Nitrogen-containing compounds and their applications

Abstract

The present invention discloses a nitrogen-containing compound and its application. Specifically, the present invention provides a nitrogen-containing compound represented by Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate, or a solvate of its pharmaceutically acceptable salt. The nitrogen-containing compound of the present invention can effectively inhibit the overexpression of KIF18A protein in some human tumor cells. [Formula 1] JPEG2025525474000210.jpg24169

Description

Detailed Description of the Invention

[0001] This application claims the benefit of Chinese Patent Application No. 2022107730353, filed June 30, 2022. This application claims the benefit of Chinese Patent Application No. 202310066234.5, filed January 16, 2023. This application claims the benefit of Chinese Patent Application No. 2023107394075, filed June 21, 2023. The entire text of the above Chinese patent application is incorporated herein by reference.

[0002] [Technical Field] The present invention relates to nitrogen-containing compounds and their applications.

[0003] [Background technology] Humans have 46 chromosomes (23 in two groups), but in cancer, this number changes due to chromosome separation during cell division, resulting in a phenomenon called aneuploidy. Aneuploidy, the presence of an abnormal number of chromosomes in cells, not only causes common genetic disorders but also serves as a marker for cancer cells. While not all cancers exhibit aneuploidy, approximately 90% of solid tumors and 75% of hematologic cancers exhibit some degree of aneuploidy.

[0004] KIF18A, a member of the kinesin-8 family, is a mitotic kinesin that moves microtubules toward the positive pole of the cell using energy released by ATP hydrolysis. KIF18A is also located at the positive pole of microtubules, where it regulates microtubule dynamic instability and exerts enzymatic activity similar to that of microtubule depolymerases. During mitosis, KIF18A can regulate spindle microtubule dynamics and chromosome amplitude, playing an important role in ensuring timely chromosome alignment during mitosis, maintaining genome stability, and ensuring smooth completion of mitosis.

[0005] KIF18A protein is overexpressed in some human tumor cells (e.g., breast cancer, ovarian cancer, and colorectal cancer) and is associated with tumor invasion and metastasis. After KIF18A protein inhibition, tumor cells with chromosomal instability exhibit delayed mitosis, multipolar spindles, and increased cell death. A relatively large number of antimitotic drugs are already in clinical use for cancer treatment, including tubulin inhibitors that can stabilize tubulin or prevent tubulin assembly. Because tubulin is a major component of the mitotic spindle, disruption of tubulin movement by these drugs results in mitotic arrest and inhibition of tumor cell proliferation. However, because tubulin inhibitors also have inhibitory effects on normal cells, these drugs have numerous toxicities and side effects. Growth of aneuploid cancer cells with characteristics of chromosomal instability (CIN) depends on KIF18A protein, whereas growth in diploid cells does not depend on KIF18A protein. Therefore, inhibition of KIF18A protein activity results in selective inhibition of tumor cell proliferation with relatively little effect on normal cells, and therefore the selectivity of KIF18A inhibitors between normal cells and tumor cells can generate a relatively good therapeutic window, and has relatively good prospects for clinical application in tumor treatment.

[0006] Summary of the Invention The present invention aims to solve the technical problem that the conventional KIF18A inhibitors have a single structure, and provides nitrogen-containing compounds and their applications. The nitrogen-containing compounds of the present invention can effectively inhibit the overexpression of KIF18A protein in some human tumor cells.

[0007] The present invention provides a nitrogen-containing compound according to formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0008] [ka]

[0009] Among them, R x is a 3- to 6-membered monocyclic cycloalkyl group, a 5- to 6-membered monocyclic heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-1 a 5-6 membered monocyclic heterocycloalkyl group substituted with one or more R x-2 a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R x-3 a 7- to 9-membered spiroheterocycloalkyl group substituted with one or more R x-4 and the above "5- to 6-membered monocyclic heterocycloalkyl group", the above "6- to 9-membered bridged heterocycloalkyl group", the above "7- to 9-membered spiro heterocycloalkyl group", the above "one or more R x-1 "5-6-membered monocyclic heterocycloalkyl group substituted with one or more R x-2 "6- to 9-membered bridged heterocycloalkyl group substituted with" and the above "one or more R x-3 In the "7- to 9-membered spiroheterocycloalkyl group substituted with one or more R", the heteroatoms independently consist of one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two types selected from N, O and S, and the "5- to 6-membered monocyclic heterocycloalkyl group", the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiroheterocycloalkyl group", the "one or more R x-1 "5-6-membered monocyclic heterocycloalkyl group substituted with one or more R x-2 "6- to 9-membered bridged heterocycloalkyl group substituted with" and the above "one or more R x-3 "7-9 membered spiroheterocycloalkyl group substituted with" is linked to ring A via the N atom, Each R x-1 , R x-2 , R x-3 and R x-4 are each independently a halogen, R N-10k , R N-10l , C 1-6 Alkyl groups, C substituted with one or more halogens 1-6Alkyl group, -OR N-a , C substituted with one or more halogens 1-6 Alkoxy groups, CN, -NR N-a R N-a or oxo, R 1 -LR 1-1 and L is *-NHSO2-, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SON2NH- or -SO2-, * representing one end connected to ring A; R 1-1 is C 1-6 alkyl group, 3- to 6-membered monocyclic cycloalkyl group, 4- to 8-membered monocyclic heterocycloalkyl group, one or more R a C replaced with 1-6 alkyl group or one or more R b In the 4- to 8-membered monocyclic heterocycloalkyl group, the heteroatoms are independently one, two or three kinds selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R a are each independently a hydroxy group, a halogen, or -NH(R a-1 ) and R a-1 is C 1-6 is an alkyl group, Each R b are each independently C 1-6 C substituted with alkyl groups or one or more hydroxy groups 1-6 is an alkyl group, G is C(R 10 ) or N, and R 10 H, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, -OH, -OR N-8a -OR N-8b and M is a phenyl group, a naphthyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R 2a 6-membered heteroaryl group substituted with one or more R 3 a 9- to 10-membered heteroaryl group substituted with one or more R 4 a 6-membered heterocycloalkenyl group substituted with one or more R 5 a phenyl group substituted with one or more R 5 a naphthyl group substituted with one or more R 6 and the above-mentioned "5-membered heteroaryl group", "6-membered heteroaryl group", "9- to 10-membered heteroaryl group", "6-membered heterocycloalkenyl group", "one or more R 2 a 6-membered heteroaryl group substituted with "one or more R 3 a 9- to 10-membered heteroaryl group substituted with "one or more R 4 "a 6-membered heterocycloalkenyl group substituted with one or more R 6 In the "5-membered heteroaryl group substituted with" the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2 , R 3 , R 4 , R 5 and R 6 are each independently oxo, halogen, or R N-4a , R N-4b , C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl group, cyano group, C 1-6 Alkoxy group, -OR N-6a or -YR N-13 and R N-6a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, Y is -C 1-6 Alkyl-, -N(C 1-6 Alkyl)-C 1-6 Alkyl-, -C(=O)NR N-a R N-a (C 1-6alkyl), -O-, -OC 1-6 Alkyl-, S, S=O, S(=O)2, -S(=O)(=NR N-13 )- or -S(=O)(=NH)-; R N-13 is R N-13a or R N-13b and Each R N-4a , R N-8a , R N-10k and R N-13a are each independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which do not contain halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl group, -OR N-a , C substituted with one or more halogens 1-6 Alkoxy group, CN, -C(=O)R N-b , -C(=O)OR N-a , -C(=O)NR N-a R N-a , -C(=NR N-a )NR N-a R N-a , -OC(=O)R N-b , -OC(=O)NR N-a R N-a , -OC 1-6 Alkyl NR N-a R N-a , -OC 1-6 Alkyl OR N-a , -SR N-a , -S(=O)R N-b , -S(=O)2R N-b , -S(=O)2NR N-a R N-a , -NR N-a R N-a , -N(R N-a )C(=O)R N-b , -N(R N-a )C(=O)OR N-b , -N(R N-a )C(=O)NR N-aR N-a , -N(R N-a )C(=NR N-a )NR N-a R N-a , -N(R N-a )S(=O)2R N-b , -N(R N-a )S(=O)NR N-a R N-a , -NR N-a C 1-6 Alkyl NR N-a R N-a , -NR N-a C 1-6 Alkyl OR N-a , -C 1-6 Alkyl NR N-a R N-a , -C 1-6 Alkyl OR N-a , -C 1-6 AlkylN(R N-a )C(=O)R N-b , -C 1-6 Alkyl OC(=O)R N-b , -C 1-6 AlkylC(=O)NR N-a R N-a , -C 1-6 AlkylC(=O)OR N-a , R N-14 and oxo; Each R N-4b , R N-8b , R N-10l and R N-13b are each independently a halogen, -OR N-a , C substituted with one or more halogens 1-6 C substituted with 0, 1, 2, 3, 4 or 5 groups selected from alkoxy groups and CN 1-6 is an alkyl group, Each R N-14 are each independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and which do not contain halogen, C 1-6Alkyl groups, C substituted with one or more halogens 1-6 Alkyl group, -OR N-a , C substituted with one or more halogens 1-6 Alkoxy group, CN, -C(=O)R N-b , -C(=O)OR N-a , -C(=O)NR N-a R N-a , -C(=NR N-a )NR N-a R N-a , -OC(=O)R N-b , -OC(=O)NR N-a R N-a , -OC 1-6 Alkyl NR N-a R N-a , -OC 1-6 Alkyl OR N-a , -SR N-a , -S(=O)R N-b , -S(=O)2R N-b , -S(=O)2NR N-a R N-a , -NR N-a R N-a , -N(R N-a )C(=O)R N-b , -N(R N-a )C(=O)OR N-b , -N(R N-a )C(=O)NR N-a R N-a , -N(R N-a )C(=NR N-a )NR N-a R N-a , -N(R N-a )S(=O)2R N-b , -N(R N-a )S(=O)NR N-a R N-a , -NR N-a C 1-6 Alkyl NR N-a R N-a , -NR N-a C 1-6 Alkyl OR N-a , -C 1-6 Alkyl NR N-a R N-a , -C 1-6 Alkyl OR N-a , -C1-6 AlkylN(R N-a )C(=O)R N-b , -C 1-6 Alkyl OC(=O)R N-b , -C 1-6 AlkylC(=O)NR N-a R N-a , -C 1-6 AlkylC(=O)OR N-a and oxo; Each R N-a are each independently H or R N-b and Each R N-b are each independently C 1-6 alkyl group, phenyl group or benzyl group, among which the above C 1-6 The alkyl group is a halogen, -OH, -OC 1-6 Alkyl groups, -NH2, -NHC 1-6 Alkyl group, -OC(=O)C 1-6 Alkyl group or -N(C 1-6 Alkyl)C 1-6 and the phenyl or benzyl group is substituted with 0, 1, 2 or 3 substituents selected from halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, -OH, -OC 1-6 Alkyl groups, -NH2, -NHC 1-6 Alkyl group, -OC(=O)C 1-6 Alkyl group or -N(C 1-6 Alkyl)C 1-6 substituted with 0, 1, 2 or 3 substituents selected from alkyl groups; W and X 2 The definition of may be written in one of the following forms: Technical proposal 1: W is *-CONR W - and X 2 is R W-1 where * represents one end connected to ring A, Technical proposal 2: W is *-NR W CO- and X 2 is R W-1 where * represents one end connected to ring A, Technical proposal 3: W is *-C(=X 1 )NR W - and X 1 , X 2 and together with the C atom therebetween form a 6-membered heteroaryl group, in which the heteroatom is one, two or three selected from N, O and S, the number of heteroatoms is 1, 2 or 3, and * represents one end connected to ring A; R W is H, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, R W-1 H, halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, And the compound represented by the above formula I can be prepared by the following conditions: Condition 1: R x is a 6- to 9-membered bridged heterocycloalkyl group or one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group substituted with Condition 2: M is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R 5 a naphthyl group substituted with one or more R 6 a 5-membered heteroaryl group substituted with one or more R 3 a 9- to 10-membered heteroaryl group substituted with one or more R 4 is a 6-membered heterocycloalkenyl group substituted with Condition 3: W is *-C(=X 1 )NR W - and X 1 , X 2 and form a 6-membered heteroaryl group together with the C atom therebetween.

