concentrated under reduced pressure at room temperature to remove the solvent, water is added to the residue, extracted twice with ethyl acetate, the organic phase is washed once with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness to obtain I-2-b (26 g, 87%). LC-MS (ESI): m / z 659.2 (M+H) + .

[0375] Synthesis of Compound I-2-a

[0376] Add I-2-b (26.0 g, 39.41 mmol) and dichloromethane (260 mL) to the reaction flask. Add triethylamine (8.0 mL, 57.56 mmol) in an ice-water bath. After stirring the reaction solution in an ice-water bath for 5 minutes, difluoroacetic anhydride (6.7 g, 38.50 mmol) was added dropwise within 15 minutes. The reaction solution was stirred in an ice-water bath for 1 hour. A small amount of methanol was added to the reaction solution, and after stirring in an ice-water bath for 5 minutes, an aqueous sodium bisulfate solution (5%) was added, the liquids were separated, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and purified by column (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) + .

[0377] Synthesis of Compound I-2

[0378] Add I-2-a (19 g, 25.75 mmol), anhydrous THF (190 mL) and Lawesson's reagent (35 g, 86.54 mmol) to the reaction flask. Heat the reaction mixture 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 ammonia water 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 ammonia water (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. Purification by column (mobile phase: (petroleum ether / dichloromethane 5:1) / ethyl acetate, 100 / 0 to 75 / 25) gave compound I-2 (6.3 g, 40%). LC-MS (ESI): m / z 605.0 (M+H) + .

[0379] Synthetic route of intermediate I-3

[0380]

[0381] Synthesis of Compound I-3

[0382] 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 thereto, isopropylsulfonyl chloride (164 mg, 1.15 mmol) was added dropwise under ice bath, and the reaction solution was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and dichloromethane (100 mL) was used for extraction. 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, 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) + .

[0383] Synthesis route of compound I-4

[0384]

[0385] Synthesis of Compound I-4

[0386] 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 reacted at room temperature for 4 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. It was separated and purified by a rapid separation column (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] + .

[0387] Synthetic route of intermediate I-5

[0388]

[0389] Synthesis of compound I-5-a

[0390] Under ice bath, add thiosemicarbazide (3g, 32.9mmol) to difluoroacetic anhydride (8.6g, 49.4mol) in 4 batches. After the addition, remove the ice bath and stir the reaction solution at 85°C for 36h. Cool the reaction solution to room temperature, adjust the pH to 7-8 with saturated sodium bicarbonate solution under ice bath, and some solids precipitate. Filter, wash the solid with water (5mL), add acetonitrile (10mL) to the solid, and dry under reduced pressure to obtain the product. The filtered filtrate is extracted 8 times with DCM:MeOH=10:1 (100mL), the organic phase is dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which is purified by column chromatography (SiO2, DCM:MeOH=10:1) to obtain the product. A total of compound I-5-a (1.6g, 32%) is 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).

[0391] Synthesis of Compound I-5

[0392] Compound I-5-a (400 mg, 2.65 mmol) was dissolved in anhydrous acetonitrile (20 mL), copper bromide (620.1 mg, 2.78 mmol) was added thereto, and 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 thereto. After the addition, the reaction solution was stirred at room temperature for 20 min and at 63°C for 12 h. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, and 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).

[0393] Synthesis route of compound 1

[0394]

[0395] Synthesis of compound 1-b

[0396] 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 thereto, and the reaction solution was heated to 70°C and stirred for 17 hours. After adding 2-bromoethyl methyl ether (69 mg, 0.50 mmol), stirring was continued at 70°C for 13 hours, the reaction solution was cooled to room temperature, water (500 mL) was added thereto, and extracted 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, the desiccant was filtered, and 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 1-b (80 mg, 48%).

[0397] Synthesis of compound 1-a

[0398] 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), potassium carbonate (44 mg, 0.32 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, heated to 100 ° C and stirred for 3 hours. The reaction solution was filtered with diatomaceous earth, 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, which 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) + .

[0399] Synthesis of compound 1

[0400] 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, the desiccant was filtered off, and 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) + .

[0401] Synthesis route of compound 2

[0402]

[0403] Synthesis of compound 2-a

[0404] 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), purged with nitrogen for 3 minutes, 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) + .

[0405] Synthesis of compound 2

[0406] 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, the desiccant was filtered off, and 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) + .

[0407] Synthesis route of compound 3

[0408]

[0409] Synthesis of compound 3-a

[0410] 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), cesium carbonate (105 mg, 0.32 mmol) were added to 1,4-dioxane (4 mL), purged with nitrogen for 3 minutes, and then sealed. 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%).

[0411] Synthesis of compound 3

[0412] 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, the desiccant was filtered off, and 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) + .

[0413] Synthesis route of compound 4

[0414]

[0415] Synthesis of compound 4-a

[0416] 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 thereto, and the mixture was stirred at room temperature for 10 minutes, and triethylamine (185 mg, 1.83 mmol) was added continuously, and isopropylsulfonyl chloride (209 mg, 1.47 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 thereto, and it was extracted with ethyl acetate (100 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, which was purified by column chromatography (mobile phase, PE / EA1 / 1) to obtain compound 4-a (177 mg, 46%). LC-MS(ESI):m / z 315.8(M+H) + .

[0418] Synthesis of compound 4

[0419] Compound I-4 (100 mg, 0.20 mmol), 4-a (97 mg, 0.31 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (26 mg, 0.040 mmol), cesium fluoride (93 mg, 0.61 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, and then heated to 100 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature and filtered with diatomaceous earth. Water (50 mL) was added to the filtrate and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried with 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, DCM / EA3 / 1) and then purified by preparative HPLC (alkaline conditions) to obtain compound 4 (53 mg, 43%). LC-MS (ESI): m / z 598.2 (M+H) + .

[0420] Synthesis route of compound 5

[0421]

[0422] Synthesis of compound 5-a

[0423] 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 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, which 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) + .

[0425] Synthesis of compound 5

[0426] Compound I-4 (100 mg, 0.20 mmol), 5-a (109 mg, 0.31 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (26 mg, 0.040 mmol), cesium fluoride (93 mg, 0.61 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL). The reaction solution was replaced with nitrogen three times and heated and stirred at 100 ° C for 12 hours. The reaction solution was filtered with diatomaceous earth, water (50 mL) was added to the filtrate, and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried with sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / EA1 / 1) and then purified by preparative HPLC (alkaline conditions) to obtain compound 5 (22 mg, 17%). LC-MS(ESI):m / z 640.2(M+H) + .

[0427] Synthesis route of compound 6

[0428]

[0429] Synthesis of compound 6-b

[0430] Add I-1-a (600 mg, 0.97 mmol), anhydrous tetrahydrofuran (10 mL) and Burgess reagent (345 mg, 1.45 mmol) to the microwave tube. After the addition, seal the microwave tube, heat to 80 ° C, and stir overnight. The next day, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was separated and purified by a rapid separation column (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] + .

[0431] Synthesis of compound 6-a

[0432] 6-b (120 mg, 0.20 mmol), I-3 (94 mg, 0.30 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (1651823-59-4) (15 mg, 0.020 mmol), potassium phosphate (127 mg, 0.60 mmol), tetrahydrofuran (10 mL) and H2O (2 mL) were added to the reaction bottle. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 65 ° C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product, which was separated and purified by a rapid separation column (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 6-a (100 mg, 71%). LC-MS(ESI):m / z 712.1[M+H] + .

[0433] Synthesis of compound 6

[0434] Add 6-a (100 mg, 0.14 mmol) and dichloromethane (10 mL) to the reaction flask. Add trifluoroacetic acid (3 mL) dropwise at room temperature. After the addition is complete, the reaction solution is reacted at room temperature for 4 hours, and the solvent is removed by concentration under reduced pressure at room temperature. Ethyl acetate is added to the residue for dilution, and the organic phase is washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product. The crude product is purified by Prep-HPLC to obtain compound 6 (50 mg, 61%). LC-MS (ESI): m / z 582.1 [M+H] + .

[0435] Synthesis route of compound 7

[0436]

[0437] Synthesis of compound 7-d

[0438] 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) were added to a three-necked flask, and the atmosphere was replaced with nitrogen twice. Pd2(dba)3 (396 mg, 0.43 mmol) was added, and the atmosphere was replaced with nitrogen three times. The reaction solution was heated at 90°C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by a rapid separation column (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain compound 7-d (2.2 g, 94%). LC-MS (ESI): m / z=271.1[M+H] + .

[0439] Synthesis of compound 7-c

[0440] At room temperature, 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (1.92 g, 8.93 mmol) and cesium carbonate (3.18 g, 9.75 mmol) were added to a DMF (15 mL) solution of 7-d (2.2 g, 8.13 mmol). After the addition, the reactants were stirred at room temperature overnight. After the reaction was completed, water was slowly added to quench the reaction, and a white solid precipitated and was filtered. The filter cake was dissolved in ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 7-c (2.4 g, 73%). LC-MS (ESI): m / z=404.9 [M+H] + .

[0441] Synthesis of compound 7-b

[0442] Under ice bath, add m-CPBA (3.2 g, 18.53 mmol) to a solution of 7-c (2.4 g, 5.93 mmol) in dichloromethane (100 mL). After addition, keep the reactants at 0°C and stir for 1 hour. After the reaction is completed, remove the solvent by rotary evaporation at room temperature, add ethyl acetate to dilute, wash with saturated sodium bicarbonate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. The crude product is separated and purified by rapid separation column (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] + .

[0443] Synthesis of compound 7-a

[0444] 7-b (800 mg, 1.83 mmol), methanol (10 mL) and dichloromethane (10 mL) were added to the reaction flask. The reactants were cooled to 0 ° C with an ice bath, sodium methoxide (297 mg, 5.49 mmol) was added, and the reaction solution was kept in an ice bath for 1 hour. 1-amino-1-cyclopropylnitrile hydrochloride (869 mg, 7.33 mmol) was added, stirred for 10 minutes, concentrated at room temperature to remove the solvent, and vacuum dried for 20 minutes. DMF (8 mL) and a small amount of 3A molecular sieves were added. After stirring for 3 minutes in an ice bath, triethylamine (0.51 mL, 3.66 mmol) and 1-amino-1-cyclopropylnitrile hydrochloride (217 mg, 1.83 mmol) were added. Then NCS (489 mg, 3.66 mmol) was added in an ice bath. The reaction solution was stirred in an ice bath for 1 hour. Dilute with ethyl acetate, wash with sodium bisulfite solution, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. The crude product was separated and purified by flash column (mobile phase: ethyl acetate / petroleum ether, 0% to 100%) to obtain 7-a (400 mg, 51%). LC-MS (ESI): m / z=430.9 [M+H] + .

[0445] Synthesis of compound 7

[0446] 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) were added to the reaction flask. After nitrogen replacement 3 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, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product. Compound 7 (18 mg, 27%) was obtained by Prep-HPLC purification. LC-MS (ESI): m / z 584.2 [M+H] + .

[0447] Synthesis route of compound 8

[0448]

[0449] Synthesis of compound 8

[0450] 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) were added to a microwave tube. The atmosphere was replaced with nitrogen three times and the tube was sealed. The reaction solution was heated at 75°C overnight. After the reaction, the mixture was cooled to room temperature, 1,4-dioxane was removed by vortexing, ethyl acetate was added to dilute, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product, which was purified by Prep-HPLC to obtain compound 8 (30 mg, 44%). LC-MS (ESI): m / z 587.2 [M+H] + .

[0451] Synthesis route of compound 9

[0452]

[0453] Synthesis of compound 9

[0454] I-4 (50 mg, 0.10 mmol), 4-isopropylsulfonylphenylboronic acid (47 mg, 0.20 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (13 mg, 0.020 mmol), cesium fluoride (47 mg, 0.31 mmol), 1,4-dioxane (9 mL) and H2O (1 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. Compound 9 (31 mg, 51%) was obtained by Prep-HPLC purification. LC-MS (ESI): m / z 593.1 [M+H] + .

[0455] Synthesis route of compound 10

[0456]

[0457] Synthesis of compound 10-1

[0458] Add 3-chloro-2-fluoro-benzoic acid (6.99 g, 40.04 mmol), dibromohydantoin (9.16 g, 32.04 mmol) and dichloromethane (80 mL) to the reaction flask. Add trifluoromethanesulfonic acid (5 mL) under ice bath. React in ice bath and then in water bath at room temperature for 3 hours. Pour the reaction solution into ice water, add ethyl acetate (80 mL), separate the liquids, and extract the aqueous phase once with dichloromethane. Wash the organic phase twice with water, combine the organic phases, wash once with sodium bisulfite aqueous solution, wash once with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter and evaporate to obtain 10-1 (8.6 g, 85%). LC-MS (ESI): m / z 250.9 (MH) - .

[0459] Synthesis of compound 10-k

[0460] 10-1 (8.6 g, 33.93 mmol) and methanol (70 mL) were added to the reaction flask. Thionyl chloride (6.5 mL) was added dropwise under ice bath stirring. The reaction solution was heated and stirred at 80°C for 4 hours. The solvent was removed by vortexing and the product was dried at an oil pump for 1 hour to obtain 10-k (9.0 g, 99%).

[0461] Synthesis of compound 10-j

[0462] 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. 10-j (10 g, 92%) was obtained by drying at room temperature. LC-MS (ESI): m / z 321.0 (M+H) + .

[0463] Synthesis of compound 10-i

[0464] 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), and acetic acid (1.5 mL) was added dropwise after stirring at room temperature for 1 hour, and stirring at room temperature was continued 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 obtain 10-i (4.0 g, 81%). LC-MS (ESI): m / z 260.8 (MH) - .

[0465] Synthesis of compound 10-h

[0466] 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. Nitrogen was replaced 3 times. The reaction solution was heated and stirred at 90°C for 6 hours. Cooled to room temperature. The reaction solution was vortexed to remove the solvent, and the crude product was purified by column (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) - .

[0467] Synthesis of compound 10-g

[0468] Add 10-h (3.5 g, 11.56 mmol), dichloromethane (25 mL) and triethylamine (4.82 mL, 34.68 mmol) to the reaction flask. Add trifluoromethanesulfonic anhydride (4.89 g, 17.34 mmol) dropwise under an ice-salt bath. Stir the reaction solution under an ice-salt bath for 1 hour (the ice is basically melted). Add sodium bicarbonate aqueous solution and stir for 5 minutes, separate the liquids, spin dry and purify through a column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to obtain compound 10-g (3.2 g, 64%).