[0010] The present invention provides a nitrogen-containing compound represented by formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0011] [ka]

[0012] Among them, R x is a 3- to 6-membered monocyclic cycloalkyl group, a 5- to 6-membered monocyclic heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-1 a 5-6 membered monocyclic heterocycloalkyl group substituted with one or more R x-2 a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R x-3 a 7- to 9-membered spiroheterocycloalkyl group substituted with one or more R x-4 and the above "5- to 6-membered monocyclic heterocycloalkyl group", the above "6- to 9-membered bridged heterocycloalkyl group", the above "7- to 9-membered spiro heterocycloalkyl group", the above "one or more R x-1 "5-6-membered monocyclic heterocycloalkyl group substituted with one or more R x-2 "6- to 9-membered bridged heterocycloalkyl group substituted with" and the above "one or more R x-3 In the "7- to 9-membered spiroheterocycloalkyl group substituted with one or more R", the heteroatoms independently consist of one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two types selected from N, O and S, and the "5- to 6-membered monocyclic heterocycloalkyl group", the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiroheterocycloalkyl group", the "one or more R x-1 "5-6-membered monocyclic heterocycloalkyl group substituted with one or more R x-2 "6- to 9-membered bridged heterocycloalkyl group substituted with" and the above "one or more R x-3"7-9 membered spiroheterocycloalkyl group substituted with" is linked to ring A via the N atom, Each R x-1 , R x-2 , R x-3 and R x-4 are each independently a halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkoxy group, R 1 -LR 1-1 and L is *-NHSO2-, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SON2NH- or -SO2-, * representing one end connected to ring A; R 1-1 is C 1-6 alkyl group, 3- to 6-membered monocyclic cycloalkyl group, 4- to 8-membered monocyclic heterocycloalkyl group, one or more R a C replaced with 1-6 alkyl group or one or more R b In the 4- to 8-membered monocyclic heterocycloalkyl group, the heteroatoms are independently one, two or three kinds selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R a are each independently a hydroxy group, a halogen, or -NH(R a-1 ) and R a-1 is C 1-6 is an alkyl group, Each R b are each independently C 1-6 alkyl group, C substituted with one or more hydroxy groups 1-6 is an alkyl group, B is a phenyl group, a naphthyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R 2a 6-membered heteroaryl group substituted with one or more R 3 a 9- to 10-membered heteroaryl group substituted with one or more R 4 a 6-membered heterocycloalkenyl group substituted with one or more R 5 a phenyl group substituted with one or more R 5 a naphthyl group substituted with one or more R 6 and the above-mentioned "5-membered heteroaryl group", "6-membered heteroaryl group", "9- to 10-membered heteroaryl group", "6-membered heterocycloalkenyl group", "one or more R 2 a 6-membered heteroaryl group substituted with "one or more R 3 a 9- to 10-membered heteroaryl group substituted with "one or more R 4 "a 6-membered heterocycloalkenyl group substituted with one or more R 6 In the "5-membered heteroaryl group substituted with" the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2 , R 3 , R 4 , R 5 , R 6 are each independently a halogen, a cyano group, an oxo group (=O), or C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or one or more R 2-1 a 3- to 10-membered cycloalkyl group substituted with one or more R 2-2 a 4- to 10-membered heterocycloalkyl group substituted with one or more R 2-3 and the above-mentioned "5- to 10-membered heteroaryl group", "4- to 10-membered heterocycloalkyl group", "one or more R 2-2 "a 4- to 10-membered heterocycloalkyl group substituted with one or more R 2-3In the "5- to 10-membered heteroaryl group substituted with," the heteroatoms are independently one, two or three types selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, Each R 2-1 , R 2-2 and R 2-3 are each independently a halogen, C 1-6 Alkyl group, oxo group, CN, hydroxy group, 3- to 6-membered monocyclic cycloalkyl group, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 an alkoxy group, a 3- to 6-membered monocyclic cycloalkyl group substituted with one or more halogen atoms, or C 1-6 is an alkoxy group, W and X 2 The definition of may be written in one of the following forms: (1)W is *-CONR W - and X 2 is R W-1 where * represents one end connected to ring A, (2)W is *-NR W CO- and X 2 is R W-1 where * represents one end connected to ring A, (3)W is *-C(=X 1 )NR W - and X 1 , X 2 and together with the C atom therebetween form a 6-membered heteroaryl group, in which the heteroatom is one, two or three selected from N, O and S, the number of heteroatoms is 1, 2 or 3, and * represents one end connected to ring A; R W is H, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, R W-1 H, halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, G is C(R10 ) or N, R 10 H, halogen, C 1-6 C substituted with alkyl groups, hydroxy groups, or one or more halogens 1-6 is an alkyl group, And the compound represented by the above formula II can be prepared by the following conditions: (1)R x is a 6- to 9-membered bridged heterocycloalkyl group or one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group substituted with (2) B is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R 5 a naphthyl group substituted with one or more R 6 a 5-membered heteroaryl group substituted with one or more R 3 a 9- to 10-membered heteroaryl group substituted with one or more R 4 is a 6-membered heterocycloalkenyl group substituted with (3)W is *-C(=X 1 )NR W - and X 1 , X 2 and form a 6-membered heteroaryl group together with the C atom therebetween.

[0013] In one embodiment, in the nitrogen-containing compound represented by the above formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, some groups in the nitrogen-containing compound represented by the above formula II are defined as follows, and the remaining groups are defined as described in any one of the other embodiments (hereinafter abbreviated as "in one embodiment").

[0014] R x is a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-2and the above-mentioned "6- to 9-membered bridged heterocycloalkyl group", the above-mentioned "7- to 9-membered spiro heterocycloalkyl group" and the above-mentioned "one or more R x-2 In the "6- to 9-membered bridged heterocycloalkyl group substituted with one or more R x-2 "6-9 membered bridged heterocycloalkyl group substituted with" is linked to ring A via a N atom, Each R x-2 are each independently C 1-6 is an alkyl group, R 1 -LR 1-1 and L is *-NHSO2-, where * represents one end connected to ring A; R 1-1 is C 1-6 an alkyl group, one or more R a C replaced with 1-6 alkyl group or one or more R b is a 3- to 6-membered monocyclic cycloalkyl group substituted with Each R a are each independently a hydroxy group, Each R b are each independently C 1-6 is an alkyl group, B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 and the above-mentioned "5-membered heteroaryl group", "9- to 10-membered heteroaryl group", "one or more R 2 "a 6-membered heteroaryl group substituted with one or more R 3In the "9- to 10-membered heteroaryl group substituted with," the heteroatoms are independently one, two or three types selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, Each R 2 are each independently C 1-6 is an alkyl group, Each R 3 are each independently a halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, one or more R 2-1 a 3- to 10-membered cycloalkyl group substituted with one or more R 2-2 and the above-mentioned "4- to 10-membered heterocycloalkyl group" or "one or more R 2-2 In the "4- to 10-membered heterocycloalkyl group substituted with," the heteroatoms are independently one, two or three types selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2-1 , R 2-2 and R 2-3 are each independently a halogen; W and X 2 The definition of may be written in one of the following forms: (1)W is *-CONR W - and X 2 is R W-1 where * represents one end connected to ring A, (2)W is *-C(=X 1 )NR W - and X 1 , X 2 and together with the C atom therebetween form a 6-membered heteroaryl group, in which the heteroatom is one, two or three selected from N, O and S, the number of heteroatoms is 1, 2 or 3, and * represents one end connected to ring A; R W is H and R W-1is H, G is C(R 10 ) or N, R 10 is H, And the compound represented by the above formula II can be prepared by the following conditions: (1)R x is a 6- to 9-membered bridged heterocycloalkyl group or one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group substituted with (2) B is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R 5 a naphthyl group substituted with one or more R 6 a 5-membered heteroaryl group substituted with one or more R 3 a 9- to 10-membered heteroaryl group substituted with one or more R 4 is a 6-membered heterocycloalkenyl group substituted with (3)W is *-C(=X 1 )NR W - and X 1 , X 2 and form a 6-membered heteroaryl group together with the C atom therebetween.

[0015] In some forms, R x is a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-2 and the above-mentioned "6- to 9-membered bridged heterocycloalkyl group", the above-mentioned "7- to 9-membered spiro heterocycloalkyl group" and the above-mentioned "one or more R x-2 In the "6- to 9-membered bridged heterocycloalkyl group substituted with one or more R x-2"6-9 membered bridged heterocycloalkyl group substituted with" is linked to ring A via a N atom, Each R x-2 are each independently C 1-6 is an alkyl group, R 1 -LR 1-1 and L is *-NHSO2-, where * represents one end connected to ring A; R 1-1 is C 1-6 an alkyl group, one or more R a C replaced with 1-6 alkyl group or one or more R b is a 3- to 6-membered monocyclic cycloalkyl group substituted with Each R a are each independently a hydroxy group, Each R b are each independently C 1-6 is an alkyl group, B is a 9- to 10-membered heteroaryl group, one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 and the above-mentioned "5-membered heteroaryl group", "9- to 10-membered heteroaryl group", "one or more R 2 "a 6-membered heteroaryl group substituted with one or more R 3 In the "9- to 10-membered heteroaryl group substituted with," the heteroatoms are independently one, two or three types selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; when the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group and the number of heteroatoms is 2, the heteroatoms are independently one or two types selected from N or O; when the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group and the number of heteroatoms is 3, the heteroatom is N; when the 9- to 10-membered heteroaryl group is a 10-membered heteroaryl group and the heteroatom is N and the number of heteroatoms is 2, the heteroatoms are located on different rings; B is one or more R 2When R is a 6-membered heteroaryl group substituted with x is an 8- to 9-membered bridged heterocycloalkyl group, and in the "8- to 9-membered bridged heterocycloalkyl group", the heteroatoms independently consist of one N atom and 0, 1 or 2 X atoms, and the X atoms independently represent one or two types selected from N, O and S, and the "8- to 9-membered bridged heterocycloalkyl group" is linked to ring A via an N atom, Each R 2 are each independently C 1-6 is an alkyl group, Each R 3 are each independently a halogen or C 1-6 is an alkyl group, U is a 4- to 10-membered heterocycloalkyl group or one or more R 2-2 and the above-mentioned "4- to 10-membered heterocycloalkyl group" or "one or more R 2-2 In the "4- to 10-membered heterocycloalkyl group substituted with," the heteroatoms are independently one, two or three types selected from N, O and S, and the number of heteroatoms is independently 2, 3 or 4; Each R 2-2 are each independently a halogen; W*-CONR W - and X 2 is R W-1 where * represents one end connected to ring A, R W is H and R W-1 is H, G is C(R 10 ) or N, R 10 is H, And the compound represented by the above formula II can be prepared by the following conditions: (1)R x is a 6- to 9-membered bridged heterocycloalkyl group or one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group substituted with (2) B is a 9- to 10-membered heteroaryl group, one or more R 3and wherein the aryl group is a 9- to 10-membered heteroaryl group substituted with one or two of the following:

[0016] In some forms, R x is a 6- to 9-membered bridged heterocycloalkyl group, one or more R x-2 a 6- to 9-membered bridged heterocycloalkyl group or a 7- to 9-membered spiro heterocycloalkyl group substituted with Each R x-2 are each independently C 1-6 is an alkyl group, R 1 -LR 1-1 and L is *-NHSO2-, R 1-1 is C 1-6 an alkyl group, one or more R a C replaced with 1-6 alkyl group or one or more R b is a 3- to 6-membered monocyclic cycloalkyl group substituted with R a is a hydroxy group, Each R b are each independently C 1-6 is an alkyl group, B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 is a 9- to 10-membered heteroaryl group substituted with Each R 2 are each independently C 1-6 is an alkyl group, Each R 3 are each independently C 1-6 is an alkyl group, U is a 4- to 10-membered heterocycloalkyl group, one or more R 2-1 a 3- to 10-membered cycloalkyl group substituted with one or more R 2-2 is a 4- to 10-membered heterocycloalkyl group substituted with Each R 2-1 are each independently a halogen; Each R 2-2 are each independently a halogen; W is *-CONH- and X 2 is H, And the compound represented by the above formula II can be prepared by the following conditions: (1)R x is a 6- to 9-membered bridged heterocycloalkyl group, (2) B is a 5-membered heteroaryl group, a naphthyl group, a 9- to 10-membered heteroaryl group, or one or more R 5 a naphthyl group substituted with one or more R 3 and wherein the aryl group is a 9- to 10-membered heteroaryl group substituted with one or two of the following:

[0017] In some forms, R x is a 6- to 9-membered bridged heterocycloalkyl group, one or more R x-2 a 6- to 9-membered bridged heterocycloalkyl group or a 7- to 9-membered spiro heterocycloalkyl group substituted with Each R x-2 are each independently C 1-6 is an alkyl group, R 1 -LR 1-1 and L is *-NHSO2-, R 1-1 is C 1-6 an alkyl group, one or more R a C replaced with 1-6 alkyl group or one or more R b is a 3- to 6-membered monocyclic cycloalkyl group substituted with R a is a hydroxy group, Each R b are each independently C 1-6 is an alkyl group, B is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R 5 a naphthyl group substituted with one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3is a 9- to 10-membered heteroaryl group substituted with Each R 2 are each independently C 1-6 is an alkyl group, Each R 3 are each independently C 1-6 is an alkyl group, U is a 4- to 10-membered heterocycloalkyl group, one or more R 2-1 a 3- to 10-membered cycloalkyl group substituted with one or more R 2-2 is a 4- to 10-membered heterocycloalkyl group substituted with Each R 2-1 are each independently a halogen; Each R 2-2 are each independently a halogen; W is *-CONH- and X 2 is H, And the compound represented by the above formula II can be prepared by the following conditions: (1)R x is a 6- to 9-membered bridged heterocycloalkyl group, (2) B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R 3 and wherein the aryl group is a 9- to 10-membered heteroaryl group substituted with one or two of the following:

[0018] In some forms, R x is a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-2 a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R x-3 is a 7-9 membered spiroheterocycloalkyl group substituted with one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, or a 7- to 9-membered spiroheterocycloalkyl group substituted with, more preferably a 6- to 9-membered bridged heterocycloalkyl group or a 7- to 9-membered spiroheterocycloalkyl group.