[0469] Synthesis of compound 10-f

[0470] 10-g (3.0 g, 6.90 mmol), anhydrous DMF (15 mL), anhydrous ethanol (7.5 mL) (molecular sieve dried) and triethylamine (2.8 mL, 20.14 mmol) were added to the reaction flask. Palladium acetate (0.090 g, 0.40 mmol) and 1,3-bis(diphenylphosphine)propane (0.38 g, 0.92 mmol) were added. The reaction solution was replaced with carbon monoxide three times. The reaction solution was heated and stirred at 70-78 ° C under carbon monoxide protection for 3 hours. Then, the reaction solution was heated and stirred at 75 ° C under carbon monoxide protection for 5 hours. The reaction solution was cooled to room temperature. Part of the solvent was removed by rotation, ice water was added, and a mixture of ethyl acetate and petroleum ether was extracted once. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to obtain compound 10-f (1.05 g, 42%). LC-MS(ESI):m / z 359.0(M+H) + .

[0471] Synthesis of compound 10-e

[0472] 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 bath. The reaction solution was stirred under ice bath for 1.5 hours. The mixture was washed once with saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, filtered, evaporated and purified by column (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) + .

[0473] Synthesis of compound 10-d

[0474] Add 10-e (166 mg, 0.43 mmol), methanol (10 mL) and dichloromethane (10 mL) to the reaction flask. Add sodium methoxide (71 mg, 1.32 mmol) under ice-water bath. Stir the reaction solution under ice-water bath for 1 hour. Add 1-amino-1-cyclopropylnitrile hydrochloride (209 mg, 1.76 mmol) under ice-water bath. Drain the organic solvent at room temperature and dry it with oil pump for 30 minutes. Add 1-amino-1-cyclopropylnitrile hydrochloride (52 mg, 0.44 mmol) and DMF (10 mL), add triethylamine (0.12 mL, 0.88 mmol) and NCS (176 mg, 1.32 mmol) under ice-water bath. Stir the reaction solution under ice-water bath for 1 hour. Add ice water to the reaction solution and extract with ethyl acetate (100 mL*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%).

[0475] Synthesis of compound 10-c

[0476] Add 10-d (153 mg, 0.41 mmol), ethanol (20 mL) and hydrazine hydrate (6 mL, 80.40 mmol) to the reaction flask. Stir the reaction solution at 90 °C for 12 hours. Concentrate the reaction solution to obtain 10-c (153 mg, 100%). LC-MS (ESI): m / z 370.9 (M+H) + .

[0477] Synthesis of compound 10-b

[0478] Add 10-c (150 mg, 0.40 mmol), dichloromethane (20 mL) and triethylamine (0.08 mL, 0.61 mmol) to the reaction flask. Add difluoroacetic anhydride (84 mg, 0.49 mmol) dropwise under an ice-water bath. Stir the reaction solution under an ice-water bath for 1 hour. Add methanol (1 mL) to the reaction solution. Concentrate the organic solvent at room temperature. Purify by column chromatography (mobile phase: dichloromethane / methanol, 100 / 1 to 10 / 1) to obtain 10-b (59 mg, 33%). LC-MS (ESI): m / z 446.9 (MH) - .

[0479] Synthesis of compound 10-a

[0480] 10-b (56 mg, 0.13 mmol), Lawesson's reagent (126 mg, 0.31 mmol) and 1,4-dioxane (10 mL) were added to the reaction flask, and the reaction solution was heated and stirred at 75 ° C for 8 hours under nitrogen protection. The reaction solution 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) + .

[0481] Synthesis of compound 10

[0482] Add 10-a (16 mg, 0.04 mmol), 1,4-dioxane (5 mL), I-3 (16 mg, 0.05 mmol) and water (1 mL), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (7 mg, 0.01 mmol) to a microwave tube, and then add potassium phosphate (20 mg, 0.09 mmol). The microwave tube was replaced with nitrogen several times, sealed, heated to 110 ° C and stirred for 11 hours. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 10 (1 mg, 5%). LC-MS (ESI): m / z 600.1 (M+H) + .

[0483] Synthesis route of compound 11

[0484]

[0485] Synthesis of compound 11-b

[0486] 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 obtain compound 11-b (291 mg, 88%). LC-MS (ESI): m / z 314.0 (M+H) + .

[0487] Synthesis of compound 11-a

[0488] 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 the reaction bottle, and then 1,4-dioxane (30 mL) and water (6 mL) were added. The mixture was stirred at 90°C for 12 hours under nitrogen protection. 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) + .

[0489] Synthesis of compound 11

[0490] 11-a (116 mg, 0.16 mmol) was added to the reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the mixture was 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 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) + .

[0491] Synthesis of compound 12

[0492]

[0493] 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) + .

[0494] Synthesis of compound 13

[0495]

[0496] 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) + .

[0497] Synthesis of compound 14

[0498]

[0499] 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) + .

[0500] Synthesis route of compound 15

[0501]

[0502] Synthesis of compound 15-g

[0503] Trifluoroacetic acid (0.066 mL, 0.86 mmol) was carefully added 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). After the addition, the reactants were heated to 90 ° C and stirred for 3 hours. After the reaction was completed, the reactants were 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 a rapid separation column (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) + .

[0504] Synthesis of compound 15-f

[0505] Add methoxy(cyclooctadiene)iridium dimer (104mg, 0.16mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (85mg, 0.32mmol), biboronic acid pinacol ester (603mg, 2.38mmol) and methyl tert-butyl ether (6mL) to the microwave tube, replace the nitrogen twice and stir at room temperature for 5 minutes. Add 15-g (0.5g, 1.58mmol) of methyl tert-butyl ether (6mL) solution, replace the nitrogen three times and seal, stir at 85℃ for 3.5 hours. The reaction solution is evaporated to dryness to obtain the borate ester intermediate.

[0506] The borate 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 nitrogen was replaced 3 times, and the reaction solution was heated to 40 ° C and stirred for 18 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, evaporated, 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) + .

[0507] Synthesis of compound 15-e

[0508] 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, replaced with nitrogen twice, Pd2(dba)3 (34 mg, 0.037 mmol) was added, and replaced 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) + .

[0509] Synthesis of compound 15-d

[0510] At room temperature, TFA (5 mL) was added to a solution of 15-e (350 mg, 0.69 mmol) in dichloromethane (20 mL). After the addition, the reactant was stirred at room temperature overnight. 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 obtain compound 15-d (250 mg, 86%). LC-MS (ESI): m / z 423.0 (M+H) + .

[0511] Synthesis of compound 15-c

[0512] At room temperature, cesium carbonate (385 mg, 1.18 mmol) and iodomethane (0.096 mL, 1.18 mmol) were added to a DMF (5 mL) solution of 15-d (250 mg, 0.59 mmol). After the addition, the reactants were stirred at room temperature overnight. After the reaction was completed, ethyl acetate was added to dilute, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The product was separated and purified by a 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) + .

[0513] Synthesis of compound 15-b

[0514] 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, 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) + .

[0515] Synthesis of compound 15-a

[0516] Add 15-b (200 mg, 0.43 mmol), methanol (10 mL) and dichloromethane (10 mL) to the reaction flask. Add sodium methoxide (69 mg, 1.28 mmol) in an ice-water bath. Stir the reaction in an ice-water bath for 1 hour. Add 1-amino-1-cyclopropylnitrile hydrochloride (202 mg, 1.70 mmol) in an ice-water bath. Remove the organic solvent at room temperature and dry with an oil pump for 30 minutes. Add 1-amino-1-cyclopropylnitrile hydrochloride (51 mg, 0.43 mmol) and DMF (10 mL). Add triethylamine (0.73 mL, 0.85 mmol) and NCS (171 mg, 1.28 mmol) in an ice-water bath. Stir the reaction solution in an ice-water bath for 1 hour. Add the reaction solution into ice water and extract twice with ethyl acetate. The organic phase was washed with water, washed with 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) + .

[0517] Synthesis of compound 15

[0518] 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), potassium phosphate (20 mg, 0.09 mmol) were added to a microwave tube, and then 1,4-dioxane (5 mL), water (1 mL) were added, nitrogen was protected, sealed, 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): d8.86(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).

[0519] Synthesis route of compound 16

[0520]

[0521] Synthesis of compound 16-b

[0522] 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 solution. After the addition, stir at 0°C under nitrogen protection, slowly warm to room temperature and stir for 12 hours. The reaction solution is directly put into the next step reaction.

[0523] Synthesis of compound 16-a

[0524] Add 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) to the reaction flask and stir at 0°C for 10 minutes. Slowly add 16-b (164 mg) dropwise to the reaction solution and stir at 0°C for 3 hours under nitrogen protection. Wash the reaction solution with saturated sodium bisulfate (30 mL). Extract the sodium bisulfate washings with dichloromethane (10 mL*3). Combine the organic phases and concentrate to obtain compound 16-a (110 mg, 91%). LC-MS (ESI): m / z 316.2 (M+H)+ .

[0525] Synthesis of compound 16

[0526] 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), potassium phosphate (52 mg, 0.25 mmol) were added to a microwave tube, and then 1,4-dioxane (8 mL), water (2 mL) were added, nitrogen was protected, sealed, 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) + .

[0527] Synthesis route of compound 17

[0528]

[0529] Synthesis of compound 17-b

[0530] Compound I-1 (50 mg, 0.081 mmol), I-3 (51 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (12 mg, 0.016 mmol), potassium carbonate (33 mg, 0.24 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, and then heated and stirred at 100°C for 6 hours. The reaction solution was filtered with diatomaceous earth, water (100 mL) was added to the filtrate, and ethyl acetate (100 mL) was used for extraction. 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) + .

[0531] Synthesis of compound 17-a

[0532] 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) + .

[0533] Synthesis of Compound 17

[0534] Add 17-a (50 mg, 0.08 mmol) and dichloromethane (8 mL) to the reaction flask and stir for 10 minutes under ice-salt bath conditions. Slowly add concentrated sulfuric acid (1 mL) to the mixture. Slowly warm the reaction solution to room temperature and stir for 3 hours. Pour the reaction solution into ice water (20 mL) and extract with dichloromethane (20 mL). The organic phase is 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) + .

[0535] Synthesis route of compound 18

[0536]

[0537] Synthesis of compound 18-f

[0538] Add bis(1.21g, 4.75mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (208mg, 0.32mmol), and methyl tert-butyl ether (10mL) to the sealed tube, add methoxy(cyclooctadiene)iridium dimer (170mg, 0.63mmol) under nitrogen protection, replace the nitrogen twice, and stir at room temperature for 10 minutes. Add 15-g (1.0g, 3.17mmol) methyl tert-butyl ether (10mL) solution, replace the nitrogen three times, and stir at 85℃ for 3.5 hours. The reaction solution is concentrated to obtain a crude borate ester.

[0539] The obtained 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, and the nitrogen was replaced twice. The reaction solution was stirred at 40 ° C for 18 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column (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) + .

[0540] Synthesis of compound 18-e

[0541] 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 replaced with nitrogen three times. The reaction solution was heated to 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) + .

[0543] Synthesis of compound 18-d

[0544] 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 solution was stirred at room temperature for 2 hours. The solvent was removed by vortexing, diluted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain 18-d (179 mg, 100%). LC-MS (ESI): m / z 405.0 (M+H) + .

[0545] Synthesis of compound 18-c

[0546] Add 18-d (171 mg, 0.42 mmol), DMF (4.2 mL) and cesium carbonate (360 mg, 1.10 mmol) to the reaction flask. Add iodomethane (0.042 mL, 0.68 mmol) dropwise in an ice bath. The reaction solution was reacted at room temperature for 2 hours. Add a small amount of methanol and ethyl acetate. Rotary evaporation was performed at room temperature for 5 minutes. Add ethyl acetate to dilute the reaction solution, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, evaporate to dryness and purify with a column (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) + .

[0547] Synthesis of compound 18-b

[0548] 18-c (175 mg, 0.42 mmol), 1,4-dioxane (20 mL), I-3 (250 mg, 0.79 mmol) and 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), sodium carbonate (206 mg, 1.94 mmol) were added to the microwave tube. The microwave tube was replaced with nitrogen, sealed, heated to 100 ° C and stirred for 3 hours. The reaction solution was concentrated and purified by column chromatography (PE / EA=5 / 1, 3 / 1) to obtain compound 18-b (176 mg, 74%). LC-MS (ESI): m / z 572.1 (M+H) + .

[0550] Synthesis of compound 18-a

[0551] 18-b (179 mg, 0.31 mmol), dichloromethane (20 mL) and m-CPBA (159 mg, 0.78 mmol) were added to the reaction flask, cooled in an ice-water bath and stirred for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench, and extracted with dichloromethane (30 mL*2). The organic phase was concentrated, purified and concentrated by column chromatography (PE / EA=3 / 1, 1 / 3) to obtain compound 18-a (170 mg, 90%). LC-MS (ESI): m / z 604.1 (M+H) + .

[0552] Synthesis of compound 18

[0553] 18-a (80 mg, 0.13 mmol), methanol (10 mL) and dichloromethane (10 mL) were added to the reaction flask. Sodium methoxide (21 mg, 0.40 mmol) was added under ice-water bath. The reaction solution 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 by oil pump for 30 minutes. 1-(Fluoromethyl)cyclopropylamine hydrochloride (17 mg, 0.13 mmol) and DMF (10 mL) were added, and triethylamine (0.04 mL, 0.27 mmol) and NCS (53 mg, 0.40 mmol) were added under ice-water bath. Stir under ice-water bath for 1 hour. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL*3). The organic phase was concentrated and purified by Prep-HPLC to obtain 18 (19.3 mg, 24%). LC-MS(ESI):m / z 605.1(M+H) + .

[0554] Synthesis route of compound 19

[0555]

[0556] Synthesis of compound 19

[0557] 18-a (87 mg, 0.14 mmol), methanol (10 mL) and dichloromethane (10 mL) were added to the reaction flask, and sodium methoxide (23 mg, 0.43 mmol) was added under ice-water bath. The reaction solution was stirred under ice-water bath for 1 hour. 1-Methylcyclopropylamine hydrochloride (62 mg, 0.58 mmol) was added under ice-water bath. The solvent was concentrated at room temperature and dried by oil pump for 30 minutes. 1-Methylcyclopropylamine hydrochloride (16 mg, 0.14 mmol) and DMF (10 mL) were added, and triethylamine (0.04 mL, 0.29 mmol) and NCS (58 mg, 0.43 mmol) were added under ice-water bath. Stir under ice-water bath for 1 hour. Water (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (10 mL*3). The organic phase was concentrated and purified by Prep-HPLC to obtain 19 (16.9 mg, 20%). LC-MS(ESI):m / z 587.1(M+H) + .

[0558] Synthesis route of compound 20

[0559]

[0560] Synthesis of compound 20-b

[0561] 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 bottle, 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 for 1 hour under nitrogen protection. The reaction solution was washed with saturated sodium bisulfate (30 mL), and the reaction solution was concentrated to obtain compound 20-b (186 mg, 87%). LC-MS (ESI): m / z 446.1 (M+NH4) + .

[0562] Synthesis of compound 20-a

[0563] 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), cesium fluoride (93 mg, 0.61 mmol) were added to a microwave tube, and then 1,4-dioxane (9 mL), water (1 mL) were added, nitrogen was protected, and the tube was 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 obtain compound 20-a (110 mg, 76%). LC-MS (ESI): m / z 711.1 (M+H) + .

[0564] Synthesis of compound 20

[0565] 20-a (110 mg, 0.16 mmol), dichloromethane (10 mL), trifluoroacetic acid (3 mL), nitrogen protection, stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 20 (66.3 mg, 70%). LC-MS (ESI): m / z 611.1 (M+H) + .

[0566] Synthesis route of compound 21

[0567]

[0568] Synthesis of compound 21

[0569] Add 20 (49 mg, 0.08 mmol), paraformaldehyde (49 mg), sodium cyanoborohydride (15 mg, 0.24 mmol) and methanol (20 mL) to the reaction flask and stir at room temperature for 12 hours. The reaction solution was concentrated and purified by preparative HPLC to give compound 21 (9.3 mg, 19%). LC-MS (ESI): m / z 625.5 (M+H)+ .

[0570] Synthesis route of compound 22

[0571]

[0572] Synthesis of compound 22-b

[0573] At room temperature, the compound toluene-4-sulfonic acid oxacyclopentane-3-yl ester (5g, 21.90mmol) was dissolved in 50mL of DMF, and potassium thioacetate (7.57g, 65.72mmol) was added. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature, 200mL of water was added to the reaction solution, and extracted with ethyl acetate (300mL). The organic phase was washed with saturated brine (200mL*5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. The crude product 22-b (2.9g, 100%) was obtained. The crude product was directly used in the next step without further purification. LC-MS (ESI): m / z=133.0[M+H] + .

[0574] Synthesis of compound 22-a

[0575] 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 about 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 ether. The organic phase was washed with saturated sodium bicarbonate solution (100 mL*2), saturated sodium thiosulfate solution (100 mL*2), and saturated brine (100 mL) in sequence, 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 (1.52g, 6.19mmol) was dissolved in 50mL of DCM, and TEA (5.26mL, 37.83mmol) was added under ice-water bath. After the reaction mixture was stirred under ice-water bath for 10 minutes, 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. 100mL of water was added to the reaction mixture, extracted with DCM (100mL), and the organic phase was washed with 10% sodium bisulfate solution (100mL) and saturated sodium bicarbonate solution (100mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 22-a (1.2g). LC-MS (ESI): m / z=330.1[M+H]+ .

[0576] Synthesis of compound 22

[0577] 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-butylphosphinoferrocene palladium 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, concentrated under reduced pressure, 100 mL of water was added to the residue, and extracted with DCM (100 mL*2). 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-HPLC (alkali 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).

[0578] Synthesis route of compound 23

[0579]

[0580] Synthesis of compound 23-c

[0581] 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 extracted with DCM (200 mL). The organic phase was washed with 10% sodium bisulfate solution (200 mL) and saturated sodium bicarbonate solution (200 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product 23-c (13.5 g, 100%). The crude product was used directly in the next step without further purification. LC-MS (ESI): m / z=262.1[M+NH4] + .

[0582] Synthesis of compound 23-b

[0583] 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 step without further purification. LC-MS (ESI): m / z=149.1[M+H] + .

[0584] Synthesis of compound 23-a

[0585] At room temperature, compound NCS (3.60 g, 26.99 mmol) was dissolved in 30 mL of acetonitrile, and 2M 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 about 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 ether. The organic phase was washed with saturated sodium bicarbonate solution (100 mL*2), saturated sodium thiosulfate solution (100 mL*2), and saturated brine (100 mL) in sequence, 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, and TEA (4.69 mL, 33.73 mmol) was added under ice-water bath. After the reaction mixture was stirred under ice-water bath for 10 minutes, 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 it was extracted with DCM (100 mL). The organic phase was washed with 10% sodium bisulfate solution (100 mL*2) and saturated sodium bicarbonate solution (100 mL) in turn, 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] + .

[0586] Synthesis of compound 23

[0587] 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-butylphosphinoferrocene palladium 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, concentrated under reduced pressure, 100 mL of water was added to the residue, and extracted with DCM (100 mL*2). 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-HPLC (alkali method, NH4HCO3) to obtain compound 23 (150 mg, 58%). LC-MS (ESI): m / z=628.2[M+H] + ; 1H 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).

[0588] Synthesis route of compound 24

[0589]

[0590] Synthesis of compound 24-b

[0591] 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 for 30 minutes under nitrogen at room temperature. 100 mL of saturated sodium bicarbonate solution was added to the reaction solution and extracted with DCM (100 mL). The organic phase was washed with saturated sodium bicarbonate solution (100 mL) and water (200 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product 24-b (665 mg). The crude product was used directly in the next step without further purification. LC-MS (ESI): m / z=264.0[M+H] + .

[0592] Synthesis of compound 24-a

[0593] At room temperature, compound 24-b (120 mg, 0.45 mmol) was dissolved in 10 mL of 1,4-dioxane, and diboric acid pinacol ester (346 mg, 1.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) dichloromethane complex (37 mg, 0.045 mmol), and potassium acetate (223 mg, 2.27 mmol) were added in sequence. The reaction mixture was stirred at 80 ° C under argon for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 10 mL of DCM, and the mixture was filtered through a short silica gel column (~10 CM). The filtrate was discarded, and the silica gel column was continuously eluted with methanol (50 mL). The methanol filtrate was concentrated under reduced pressure, and the residue was vacuum dried for 30 minutes to obtain a crude product 24-a (100 mg). The crude product was directly used in the next step without further purification. LC-MS (ESI): m / z=230.0[M+H]+ .

[0594] Synthesis of compound 24

[0595] 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-butylphosphinoferrocene palladium 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, concentrated under reduced pressure, 50 mL of water was added to the residue, and extracted with DCM (50 mL*2). 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-HPLC (alkali method, NH4HCO3) to obtain compound 24 (15.4 mg, 25%). LC-MS (ESI): m / z=594.1[M+H] + .

[0596] Synthesis route of compound 25

[0597]

[0598] Synthesis of compound 25-b

[0599] Add isopropyl disulfide (606 mg, 4.03 mmol) and acetic acid (0.461 mL, 8.06 mmol) to the reaction flask. Stir the mixture in an ice-salt bath for 5 minutes, then add sulfonyl chloride (1632 mg, 12.10 mmol) dropwise over 10 minutes. The reaction solution is reacted at -20°C to room temperature for 3 hours, and then at 35°C for 1 hour. Remove the solvent by rotary evaporation at room temperature to obtain 25-b (900 mg, 88%).

[0600] Synthesis of compound 25-a

[0601] Add 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) to the reaction flask. Add 25-b (102 mg, 0.81 mmol) dropwise under ice bath. Stir the reaction solution in ice bath for 1 hour. Place in the lower layer of the refrigerator overnight. Remove the solvent by rotary evaporation, dilute with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 25-a (120 mg, 80%). LC-MS (ESI): m / z 300.1 (M+H) + .

[0602] Synthesis of compound 25

[0603] Add 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) into a microwave tube. Replace with nitrogen 5 times. Heat and stir the reaction solution for 18 hours. The upper organic phase of the reaction solution was spin-dried, dissolved in DMF and purified by 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).

[0604] Synthesis route of compound 26

[0605]

[0606] Synthesis of compound 26-b

[0607] Add 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) to a microwave tube. Seal the reaction mixture and heat and stir at 70 ° C for 18 hours. Continue to heat and stir the reaction solution at 70 ° C for 4 hours. The reaction solution is cooled to room temperature, ice water is added, and extracted with ethyl acetate. The organic phase is washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain 26-b (125 mg, 74%). LC-MS (ESI): m / z 675.9 (M+H) + .

[0608] Synthesis of compound 26-a

[0609] Add 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) to a microwave tube. Replace the microwave tube with nitrogen 4 times and seal it. The reaction solution was heated and stirred at 100°C for 3 hours. Add Pd(dppf)Cl2 (18 mg, 0.025 mmol), replace the microwave tube with nitrogen 4 times and seal it. The reaction solution was heated and stirred at 100°C for 18 hours. The reaction solution was cooled, ethyl acetate was added, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column (mobile phase: dichloromethane / methanol, 100 / 0 to 0 / 100) to obtain 26-a (120 mg, 85%). LC-MS(ESI):m / z 785.1(M+H) + .

[0610] Synthesis of compound 26

[0611] Add 26-a (120 mg, 0.15 mmol) and dichloromethane (2 mL) to the reaction flask. Add trifluoroacetic acid (0.7 mL) dropwise under ice bath. After addition, the reaction solution is naturally warmed to room temperature and reacted for 2 hours. The reaction solution is spin-dried. Add saturated sodium bicarbonate aqueous solution and anhydrous potassium carbonate solid to the residue, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by column (DCM / MeOH, 100 / 0 to 85 / 15) to obtain crude product preparation purification (ammonium bicarbonate), and obtain 26 (22.2 mg, 23%). LC-MS (ESI): m / z 655.2 (M+H) + ; 1 H 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).

[0612] Synthetic routes of compounds 27 and 28

[0613]

[0614] Synthesis of compounds 27, 28

[0615] 17-a (100 mg, 0.17 mmol) and Mn(TMHD)3 (18 mg, 0.030 mmol) were added to a two-necked bottle. Isopropanol (2 mL) and dichloromethane (1 mL) were slowly added along the wall of the bottle under the protection of an air balloon in an ice bath. Phenylsilane (46 mg, 0.43 mmol) was added dropwise. The reaction solution 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 liquids were separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain 27 (14.8 mg, 14%) and 28 (21.8 mg, 21%).

[0616] 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).

[0617] Compound 28, LC-MS (ESI): m / z 616.1 (M+H) + ; 1 H 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).

[0618] Synthesis route of compound 29

[0619]

[0620] Synthesis of compound 29-f

[0621] 4-Hydroxycyclohexanone glycol acetal (3.16 g, 19.97 mmol), DCM (50 mL) and triethylamine (8.33 mL, 59.92 mmol) were added to the reaction flask. TsCl (5.71 g, 29.95 mmol) and DMAP (0.24 g, 2.00 mmol) were added under ice bath. The reaction solution was stirred in ice bath for 10 minutes and 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, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 29-f (6.2 g, 99%).

[0622] Synthesis of compound 29-e

[0623] Add 29-f (1.2 g, 3.84 mmol), potassium thioacetate (0.71 g, 6.15 mmol) and DMF (10 mL) to the reaction flask. Heat the reaction solution at 80°C and stir for 7 hours. Add ice water to the reaction solution and extract twice with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 29-e (800 mg, 96%). LC-MS (ESI): m / z 217.0 (M+H) + .

[0624] Synthesis of compound 29-d

[0625] Add 29-e (800 mg, 3.70 mmol), 2-iodopropane (0.94 mL, 9.41 mmol) and anhydrous ethanol (15 mL) to the reaction flask. Add potassium tert-butoxide (1060 mg, 9.45 mmol) under ice bath. Stir the reaction solution in ice bath for 10 minutes and then stir at room temperature overnight. Rotate to remove the solvent, add ethyl acetate and ice water, separate the liquids, extract the aqueous phase with ethyl acetate once, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 75 / 25) to obtain 29-d (600 mg, 75%).

[0626] Synthesis of compound 29-c

[0627] Add 29-d (600 mg, 2.77 mmol), tetrahydrofuran (10 mL) and aqueous hydrochloric acid (4 mL, 4 M) to the reaction flask. Stir the reaction solution at room temperature overnight. Remove the tetrahydrofuran at room temperature, add purified water, and extract twice with dichloromethane. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 29-c (470 mg, 98%).

[0628] Synthesis of compound 29-b

[0629] Add 29-c (470 mg, 2.73 mmol) and anhydrous tetrahydrofuran (5 mL) to the reaction flask. Slowly add LHMDS tetrahydrofuran solution (1M, 4.0 mL, 4.00 mmol) at -78°C. The reaction solution is reacted at -78°C for 1 hour. Slowly add N-phenylbis(trifluoromethanesulfonyl)imide (1300 mg, 3.64 mmol) in anhydrous tetrahydrofuran (5 mL) at -78°C. The reaction solution is reacted at -78°C to room temperature for 2 hours. Place in the refrigerator overnight. Add ethyl acetate and petroleum ether, wash twice with water, wash with 5% sodium bicarbonate aqueous solution, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 29-b (830 mg, 100%).

[0630] Synthesis of compound 29-a

[0631] Add 1,4-dioxane (10 mL) solution of bis(pyrazol)-1-ylpyridinium chloride (860 mg, 3.39 mmol), Pd(dppf)Cl2.CH2Cl2 (100 mg, 0.12 mmol), potassium acetate (800 mg, 8.15 mmol) and 29-b (830 mg, 2.73 mmol) to a microwave tube. Replace with nitrogen three times, seal, and heat and stir the reaction solution at 90 °C for 5 hours. Cool the reaction solution to room temperature, add ethyl acetate and petroleum ether, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10) to obtain 29-a (440 mg, 57%).