[0019] In one embodiment, each Rx-1 , R x-2 , R x-3 and R x-4 are each independently a halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, preferably a halogen or C 1-6 alkyl group, more preferably C 1-3 The alkyl group is F, Cl or Br.

[0020] In some forms, R x is a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-2 a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R x-3 is a 7-9 membered spiro heterocycloalkyl group substituted with

[0021] Each R x-1 , R x-2 , R x-3 and R x-4 are each independently a halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group, preferably a halogen or C 1-6 alkyl group, more preferably C 1-3 The alkyl group is F, Cl or Br.

[0022] In some forms, R x is a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group substituted with Each R x-2 are each independently C 1-6 It is an alkyl group.

[0023] In one embodiment, each R x-1 , R x-2 , R x-3 and R x-4 are each independently C 1-6It is an alkyl group.

[0024] In one aspect, L is *-NHSO2-.

[0025] In one embodiment, L is —NHSO 2 — or —NH—.

[0026] In some forms, R 1-1 is C 1-6 an alkyl group, a 3- to 6-membered monocyclic cycloalkyl group, one or more R b a 3- to 6-membered monocyclic cycloalkyl group substituted with one or more R a C replaced with 1-6 alkyl group, preferably C 1-3 an alkyl group, one or more R a C replaced with 1-3 alkyl group or one or more R b In one embodiment, R is a 3- to 6-membered monocyclic cycloalkyl group substituted with a is a hydroxy group.

[0027] In one embodiment, each R b are each independently C 1-6 It is an alkyl group.

[0028] In some forms, R 1-1 is C 1-6 an alkyl group, one or more R b a 3- to 6-membered monocyclic cycloalkyl group substituted with one or more R a C replaced with 1-6 is an alkyl group, R a is a hydroxy group, Each R b are each independently C 1-6 It is an alkyl group.

[0029] In one embodiment, B is a phenyl group, a naphthyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, one or more R 5a naphthyl group substituted with one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 a 9- to 10-membered heteroaryl group substituted with one or more R 4 and preferably a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or a 6-membered heterocycloalkenyl group substituted with one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 and more preferably a 9- to 10-membered heteroaryl group substituted with one or more R 3 is a 9- to 10-membered heteroaryl group substituted with

[0030] In some embodiments, B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 is a 9- to 10-membered heteroaryl group substituted with

[0031] In one embodiment, in B, the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group having two heteroatoms, each of which is one or two heteroatoms independently selected from N or O.

[0032] In one embodiment, in B, the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group, the number of heteroatoms is 3, and the heteroatom is N.

[0033] In one embodiment, in B, the 9- to 10-membered heteroaryl group is a 10-membered heteroaryl group, the heteroatom is N, the number of heteroatoms is 2, and the heteroatoms are located in different rings.

[0034] In some embodiments, B is one or more R 2 When R is a 6-membered heteroaryl group substituted with x is an 8- to 9-membered bridged heterocycloalkyl group.

[0035] In one embodiment, each R 2 , R 3 , R 4 , R 5 , R 6 are each independently a halogen, an oxo group, or C 1-6 alkyl group, preferably C 1-3 It is an alkyl group.

[0036] In one embodiment, each R 2 , R 3 , R 4 , R 5 , R 6 are each independently a halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 It is an alkyl group.

[0037] In one embodiment, each R 2 are each independently C 1-6 It is an alkyl group.

[0038] In one embodiment, each R 3 are each independently a halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 It is an alkyl group.

[0039] In one embodiment, each R 3 are each independently a halogen or C 1-6 It is an alkyl group.

[0040] In one embodiment, B is a 9-10 membered heteroaryl group, one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 is a 9- to 10-membered heteroaryl group substituted with Each R 2 are each independently C 1-6 is an alkyl group, Each R 3 are each independently a halogen or C 1-6 It is an alkyl group.

[0041] In some embodiments, B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, one or more R 2 a 6-membered heteroaryl group substituted with one or more R 3 is a 9- to 10-membered heteroaryl group substituted with Each R 2 , R 3 are each independently a halogen or C 1-6 It is an alkyl group.

[0042] In some embodiments, U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, one or more R 2-1 a 3- to 10-membered cycloalkyl group substituted with one or more R 2-2 a 4- to 10-membered heterocycloalkyl group substituted with, preferably a 4- to 9-membered heterocycloalkyl group, one or more R 2-1 a 3- to 8-membered cycloalkyl group substituted with one or more R 2-2 is a 4- to 9-membered heterocycloalkyl group substituted with one or more R 2-2 is a 4- to 9-membered heterocycloalkyl group substituted with

[0043] In one embodiment, the 4- to 10-membered heterocycloalkyl group in U is a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, or a 7- to 9-membered spiroheterocycloalkyl group.

[0044] In one embodiment, each R 2-1 , R 2-2 and R 2-3 are each independently a halogen, C 1-6 Alkyl group, hydroxy group, C 1-6 C substituted with an alkoxy group or one or more halogens 1-6 It is an alkyl group, preferably a halogen, more preferably F, Cl or Br.

[0045] In one embodiment, U is a 4- to 10-membered heterocycloalkyl group or one or more R 2-2 is a 4- to 10-membered heterocycloalkyl group substituted with Each R 2-2 are each independently a halogen.

[0046] In some embodiments, U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, one or more R 2-1 a 3- to 10-membered cycloalkyl group substituted with one or more R 2-2 is a 4- to 10-membered heterocycloalkyl group substituted with Each R 2-1 and R 2-2 are each independently a halogen, C 1-6 Alkyl group, hydroxy group, C 1-6 C substituted with an alkoxy group or one or more halogens 1-6 It is an alkyl group, preferably F, Cl or Br.

[0047] In one embodiment, G is C(R 10 )

[0048] In one embodiment, G is C(R 10 ) or N, and R 10 is H.

[0049] In some forms, R 10 H, halogen, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 It is an alkyl group, preferably H.

[0050] In one embodiment, G is C(R 10 ) and R 10 is H.

[0051] In some forms, R W is H.

[0052] In some forms, R W-1is H.

[0053] In one form, W is *-CONR W - and X 2 is R W-1 and R W-1 is H or halogen, preferably H, R W is H.

[0054] In one aspect, the compound of formula II above can be prepared by the following procedure: (a)R x is a 6- to 9-membered bridged heterocycloalkyl group, (b) B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R 4 a 6-membered heterocycloalkenyl group substituted with one or more R 3 is a 9- to 10-membered heteroaryl group substituted with one or more R 3 and wherein the aryl group is a 9- to 10-membered heteroaryl group substituted with one or two of the following:

[0055] In one embodiment, in the compound of formula II above, R x is a 6- to 9-membered bridged heterocycloalkyl group or one or more R x-2 is a 6- to 9-membered bridged heterocycloalkyl group substituted with

[0056] In one embodiment, in the compound of formula II above, B is a 9-10 membered heteroaryl group, one or more R 3 is a 9- to 10-membered heteroaryl group substituted with

[0057] In one embodiment, the nitrogen-containing compound shown in formula II above is

[0058] [ka]

[0059] and each V1 is independently C or N; V2 is N or CR 11 is preferably N, D is a partially saturated or unsaturated 5- or 6-membered carbocyclic ring, or a partially saturated or unsaturated 5- or 6-membered heterocyclic ring, and the 5- or 6-membered carbocyclic ring or the 5- or 6-membered heterocyclic ring may optionally contain 0, 1, 2, or 3 R 11 In the above "5- to 6-membered heterocycle", the heteroatom is N, O, or S, and the number of heteroatoms is independently 1, 2, 3, or 4; R 11 is hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more halogens 1-6 It is an alkyl group.

[0060] In one embodiment, the above-mentioned "5- to 6-membered monocyclic heterocycloalkyl group" is a 5- to 6-membered heterocycloalkyl group each independently containing 1 or 2 heteroatoms, and preferably

[0061] [ka]

[0062] is.

[0063] In one embodiment, the above-mentioned "6- to 9-membered bridged heterocycloalkyl groups" are each independently 6- to 9-membered bridged heterocycloalkyl groups containing one or two heteroatoms, and preferably

[0064] [ka]

[0065] is.

[0066] In one embodiment, the above-mentioned "6- to 9-membered bridged heterocycloalkyl group" is a 6- to 9-membered bridged heterocycloalkyl group each independently containing one or two heteroatoms, and is preferably any one of the following fragments, i.e.,

[0067] [ka]

[0068] is.

[0069] In one embodiment, the above "7- to 9-membered spiroheterocycloalkyl group" is a 7- to 9-membered spiroheterocycloalkyl group each independently containing one or two heteroatoms, and is preferably any one of the following fragments:

[0070] [ka]

[0071] is.

[0072] In one embodiment, the "halogen" is each independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0073] In one embodiment, the above "C 1-6 The "alkyl groups" are each independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group, and are preferably a methyl group or an ethyl group.

[0074] In some forms, R 1-1 In the above C 1-6 The alkyl group is an ethyl group or an isopropyl group.

[0075] In one embodiment, the above-mentioned "3- to 6-membered monocyclic cycloalkyl groups" are each independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and preferably a cyclopropyl group.

[0076] In one embodiment, the above "C 1-6 The "alkoxy group" is each independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, or a tert-butoxy group, and is preferably a methoxy group or an ethoxy group.

[0077] In one embodiment, the above-mentioned "4- to 8-membered monocyclic heterocycloalkyl group" is a "4- to 8-membered monocyclic heterocycloalkyl group" containing one O atom, and preferably

[0078] [ka]

[0079] is.

[0080] In one embodiment, the above-mentioned "5-membered heteroaryl group" is a 5-membered heteroaryl group in which "the heteroatom is one or two types selected from N and S", and preferably any one of the following fragments, i.e.,

[0081] [ka]

[0082] is.

[0083] In one embodiment, the "6-membered heteroaryl group" is independently any one of the following fragments:

[0084] [ka]

[0085] is.

[0086] In one embodiment, the above "9- to 10-membered heteroaryl group" is independently any one of the following fragments:

[0087] [ka] JPEG2025525474000013.jpg173169

[0088] is.

[0089] In one embodiment, the above "9- to 10-membered heteroaryl group" is independently any one of the following fragments:

[0090] [ka] JPEG2025525474000015.jpg224169

[0091] is.

[0092] In one embodiment, the "6-membered heterocycloalkenyl group" is a 6-membered heterocycloalkenyl group in which each heteroatom is independently N and the number of heteroatoms is 1 or 2, and preferably any one of the following fragments:

[0093] [ka]

[0094] is.

[0095] In one embodiment, the above-mentioned "3- to 10-membered cycloalkyl group" is each independently a 3- to 6-membered monocyclic cycloalkyl group or a 6- to 8-membered spirocycloalkyl group, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,

[0096] [ka]

[0097] is.

[0098] In one embodiment, the above-mentioned "4- to 10-membered heterocycloalkyl groups" are each independently a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 8-membered spiroheterocycloalkyl group, or a 7- to 9-membered bridged heterocycloalkyl group, preferably

[0099] [ka]

[0100] is.

[0101] In one embodiment, the above-mentioned "4- to 10-membered heterocycloalkyl groups" are each independently a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 8-membered spiroheterocycloalkyl group, or a 7- to 9-membered bridged heterocycloalkyl group, preferably

[0102] [ka]

[0103] is.

[0104] In one embodiment, the "6- to 10-membered aryl group" is a phenyl group.

[0105] In one embodiment, the above-mentioned "5- to 10-membered heteroaryl group" is a 5- to 6-membered heteroaryl group having one or two heteroatoms, the heteroatom being N, and preferably

[0106] [ka]

[0107] is.

[0108] In some cases, W is *-C(X 1 )NR W - and X 1, X 2 and when they form a 6-membered heteroaryl group together with the C atom therebetween, the heteroatom in the "6-membered heteroaryl group" is N, and the number of heteroatoms is 1 or 2.

[0109] In some forms, R x is one of the following fragments:

[0110] [ka]

[0111] is.

[0112] In some forms, R x is one of the following fragments:

[0113] [ka]

[0114] is.

[0115] In one embodiment, R1 is a fragment of any one of the following:

[0116] [ka]

[0117] is.

[0118] In one embodiment, B is any one of the following fragments (in the fragments below, the dashed line on the left represents the bond connected to U):

[0119] [ka]

[0120] is.

[0121] In one embodiment, B is any one of the following fragments (in the fragments below, the dashed line on the left represents the bond connected to U):

[0122] [ka] JPEG2025525474000026.jpg80169

[0123] is. In one embodiment, U is

[0124] [ka]

[0125] is.

[0126] In one embodiment, U is any one of the following fragments:

[0127] [ka]

[0128] is.

[0129] The present invention relates to any one of the following nitrogen-containing compounds:

[0130] [ka] JPEG2025525474000030.jpg174169JPEG2025525474000031.jpg247169JPEG2025525474000032.jpg24016 9JPEG2025525474000033.jpg227169JPEG2025525474000034.jpg228169JPEG2025525474000035.jpg48169

[0131] Further provided are:

[0132] The present invention provides (1) The nitrogen-containing compound shown in the above formula I, the nitrogen-containing compound shown in the above formula II, the nitrogen-containing compound, a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound shown in the above formula I, the nitrogen-containing compound shown in the above formula II, or the nitrogen-containing compound), a stereoisomer thereof (referring to the nitrogen-containing compound shown in the above formula I, the nitrogen-containing compound shown in the above formula II, or the nitrogen-containing compound), a tautomer thereof (referring to the nitrogen-containing compound shown in the above formula I, the nitrogen-containing compound shown in the above formula II, or the nitrogen-containing compound), a pharmaceutically acceptable salt ... metabolites thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), prodrugs thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), isotopically labeled derivatives thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), solvates thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), or solvates of pharmaceutically acceptable salts thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), and (2) Further provided is a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

[0133] The present invention relates to the use of a nitrogen-containing compound represented by the above formula I, a nitrogen-containing compound represented by the above formula II, the above nitrogen-containing compound, a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a stereoisomer thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a tautomer thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a pharmaceutically acceptable salt ... The present invention further provides applications of a metabolite thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), a prodrug thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), a solvate thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound).

[0134] The present invention relates to the use of a nitrogen-containing compound represented by the above formula I, a nitrogen-containing compound represented by the above formula II, the above nitrogen-containing compound, a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a stereoisomer thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a tautomer thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a metabolite thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a nitrogen-containing compound represented by the above formula I, Further provided is an application of a prodrug thereof (referring to the nitrogen-containing compound shown in formula II above or the nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), a solvate thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the nitrogen-containing compound), wherein the drug is used to treat a disease associated with the KIF18A protein mechanism of action, such as cancer, and also, for example, cancer associated with the KIF18A protein mechanism of action.

[0135] In some embodiments, the cancer is ovarian cancer, colon cancer, or ductal carcinoma of the breast.

[0136] The present invention relates to the use of a nitrogen-containing compound represented by the above formula I, a nitrogen-containing compound represented by the above formula II, the above nitrogen-containing compound, a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a stereoisomer thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a tautomer thereof (referring to the nitrogen-containing compound represented by the above formula I, the nitrogen-containing compound represented by the above formula II, or the above nitrogen-containing compound), a pharmaceutically acceptable salt ... The present invention further provides an application of a metabolite thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), a prodrug thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), a solvate thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the nitrogen-containing compound shown in formula I above, the nitrogen-containing compound shown in formula II above, or the above nitrogen-containing compound), wherein the drug is used to treat cancer.

[0137] In some embodiments, the cancer is ovarian cancer, colon cancer, or ductal carcinoma of the breast.

[0138] Terminology In the present invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Specifically, reference can be made to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0139] In the present invention, in the structural fragment

[0140] [ka]

[0141] indicates that the structural fragment is connected to the remainder of the molecule via that bond. For example,

[0142] [ka]

[0143] refers to a cyclohexyl group.

[0144] In the present invention, the term "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

[0145] In the present invention, the term "saturated" refers to a group that is fully saturated with hydrogen.

[0146] As used herein, the term "partially saturated" refers to a group that is partially saturated with hydrogen.

[0147] In the present invention, the term "unsaturated" refers to an aromatic group.

[0148] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0149] As used herein, the term "alkyl group" refers to a straight- or branched-chain saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.

[0150] In the present invention, the term "alkoxy group" refers to the group R Y -O-, R Y has the same definition as the term “alkyl group.” Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0151] In the present invention, the term "cycloalkyl group" refers to a monocyclic cycloalkyl group, a bridged cycloalkyl group or a spirocycloalkyl group.

[0152] As used herein, the term "monocyclic cycloalkyl group" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3 to C6) in a monocyclic ring.

[0153] [ka]

[0154] Including, but not limited to, the following:

[0155] As used herein, the term "carbocycle" refers to a cyclic hydrocarbon group having a specified number of carbon atoms (e.g., C5-C6) that shares two atoms and one bond with the rest of the molecule, such as

[0156] [ka]

[0157] .

[0158] As used herein, the term "heterocyclo" refers to a cyclic group having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which shares two atoms and one bond with the rest of the molecule, e.g.,

[0159] [ka]

[0160] .

[0161] In the present invention, the term "bridged cycloalkyl group" refers to a group having a specified number of carbon atoms (e.g., C4 to C6) that is a polycyclic ring (e.g., two or three rings) and shares two or more carbon atoms between the monocyclic rings. 10 A bridged cycloalkyl group refers to a cyclic saturated monovalent hydrocarbon group having

[0162] [ka]

[0163] Including, but not limited to, the following:

[0164] As used herein, the term "spirocycloalkyl group" refers to a cyclic saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C5 to C9) that is polycyclic (e.g., 2 or 3) and shares one carbon atom between the monocyclic rings. A spirocycloalkyl group is:

[0165] [ka]

[0166] Including, but not limited to, the following:

[0167] As used herein, the term "heterocycloalkenyl group" refers to one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 It refers to a cyclic, partially unsaturated hydrocarbon group that has a double bond, is a monocyclic ring, is not aromatic, and has a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). A heterocycloalkenyl group is linked to the remainder of the molecule through a carbon atom or heteroatom. A heterocycloalkenyl group is:

[0168] [ka]

[0169] Including, but not limited to, the following:

[0170] As used herein, the term "cycloalkenyl group" refers to one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 A cycloalkenyl group refers to a cyclic, partially unsaturated hydrocarbon group having a specified number of carbon atoms (e.g., 5-6 members), which has a double bond, is monocyclic, is not aromatic, and is linked to the rest of the molecule through a carbon atom.

[0171] In the present invention, the term "heterocycloalkyl group" refers to a monocyclic heterocycloalkyl group, a bridged heterocycloalkyl group, or a spiroheterocycloalkyl group.

[0172] As used herein, the term "monocyclic heterocycloalkyl group" refers to a cyclic, saturated monovalent group that is a monocyclic ring and has a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). A monocyclic heterocycloalkyl group is connected to the remainder of the molecule through a carbon atom or heteroatom. A monocyclic heterocycloalkyl group is:

[0173] [ka]

[0174] Including, but not limited to, the following:

[0175] As used herein, the term "bridged heterocycloalkyl group" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 4-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is a polycyclic ring (e.g., 2 or 3), sharing two or more carbon atoms and / or heteroatoms between monocyclic rings. A bridged heterocycloalkyl group is connected to the remainder of the molecule through a ring with a heteroatom or a ring without a heteroatom, while a bridged heterocycloalkyl group is connected to the remainder of the molecule through a carbon atom or a heteroatom. A bridged heterocycloalkyl group is

[0176] [ka]

[0177] Including, but not limited to, the following:

[0178] As used herein, the term "spiroheterocycloalkyl group" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 7-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is a polycyclic ring (e.g., 2 or 3 rings) sharing one carbon atom between the monocyclic rings. A spiroheterocycloalkyl group is connected to the remainder of the molecule through a ring with or without a heteroatom, and a spiroheterocycloalkyl group is connected to the remainder of the molecule through a carbon atom or a heteroatom. A spiroheterocycloalkyl group is

[0179] [ka]

[0180] Including, but not limited to, the following:

[0181] In the present invention, the term "heteroaryl group" refers to a cyclic unsaturated group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic, and in the case of a polycyclic ring, shares two atoms and one bond between the monocyclic rings, and at least one ring is aromatic. Heteroaryl groups are linked to the rest of the molecule through a carbon atom or heteroatom, while heteroaryl groups are linked to the rest of the molecule through a ring with or without a heteroatom, and heteroaryl groups are linked to the rest of the molecule through a ring with or without aromaticity. Heteroaryl groups are

[0182] [ka]

[0183] Including, but not limited to, the following:

[0184] In the present invention, the term "aryl group" refers to a monocyclic or polycyclic (e.g., 2 or 3) ring, which, if polycyclic, shares two atoms and one bond between the monocyclic rings, and in which at least one ring has aromaticity, and has a specified number of carbon atoms (e.g., C6 to C8). 10 Aryl refers to a cyclic unsaturated hydrocarbon group having an aromatic ring. An aryl group is linked to the rest of the molecule through an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0185] In the present invention, the term "medicinal auxiliary materials" refers to all substances contained in drug formulations other than active drug ingredients, and is generally divided into two categories: excipients and additives. Specifically, reference can be made to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0186] In the present invention, the term "solvate" refers to a substance formed by combining a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates. Solvates include, but are not limited to, monohydrates.

[0187] In the present invention, the term "stereoisomer" refers to cis-trans isomers or optical isomers. Cis-trans isomers are isomers caused by the inability to freely rotate double bonds or single bonds of ring carbon atoms, while optical isomers are stereoisomers with different optical properties caused by the lack of antiaxial symmetry in the molecule.

[0188] In the present invention, the term "isotopically labeled derivative" refers to a compound in which the isotopic abundance of one or more atoms differs from its natural abundance. For example, one or more atoms in the compound are replaced with atoms that naturally occupy a relatively low mass number - one hydrogen atom in the compound is replaced with deuterium. Also, for example, a compound having the structure of the present invention may be substituted with "deuterium" or "tritium" in addition to replacing hydrogen with "deuterium" or "tritium" or, alternatively, 18 F-fluorine labeling ( 18 F isotope) to replace fluorine, or 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon label, 11 C-, 13 C-, or 14 Compounds replacing carbon atoms with C-isotopes are included within the scope of this invention.

[0189] In the present invention, the term "prodrug" refers to any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound represented by Formula I). For example, a carboxyl group-containing compound can form a physiologically hydrolyzable ester, which, upon hydrolysis in vivo, yields the compound represented by Formula I itself, acting as a prodrug. Such prodrugs are preferably administered orally, since hydrolysis often occurs primarily under the influence of digestive enzymes. If the ester itself is active or hydrolysis occurs in the blood, it can be administered parenterally. Alternatively, the prodrug can be converted to the compound of the present invention by chemical or biochemical methods in an in vivo environment.

[0190] In the present invention, the term "tautomer" refers to a functional isomer resulting from the rapid migration of an atom in a molecule between two positions.

[0191] As used herein, the term "metabolite" refers to a substance produced or consumed in a metabolic process.

[0192] By arbitrarily combining the above-mentioned preferred conditions without departing from the common knowledge in the art, each of the relatively preferred embodiments of the present invention can be obtained.

[0193] All of the reagents and raw materials used in the present invention are commercially available.

[0194] The positive effect of the present invention is that the nitrogen-containing compounds of the present invention can effectively inhibit the overexpression of KIF18A protein in some human tumor cells.

[0195] [Mode for Carrying Out the Invention] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the examples described. In the following examples, experimental methods for which specific conditions are not specified are selected according to conventional methods and conditions or product instructions.