[0632] Synthesis of compound 29

[0633] 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) to a microwave tube. Replace the reaction liquid with nitrogen three times, seal it, and heat and stir it at 100 ° C for 3.5 hours. The reaction liquid is cooled to room temperature. Add Pd (dtbpf) Cl2 (50 mg, 0.077 mmol), cesium fluoride (60 mg, 0.40 mmol) and 1,4-dioxane (2 mL). Replace the reaction liquid with nitrogen three times, seal it, and heat and stir it at 100 ° C for 4 hours. The reaction liquid is cooled to room temperature. Add the reaction liquid into ice water and extract it 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 obtain a crude product (130 mg). The crude product (40 mg) was purified by preparative HPLC (ammonium bicarbonate) to obtain 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).

[0634] Synthetic routes of compounds 30 and 31

[0635]

[0636] Synthesis of compounds 30, 31

[0637] Add 29 (85 mg, 0.15 mmol) and acetone (4 mL) to the reaction flask. Add a solution of Oxone (60 mg, 0.098 mmol) in water (2 mL) dropwise under ice bath. After the addition, the reaction mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 1 hour. Add Oxone (5 mg, 0.008 mmol) and stir the reaction mixture at room temperature for 30 minutes. Add ethyl acetate to the reaction solution, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify by preparative HPLC (ammonium bicarbonate) to obtain 30 (25 mg, 29%) as a white solid and 31 (16 mg, 18%) as a white solid.

[0638] 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).

[0639] 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).

[0640] Synthesis route of compound 32

[0641]

[0642] Synthesis of compound 32-b

[0643] 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) + .

[0644] Synthesis of compound 32-a

[0645] 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, and 1,4-dioxane (4 mL) and water (1 mL) were added. The tube was sealed with nitrogen protection 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) + .

[0646] Synthesis of compound 32

[0647] 32-a (41 mg, 0.06 mmol) was added to the reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the mixture was 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 then ethyl acetate (10 mL) was added to the reaction flask and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (10 mL*3) and purified by preparative HPLC to obtain compound 32 (18.3 mg, 54%). LC-MS (ESI): m / z 599.1 (M+H) + .

[0648] Synthesis route of compound 33

[0649]

[0650] Synthesis of compound 33-b

[0651] At room temperature, the 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 turn, and 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).

[0652] Synthesis of compound 33-a

[0653] At room temperature, the compound triphenylphosphine dichloride (814 mg, 2.44 mmol) was dissolved in 10 mL of chloroform, and triethylamine (0.46 mL, 3.30 mmol) was added dropwise under an ice-water bath. After the addition was completed, 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 chloroform (5 mL) solution of compound 33-b (600 mg, 2.53 mmol) was added to the above reaction solution and stirred under an ice-water bath for 20 minutes. Under an ice-water bath, a chloroform (5 mL) and triethylamine (0.17 mL, 1.22 mmol) solution of compound 1,2,3,6-tetrahydropyridine-4-boric acid pinacol ester hydrochloride (200 mg, 0.81 mmol) was added to the above reaction solution. 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 separated and purified by a rapid separation column (DCM / MeOH=10:1) to obtain a 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] + .

[0654] Synthesis of compound 33

[0655] 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, concentrated under reduced pressure, 100 mL of water was added to the residue, and extracted with ethyl acetate (100 mL*2). 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-HPLC (alkali 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).

[0656] Synthesis route of compound 34

[0657]

[0658] Synthesis of compound 34-c

[0659] 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) 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. The crude product compound 34-c (300 mg, 96%) was obtained. LC-MS (ESI): m / z 281.8 [M+H] + .

[0660] Synthesis of compound 34-b

[0661] 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, and then isopropylsulfonyl chloride (0.17 mL, 1.52 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it 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 a crude product. The crude product was purified by a rapid separation column (mobile phase: methanol / dichloromethane: 0% to 10%) to obtain compound 34-b (250 mg, 85%). LC-MS (ESI): m / z=388.4[M+H] + .

[0662] Synthesis of compound 34-a

[0663] I-4 (250 mg, 0.51 mmol), 34-b (238 mg, 0.61 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (66 mg, 0.10 mmol), cesium fluoride (233 mg, 1.53 mmol), 1,4-dioxane (18 mL) and H2O (2 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, 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 rapid separation column (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] + .

[0664] Synthesis of compound 34

[0665] 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. 69(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).

[0666] Synthesis route of compound 35

[0667]

[0668] Synthesis of compound 35-b

[0669] 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.

[0670] Synthesis of compound 35-a

[0671] 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), (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) were added to the microwave tube, the mixture was replaced with nitrogen three times, 1,4-dioxane (1.5 mL) was added to the microwave tube, and the tube was replaced with nitrogen three times and sealed. The reaction solution 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) + .

[0672] Synthesis of compound 35

[0673] 35-a (28 mg, 0.04 mmol), dichloromethane (3 mL), trifluoroacetic acid (1 mL) were added to the reaction flask, and stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, potassium carbonate (3 g), water (20 mL), and ethyl acetate (20 mL) were added to the residue, and the mixed solution was stirred at room temperature for 2 hours. It was extracted with ethyl acetate (20 mL*2), 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) + .

[0674] Synthetic route of compound 36

[0675]

[0676] Synthesis of compound 36

[0677] Under an ice-water bath, LiCl (63 mg, 1.49 mmol) and NaBH4 (56 mg, 1.49 mmol) were added to a solution of 34-a (100 mg, 0.16 mmol) in THF (10 mL) and ethanol (5 mL) in sequence. 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 water was added to carefully quench the reaction. 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 obtain compound 36 (15 mg, 15%). LC-MS (ESI): m / z 628.2 [M+H] + .

[0678] Synthetic route of compound 37

[0679]

[0680] Synthesis of compound 37-b

[0681] 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 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 a rapid separation column (PE / EA = 2: 1) to obtain compound 37-b (538 mg, 55%). LC-MS (ESI): m / z = 622.0 [M + H] + .

[0682] Synthesis of compound 37-a

[0683] At room temperature, compound 37-b (76 mg, 0.12 mmol) was dissolved in 20 mL of 1,4-dioxane, and water (2 mL), compound I-3 (50 mg, 0.16 mmol), [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (18 mg, 0.024 mmol), potassium carbonate (51 mg, 0.37 mmol) were added in sequence, and 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, extracted with ethyl acetate (50 mL*2), 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) to obtain compound 37-a (75 mg, 85%). LC-MS (ESI): m / z=731.1[M+H] + .

[0684] Synthesis of compound 37

[0685] 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 for 1.5 hours under nitrogen at room temperature. 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 HNMR (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),3.74-3.63(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).

[0686] Synthesis route of compound 38

[0687]

[0688] Synthesis of compound 38

[0689] 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, the residue was dissolved in ethyl acetate, saturated sodium bicarbonate aqueous solution and anhydrous sodium sulfate solid were added, the liquids were separated, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified (ammonium bicarbonate) to obtain 38 (12 mg, 23%). LC-MS (ESI): m / z 614.1 (M+H) + ; 1H 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).

[0690] Synthetic route of compound 39

[0691]

[0692] Synthesis of compound 39-b

[0693] In 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 bottle, and then tert-butyl 4-chlorosulfonylpiperidine-1-carboxylate (0.39 mL, 1.79 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it 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 compound 39-b (500 mg, 92%). LC-MS (ESI): m / z=457.2[M+H] + .

[0694] Synthesis of compound 39-a

[0695] I-4 (50 mg, 0.10 mmol), 39-b (93 mg, 0.20 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (13 mg, 0.020 mmol), cesium fluoride (47 mg, 0.31 mmol), 1,4-dioxane (9 mL) and H2O (1 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue to dilute. The organic phase was washed with water, 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 rapid separation column (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] + .

[0696] Synthesis of compound 39

[0697] 39-a (50 mg, 0.068 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 the residue for dilution, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product. Compound 39 (25 mg, 58%) was obtained by Prep-HPLC purification. LC-MS (ESI): m / z 639.2 [M+H] + .

[0698] Synthetic route of compound 40

[0699]

[0700] Synthesis of compound 40-b

[0701] 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, extracted with dichloromethane (100 mL), and the organic phase was washed with 10% sodium bisulfate solution (100 mL), 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] + .

[0702] Synthesis of compound 40-a

[0703] At room temperature, the compound triphenylphosphine dichloride (488mg, 1.47mmol) was dissolved in 10mL of chloroform, and triethylamine (275uL, 1.98mmol) was added dropwise under an ice-water bath. After the addition was completed, 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 chloroform (2mL) solution of compound 40-b (208mg, 1.52mmol) was added to the above reaction solution and stirred under an ice-water bath for 20 minutes. Under an ice-water bath, a chloroform (5mL) and triethylamine (102uL, 0.73mmol) solution of the compound 1,2,3,6-tetrahydropyridine-4-boric acid pinacol ester hydrochloride (120mg, 0.49mmol) was added to the above reaction solution. 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 separated and purified by a rapid separation column (DCM / MeOH=10:1) to obtain a crude compound 40-a (160 mg). The crude product was used directly in the next step without further purification. LC-MS (ESI): m / z=329.2 [M+H] + .

[0704] Synthesis of compound 40

[0705] 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, concentrated under reduced pressure, 100 mL of water was added to the residue, and extracted with ethyl acetate (100 mL*2). 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-HPLC (alkali method, NH4HCO3) to obtain compound 40 (3 mg, 2.4%). LC-MS (ESI): m / z=611.1[M+H] + .

[0706] Synthesis of comparative compound 1′

[0707]

[0708] Synthesized according to WO2021055744A1 method.

[0709] Synthetic route of compound 41

[0710]

[0711] Synthesis of compound 41-b

[0712] 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, 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 10 / 1) to obtain 41-b (1.12 g, 93%).

[0713] Synthesis of compound 41-a

[0714] Compound 41-b (100 mg, 0.43 mmol) was dissolved in 1,4-dioxane (10 mL), and diboric acid pinacol ester (163 mg, 0.64 mmol), 1,1-bis(diphenylphosphine)diferronichloridopalladium (31 mg, 0.042 mmol), potassium acetate (126 mg, 1.28 mmol) were added thereto, and the reaction solution was stirred at 85°C for 12 hours under nitrogen protection. The reaction solution was filtered with diatomaceous earth and concentrated under reduced pressure to obtain 41-a (80 mg, 94%). LC-MS (ESI): m / z 199.1 (M+H) + .

[0715] Synthesis of compound 41

[0716] Compound I-4 (200 mg, 0.41 mmol), 41-a (162 mg, 0.82 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (53 mg, 0.082 mmol), cesium fluoride (186 mg, 1.22 mmol) were added to 1,4-dioxane (27 mL) and water (3 mL), and the reaction solution was replaced with nitrogen three times, and then heated and stirred at 100°C for 6 hours. The reaction solution was filtered with diatomaceous earth, water (100 mL) was added to the filtrate, and extracted with dichloromethane (100 mL), the organic phase was washed with saturated brine (100 mL), dried with sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA1 / 1), and part of the product was purified by preparative HPLC (alkaline conditions) to obtain compound 41 (25 mg, 11%). LC-MS(ESI):m / z 563.2(M+H) + .

[0717] Synthesis route of compound 42

[0718]

[0719] Synthesis of compound 42

[0720] Compound 41 (50 mg, 0.089 mmol) was dissolved in dichloromethane (6 mL), and m-chloroperoxybenzoic acid (20 mg, 0.12 mmol) was added thereto. After the reaction solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution (10 mL) was added thereto, and the mixture was extracted with dichloromethane (50 mL). The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 42 (13 mg, 25%). LC-MS (ESI): m / z 579.1 (M+H) + .

[0721] Synthetic route of compound 43

[0722]

[0723] Synthesis of compound 43

[0724] Compound 41 (100 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (90 mg, 0.52 mmol) was added thereto. After the reaction solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution (50 mL) was added thereto, and the mixture was extracted with dichloromethane (50 mL). The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (basic conditions) to obtain compound 43 (32 mg, 30%). LC-MS (ESI): m / z 595.1 (M+H) + .

[0725] Synthetic routes of compounds 44 and 45

[0726]

[0727] Synthesis of compound 44-f-2

[0728] 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] + .

[0729] Synthesis of compound 44-e

[0730] 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, cooled to room temperature, concentrated under reduced pressure, and the residue was vacuum dried for 1 hour to obtain compound 44-e (3.0 g, 100%). LC-MS (ESI): m / z=519.0 [M+H] + .

[0731] Synthesis of compound 44-d

[0732] At room temperature, compound 44-e (1.0 g, 1.93 mmol) was dissolved in 15 mL of DCM, 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 was clear. After the addition was completed, the reaction mixture was stirred for 30 minutes under ice-water bath, 5 mL of methanol was added, and stirring was 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 with 10% NaHSO4 solution (100 mL), saturated sodium bicarbonate solution (100 mL), and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 44-d (1.15 g, 100%). LC-MS (ESI): m / z=597.1[M+H] + .

[0733] Synthesis of compound 44-c

[0734] At room temperature, compound 44-d (1.15 g, 1.93 mmol) was dissolved in 20 mL of anhydrous THF, Lawesson's reagent (1.95 g, 4.81 mmol) was added, and the reaction mixture was stirred at 80 ° C under nitrogen for 5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution (100 mL), 10% NaHSO4 solution (100 mL), and saturated brine (100 mL) in sequence, 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) to obtain a crude product. The crude product was suspended in methyl tert-butyl ether (15 mL), ultrasonically dispersed for 5 minutes, the mixture was filtered, the filter cake was rinsed with methyl tert-butyl ether (5 mL), the filter cake was collected, and vacuum dried for 1 hour to obtain compound 44-c (330 mg, 29%). LC-MS (ESI): m / z = 595.1 [M+H] +

[0735] Synthesis of compound 44-b

[0736] 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, concentrated under reduced pressure, 100 mL of water was added to the residue, and extracted with DCM (100 mL*2). 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 a rapid separation column (PE / EA=1:1) to obtain compound 44-b (110 mg, 87%). LC-MS (ESI): m / z=704.3[M+H] + .

[0737] Synthesis of compound 44-a

[0738] 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), bromomethylcyclopropane (24 uL, 0.25 mmol) were added in sequence, and the reaction mixture was stirred at 50 ° C overnight. The reaction solution was cooled to room temperature, 50 mL of water was added to quench the reaction, and 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 a crude product. The crude product was separated and purified by a rapid separation column (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] + .

[0739] Synthesis of compounds 44 and 45

[0740] 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 (alkali 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] + .

[0741] Synthetic route of compound 46

[0742]

[0743] Synthesis of Compound I-6

[0744] 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 obtain a crude product. Compound I-6 (56 mg, 80%) was obtained by separation and purification by rapid separation column (mobile phase: petroleum ether / ethyl acetate, 0% to 100%). LC-MS (ESI): m / z 506.9 [M+H]+ .

[0745] Synthesis of compound 46-b

[0746] The compound 5-bromo-2-(isopropylthio)pyridine (200 mg, 0.86 mmol) was dissolved in 1,4-dioxane (20 mL), and diboric acid pinacol ester (328 mg, 1.29 mmol), 1,1-bis(diphenylphosphine)diferroni palladium dichloride (63 mg, 0.086 mmol), potassium acetate (254 mg, 2.59 mmol) were added thereto. The reaction solution was stirred at 95°C for 6 hours under nitrogen protection. After filtering the reaction solution with diatomaceous earth, it was concentrated under reduced pressure to obtain 46-b (169 mg, 99%). LC-MS (ESI): m / z 198.1 (M+H) + .

[0747] Synthesis of compound 46-a

[0748] Compound I-6 (200 mg, 0.39 mmol), 46-b (155 mg, 0.79 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (51 mg, 0.079 mmol), cesium fluoride (180 mg, 1.18 mmol) were added to 1,4-dioxane (27 mL) and water (3 mL), the reaction solution was replaced with nitrogen three times, and then heated and stirred at 100°C for 6 hours. The reaction solution was filtered with diatomaceous earth, water (100 mL) was added to the filtrate, extracted with dichloromethane (100 mL), the organic phase was washed with saturated brine (100 mL), dried with sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA1 / 1) to obtain compound 46-a (170 mg, 74%).

[0749] Synthesis of compound 46

[0750] 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 thereto. After the reaction solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution (50 mL) was added thereto, and the mixture was extracted with dichloromethane (50 mL). The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (basic conditions) to obtain compound 46 (57 mg, 65%). LC-MS (ESI): m / z 596.2 (M+H) + .

[0751] Synthetic route of compound 47

[0752]

[0753] Synthesis of compound 47

[0754] 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 thereto. After the reaction solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution (50 mL) was added thereto, and the mixture was extracted with dichloromethane (50 mL). The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (basic conditions) to obtain compound 47 (60 mg, 66%). LC-MS (ESI): m / z 612.2 (M+H) + .

[0755] Synthesis route of compound 48

[0756]

[0757] Synthesis of compound 48-d

[0758] 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 replaced with nitrogen three times and then stirred at 65°C for 8 hours. After the reaction solution was filtered through celite, water (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 48-d (200 mg, 93%).

[0759] Synthesis of compound 48-c

[0760] Under nitrogen at room temperature, the compound 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 was completed, the mixture was stirred at -78 ° C under nitrogen for 30 minutes, and then isopropyl disulfide (2.98 mL, 18.71 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred under nitrogen at room temperature for 1 hour. At room temperature, 100 mL of saturated ammonium chloride solution was slowly added to the reaction solution, and then 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. The residue was separated and purified by a rapid separation column (PE / EA=10:1) to obtain compound 48-c (750 mg, 26%). LC-MS (ESI): m / z = 188.1 [M+H] + .

[0761] Synthesis of compound 48-b

[0762] 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 thereto. After the reaction solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution (50 mL) was added thereto, and 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) + .

[0763] Synthesis of compound 48-a

[0764] Compound 48-b (60 mg, 0.29 mmol), 48-d (200 mg, 0.29 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (38 mg, 0.059 mmol), cesium fluoride (133 mg, 0.88 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, and then heated and stirred at 75°C for 3 hours. The reaction solution was filtered with diatomaceous earth, water (50 mL) was added to the filtrate, and extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL), dried with sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA1 / 2) to obtain compound 48-a (40 mg, 19%). LC-MS (ESI): m / z 726.2 (M+H) + .

[0765] Synthesis of compound 48

[0766] 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, the desiccant was filtered off, and 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) + .

[0767] Synthetic route of compound 49

[0768]

[0769] Synthesis of compound 49-b

[0770] 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 thereto. After the reaction solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution (50 mL) was added thereto, 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 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) + .

[0771] Synthesis of compound 49-a

[0772] Compound 49-b (64 mg, 0.29 mmol), 48-d (200 mg, 0.29 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (38 mg, 0.059 mmol), cesium fluoride (133 mg, 0.88 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, and then heated and stirred at 73°C for 3 hours. The reaction solution was filtered with diatomaceous earth, water (50 mL) was added to the filtrate, and extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL), dried with sodium sulfate, the desiccant was filtered off, 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 49-a (55 mg, 25%). LC-MS (ESI): m / z 742.3 (M+H) + .

[0773] Synthesis of compound 49

[0774] 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, the desiccant was filtered off, and 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) + .

[0775] Synthetic route of compound 50

[0776]

[0777] Synthesis of compound 50-a

[0778] In 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 bottle, and then benzenesulfonyl chloride (0.19 mL, 1.50 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it 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 a crude product. The crude product was purified by a rapid separation column (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] + .

[0779] Synthesis of compound 50

[0780] I-6 (50 mg, 0.099 mmol), 50-a (52 mg, 0.15 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (13 mg, 0.020 mmol), cesium fluoride (45 mg, 0.30 mmol), 1,4-dioxane (9 mL) and H2O (1 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, 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 rapid separation column (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] + .

[0781] Synthetic route of compound 51

[0782]

[0783] Synthesis of compound 51-a

[0784] In 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 bottle, and then 3-pyridinesulfonyl chloride (0.18 mL, 1.50 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it 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 crude compound 51-a (100 mg, 29%). LC-MS (ESI): m / z=351.2[M+H] + .

[0785] Synthesis of compound 51

[0786] I-6 (50 mg, 0.099 mmol), 51-a (52 mg, 0.15 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (13 mg, 0.020 mmol), cesium fluoride (45 mg, 0.30 mmol), 1,4-dioxane (9 mL) and H2O (1 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Compound 51 (25 mg, 39%) was obtained by Prep-HPLC purification. LC-MS (ESI): m / z=651.2[M+H] + .

[0787] Synthesis route of compound 52

[0788]

[0789] Synthesis of compound 52-b

[0790] 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), 1,4-dioxane (8 mL) were added to the microwave tube. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 75 ° C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, 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 rapid separation column (mobile phase: ethyl acetate / petroleum ether: 0% to 100%) to obtain compound 52-b (50 mg, 21%). LC-MS (ESI): m / z = 748.3 [M + H] + .

[0791] Synthesis of compound 52-a

[0792] 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 the residue for dilution, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product. Compound 52-a (22 mg, 64%) was obtained by purification by Prep-HPLC. LC-MS (ESI): m / z 518.1 [M+H] + .

[0793] Synthesis of compound 52

[0794] In 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, and then isopropylsulfonyl chloride (4 μL, 0.035 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it 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 a crude product. Compound 52 (5 mg, 28%) was obtained by Prep-HPLC purification. LC-MS (ESI): m / z 624.1 [M+H] + .

[0795] Synthesis route of compound 53

[0796]

[0797] Synthesis of compound 53-d

[0798] Add 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) to the reaction flask. Stir the reaction solution at 80°C for 15 hours. Cool the reaction solution to room temperature, spin off the solvent, dilute with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 53-d (1.2 g, 99%). LC-MS (ESI): m / z 191.2 (M+H) + .

[0799] Synthesis of compound 53-c

[0800] 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 with water twice, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain 53-c (1.61 g, 95%). LC-MS (ESI): m / z 269.1 (M+H) + .

[0801] Synthesis of compound 53-b

[0802] Add 53-c (101 mg, 0.38 mmol) to the reaction flask, and add chlorosulfonic acid (1 mL) dropwise under a water bath. Heat and stir the reaction solution at 65 ° C for 6 hours. Cool the reaction solution to room temperature, add ice water, and extract with ethyl acetate. Wash the organic phase with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a solid crude product. Add the crude product to the reaction flask, add anhydrous dichloromethane (5 mL) and dibromohydantoin (118 mg, 0.41 mmol) under an ice bath. Stir for 5 minutes under an ice bath and then add trifluoromethanesulfonic acid (0.1 mL, 1.13 mmol) (8 drops). After addition, stir the reaction solution under an ice bath for 3 hours. Add ice water to the reaction solution, separate the liquids, and extract the aqueous phase with dichloromethane once. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness to obtain a crude product, and dissolve in dichloromethane to obtain solution A. Add 1-amino-1-cyclopropyl cyanide hydrochloride (89 mg, 0.75 mmol) to the reaction flask, add pyridine (0.5 mL) and anhydrous dichloromethane (5 mL) under ice bath, stir under ice bath for 5 minutes and then add solution A dropwise. After the addition, stir the reaction solution under ice bath for 5 minutes and then stir at room temperature for 2 hours. Rotate to remove the solvent, blow dry, dilute the obtained crude product with ethyl acetate, add saturated brine and a small amount of sodium bisulfate, separate the layers, and extract the aqueous phase twice with ethyl acetate / tetrahydrofuran. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 53-b (185 mg, 100%). LC-MS (ESI): m / z 491.0 (M+H) + .

[0803] Synthesis of compound 53-a

[0804] Add 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 cesium fluoride (720 mg, 4.74 mmol) in water (4 mL) to the reaction flask. Heat the reaction solution at 100 °C with nitrogen protection for 2 hours, add Pd(dtbpf)Cl2 (20 mg, 0.031 mmol), continue heating and stirring at 100 °C with nitrogen protection for 2 hours, add I-3 (90 mg, 0.29 mmol) and anhydrous potassium phosphate (60 mg, 0.28 mmol). Continue heating and stirring the reaction solution at 100 °C for 4 hours under nitrogen protection. Cool to room temperature. Add Pd(dtbpf)Cl2 (20 mg, 0.031 mmol). The reaction liquid was heated and stirred at 100°C for 5 hours under nitrogen protection. The reaction liquid was cooled to room temperature, the water phase was separated, a small amount of saturated brine was added to the residue where 1,4-dioxane was located, and the water phase was separated again. The aqueous phases were combined and extracted twice with ethyl acetate. The 1,4-dioxane phase was combined with the ethyl acetate extract, evaporated to dryness, and the crude product was purified by reverse phase column (C8, 10mM ammonium bicarbonate aqueous solution, acetonitrile) to obtain 53-a (90mg, 46%). LC-MS (ESI): m / z 522.2 (M+H) + .

[0805] Synthesis of compound 53

[0806] Add 53-a (90 mg, 0.17 mmol) and tetrahydrofuran (5 mL) to the reaction flask. Add pyridine (0.18 mL, 2.21 mmol) under ice bath, and add trifluoroacetic anhydride (0.15 mL, 0.52 mmol) dropwise. Stir the reaction solution in ice bath for 15 minutes and then stir at room temperature for 4 hours. Remove the solvent by vortexing, dilute with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify by preparative HPLC (ammonium bicarbonate) to obtain 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).

[0807] Synthesis route of compound 54

[0808]

[0809] Synthesis of compound 54-c

[0810] 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) were added to the reaction bottle, 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. A crude compound 54-c (300 mg) was obtained.

[0811] Synthesis of compound 54-b

[0812] In 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, and then isopropylsulfonyl chloride (0.17 mL, 1.52 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it 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 a crude product. The crude product was purified by a rapid separation column (mobile phase: methanol / dichloromethane: 0% to 10%) to obtain compound 54-b (250 mg, 85%). LC-MS (ESI): m / z=388.4[M+H] + .

[0813] Synthesis of compound 54-a

[0814] I-6 (200 mg, 0.39 mmol), 54-b (183 mg, 0.47 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (51 mg, 0.079 mmol), cesium fluoride (180 mg, 1.18 mmol), 1,4-dioxane (18 mL) and H2O (2 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, 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 rapid separation column (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] + .

[0815] Synthesis of compound 54

[0816] 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 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 54 (100 mg, 52%). LC-MS (ESI): m / z 660.1 [M+H] + .

[0817] Synthetic route of compound 55

[0818]

[0819] Synthesis of compound 55

[0820] 54 (50 mg, 0.076 mmol), ammonium chloride (41 mg, 0.76 mmol), DMF (5 mL) and DIPEA (0.066 mL, 0.38 mmol) were added to the reaction flask, and then HATU (58 mg, 0.015 mmol) was slowly added 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, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to obtain compound 55 (10 mg, 20%). LC-MS (ESI): m / z 659.1 [M+H] + .

[0821] Synthetic route of compound 56

[0822]

[0823] Synthesis of compound 56-a

[0824] SelectFluor II (1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate) (256 mg, 0.80 mmol) and AcOH (0.2 mL) were added to a solution of 35-a (150 mg, 0.20 mmol) in acetonitrile (10 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 at low temperature under reduced pressure. The crude product was extracted with ethyl acetate, and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was separated and purified by a rapid separation column (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] + .

[0825] Synthesis of compound 56

[0826] 56-a (30 mg, 0.039 mmol) and dichloromethane (5 mL) were added to the reaction flask. Trifluoroacetic acid (1 mL) was added dropwise at room temperature. After the addition was completed, the reaction solution was reacted at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure at room temperature, and dichloromethane was added to the residue for dilution. The organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Compound 56 (15 mg, 60%) was obtained by separation and purification by Prep-HPLC. LC-MS (ESI): m / z 637.2 [M+H] + .

[0827] Synthetic route of compound 57

[0828]

[0829] Synthesis of Compound 57

[0830] 35 (50 mg, 0.08 mmol) and dichloromethane (8 mL) were added to the reaction flask, 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) +.1HNMR(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).

[0831] Synthetic route of compound 58

[0832]

[0833] Synthesis of compound 58-d

[0834] Add 44-e (980 mg, 1.89 mmol), triethylamine (477 mg, 4.72 mmol) and dichloromethane (60 mL) to the reaction flask and stir for 10 minutes in an ice-water bath. Slowly add trifluoroacetic anhydride (475 mg, 2.26 mmol) dropwise to the reaction solution. After the addition, stir the reaction solution for 3 hours in an ice-water bath under nitrogen protection. Wash the reaction solution with saturated sodium bisulfate (40 mL*2) and water (30 mL) once, and concentrate the organic phase to obtain compound 58-d (1100 mg, 95%). LC-MS (ESI): m / z 632.1 (M+NH4) + .