[0196] Example 1 Preparation of Compound 1

[0197] [ka]

[0198] The synthetic route of compound 1 is as follows.

[0199] [ka]

[0200] Specific methods for preparing Compound 1 include the following:

[0201] Step 1: Synthesis of Compound 1B Compound 1A (2.0 g, 9.7 mmol) was dissolved in tert-butanol (20 mL), followed by the addition of triethylamine (1.95 g, 19.4 mmol) and diphenylphosphate azide (4.0 g, 14.55 mmol), in that order. After each addition, the mixture was purged with nitrogen gas three times, then heated to 80 °C under nitrogen gas protection and reacted for 16 hours. TLC showed the reaction was complete, and the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, and spun to dryness. The residue was purified by silica gel column chromatography to give compound 1B (500 mg, white solid, 18.5% yield). MS (ESI): m / z 278.9 [M+1] + .

[0202] Step 2: Synthesis of compound 1C Compound 1B (200 mg, 0.72 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.5 mL), and 2-(4,4-difluorocyclohexan-1-en-1-yl)boronic acid pinacol ester (264 mg, 1.1 mmol), cesium carbonate (469 mg, 1.44 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (20 mg, 0.033 mmol) were added thereto at room temperature in that order. After the addition, the reaction mixture was purged with nitrogen gas three times, and then heated to 90°C under nitrogen gas protection and reacted for 16 hours. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried, and rotovapped. The residue was purified by silica gel column chromatography to give compound 1C (200 mg, off-white solid, 55.5% yield). MS (ESI): m / z 317.1 [M+1] + .

[0203] Step 3: Synthesis of compound 1D Compound 1C (200 mg, 0.63 mmol) was dissolved in methanol (5 mL) and 10% wet palladium on carbon (50 mg) was added. After the addition, the reaction mixture was purged with hydrogen gas three times and then reacted at 15 psi and 50°C for 4 hours. TLC showed the reaction was complete, and the mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (5 mL), and the filtrate was rotary evaporated to give compound 1D (200 mg, pale yellow solid, 99.4% yield). MS (ESI): m / z 263.1 [M-55] + .

[0204] Step 4: Synthesis of Compound 1E Compound 1D (190 mg, 0.63 mmol) was dissolved in 8% hydrochloric acid ethanol solution (2 mL), and the reaction mixture was purged with nitrogen gas three times and then reacted at 40° C. for 2 hours. TLC showed that the reaction was complete, and the mixture was concentrated to remove the solvent, yielding compound 1E (100 mg, yellow solid, 76.7% yield).

[0205] Step 5: Synthesis of compound 1F Compound 1E1 (141 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and then oxalyl chloride (233 mg, 1.82 mmol) and N,N-dimethylformamide (0.5 drops) were added dropwise, followed by reaction at room temperature for 30 minutes. TLC showed the reaction was complete. The mixture was concentrated, and the resulting residue was added with toluene (2 mL), 4-dimethylaminopyridine (223 mg, 1.82 mmol), and compound 1E (100 mg, 0.46 mmol). After addition, the reaction mixture was purged with nitrogen gas three times and then reacted at 100 °C for 1 hour. TLC showed the reaction was complete. The mixture was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried and rotary evaporated. The residue was purified by thin layer chromatography to give compound 1F (40 mg, yellow oil, 17.1% yield). MS (ESI): m / z 510.1 [M+1] + .

[0206] Step 6: Synthesis of Compound 1 Compound 1F (40 mg, 0.08 mmol) and 2-hydroxyethane-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Cuprous iodide (30 mg, 0.16 mmol), potassium phosphate (50 mg, 0.24 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.08 mmol) were added sequentially. After the addition, the reaction mixture was heated to 120 °C and reacted for 4 h. After TLC showed the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried, and rotary evaporated. The residue was purified by TLC plate chromatography to give the crude compound, which was then purified by HPLC to give compound 1 (15 mg, pale yellow solid, 18.5% yield). MS (ESI): m / z 555.2 [M+1] + . 1 H NMR (300 MHz, dmso) δ 13.49 (s, 1H), 10.15 (br.s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.26 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.6, 2.0 Hz, 1H), 4.93 (br.s, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.33 (t, J = 6.6 Hz, 2H), 3.22 (ddd, J = 8.9, 4.2, 1.7 Hz, 1H), 2.95 (t, J = 5.0 Hz, 4H), 2.19 - 1.78 (m, 8H), 1.67 (s, 4H), 0.37 (s, 4H).

[0207] Example 2 Preparation of Compound 2

[0208] [ka]

[0209] The synthetic route of compound 2 is as follows.

[0210] [ka]

[0211] Specific methods for preparing compound 2 include the following:

[0212] Step 1: Synthesis of compound 2B Compound 2A (500 mg, 2.78 mmol) was dissolved in N-methylpyrrolidone (5 mL) and 4,4-difluoroperidine hydrochloride (530 mg, 3.34 mmol) and N,N-diisopropylethylamine (720 mg, 5.56 mmol) were added. After the addition, the reaction mixture was purged with nitrogen gas three times and then reacted at 120 °C for 16 hours. TLC showed the reaction was complete, and the mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, and rotary evaporated. The residue was purified by silica gel column chromatography to give compound 2B (700 mg, yellow oil, 95.2% yield). MS (ESI): m / z 265.1 [M+1] + .

[0213] Step 2: Synthesis of compound 2C Compound 1E1 (117 mg, 0.38 mmol) was dissolved in dichloromethane (2 mL), and then oxalyl chloride (192 mg, 1.52 mmol) and N,N-dimethylformamide (1 drop) were added dropwise, followed by reaction at room temperature for 30 minutes. The solvent was then removed, and toluene (2 mL), 4-dimethylaminopyridine (184 mg, 1.52 mmol), and compound 2B (100 mg, 0.38 mmol) were added. The reaction mixture was purged with nitrogen gas three times and then reacted at 100 °C for 1 hour. TLC showed the reaction was complete. The mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and rotary evaporated. The residue was purified by TLC plate chromatography to give compound 2C (50 mg, yellow solid, 23.8% yield). MS (ESI): m / z 556.1 [M+1] + .

[0214] Step 3: Synthesis of Compound 2 Compound 2C (50 mg, 0.09 mmol) and 2-hydroxyethane-1-sulfonamide (23 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Cuprous iodide (34 mg, 0.18 mmol), potassium phosphate (58 mg, 0.27 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (13 mg, 0.09 mmol) were added sequentially. After the addition, the reaction mixture was heated to 120 °C and reacted for 4 h. After TLC showed the reaction was complete, the mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (30 mL x 3), dried, and rotary evaporated. The residue was purified by TLC plate chromatography to give the crude compound, which was then purified by HPLC to give compound 2 (10 mg, pale yellow solid, 18.5% yield). MS (ESI): m / z 601.2 [M+1] + . 1 H NMR (300 MHz, dmso) δ 12.04 (s, 1H), 10.10 (br.s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.79 - 7.64 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.11 - 6.96 (m, 2H), 4.97 (br.s, 1H), 3.76 (t, J = 6.4 Hz, 6H), 3.34 (d, J = 6.5 Hz, 2H), 2.85 (s, 4H), 2.04 - 1.79 (m, 4H), 1.28 (s, 4H), 0.21 (s, 4H).

[0215] Example 3 Preparation of Compound 3

[0216] [ka]

[0217] The synthetic route of compound 3 is as follows.

[0218] [ka]

[0219] Specific methods for preparing compound 3 include the following:

[0220] Step 1: Synthesis of Compound 3B Compound 3A (500 mg, 1.17 mmol, synthesized with reference to the preparation method described in WO2020132648A1) was dissolved in N,N-dimethylformamide (5 mL), and then compound 3A1 (344 mg, 2.34 mmol) and potassium carbonate (323 mg, 2.34 mmol) were added. After the addition, the mixture was reacted at 120 °C for 16 hours. TLC showed the reaction was complete, and the mixture was diluted with water (30 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried, and rotary evaporated. The residue was purified by thin layer chromatography to give compound 3B (350 mg, white solid, 57.6% yield). MS (ESI): m / z 260.5 [M / 2+1] + .

[0221] Step 2: Synthesis of Compound 3 3B (143.0 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and then potassium phosphate (116.9 mg, 0.6 mmol), 2-hydroxyethane-1-sulfonamide (69.0 mg, 0.6 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (19.6 mg, 0.1 mmol), and cuprous iodide (52.5 mg, 0.3 mmol) were added in this order, followed by reaction at 120°C for 3 hours under nitrogen gas. TLC showed the reaction was complete. The reaction mixture was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with saturated brine (4.0 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by thin layer chromatography to give compound 3 (21.3 mg, white solid, 13.7% yield). MS (ESI): m / z 565.2 [M+1] + 1 H NMR (300 MHz, dmso) δ 11.02 (s, 1H), 10.08 (br.s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.19 (s, 1H), 7.00 (dd, J = 8.5, 1.9 Hz, 1H), 4.91 (br.s, 1H), 3.92 - 3.78 (m, 4H), 3.73 (t, J = 6.5 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 2.93 (dd, J = 10.6, 3.1 Hz, 2H), 2.80 (d, J = 10.4 Hz, 2H), 2.29 (s, 3H), 2.24 (s, 2H), 2.03 - 1.81 (m, 6H), 1.69 - 1.42 (m, 4H).

[0222] Example 4 Preparation of Compound 4

[0223] [ka]

[0224] The synthetic route of compound 4 is as follows.

[0225] [ka]

[0226] Specific methods for preparing compound 4 include the following:

[0227] Step 1: Synthesis of compound 4B Compound 3A (500 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then compound 4A1 (344 mg, 2.34 mmol) and potassium carbonate (323 mg, 2.34 mmol) were added. After the addition, the mixture was reacted at 120 °C for 16 hours. TLC showed the reaction was complete, and the mixture was diluted with water (30 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried, and rotary evaporated. The residue was purified by thin layer chromatography to give compound 4B (75 mg, white solid, 12.7% yield). MS (ESI): m / z 253.5 [M / 2+1] + .

[0228] Step 2: Synthesis of Compound 4 4B (75.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and then potassium phosphate (58.4 mg, 0.3 mmol), 2-hydroxyethane-1-sulfonamide (34.5 mg, 0.3 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10.0 mg, 0.05 mmol), and cuprous iodide (27.0 mg, 0.15 mmol) were added in that order, and the mixture was allowed to react at 120°C for 3 hours in a nitrogen gas atmosphere. TLC showed the reaction was complete, and the reaction mixture was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by thin-layer chromatography. The product was further purified by HPLC to give compound 4 (28.0 mg, white solid, 30% yield). MS (ESI): m / z 551.2 [M+1] + 1 H NMR (300 MHz, dmso) δ 11.58 (s, 1H), 10.03 (br.s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.97 (br.s, 1H), 3.82 (s, 4H), 3.74 (t, J = 6.6 Hz, 2H), 3.39 (s, 4H), 3.31 (t, J = 6.6 Hz, 2H), 2.46-2.42 (m, 2H), 2.28 (s, 3H), 2.18 - 2.04 (m, 2H), 1.94 (ddd, J = 20.2, 13.6, 6.3 Hz, 4H), 1.71 (d, J = 5.6 Hz, 2H).

[0229] Example 5 Preparation of Compound 5

[0230] [ka]

[0231] The synthetic route to compound 5 is as follows.

[0232] [ka]

[0233] Specific methods for preparing compound 5 include the following:

[0234] Step 1: Synthesis of Compound 5B Compound 3A (500 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then compound 5A1 (302 mg, 2.34 mmol) and potassium carbonate (323 mg, 2.34 mmol) were added. The mixture was reacted at 120 °C for 16 hours. TLC showed the reaction was complete, and the mixture was diluted with water (30 mL). The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried, and rotary evaporated. The residue was purified by thin layer chromatography to give compound 5B (130 mg, white solid, 22.6% yield). MS (ESI): m / z 246.5 [M / 2+1] + .