[0835] Synthesis of compound 58-c

[0836] Add 58-d (1100 mg, 1.79 mmol), Lawesson's reagent (1807 mg, 4.47 mmol) and tetrahydrofuran (100 mL) to the reaction flask. Stir at 85 ° C for 5 hours under nitrogen protection. Concentrate the reaction solution. Add toluene (70 mL), sodium carbonate (7.5 g) and water (75 mL) to the concentrated crude product. Stir the mixed solution at room temperature for 2 hours. Separate the liquids, concentrate the organic phase, and obtain compound 58-c (241 mg, 22%) by column chromatography (petroleum ether / ethyl acetate = 100 / 0; 100 / 70). LC-MS (ESI): m / z 613.1 (M+H) + .

[0837] Synthesis of compound 58-b

[0838] 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 then 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, the residue was washed with ethyl acetate (10 mL*3), the organic phase was concentrated under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 100 / 0, 10 / 20) was used to obtain compound 58-b (240 mg, 84%). LC-MS (ESI): m / z 722.3 (M+H) + .

[0839] Synthesis of compound 58-a

[0840] 58-b (45 mg, 0.06 mmol), trifluoroethyl trifluoromethanesulfonate (43 mg, 0.19 mmol), cesium carbonate (220 mg, 0.68 mmol), N,N-dimethylformamide (4 mL) were added to the reaction bottle and stirred at room temperature for 8 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (15 mL*2), and 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) + .

[0841] Synthesis of compound 58

[0842] 58-a (12 mg, 0.015 mmol), methanesulfonic acid (120 mg, 1.25 mmol), and dichloromethane (8 mL) were added to the reaction flask and stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL), extracted with dichloromethane (10 mL*2), and the organic phase was concentrated under reduced pressure and purified by preparative HPLC to give compound 58 (2.9 mg, 28%). LC-MS (ESI): m / z 684.1 (M+H) + .

[0843] Synthesis of compound 59

[0844]

[0845] 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) + .

[0846] Synthesis of compound 60

[0847]

[0848] 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) + .

[0849] Synthetic route of compound 61

[0850]

[0851] Synthesis of compound 61-a

[0852] 58-b (50 mg, 0.07 mmol), 1-BOC-(3-iodomethyl)azetidine (83 mg, 0.28 mmol), potassium carbonate (10 mg, 0.07 mmol), N,N-dimethylformamide (4 mL) were added to the reaction bottle 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) + .

[0853] Synthesis of compound 61

[0854] 61-a (31 mg, 0.035 mmol), methanesulfonic acid (120 mg, 1.25 mmol), and dichloromethane (8 mL) were added to the reaction flask and stirred at room temperature for 3 hours. Ammonia methanol (0.12 mL) was added to the reaction solution to quench the reaction, and the organic phase was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 61 (6.2 mg, 26%). LC-MS (ESI): m / z 671.3 (M+H) + .

[0855] Synthesis of compound 62

[0856]

[0857] 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) + .

[0858] Synthetic route of compound 63

[0859]

[0860] Synthesis of compound 63-d

[0861] At room temperature, compound I-1 (100 mg, 0.16 mmol) was dissolved in 10 mL of toluene, and diboric acid pinacol ester (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), ...) were added in sequence. 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 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 a crude product 63-d (107 mg). The crude product was directly used in the next step without further purification. LC-MS (ESI): m / z=667.2 [M+H] + .

[0862] Synthesis of compound 63-c

[0863] Under nitrogen at room temperature, the compound 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 was completed, the mixture was stirred at -78 ° C under nitrogen for 30 minutes, and then isopropyl disulfide (2.98 mL, 18.71 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred under nitrogen at room temperature for 1 hour. At room temperature, 100 mL of saturated ammonium chloride solution was slowly added to the reaction solution, and then 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. The residue was separated and purified by a rapid separation column (PE / EA=10 / 1) to obtain compound 63-c (750 mg, 26%). LC-MS (ESI): m / z = 188.1 [M+H] + .

[0864] Synthesis of compound 63-b

[0865] 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 for 30 minutes under nitrogen at room temperature. 100 mL of saturated sodium bicarbonate solution was added to the reaction solution and extracted with DCM (100 mL). The organic phase was washed with saturated sodium bicarbonate solution (100 mL) and water (200 mL) in turn, 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=3:1) to obtain compound 63-b (188 mg, 80%). LC-MS (ESI): m / z=220.1[M+H] + .

[0866] Synthesis of compound 63-a

[0867] 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, concentrated under reduced pressure, 100 mL of water was added to the residue, and 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 a crude compound 63-a (80 mg, 69%). The crude product was directly used in the next step without further purification. LC-MS (ESI): m / z=724.3[M+H] + .

[0868] Synthesis of compound 63

[0869] 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 for 1.5 hours under nitrogen at room temperature. 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, 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] + .

[0870] Synthetic route of compound 64

[0871]

[0872] Synthesis of compound 64-c

[0873] 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. Then, trifluoromethanesulfonic anhydride (1.64 g, 5.81 mmol) was added dropwise under an ice bath. After the reaction solution was stirred at room temperature for 4 hours, water (100 mL) was added thereto, and 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).

[0874] Synthesis of compound 64-b

[0875] Compound 64-c (500 mg, 1.40 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added thereto, the reaction solution was stirred at room temperature for 2 hours, the reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with dichloromethane solution (100 mL) containing 10% methanol, 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 thereto, isopropylsulfonyl chloride (300 mg, 2.10 mmol) was added dropwise under ice-water bath, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain 64-b (166 mg, 33%).

[0876] Synthesis of compound 64-a

[0877] Compound 64-b (74 mg, 0.20 mmol), 48-d (200 mg, 0.29 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (40 mg, 0.062 mmol), cesium fluoride (133 mg, 0.88 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, and then heated and stirred at 90°C for 3 hours. The reaction solution was filtered with diatomaceous earth, water (50 mL) was added to the filtrate, and extracted with dichloromethane (50 mL), the organic phase was washed with saturated brine (50 mL), dried with sodium sulfate, the desiccant was filtered off, 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 64-a (44 mg, 28%). LC-MS (ESI): m / z 769.2 (MH) - .

[0878] Synthesis of compound 64

[0879] 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, the desiccant was filtered off, and 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) - .

[0880] Synthetic route of compound 65

[0881]

[0882] Synthesis of compound 65-g

[0883] 6-bromo-4-chloroindole (660 mg, 2.86 mmol), N,N-diisopropylethylamine (1110 mg, 8.59 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol) and di-tert-butyl dicarbonate (1250 mg, 5.73 mmol) and dichloromethane (100 mL) were added to the reaction bottle. After the addition, the reaction solution was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was washed with saturated sodium bisulfate (20 mL), the organic phase was concentrated, and compound 65-g (610 mg, 64%) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1).

[0884] Synthesis of compound 65-f

[0885] 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 3 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) + .

[0886] Synthesis of compound 65-e

[0887] 65-f (620 mg, 1.68 mmol), dichloromethane (6 mL), trifluoroacetic acid (2 mL) were added to the reaction flask and stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (20 mL) was added to the residue, and extracted with dichloromethane (20 mL*2). The organic phase was concentrated under reduced pressure and column chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 3) was used to obtain compound 65-e (409 mg, 90%).

[0888] Synthesis of compound 65-d

[0889] Add 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), N,N-dimethylformamide (10 mL) to the reaction bottle. Stir at room temperature for 4 hours under nitrogen protection. Add saturated brine (50 mL) to the reaction solution and extract with ethyl acetate (50 mL*3). The organic phase was concentrated under reduced pressure and column chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 1) was used to obtain compound 65-d (390 mg, 61%). LC-MS (ESI): m / z 422.1 (M+H) + .

[0890] Synthesis of compound 65-c

[0891] 65-d (390 mg, 0.93 mmol), m-chloroperbenzoic acid (469 mg, 2.31 mmol) and ethyl acetate (40 mL) were added to the reaction flask, and the mixture was stirred in an ice-water bath for 10 minutes, and then the temperature was raised to room temperature and stirred for 3 hours. Saturated sodium bicarbonate aqueous solution (40 mL) was added to the reaction solution, the liquids were separated, the organic phase was concentrated, and the compound 65-c (292 mg, 70%) was obtained by column chromatography (dichloromethane / methanol=100 / 0, 10 / 1). LC-MS (ESI): m / z 454.0 (M+H) + .

[0892] Synthesis of compound 65-b

[0893] Add 65-c (120 mg, 0.26 mmol), methanol (10 mL) and dichloromethane (10 mL) to the reaction flask. Add sodium methoxide (43 mg, 0.79 mmol) under ice-water bath. Stir the reaction solution under ice-water bath for 1 hour. Add 1-cyanocyclopropylamine hydrochloride (125 mg, 1.06 mmol) under ice-water bath and stir for 15 minutes. Concentrate the solvent at room temperature and dry it with oil pump for 1 hour. Then add 1-cyanocyclopropylamine hydrochloride (31 mg, 0.26 mmol) and N,N-dimethylformamide (10 mL). Add N,N-dimethylaminopyridine (65 mg, 0.53 mmol) and EDCI (152 mg, 0.79 mmol) under ice-water bath, stir under ice-water bath, then raise the temperature to room temperature and stir for 2 hours. Add water (100 mL) to the reaction solution and extract with ethyl acetate (100 mL*3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=3 / 1, 1 / 3) to obtain 65-b (73 mg, 63%). LC-MS (ESI): m / z 432.1 (M+H) + .

[0894] Synthesis of compound 65-a

[0895] 65-b (73 mg, 0.17 mmol), m-chloroperbenzoic acid (44 mg, 0.25 mmol) and dichloromethane (20 mL) were added to the reaction flask and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (40 mL) was added to quench and the liquids were separated. The organic phase was concentrated and column chromatography (petroleum ether / ethyl acetate = 6 / 1 to 1 / 1) was performed to obtain compound 65-a (63 mg, 83%). LC-MS (ESI): m / z 448.0 (M+H) + .

[0896] Synthesis of compound 65

[0897] 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) were added to the reaction flask, and nitrogen was replaced three times. The reaction solution was heated to 100 ° C and stirred for 8 hours. The reaction solution was concentrated under reduced pressure, the residue was washed with ethyl acetate (10 mL*3), the organic phase was concentrated under reduced pressure, and purified by preparative HPLC to obtain compound 65 (6.2 mg, 15%). LC-MS (ESI): m / z 601.0 (M+H) + .

[0898] Synthetic route of compound 66

[0899]

[0900] Synthesis of compound 66-a

[0901] 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), 2-bromoacetamide (49 mg, 0.36 mmol) were added in sequence, and the reaction mixture was stirred for 36 hours under nitrogen at room temperature. 50 mL of saturated brine was added to the reaction solution, and then extracted 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 distilled under reduced pressure to obtain compound 66-a (crude product, 48 mg, 89%), which was directly used in the next step. LC-MS (ESI): m / z=761.3[M+H] + .

[0902] Synthesis of compound 66

[0903] 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 (alkali method, NH4HCO3 system) to obtain compound 66 (12.8 mg, 32%). LC-MS (ESI): m / z=641.2[M+H] + .

[0904] Synthetic route of compound 67

[0905]

[0906] Synthesis of compound 67-d

[0907] Add tert-butyl 3,3-difluoro-4-oxopiperidin-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) into the reaction flask. Add triethylamine (20.0 mL, 143.89 mmol) dropwise. After addition, the reaction solution was reacted at room temperature for 18 hours. Add saturated sodium bicarbonate solution to quench the reaction, separate the liquids, wash the organic phase with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness and purify by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to obtain 67-d (8.1 g, 93%).

[0908] Synthesis of compound 67-c

[0909] Add 67-d (1.15 g, 3.13 mmol) and dichloromethane (8 mL) to the reaction flask. Add trifluoroacetic acid (3 mL) dropwise at room temperature. Stir the reaction solution at room temperature for 2 hours. Remove the solvent by vortexing and dry it at an oil pump. Add petroleum ether and methyl tert-butyl ether to the residue and slurry it. Filter it, wash the solid with petroleum ether, and dry it at an oil pump to obtain 67-c (1.19 g, 100%). LC-MS (ESI): m / z 267.9 (M+H) + .

[0910] Synthesis of compound 67-b

[0911] Add 67-c (1.19 g, 3.13 mmol) and dichloromethane (10 mL) to the reaction flask. Add triethylamine (2.0 mL, 14.3 mmol) under ice bath, and add isopropylsulfonyl chloride (0.60 g, 4.21 mmol) dropwise under ice bath. After addition, the reaction solution was reacted under ice bath for 1 hour and then stirred at room temperature for 3 hours. Saturated sodium bicarbonate was added to the reaction solution to quench the reaction. Separate the liquid, extract the aqueous phase once with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate to dryness. The crude product was purified by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain 67-b (700 mg, 60%).

[0912] Synthesis of compound 67-a

[0913] Add 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) to the reaction flask. Replace with nitrogen three times, and add a solution of cesium fluoride (210 mg, 1.38 mmol) in water (1 mL) dropwise with stirring. Heat and stir the reaction solution at 50 °C for 2 hours under nitrogen protection. Cool the reaction solution to room temperature and dilute with ethyl acetate. Wash the organic phase twice with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a crude product. The crude product was purified by column (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) + .

[0914] Synthesis of compound 67

[0915] Add 67-a (80 mg, 0.11 mmol) and dichloromethane (3 mL) to the reaction flask. Add trifluoroacetic acid (0.7 mL) at room temperature. Stir the reaction solution at room temperature for 2 hours. Rotate to remove the solvent, dilute the residue with ethyl acetate, add saturated sodium bicarbonate and anhydrous potassium carbonate, and stir at room temperature for 20 minutes. Separate the liquid, extract the aqueous phase once with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and prepare and purify the crude product (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).

[0916] Synthetic route of compound 68

[0917]

[0918] Synthesis of compound 68-b

[0919] Add LHMDS tetrahydrofuran solution (1M, 17mL, 17.00mmol) to the reaction bottle. Under nitrogen protection at -78℃, slowly add a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (2.9g, 13.35mmol) in anhydrous THF (20mL) over 30 minutes. The reaction solution was reacted at -78℃ for 30 minutes. Slowly add a solution of N-phenylbis(trifluoromethanesulfonyl)imide (5.72g, 16.02mmol) in anhydrous THF (20mL) at -78℃. After the addition, the reaction solution was reacted at -78℃ to room temperature for 1 hour. The solvent was removed by vortexing, and ethyl acetate and petroleum ether were added to the residue, washed with ice water, water, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 85 / 15) to obtain 68-b (200mg, 4.3%).

[0920] Synthesis of compound 68-a

[0921] Add 68-b (200 mg, 0.57 mmol) and dichloromethane (2 mL) to the reaction flask. Trifluoroacetic acid (0.7 mL) was added dropwise under a room temperature water bath. The reaction solution was stirred at room temperature for 2 hours. The solvent was removed by vortexing and dried by oil pump to obtain a solid crude product. The above crude product and dichloromethane (20 mL) were added to the reaction flask, and triethylamine (0.32 mL, 2.30 mmol) and 2-propylsulfonyl chloride (120 mg, 0.84 mmol) were added to the ice bath. The reaction solution was stirred at room temperature for 2 hours from the ice bath to room temperature, and triethylamine (0.32 mL, 2.30 mmol) and 2-propylsulfonyl chloride (120 mg, 0.84 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The solvent was removed by vortexing. The crude product was purified by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain compound 68-a (200 mg, 98%).

[0922] Synthesis of compound 68

[0923] Add 68-a (100 mg, 0.28 mmol), bis(pinacol borate) (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) to a microwave tube. Replace with nitrogen and add anhydrous toluene (10 mL). Replace with nitrogen again 3 times. Seal and heat the reaction solution at 80 °C with stirring for 4 hours. Cool the reaction solution to room temperature and remove the solvent by vortexing. Dissolve the crude product with 1,4-dioxane (4 mL), add to a microwave tube, add 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). Replace with nitrogen 3 times and seal. Heat and stir the reaction solution 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, evaporated, and the crude product was dissolved in 1,4-dioxane (4 mL) again, added to a microwave tube, and Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), cesium fluoride (170 mg, 1.12 mmol) and water (1 mL) were added. Nitrogen was replaced 3 times and 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, and the crude product was purified by column (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 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).

[0924] Synthetic route of compound 69

[0925]

[0926] Synthesis of compound 69-b

[0927] Add tert-butyl 3-fluoro-4-oxopiperidin-1-carboxylate (1.5 g, 6.91 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (2.96 g, 8.29 mmol) and anhydrous dichloromethane (20 mL) to the reaction flask. Add DBU (3.15 g, 20.72 mmol) dropwise at 60 °C under nitrogen protection. Heat the reaction solution to 70 °C and react for 4 hours. Remove the solvent by vortexing, add ethyl acetate / petroleum ether (1:1) to the residue, wash with water twice, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a crude product. Add dichloromethane (10 mL) and trifluoroacetic acid (3.5 mL) to the crude product, and stir the reaction solution at room temperature for 3 hours. Remove the solvent by vortexing, and dry with an oil pump to obtain a crude product. Add dichloromethane (20 mL) to the crude product, add triethylamine (4.5 mL, 32.38 mmol) under ice bath, and add 2-propylsulfonyl chloride (1.5 mL) dropwise. After the addition, the reaction solution was stirred at room temperature in an ice bath for 4 hours. The solvent was removed by vortexing, and ethyl acetate / petroleum ether (1:1) was added to the residue, washed with water twice, 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: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain 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).

[0928] Synthesis of compound 69-a

[0929] Add 69-b (150 mg, 0.42 mmol), 63-d 110 mg, 0.17 mmol), and Pd(dtbpf)Cl2 (15 mg, 0.023 mmol) to the reaction flask. Replace with nitrogen three times, and add a solution of cesium fluoride (130 mg, 0.86 mmol) in water (1 mL) dropwise while stirring. Heat and stir the reaction solution at 55 °C for 2 hours under nitrogen protection. The reaction solution is cooled to room temperature, diluted with ethyl acetate, washed with water twice, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product is purified by column (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) + .

[0930] Synthesis of compound 69

[0931] Add 69-a (50 mg, 0.067 mmol) and dichloromethane (2 mL) to the reaction flask. Add trifluoroacetic acid (0.7 mL) dropwise at room temperature. Stir the reaction solution at room temperature for 2 hours. Rotate to remove the solvent and dry it with an oil pump. Add saturated sodium bicarbonate aqueous solution, ethyl acetate and anhydrous potassium carbonate to the residue. Stir the reaction mixture at room temperature for 3 minutes. Separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter and evaporate to dryness. The crude product is purified by column (mobile phase: dichloromethane / ethyl acetate, 100 / 0 to 70 / 30), and purified by preparative HPLC (ammonium bicarbonate) to obtain 69 (2.6 mg, 6.3%). LC-MS (ESI): m / z 616.2 (M+H) + .

[0932] Synthetic route of compound 70

[0933]

[0934] Synthesis of compound 70-c

[0935] Add 4-oxopiperidone hydrochloride (2.72 g, 20.06 mmol), acetone (30 mL) and water (15 mL) to the reaction flask. Add anhydrous potassium carbonate (7.21 g, 52.16 mmol) in an ice bath, and then drop 2-propylsulfonyl chloride (3.38 mL, 30.09 mmol). The reaction solution was stirred at room temperature for 18 hours after ice bath. Add saturated sodium bicarbonate solution to quench the reaction, extract with dichloromethane 3 times, combine the organic phases, wash once with saturated brine, add anhydrous sodium sulfate and anhydrous magnesium sulfate to dry, filter, evaporate to dryness, and wash the crude product twice with petroleum ether to obtain compound 70-c (2.7 g, 66%).

[0936] Synthesis of compound 70-b

[0937] Add N,N-dimethylformamide (3.18mL, 39.46mmol) and dichloromethane (60mL) to the reaction flask. Slowly drop a solution of phosphorus tribromide (2.97mL, 31.57mmol) in dichloromethane (10mL) under an ice bath. After addition, stir the reaction solution in an ice bath for 1 hour. Add a solution of 70-c (2.7g, 13.15mmol) in dichloromethane (20mL) under an ice bath. After addition, stir the reaction solution at room temperature overnight. Stir the reaction solution in an ice bath for 5 minutes, and slowly drop a saturated sodium bicarbonate solution until no bubbles are generated. Separate the liquid, extract the aqueous phase with dichloromethane twice, combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30) to obtain compound 70-b (1.6g, 41%). LC-MS (ESI): m / z 313.1 (M+NH4) + .

[0938] Synthesis of compound 70-a

[0939] 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 with nitrogen and add 1,4-dioxane (10 mL). Replace with nitrogen 3 times and seal. Heat and stir the reaction solution at 80°C for 6 hours. Cool the reaction solution to room temperature, take out the reaction solution (2 mL) and directly proceed to the next step. Dilute the remaining reaction solution with ethyl acetate, wash once with saturated brine, extract the aqueous phase with ethyl acetate 3 times, combine the organic phases, evaporate to dryness, and dry with an oil pump to obtain the crude product of 70-a (463 mg, 100%). LC-MS (ESI): m / z 344.2 (M+H) + .

[0940] Synthesis of compound 70

[0941] Add 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) to the reaction flask. Replace with nitrogen three times and seal. Heat the reaction solution at 100°C and stir 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 (take 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) + . 1H 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).

[0942] Synthetic route of compound 71

[0943]

[0944] Synthesis of compound 71

[0945] Add 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) to the reaction flask. Stir the reaction mixture at room temperature for 10 minutes, then add sodium triacetoxyborohydride (200 mg, 0.95 mmol). After stirring the reaction solution at room temperature for 2 hours, add sodium triacetoxyborohydride (72 mg, 0.34 mmol), stir at room temperature for 1 hour, and place in the refrigerator to freeze overnight. Add ice water to the reaction solution to quench the reaction, extract twice with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and evaporate to dryness, and purify the crude product 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).

[0946] Synthetic route of compound 72

[0947]

[0948] Synthesis of compound 72-b

[0949] Add 70-b (630 mg, 2.13 mmol), tetrahydrofuran (20 mL) and anhydrous methanol (10 mL) to the reaction flask. After stirring for 5 minutes under ice bath, add anhydrous cerium (III) chloride (786 mg, 3.19 mmol) and sodium borohydride (90 mg, 2.38 mmol), and a large number of bubbles are generated. Stir the reaction solution in an ice bath for 1 hour. Add water (10 mL) to the reaction solution to quench, remove the solvent at room temperature, add a small amount of anhydrous sodium sulfate solid, extract with ethyl acetate 3 times, dry the organic phase with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a crude product. Add the crude product to the reaction flask, add anhydrous tetrahydrofuran (10 mL), add sodium hydrogen (170 mg, 4.25 mmol) under ice bath, stir the reaction solution in an ice bath for 1 hour, warm to room temperature and stir for 15 minutes, and add iodomethane (0.45 mL, 5.55 mmol). The reaction solution was stirred at room temperature for 2 hours, dried by rotation, 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%).

[0950] Synthesis of compound 72-a

[0951] Add 72-b (350 mg, 1.12 mmol), bis-pinacol borate (342 mg, 1.35 mmol), Pd(dppf)Cl2·CH2Cl2 (46 mg, 0.056 mmol) and potassium acetate (330 mg, 3.36 mmol) to a microwave tube. Replace with nitrogen and add 1,4-dioxane (10 mL). Replace with nitrogen 3 times and seal. Heat and stir the reaction solution at 80°C for 8 hours. Cool the reaction solution to room temperature, dilute the reaction solution with ethyl acetate, wash with water, extract the aqueous phase with ethyl acetate once, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify by column (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) + .

[0952] Synthesis of compound 72

[0953] Add 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) to the reaction flask. Replace with nitrogen three times. Heat and stir the reaction solution at 100°C for 3 hours. Cool to room temperature. The reaction solution is diluted with ethyl acetate, washed with saturated brine, evaporated to dryness, and the crude product is 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).

[0954] Synthetic routes of compounds 73 and 74

[0955]

[0956] Synthesis of compound 73-a

[0957] Add 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) to the reaction flask. Replace with nitrogen three times. Heat and stir the reaction solution at 100 ° C for 2 hours. The reaction solution is cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, evaporated to dryness, and the crude product is purified by column (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) + .

[0958] Synthesis of compounds 73 and 74

[0959] 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) were added to the reaction flask. After stirring the reaction solution at room temperature for 1 hour, sodium cyanoborohydride (50 mg, 0.80 mmol) was added. After continuing to stir for 30 minutes, sodium cyanoborohydride (50 mg, 0.80 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes, most of the solvent was removed by vortexing at room temperature, saturated brine was added, extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, filtered, evaporated, dried with nitrogen, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain 73 (28 mg, 21%), and the other component was purified again by preparative TLC (8% MeOH / DCM) to obtain 74 (22 mg, 16%).

[0960] 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).

[0961] 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).

[0962] Synthetic route of compound 75

[0963]

[0964] Synthesis of compound 75-a

[0965] Add 70-b (330 mg, 1.11 mmol) and anhydrous methanol (10 mL) to the reaction flask. Add sodium borohydride (22 mg, 0.58 mmol) after stirring in an ice bath for 5 minutes. Add sodium borohydride (30 mg, 0.79 mmol) after stirring in an ice bath for 5 minutes. Stir the reaction solution in an ice bath for 1 hour. Add saturated aqueous ammonium chloride solution to the reaction solution, spin off the methanol, and extract with ethyl acetate twice. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and evaporate to obtain a 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 in an ice bath. After addition, stir the reaction solution in an ice bath for 1 hour. Spin off the solvent, dry with an oil pump, and add anhydrous tetrahydrofuran (10 mL) to the residue. Lithium aluminum hydride tetrahydrofuran solution (1M, 2.5mL, 2.50mmol) was slowly added dropwise in an ice-salt bath over 20 minutes. 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, and the reaction solution continued to stir for 15 minutes. Ethyl acetate was added to dilute the reaction solution and stirred at room temperature for 15 minutes. Filter, evaporate to dryness, and purify by column (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to obtain compound 75-a (95mg, 30%). LC-MS (ESI): m / z 281.9 (M+H) + .

[0966] Synthesis of compound 75

[0967] Add 75-a (95 mg, 0.34 mmol), bis-pinacol borate (128 mg, 0.50 mmol), Pd(dppf)Cl2.CH2Cl2 (15 mg, 0.018 mmol) and potassium acetate (100 mg, 1.02 mmol) to a microwave tube. Replace with nitrogen and add 1,4-dioxane (4 mL). Replace with nitrogen 3 times and seal. Heat and stir the reaction solution at 80°C for 20 hours. Cool the reaction solution to room temperature and add 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). Replace with nitrogen 3 times and seal. Heat and stir the reaction solution 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 reaction mixture was replaced with nitrogen and heated at 100°C with stirring for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, and the aqueous phase was extracted with ethyl acetate once. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated, 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).

[0968] Synthetic route of compound 76

[0969]

[0970] Synthesis of compound 76

[0971] Add 68-a (100 mg, 0.28 mmol), bipyraclostrobin (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) to a microwave tube. Replace with nitrogen. Add anhydrous toluene (10 mL). Replace with nitrogen 3 times and seal. Heat and stir the reaction solution at 80 °C for 4 hours. Cool the reaction solution to room temperature, 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 with nitrogen 3 times and seal. Heat and stir the reaction solution 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, evaporated to dryness, and 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).

[0972] Synthetic route of compound 77

[0973]

[0974] Synthesis of compound 77-i

[0975] 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, and then pyridine (4.21 mL, 52.06 mmol) was added dropwise under nitrogen at room temperature. After the addition was completed, the mixture was stirred at 48°C for 18 hours under nitrogen conditions. The reaction solution was cooled to room temperature, the mixture was poured into 50 mL of ice-water mixture, extracted with dichloromethane (50 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was vacuum dried for 2 hours to obtain about 10 g (theoretically 4.89 g) of crude product (77-i, 100%), which was used directly in the next step.

[0976] Synthesis of compound 77-h

[0977] At room temperature, 77-i (4.89 g, 13.01 mmoL) was suspended in 50 mL of methanol, and KOH (1.88 g, 33.50 mmoL) was added in batches. The reaction mixture was stirred overnight under nitrogen at room temperature. After the reaction mixture was concentrated to about 20 mL under reduced pressure, 50 mL of water was added, and the pH was adjusted to 6 with 1 M hydrochloric acid, extracted with ethyl acetate (50 mL*2), and 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 in vacuo 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 a rapid separation column (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] - .