[0235] Step 2: Synthesis of Compound 5 Compound 5B (100 mg, 0.203 mmol) and 2-hydroxyethane-1-sulfonamide (38.12 mg, 0.305 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (38.8 mg, 0.203 mmol), potassium phosphate (86.5 mg, 0.406 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (14.45 mg, 0.101 mmol) were added sequentially. After the addition, the mixture was reacted at 120 °C for 4 h under a nitrogen atmosphere. After TLC showed the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried, and rotary evaporated. The residue was purified by thin-layer chromatography to give compound 5 (5 mg, pale yellow solid, 4.59% yield). MS (ESI): m / z 537.2 [M+1]+ . 1 H NMR (300 MHz, dmso) δ 10.91 (s, 1H), 10.03 (br.s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 6.92 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.91 (br.s, 1H), 4.11 (d, J = 6.7 Hz, 1H), 3.91 - 3.77 (m, 4H), 3.73 (t, J = 6.5 Hz, 2H), 3.28-3.26 (m, 1H), 3.09 (s, 2H), 2.90 - 2.80 (m, 1H), 2.29 (s, 3H), 2.08 - 1.82 (m, 7H), 1.48 (d, J = 4.2 Hz, 2H).

[0236] Example 6 Preparation of Compound 6

[0237] [ka]

[0238] The synthetic route to compound 6 is as follows.

[0239] [ka]

[0240] Specific methods for preparing compound 6 include the following:

[0241] Step 1: Synthesis of compound 6B 6A (500.0 mg, 2.3 mmol) was dissolved in N,N-dimethylpyrrolidone (5.0 mL), followed by the addition of N,N-diisopropylethylamine (1.4 g, 9.0 mmol) and 4,4-difluoroperidine hydrochloride (722.2 mg, 4.6 mmol), and the reaction mixture was incubated in a sealed flask at 150 °C for 5 hours. After cooling, the reaction mixture was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (40.0 mL x 2). The combined organic phase was washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, and then rotary evaporated. The resulting residue was purified by silica gel column chromatography and rotary evaporated under reduced pressure to give 6B (452 mg, yellow solid, 76.3% yield). MS (ESI): m / z 264.1 [M+1] + .

[0242] Step 2: Synthesis of compound 6D Compound 6C (5.0 g, 22.8 mmol) was dissolved in methanol (50 mL). Thionyl chloride (3.5 g, 29.6 mmol) was added dropwise to the reaction mixture at 0°C. After the addition, the reaction mixture was stirred at 60°C for 5 hours. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to give compound 6D (5.0 g, white solid, 94.0% yield). MS (ESI): m / z 232.0 [M+1] + .

[0243] Step 3: Synthesis of compound 6E Compound 6D (1.0 g, 4.29 mmol) was weighed and poured into a sealed can. N-methylpyrrolidone (10 mL), 6-aza-spiro[2.5]octane hydrochloride (760 mg, 5.15 mmol), and N,N-diisopropylethylamine (1.7 g, 12.9 mmol) were then added. After the addition, the reaction mixture was heated to 120 °C and reacted for 16 hours. TLC showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (80 mL x 3), dried, and rotary evaporated. The residue was purified by silica gel column chromatography to give compound 6E (1.2 g, pale yellow oil, 86.3% yield). MS (ESI): m / z 324.1 [M+1] + , 326.1 [M+3] + .

[0244] Step 4: Synthesis of Compound 1E1 Compound 6E (1.2 g, 3.70 mmol) was dissolved in methanol (10 mL), water (10 mL), and tetrahydrofuran (5 mL). Lithium hydroxide monohydrate (156 mg, 3.70 mmol) was added in an ice bath. After the addition, the reaction mixture was allowed to react at room temperature for 16 hours. TLC showed the reaction was complete. The methanol and tetrahydrofuran were removed, and 1N hydrochloric acid was added to adjust the pH to 5-6. The mixture was then extracted with dichloromethane / methanol (10:1, 100 mL x 3), dried, and spun to dryness. The residue was purified by silica gel column chromatography to give compound 1E1 (1.0 g, white solid, 87.1% yield). MS (ESI): m / z 310.0 [M+1] + .

[0245] Step 5: Synthesis of compound 6G Compound 1E1 (50.0 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), oxalyl chloride (50.0 mg, 0.4 mmol) was added at room temperature, and then half a drop of N,N-dimethylformamide was added and the mixture was reacted at 25 °C for 10 minutes. TLC showed the reaction was complete, and the residue obtained by rotary evaporation was dissolved in anhydrous tetrahydrofuran (2.0 mL). Next, a solution of N,N-dimethyl-4-aminopyridine (79.1 mg, 0.6 mmol) and compound 6B (42.5 mg, 0.2 mmol) in toluene (1.0 mL) was added. The reaction mixture was stirred at 100°C for 1 hour. TLC showed the reaction was complete. The reaction mixture was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (20.0 mL x 2). The combined organic phase was washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and rotary evaporated under reduced pressure to give compound 6G (63 mg, yellow solid, 70.3% yield). MS (ESI): m / z 555.2 [M+1] + .

[0246] Step 6: Synthesis of Compound 6 Compound 6G (63.0 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). Anhydrous potassium phosphate (48.3 mg, 0.2 mmol), 2-hydroxyethane-1-sulfonamide (21.3 mg, 0.2 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8.1 mg, 0.06 mmol), and cuprous iodide (21.7 mg, 0.1 mmol) were added sequentially and the mixture was incubated at 120 °C under a nitrogen atmosphere for 3 h. After TLC showed the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried, and rotary evaporated. The residue was purified by TLC plate chromatography to give the crude compound, which was then purified by HPLC to give compound 6 (19.4 mg, white solid, 28.5% yield). MS (ESI): m / z 600.2 [M+1] + 1H NMR (300 MHz, dmso) δ 13.13 (s, 1H), 10.22 (br.s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 8.6, 1.9 Hz, 1H), 4.94 (br.s, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.57 - 3.44 (m, 4H), 3.36 (d, J = 6.4 Hz, 2H), 3.00 (d, J = 3.6 Hz, 4H), 2.27 (ddd, J = 19.7, 14.4, 5.5 Hz, 4H), 2.14 - 1.34 (m, 4H), 0.39 (s, 4H).

[0247] Example 7 Preparation of Compound 7

[0248] [ka]

[0249] The synthetic route to compound 7 is as follows.

[0250] [ka]

[0251] Specific methods for preparing compound 7 include:

[0252] Step 1: Synthesis of compound 7B Compound 7A (500 mg, 2.29 mmol) was dissolved in acetonitrile (10 mL) and N,N-diisopropylethylamine (739.7 mg, 5.73 mmol) and compound 4,4-difluoroperidine hydrochloride (400 mg, 2.52 mmol) were added sequentially at room temperature. After the addition, the reaction mixture was allowed to react at room temperature for 16 hours. TLC showed the reaction was complete, and the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate to give compound 7B (757 mg, white solid, 108.9% yield). MS (ESI): m / z 304.1 [M+1] + .

[0253] Step 2: Synthesis of compound 7C Compound 7B (300 mg, 0.99 mmol) was added to a solution of aqueous ammonia (6 mL) and reacted in a sealed vessel at 160 °C for 4 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and rotary evaporated. The residue was purified by silica gel column chromatography to give compound 7C (94 mg, white solid, 33.4% yield). MS (ESI): m / z 285.1 [M+1] + .

[0254] Step 3: Synthesis of compound 7D Compound 1E1 (80.5 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL) and oxalyl chloride (58 mg, 0.65 mmol) and N,N-dimethylformamide (0.5 drops) were added dropwise in an ice bath. The mixture was then incubated at room temperature for 30 minutes. TLC showed the reaction was complete. The mixture was then dried over a rotary evaporator. Toluene (2 mL), 4-dimethylaminopyridine (127.3 mg, 1.04 mmol), and a toluene solution (2 mL) of compound 7C (74 mg, 0.26 mmol) were added in that order. The reaction mixture was then incubated at 100 °C under nitrogen gas protection for 1 hour. TLC showed the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and rotary evaporated. The residue was purified by thin-layer chromatography to give compound 7D (55 mg, yellow solid, 36.7% yield). MS (ESI): m / z 576.1 [M+1] + .

[0255] Step 6: Synthesis of Compound 7 Compound 7D (45 mg, 0.078 mmol) and 2-hydroxyethane-1-sulfonamide (14.7 mg, 0.117 mmol) were dissolved in N,N-dimethylformamide (1 mL), and cuprous iodide (15.0 mg, 0.078 mmol), potassium phosphate (33.2 mg, 0.156 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5.6 mg, 0.039 mmol) were added sequentially. After the addition, the reaction mixture was incubated at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried, rotary evaporated, and then purified by HPLC to give compound 7 (2 mg, yellow solid, 4.1% yield). MS (ESI): m / z 621.2 [M+1] + .

[0256] Example 8 Preparation of Compound 8

[0257] [ka]

[0258] The synthetic route to compound 8 is as follows.

[0259] [ka]

[0260] Specific methods for preparing compound 8 include the following:

[0261] Step 1: Synthesis of compound 8-B Compound 8-A (2.0 g, 7.27 mmol) was dissolved in N-methylpyrrolidone (50 mL), N,N-diisopropylethylamine (2.8 g, 21.9 mmol), and 4,4-difluoroperidine hydrochloride (1.5 g, 9.4 mmol) were added, and the mixture was stirred at 100 °C for 3 h. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 8-B (2.0 g, yellow solid, 87.1% yield). MS (ESI): m / z 317.0 [M+1] + .

[0262] Step 2: Synthesis of compound 8-C Compound 8-B (860.0 mg, 2.72 mmol) was dissolved in dioxane (10.0 mL), and tert-butyl carbamate (640.0 mg, 5.44 mmol), cesium carbonate (1.78 g, 5.44 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (235.0 mg, 0.41 mmol), and palladium acetate (50.0 mg, 0.21 mmol) were added. The mixture was then reacted at 100 °C for 4 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50.0 mL), and extracted with ethyl acetate (30.0 mL × 2). The combined organic phase was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography and rotary dried under reduced pressure to give compound 8-C (800 mg, brown solid, 83.3% yield). MS (ESI): m / z 354.2 [M+1] + .

[0263] Step 3: Synthesis of compound 8-D Compound 8-C (400.0 mg, 1.13 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), and 2,6-dimethylpyridine (364 mg, 3.4 mmol) and trimethylsilyl trifluoromethanesulfonate (755 mg, 3.4 mmol) were added sequentially at room temperature. The mixture was then stirred at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with ice water (40 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to give crude compound 8-D (300 mg). MS (ESI): m / z 254.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ(ppm) 8.20 (s, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 4.35 (t, J = 8.0 Hz, 4H), 2.14 - 2.04 (m, 4H).

[0264] Step 4: Synthesis of compound 8-E Compound 1E1 (330.0 mg, 1.1 mmol) was dissolved in dichloromethane (10 mL) and, in an ice bath, oxalyl chloride (415 mg, 3.3 mmol) and N,N-dimethylformamide (0.5 drops) were added dropwise, followed by stirring at room temperature for 30 minutes. When TLC showed the reaction was complete, the reaction mixture was spun dry and then dissolved in anhydrous tetrahydrofuran (6 mL). A solution of compound 8-D (300 mg, 1.1 mmol) and N,N-diisopropylethylamine (426 mg, 3.3 mmol) in tetrahydrofuran (8 mL) was added at room temperature and stirred at 50 °C for 1 hour under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 8-E (300 mg, light yellow solid, 50.1% yield). MS (ESI): m / z 273.1 [M / 2+1] + .

[0265] Step 5: Synthesis of Compound 8 Compound 8-E (100 mg, 0.18 mmol) and 2-hydroxyethane-1-sulfonic acid (46.3 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cuprous iodide (35.0 mg, 0.18 mmol), potassium phosphate (78 mg, 0.37 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (26 mg, 0.18 mmol) were added sequentially. The mixture was then stirred at 120 °C for 3 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 8 (60 mg, off-white solid). MS (ESI): m / z 590.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.88 (s, 1H), 10.20 (br.s, 1H), 8.82 (s, 1H), 8.10 - 8.02 (m, 2H), 7.54 (d, J = 1.0 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 8.7, 2.1 Hz, 1H), 4.99 (br.s, 1H), 4.51 - 4.35 (m, 4H), 3.74 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.03 - 2.89 (m, 4H), 2.26 - 2.00 (m, 5H), 1.91 - 1.50 (m, 3H), 0.39 (s, 4H).

[0266] Example 9 Preparation of Compound 9

[0267] [ka]

[0268] The synthetic route to compound 9 is as follows.

[0269] [ka]

[0270] The method for producing compound 9 specifically includes the following:

[0271] Step 1: Synthesis of compound 9-B Compound 6C (50 mg, 0.23 mmol) was dissolved in thionyl chloride (1 mL) and stirred at 80 °C for 2 hours. TLC showed the reaction was complete, and the reaction solution was stripped under reduced pressure to give a crude intermediate. Compound 6B (60 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.91 mmol) were dissolved in tetrahydrofuran (1 mL). A solution of the intermediate in tetrahydrofuran (0.5 mL) was then added dropwise to the above reaction solution and stirred at 50 °C for 2 hours. TLC showed the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, stripped under reduced pressure, and the residue was purified by column chromatography to give compound 9-B (110 mg, yellow solid). MS (ESI): m / z 464.1 [M+1] + .