[0978] Synthesis of compound 77-g

[0979] 77-h (3.15 g, 10.92 mmol) was dissolved in 20 mL of DMF at room temperature, and NaH (655 mg, 16.38 mmol, 60%) was added in batches under nitrogen conditions in an ice-water bath, and then the mixture was stirred for 30 minutes under nitrogen at room temperature, and iodomethane (1.02 mL, 16.38 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred for 2 hours under nitrogen at room temperature. In an ice-water bath, the reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL*2), the organic phase was washed with saturated brine (100 mL*5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was suspended in methanol (10 mL) and stirred for 30 minutes. The mixture was filtered, the filter cake was washed with methanol (10 mL), the solid was collected, and vacuum dried for 2 hours to obtain 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).

[0980] Synthesis of compound 77-f

[0981] At room temperature, 77-g (700 mg, 2.31 mmol) was suspended in 20 mL of ethanol, hydrazine hydrate (4 mL, 67.92 mmol, 85%) was added, and the reaction mixture was stirred at 85°C under nitrogen for 72 hours. The reaction mixture was cooled in an ice-water bath, filtered, the filter cake was washed with ethanol (10 mL), the solid was collected, and vacuum dried for 2 hours to obtain compound 77-f (305 mg, 44%). LC-MS (ESI): m / z=302.0 [M+H] + .

[0982] Synthesis of compound 77-e

[0983] 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, the filter cake was washed with DCM (5 mL), the solid was collected, and vacuum dried for 2 hours to obtain compound 77-e (238 mg, 65%). LC-MS (ESI): m / z=379.9 [MS+H] + .

[0984] Synthesis of compound 77-d

[0985] 77-e (238 mg, 0.62 mmol) was dissolved in 10 mL of 1,4-dioxane at room temperature, Lawesson's reagent (379 mg, 0.94 mmol) was added, and the reaction mixture was stirred at 80 ° C for 3 hours under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of dichloromethane, washed with saturated sodium bicarbonate (100 mL) and water (100 mL) in sequence, 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 a rapid separation column (PE / EA=1:1) to obtain compound 77-d (172 mg, 73%). LC-MS (ESI): m / z=378.0 [M+H] + .

[0986] Synthesis of compound 77-c

[0987] 77-d (172 mg, 0.45 mmoL) was dissolved in 10 mL of 1,4-dioxane at room temperature, and tris(dibenzylideneacetone)dipalladium (42 mg, 0.045 mmoL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (52 mg, 0.091 mmoL), DIPEA (225 uL, 1.36 mmoL), methyl 3-mercaptopropionate (56 uL, 0.50 mmoL) were added in sequence, and 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 a rapid separation column (PE / EA=1:1) to obtain compound 77-c (170 mg, 90%). LC-MS (ESI): m / z=418.5 [M+H] + .

[0988] Synthesis of compound 77-b

[0989] 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 under nitrogen in an ice-water bath. After addition, the mixture was reacted for 2 hours under nitrogen in an ice-water bath. Saturated sodium bicarbonate (50 mL) was added to the reaction mixture, 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 a rapid separation column (DCM / MeOH=20:1) to obtain compound 77-b (205 mg, crude product). LC-MS (ESI): m / z=450.1[M+H] + .

[0990] Synthesis of compound 77-a

[0991] 77-b (120 mg, 0.27 mmol) was dissolved in a mixed solvent 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 for 60 minutes under nitrogen at room temperature. 1-aminocyclopropylnitrile hydrochloride (127 mg, 1.07 mmol) was added under an ice-water bath, and the reaction mixture was stirred for 15 minutes under an ice-water bath. The mixture was concentrated under reduced pressure and dried in vacuo for 2 hours. The residue was dissolved in dry DMF (5 mL), and 1-aminocyclopropylnitrile hydrochloride (32 mg, 0.27 mmol), triethylamine (74 uL, 0.53 mmol), and NCS (107 mg, 0.80 mmol) were added in sequence under an ice-water bath, and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added to quench the reaction and extracted with ethyl acetate (50 mL*2). The organic phase was washed with water (100 mL) and saturated brine (100 mL*3) in sequence, 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 (DCM / MeOH=10:1) to obtain compound 77-a (90 mg, 76%). LC-MS (ESI): m / z=444.1 [M+H] + .

[0992] Synthesis of compound 77

[0993] 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, concentrated under reduced pressure, and the residue was separated and purified by a rapid separation column (PE / EA=1:3) to obtain a crude product. The crude product was separated and purified by Prep-HPLC (alkali method, NH4HCO3 system) to obtain compound 77 (13.5 mg, 33%). LC-MS (ESI): m / z=597.2[M+H] + .

[0994] Synthetic route of compound 78

[0995]

[0996] Synthesis of compound 78-g

[0997] Under ice bath, 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). After addition, the reactant was stirred at room temperature overnight. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added and stirred for 30 minutes. The liquid was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was separated and purified by rapid separation column (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).

[0998] Synthesis of compound 78-f

[0999] 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) to the sealed tube, add methoxy(cyclooctadiene)iridium dimer (102 mg, 0.38 mmol) under nitrogen protection, replace the nitrogen twice, and stir at room temperature for 10 minutes. Add 15-g (600 mg, 1.90 mmol) of methyl tert-butyl ether (10 mL) solution, replace the nitrogen three times, and stir at 85 ° C for 3.5 hours. The reaction solution is concentrated to obtain a crude borate ester.

[1000] Toluene (20 mL) and water (10 mL) were added to the obtained crude borate, and 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) were added, and the atmosphere was replaced with nitrogen twice. The reaction solution was stirred at 40 ° C for 18 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column (mobile phase: ethyl acetate / petroleum ether 0% to 50%) to obtain compound 78-f (300 mg, 36%). LC-MS (ESI): m / z=443.0 (M+H) + .

[1001] Synthesis of compound 78-e

[1002] 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) were added to a three-necked flask, and the atmosphere was replaced with nitrogen twice. Pd2(dba)3 (31 mg, 0.034 mmol) was added and the atmosphere was replaced with nitrogen three times. The reaction solution was heated to reflux at 85°C for 2 hours. The reaction solution was cooled to room temperature, evaporated to dryness, and purified by column chromatography (mobile phase: 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] + .

[1003] Synthesis of compound 78-d

[1004] At room temperature, TFA (3 mL) was added to a solution of 78-e (300 mg, 0.62 mmol) in dichloromethane (10 mL). After the addition, the reaction was stirred at room temperature overnight. 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 obtain compound 78-d (200 mg, 81%). LC-MS (ESI): m / z=398.8 [M+H] + .

[1005] Synthesis of compound 78-c

[1006] At room temperature, cesium carbonate (327 mg, 1.00 mmol) and iodomethane (0.081 mL, 1.00 mmol) were added to a solution of 78-d (200 mg, 0.50 mmol) in DMF (10 mL). After addition, the reactants were stirred at room temperature overnight. After the reaction was completed, ethyl acetate was added to dilute, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Compound 78-c (200 mg, 96%) was obtained by separation and purification by rapid separation column (mobile phase: ethyl acetate / petroleum ether 0% to 50%). LC-MS (ESI): m / z=413.1[M+H] + .

[1007] Synthesis of compound 78-b

[1008] Under ice bath, add m-CPBA (251 mg, 1.45 mmol) to a solution of 78-c (200 mg, 0.48 mmol) in dichloromethane (10 mL). After addition, keep the reactant at 0°C and stir for 1 hour. After the reaction is completed, remove the solvent by rotary evaporation at room temperature, add ethyl acetate to dilute, wash with saturated sodium bicarbonate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. The crude product is separated and purified by rapid separation column (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] + .

[1009] Synthesis of compound 78-a

[1010] 78-b (160 mg, 0.36 mmol), methanol (10 mL) and dichloromethane (10 mL) were added to the reaction flask. The reactants were cooled to 0 ° C with 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-cyclopropyl cyanide hydrochloride (171 mg, 1.44 mmol) was added, the solvent was concentrated 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 for 3 minutes in an ice bath, triethylamine (0.10 mL, 0.72 mmol) and 1-amino-1-cyclopropyl cyanide hydrochloride (43 mg, 0.36 mmol) were added. Then NCS (96 mg, 0.72 mmol) was added in an ice bath. The reaction solution was stirred in an ice bath for 1 hour. Dilute with ethyl acetate, wash with sodium bisulfite solution, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. The crude product was separated and purified by flash column (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] + .

[1011] Synthesis of compound 78

[1012] 78-a (50 mg, 0.11 mmol), I-3 (54 mg, 0.17 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (15 mg, 0.023 mmol), cesium fluoride (52 mg, 0.34 mmol), 1,4-dioxane (9 mL) and H2O (1 mL) were added to the reaction flask. After nitrogen replacement 3 times, the reaction solution was heated and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and ethyl acetate was added to the residue for dilution. The organic phase was washed with water, 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 rapid separation column (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] + .

[1013] Synthetic route of compound 79

[1014]

[1015] Synthesis of compound 79-b

[1016] 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 thereto. After the reaction solution was stirred at room temperature for 1.5 hours, the reaction solution was concentrated, water (3 mL) was added thereto, and a 6M 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, and the solid was dried to obtain 79-b (188 mg, 97%).

[1017] Synthesis of compound 79-a

[1018] Compound 79-b (230 mg, 0.58 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). Under an ice-water bath, (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. 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%).

[1019] Synthesis of compound 79

[1020] Compound 79-a (84 mg, 0.17 mmol), I-3 (81 mg, 0.26 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (22 mg, 0.034 mmol), cesium fluoride (78 mg, 0.51 mmol) were added to 1,4-dioxane (18 mL) and water (2 mL), the reaction solution was replaced with nitrogen three times, and heated and stirred at 90°C for 6 hours. The reaction solution was filtered with diatomaceous earth, water (50 mL) was added to the filtrate, extracted with dichloromethane (50 mL), the organic phase was washed with saturated brine (50 mL), dried with sodium sulfate, the desiccant was filtered off, 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) and then purified by preparative HPLC (alkaline conditions) to obtain compound 79 (41 mg, 40%). LC-MS(ESI):m / z 598.2(MH) - ; 1 HNMR(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).

[1021] Synthetic route of compound 80

[1022]

[1023] Synthesis of compound 80-f

[1024] 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 thereto, and 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%).

[1025] Synthesis of compound 80-e

[1026] Compound 80-f (300 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium carbonate (630 mg, 1.93 mmol) and 2-bromo-5-trifluoromethyl-1,3,4-thiazole (451 mg, 1.94 mmol) were added thereto, and the reaction solution was stirred at 50°C for 12 hours. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL), and 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, which was purified by column chromatography (mobile phase, PE / EA 10 / 1) to obtain compound 80-e (350 mg, 71%).

[1027] Synthesis of compound 80-d

[1028] 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(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), diisopropylethylamine (212 mg, 1.64 mmol) were added to 1,4-dioxane (15 mL). The reaction solution was replaced with nitrogen three times and stirred in an oil bath at 80°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, PE / EA 10 / 1) to obtain compound 80-d (187 mg, 81%).

[1029] Synthesis of compound 80-c

[1030] 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 thereto under an ice-water bath, and the reaction solution was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, and extracted with dichloromethane (50 mL), and 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, which was purified by column chromatography (mobile phase, PE / EA 1 / 1) to obtain compound 80-c (200 mg, 99%).

[1031] Synthesis of compound 80-b

[1032] Compound 80-c (200 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL). Sodium methoxide (71 mg, 1.31 mmol) was added thereto in an ice-water bath. The reaction solution was stirred in an ice-water bath for 30 minutes. 1-amino-1-cyclopropyl cyanide hydrochloride (156 mg, 1.32 mmol) was added thereto and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure and vacuum dried on an oil pump for 3 hours. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1-amino-1-cyclopropyl cyanide hydrochloride (104 mg, 0.88 mmol), dimethylaminopyridine (54 mg, 0.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL) in sequence, dried over sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA3 / 1) to obtain 80-b (18 mg, 9%). LC-MS (ESI): m / z 434.0 (M+H) + .

[1033] Synthesis of compound 80-a

[1034] Compound 80-b (18 mg, 0.041 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (33 mg, 0.19 mmol) was added thereto under an ice-water bath, and the reaction solution was stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, and 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 concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 3 / 1) to obtain compound 80-a (18 mg, 96%). LC-MS (ESI): m / z 450.0 (M+H) + .

[1035] Synthesis of compound 80

[1036] Compound 80-a (18 mg, 0.040 mmol), I-3 (19 mg, 0.060 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (8 mg, 0.012 mmol), cesium fluoride (18 mg, 0.12 mmol) were added to 1,4-dioxane (9 mL) and water (1 mL), and the reaction solution was replaced with nitrogen three times, and then heated to 100 ° C and stirred for 5 hours. The reaction solution was filtered with diatomaceous earth, water (50 mL) was added to the filtrate, and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried with 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 / 2) and then purified by preparative HPLC (alkaline conditions) to obtain compound 80 (2 mg, 8.3%). LC-MS(ESI):m / z 603.0(M+H) + .

[1037] Synthetic route of compound 81

[1038]

[1039] Synthesis of compound 81-d

[1040] Add 3-bromo-5-(chlorosulfonyl)-2-fluorobenzoic acid (950mg, 2.99mmol) to the reaction flask. Add anhydrous methanol (20mL) dropwise under ice bath, and then slowly add thionyl chloride (2mL). Heat and stir the reaction solution at 80℃ for 3 hours. The reaction solution is dried by rotation, added with a small amount of ice water, and then a small amount of anhydrous sodium sulfate solid is added. The solid precipitates, is filtered, and dried to obtain crude product 1 (600mg). Add thionyl chloride (3mL) dropwise to crude product 1, and the reaction mixture is heated to 80℃ and stirred for 3 hours. Rotate to remove the solvent to obtain crude product 2. Add 1...

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 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 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, 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 "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 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", 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 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, "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 "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", one or more R 5-7 Substituted "4-8 membered heterocycloalkenyl containing 1-3 heteroatoms 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 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; 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, "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 "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 "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; 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 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"; 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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