[0272] Step 2: Synthesis of compound 9-C Compound 9-B (110 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 3A1 (70 mg, 0.47 mmol) and potassium carbonate (66 mg, 0.47 mmol) were added. The mixture was then stirred at 120 °C for 12 hours. TLC showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 9-C (80 mg, yellow solid, 60% yield). MS (ESI): m / z 555.2 [M+1] + .

[0273] Step 3: Synthesis of Compound 9 Compound 9-C (80 mg, 0.14 mmol) and 2-hydroxyethane-1-sulfonamide (37 mg, 0.28 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (61 mg, 0.28 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.07 mmol) were added. The reaction mixture was purged with nitrogen gas three times and then stirred at 120 °C for 16 h. TLC showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography to obtain the crude compound, which was then purified by prep-HPLC to obtain compound 9 (23 mg, pale yellow solid). MS (ESI): m / z 600.2 [M+1] + 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.73 (s, 1H), 10.05 (br.s, 1H), 8.32 (s, 1H), 8.11 - 7.99 (m, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.65 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.46 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.5, 2.0 Hz, 1H), 4.95 (br.s, 1H), 3.74 (t, J = 6.6 Hz, 2H), 3.51 - 3.40 (m, 4H), 3.31 - 3.26 (m, 2H), 3.01 (dd, J = 10.7, 3.5 Hz, 2H), 2.80 (d, J = 10.6 Hz, 2H), 2.28 - 2.16 (m, 6H), 2.03 - 1.92 (m, 2H), 1.63 - 1.44 (m, 4H).

[0274] Example 10 Preparation of Compound 10

[0275] [ka]

[0276] Synthetic Route:

[0277] [ka]

[0278] Manufacturing method: Step 1: Synthesis of compound 10 Compound 8-E (70 mg, 0.128 mmol) and methanesulfonamide (16 mg, 0.384 mmol) were dissolved in N,N-dimethylformamide (1 mL), and cuprous iodide (15 mg, 0.077 mmol), potassium phosphate (77 mg, 0.371 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.110 mmol) were added sequentially. The reaction mixture was then purged with nitrogen gas three times and stirred at 100 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by HPLC preparative to give compound 10 (10 mg, off-white solid). MS (ESI): m / z 560.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.88 (s, 1H), 10.24 (br.s, 1H), 8.83 (s, 1H), 8.08 (dd, J = 4.9, 3.8 Hz, 2H), 7.54 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.7, 2.1 Hz, 1H), 4.48 - 4.37 (m, 4H), 3.11 (s, 3H), 3.03 - 2.95 (m, 4H), 2.23 - 1.99 (m, 5H), 1.88 - 1.59 (m, 3H), 0.39 (s, 4H).

[0279] Example 11 Preparation of Compound 11

[0280] [ka]

[0281] Synthetic Route:

[0282] [ka]

[0283] Manufacturing method: Step 1: Synthesis of compound 11-B Compound 8-A (1.0 g, 3.61 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylenediamine (1.4 g, 10.8 mmol), and morpholine (410 mg, 4.69 mmol) were added, and the mixture was stirred at 100 °C for 4 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 11-B (1 g, yellow oil, 97.8% yield). MS (ESI): m / z 283.0 [M+1]+ .

[0284] Step 2: Synthesis of compound 11-C Compound 11-B (1.0 g, 3.53 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (833 mg, 7.06 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (340 mg, 0.71 mmol), cesium carbonate (2.3 g, 7.06 mmol), and palladium acetate (80 mg, 0.35 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 11-C (1.0 g, yellow solid, 88.7% yield). MS (ESI): m / z 320.2 [M+1] + .

[0285] Step 3: Synthesis of compound 11-D Compound 11-C (500 mg, 1.57 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), and 2,6-dimethylpyridine (504 mg, 4.71 mmol) and trimethylsilyl trifluoromethanesulfonate (1.1 g, 4.71 mmol) were added sequentially at room temperature. The mixture was then stirred at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction mixture was diluted with ice water (50 mL), adjusted to pH 7-8 with saturated ammonium bicarbonate solution, and then extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 11-D (300 mg, yellow oil). MS (ESI): m / z 220.1 [M+1] + .

[0286] Step 4: Synthesis of compound 11-E Compound 1E1 (214 mg, 0.68 mmol) was dissolved in dichloromethane (5.0 mL) and oxalyl chloride (263 mg, 2.04 mmol) was added dropwise. The mixture was then stirred at room temperature for 30 minutes. TLC showed the reaction was complete. The reaction mixture was then rotovapped and dissolved in anhydrous tetrahydrofuran (10 mL). Compound 11-D (150 mg, 0.68 mmol) and N,N-diisopropylethylenediamine (268 mg, 2.04 mmol) were added sequentially at room temperature. The mixture was then stirred at 50 °C for 1 hour. TLC showed the reaction was complete. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 11-E (110 mg, yellow solid, 34.3% yield). MS (ESI): m / z 511.1 [M+1] + .

[0287] Step 5: Synthesis of Compound 11 Compound 11-E (100 mg, 0.20 mmol) and 2-hydroxyethane-1-sulfonamide (30 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (84 mg, 0.40 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 3 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (8 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 11 (15 mg, yellow solid). MS (ESI): m / z 556.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.95 (s, 1H), 10.19 (s, 1H), 8.79 (s, 1H), 8.12 - 8.03 (m, 2H), 7.52 (d, J = 1.1 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.6, 2.2 Hz, 1H), 4.92 (s, 1H), 4.29 - 4.23 (m, 4H), 3.79 - 3.76 (m, 4H), 3.34 (t, J = 6.4 Hz, 2H), 3.16 (t, J = 9.3, 4.4 Hz, 2H), 3.00 - 2.94 (m, 4H), 1.83 - 1.61 (m, 3H), 1.44 - 1.39 (m, 1H), 0.38 (s, 4H).

[0288] Example 12 Production of Compound 12

[0289]

change

[0290] Synthetic road:

[0291]

change

[0292] Manufacturing method: ステップ1: Synthesis of Compound 12-B Compound 8-A (500 mg, 1.81 mmol) was dissolved in N-methylpyrrolidone (30 mL), N,N-diisopropylethylenediamine (938 mg, 13.0 mmol), and piperidine hydrochloride (308 mg, 3.62 mmol) were added, and the mixture was stirred at 100 °C for 4 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 12-B (400 mg, yellow oil, 78.8% yield). MS (ESI): m / z 281.0 [M+1] + .

[0293] Step 2: Synthesis of compound 12-C Compound 12-B (400 mg, 1.42 mmol) was dissolved in dioxane (5.0 mL), and tert-butyl carbamate (336 mg, 2.84 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (145 mg, 0.28 mmol), cesium carbonate (932 mg, 2.84 mmol), and palladium acetate (32 mg, 0.14 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50.0 mL × 2). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography and rotary evaporated under reduced pressure to give compound 12-C (200 mg, yellow solid, 44.3% yield). MS (ESI): m / z 318.2 [M+1] + .

[0294] Step 3: Synthesis of compound 12-D Compound 12-C (200.0 mg, 0.63 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), and 2,6-dimethylpyridine (203 mg, 1.89 mmol) and trimethylsilyl trifluoromethanesulfonate (420 mg, 1.89 mmol) were added sequentially at room temperature. The mixture was then stirred at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction mixture was diluted with ice water (20 mL), adjusted to pH 7-8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to give crude compound 12-D (150 mg, yellow oil). MS (ESI): m / z 218.1 [M+1] + .

[0295] Step 4: Synthesis of compound 12-E Compound 1E1 (214 mg, 0.69 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (263 mg, 2.07 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 12-D (150 mg, 0.69 mmol) and N,N-diisopropylethylenediamine (268 mg, 2.07 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 1 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 12-E (110 mg, yellow solid, 31.3% yield). MS (ESI): m / z 509.2 [M+1] + .

[0296] Step 5: Synthesis of Compound 12 Compound 12-E (100 mg, 0.20 mmol) and 2-hydroxyethane-1-sulfonamide (30 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (84 mg, 0.40 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 3 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 12 (28 mg, off-white solid). MS (ESI): m / z 554.3 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.80 (s, 1H), 10.15 (br.s, 1H), 8.72 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 1.1 Hz, 1H), 7.49 (d, J = 1.0 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 8.6, 2.1 Hz, 1H), 4.94 (br.s, 1H), 4.34 - 4.21 (m, 4H), 3.75 (t, J = 6.5 Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.02 - 2.93 (m, 4H), 1.83 - 1.58 (m, 10H), 0.38 (s, 4H).

[0297] Example 13 Preparation of Compound 13

[0298] [ka]

[0299] Synthetic Route:

[0300] [ka]

[0301] Manufacturing method: Step 1: Synthesis of compound 13 Compound 8-E (70 mg, 0.128 mmol) and 1-methylcyclopropane-1-sulfonamide (23 mg, 0.384 mmol) were dissolved in N,N-dimethylformamide (1 mL), and cuprous iodide (15 mg, 0.077 mmol), potassium phosphate (77 mg, 0.371 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.110 mmol) were added sequentially. The reaction mixture was then purged with nitrogen gas three times and stirred at 100 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC preparative to give compound 13 (25 mg, off-white solid, 32.59%). MS (ESI): m / z 600.3 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.92 (s, 1H), 10.25 (br.s, 1H), 8.84 (s, 1H), 8.12 - 8.00 (m, 2H), 7.55 (d, J = 1.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.6, 2.1 Hz, 1H), 4.48 - 4.39 (m, 4H), 3.01 - 2.92 (m, 4H), 2.22 - 2.01 (m, 5H), 1.90 - 1.61 (m, 3H), 1.40 (s, 3H), 1.25 - 1.17 (m, 2H), 0.88 - 0.79 (m, 2H), 0.41 (s, 4H).

[0302] Example 14 Preparation of Compound 14

[0303] [ka]

[0304] Synthetic Route:

[0305] [ka]

[0306] Manufacturing method: Step 1: Synthesis of compound 14B Compound 14A (900 mg, 4.74 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylenediamine (1.2 g, 9.48 mmol), and 4,4-difluoroperidine hydrochloride (900 mg, 5.69 mmol) were added, and the mixture was stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 14B (1.0 g, yellow solid, 76.9% yield). MS (ESI): m / z 275.1 [M+1] + .

[0307] Step 2: Synthesis of compound 14C Compound 14B (1.0 g, 3.64 mmol) was dissolved in dioxane (10.0 mL), and tert-butyl carbamate (854 mg, 7.28 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (348 mg, 0.73 mmol), cesium carbonate (2.37 mg, 7.28 mmol), and palladium acetate (81 mg, 0.36 mmol) were added. The mixture was then reacted at 100 °C for 16 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 14C (1.0 g, yellow solid, 77.3% yield). MS (ESI): m / z 356.2 [M+1] + .

[0308] Step 3: Synthesis of compound 14D Compound 14C (100 mg, 0.28 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (2 mL, 8%) and then stirred at room temperature for 16 hours. TLC showed the reaction was complete, and the reaction solution was evaporated to dryness under reduced pressure to give crude compound 14D (100 mg). MS (ESI): m / z 256.1 [M+1] + .

[0309] Step 4: Synthesis of Compound 14E Compound 1E1 (87 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL) and oxalyl chloride (90 mg, 0.70 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotary evaporated. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 14D (72 mg, 0.28 mmol) and N,N-diisopropylethylenediamine (146 mg, 1.12 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 14E (80 mg, yellow solid, 51.8% yield). MS (ESI): m / z 547.1 [M+1] + .

[0310] Step 5: Synthesis of compound 14 Compound 14E (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 3 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give compound 14 (14 mg, off-white solid). MS (ESI): m / z 592.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.21 (br.s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.6, 2.1 Hz, 1H), 5.08 - 5.05 (m, 2H), 4.98 - 4.89 (m, 3H), 3.75 (t, J = 6.5 Hz, 2H), 3.60 - 3.54 (m, 4H), 3.35 (t, J = 6.5 Hz, 2H), 3.00 - 2.94 (m, 4H), 2.10 - 1.96 (m, 5H), 1.81 - 1.56 (m, 3H), 0.38 (s, 4H).

[0311] Example 15 Preparation of Compound 15

[0312] [ka]

[0313] Synthetic Route:

[0314] [ka]

[0315] Manufacturing method: Step 1: Synthesis of compound 15B Compound 15A (900 mg, 5.31 mmol) was dissolved in dichloromethane (10 mL), metachloroperbenzoic acid (1.8 g, 10.6 mmol) was added, and the mixture was stirred at room temperature for 12 hours. TLC showed the reaction was complete, and the reaction mixture was stripped under reduced pressure. The residue was purified by silica gel column chromatography to give crude compound 15B (1.15 g, yellow solid). MS (ESI): m / z 186.0 [M+1] + .

[0316] Step 2: Synthesis of compound 15C Crude compound 15B (1.15 g) was dissolved in phosphorus oxychloride (7 mL) and then stirred at 115 °C for 12 hours. TLC showed the reaction was complete, and the reaction solution was desolvated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), then adjusted to pH = 8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 15C (350 mg, yellow solid). MS (ESI): m / z 203.9 [M+1] + .

[0317] Step 3: Synthesis of compound 15D Compound 15C (350 mg, 1.72 mmol) was dissolved in N-methylpyrrolidone (5 mL), potassium carbonate (711 mg, 5.15 mmol) and 4,4-difluoroperidine hydrochloride (406 mg, 2.57 mmol) were added, and the mixture was stirred at 120 °C for 12 hours. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 15D (380 mg, yellow liquid, 76.5% yield). MS (ESI): m / z 289.0 [M+1] + .

[0318] Step 4: Synthesis of Compound 15E Compound 15D (350 mg, 1.21 mmol) was dissolved in dioxane (5.0 mL), and tert-butyl carbamate (284 mg, 2.42 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (116 mg, 0.24 mmol), cesium carbonate (792 mg, 2.42 mmol), and palladium acetate (27 mg, 0.12 mmol) were added. The mixture was then stirred at 110 °C for 16 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 15E (400 mg, yellow solid, 89.3% yield). MS (ESI): m / z 370.1 [M+1] + .

[0319] Step 5: Synthesis of compound 15F Compound 15E (100 mg, 0.27 mmol) was dissolved in a solution of hydrochloric acid and ethyl acetate (2.0 mL, 8%) and stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 15F (100 mg, yellow oil). MS (ESI): m / z 270.1 [M+1] + .

[0320] Step 6: Synthesis of Compound 15G Compound 1E1 (84 mg, 0.27 mmol) was dissolved in dichloromethane (2.0 mL) and oxalyl chloride (86 mg, 0.675 mmol) was added dropwise, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction mixture was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 15F (73.0 mg, 0.27 mmol) and N,N-diisopropylethylenediamine (105 mg, 0.81 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 15G (110 mg, yellow solid, 72.3% yield). MS (ESI): m / z 561.1 [M+1] + .

[0321] Step 7: Synthesis of Compound 15 Compound 15G (50.0 mg, 0.09 mmol) and 2-hydroxy-1-sulfonamide (14 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cuprous iodide (2 mg, 0.01 mmol), potassium phosphate (38 mg, 0.18 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (2.5 mg, 0.02 mmol) were added sequentially. The mixture was then stirred at 120 °C for 3 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 15 (38 mg, yellow solid). MS (ESI): m / z 606.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.91 (s, 1H), 10.20 (br.s, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 8.6, 2.1 Hz, 1H), 4.95 (br.s, 1H), 3.83 - 3.74 (m, 6H), 3.35 (t, J = 6.4 Hz, 2H), 3.02 - 2.94 (m, 4H), 2.24 - 2.05 (m, 5H), 1.89 - 1.60 (m, 3H), 0.38 (s, 4H).

[0322] Example 16 Preparation of Compound 16

[0323] [ka]

[0324] Synthetic Route:

[0325] [ka]

[0326] Manufacturing method: Step 1: Synthesis of compound 16B Compound 16A (5.0 g, 25.1 mmol) was dissolved in methanol (25 mL), potassium hydroxide solution (50 mL, 2 mol / L) was added, and the mixture was stirred at 70 °C for 2 h. TLC showed the reaction was complete, and the mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 16B (3.0 g, yellow solid, 70.5% yield). MS (ESI): m / z 170.0 [M+1] + .

[0327] Step 2: Synthesis of compound 16C Compound 16B (3.0 g, 17.7 mmol) was dissolved in phosphorus oxychloride (30 mL) and then stirred at 120 °C for 16 hours. TLC showed the reaction was complete, and the mixture was cooled to room temperature and desolvated under reduced pressure. The residue was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 16C (3.0 g, yellow solid, 90.4% yield). MS (ESI): m / z 188.0 [M+1] + .

[0328] Step 3: Synthesis of compound 16D Compound 16C (3.0 g, 16.0 mmol) was dissolved in N-methylpyrrolidone (30 mL), N,N-diisopropylethylamine (6.2 g, 48.0 mmol), and 4,4-difluoroperidine hydrochloride (3.3 g, 20.8 mmol) were added, and the mixture was stirred at 100 °C for 3 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, poured into ice water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified using a silica gel column to give compound 16D (4.0 g, yellow oil, 91.8% yield). MS (ESI): m / z 273.1 [M+1] + .

[0329] Step 4: Synthesis of compound 16E Compound 16D (200 mg, 0.74 mmol) was dissolved in dioxane (3 mL), and tert-butyl carbamate (130 mg, 1.11 mmol), cesium carbonate (479 mg, 1.48 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (35 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium (34 mg, 0.04 mmol) were added. The mixture was then stirred at 100 °C for 4 h under nitrogen gas protection. When the reaction was complete as determined by TLC, it was cooled to room temperature, poured into ice water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 16E (150 mg, yellow oil, 56.8% yield). MS (ESI): m / z 354.2 [M+1] + .

[0330] Step 5: Synthesis of compound 16F Compound 16E (700 mg, 1.98 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (10 mL, 8%) and stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL). The pH was adjusted to 8 by adding aqueous ammonia, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 16F (400 mg, yellow solid). MS (ESI): m / z 254.1 [M+1] + .

[0331] Step 6: Synthesis of compound 16G Compound 1E1 (487 mg, 1.58 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (500 mg, 3.95 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was stripped under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 16F (400 mg, 1.58 mmol) and N,N-diisopropylethylenediamine (609 mg, 4.74 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and stripped under reduced pressure. The residue was purified using a silica gel column to give compound 16G (70 mg, yellow solid, 8.1% yield). MS (ESI): m / z 545.1 547.1 [M+1] + .

[0332] Step 7: Synthesis of Compound 16 Compound 16G (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 16 (7 mg, yellow solid). MS (ESI): m / z 590.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.30 (s, 1H), 10.24 (br.s, 1H), 8.16 - 7.74 (m, 3H), 7.67 - 7.48 (m, 1H), 7.26 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 5.05 (br.s, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.61 - 3.54 (m, 4H), 3.34 (t, J = 6.5 Hz, 2H), 3.00 - 2.93 (m, 4H), 2.33 - 2.16 (m, 5H), 1.85 - 1.60 (m, 3H), 0.38 (s, 4H).

[0333] Example 17 Production of Compound 17

[0334]

change

[0335] Synthetic road:

[0336]

change

[0337] Manufacturing method: ステップ1:Synthesis of compound 17B 2-Fluoro-4-bromobenzoic acid (173 mg, 0.79 mmol) was dissolved in thionyl chloride (5 mL) and stirred at 80 °C for 2 h. TLC showed the reaction was complete, and the reaction solution was desolvated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (2 mL), and compound 8-D (200 mg, 0.79 mmol) and N,N-diisopropylethylenediamine (408 mg, 3.16 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 2 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1 (volume ratio)) to give compound 17B (110 mg, yellow solid, 30.7% yield). MS (ESI): m / z 454.0 [M+1] + .

[0338] Step 2: Synthesis of compound 17C Compound 17B (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 3-azabicyclo[3.2.1]octane hydrochloride (38 mg, 0.26 mmol) and potassium carbonate (60 mg, 0.44 mmol) were added. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 17C (70 mg, yellow solid, 66.2% yield). MS (ESI): m / z 545.1 [M+1] + .

[0339] Step 3: Synthesis of compound 17 Compound 17C (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 17 (16 mg, yellow solid). MS (ESI): m / z 590.2 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.54 (s, 1H), 10.04 (br.s, 1H), 8.89 (s, 1H), 8.09 (d, J = 1.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.5, 2.0 Hz, 1H), 4.95 (br.s, 1H), 4.44 - 4.36 (m, 4H), 3.75 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 3.06 - 2.95 (m, 2H), 2.80 (d, J = 10.5 Hz, 2H), 2.29 - 2.21 (m, 2H), 2.14 - 1.95 (m, 6H), 1.63 - 1.47 (m, 4H).

[0340] Example 18 Preparation of Compound 18

[0341] [ka]

[0342] Synthetic Route:

[0343] [ka]

[0344] Manufacturing method: Step 1: Synthesis of compound 18B Compound 18A (5 g, 25.9 mmol) was dissolved in isopropyl alcohol (50 mL), and sodium carbonate (6.84 g, 64.8 mmol) and 4,4-difluoroperidine hydrochloride (4.09 g, 25.9 mmol) were added sequentially in an ice bath. The mixture was then stirred at room temperature for 12 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1 (volume ratio)) to give compound 18B (4.4 g, yellow solid, 61.2% yield). MS (ESI): m / z 278.0 [M+1] + .

[0345] Step 2: Synthesis of compound 18C Compound 18B (4.4 g, 15.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Under nitrogen gas protection, vinylmagnesium bromide solution (55.3 mL, 55.3 mmol) was added dropwise to the reaction mixture at -70 °C, and the mixture was allowed to warm to room temperature within 1 hour. TLC showed the reaction was complete, and the reaction mixture was slowly poured into saturated ammonium chloride (100 mL) in an ice bath and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 18C (1.9 g, yellow oil, 44.3% yield). MS (ESI): m / z 272.1 [M+1] + .

[0346] Step 3: Synthesis of compound 18D Compound 18C (1.9 g, 7.0 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and sodium bicarbonate (420 mg, 10.5 mmol) was added in an ice bath. The mixture was stirred for 10 minutes in an ice bath. Iodomethane (1.19 g, 8.4 mmol) was then added dropwise to the reaction mixture in an ice bath, followed by stirring at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction mixture was slowly poured into saturated ammonium chloride (100 mL) in an ice bath and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 18D (1.2 g, yellow oil, 60% yield). MS (ESI): m / z 286.1 [M+1] + .

[0347] Step 4: Synthesis of compound 18E Compound 18D (1.15 g, 4.0 mmol) was dissolved in anhydrous dioxane (50 mL), and tert-butyl carbamate (707 mg, 6.0 mmol), cesium carbonate (2.62 g, 8.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (192 mg, 0.4 mmol), and tris(dibenzylideneacetone)dipalladium (184 mg, 0.2 mmol) were added. The mixture was then stirred at 100 °C for 4 h under nitrogen gas protection. After TLC showed the reaction was complete, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 18E (1.2 g, yellow oil, 81.9% yield). MS (ESI): m / z 367.2 [M+1] + .

[0348] Step 5: Synthesis of compound 18F Compound 18E (500 mg, 1.36 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (10 mL, 8%) and stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL). Aqueous ammonia was added until the pH reached 8, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 18F (400 mg, yellow solid). MS (ESI): m / z 267.1 [M+1] + .

[0349] Step 6: Synthesis of compound 18G Compound 1E1 (468 mg, 1.50 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (477 mg, 3.75 mmol) was added dropwise in an ice bath. The mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was desolvated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 18F (400 mg, 1.50 mmol) and N,N-diisopropylethylenediamine (582 mg, 4.50 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 18G (500 mg, yellow solid, 59.6% yield). MS (ESI): m / z 558.2 [M+1] + .

[0350] Step 7: Synthesis of Compound 18 Compound 18G (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.39 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 18 (7 mg, pale yellow solid). MS (ESI): m / z 603.3 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.87 (s, 1H), 10.14 (br.s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 3.0 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 6.45 (d, J = 3.0 Hz, 1H), 4.94 (br.s, 1H), 4.03 (s, 3H), 3.74 (t, J = 6.5 Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.29 - 3.24 (m, 4H), 3.00 - 2.93 (m, 4H), 2.31 -2.13 (m, 5H), 1.94 - 1.51 (m, 3H), 0.37 (s, 4H).

[0351] Example 19 Preparation of Compound 19

[0352] [ka]

[0353] Synthetic Route:

[0354] [ka]

[0355] Manufacturing method: Step 1: Synthesis of compound 19 Compound 17C (70 mg, 0.13 mmol) and methanesulfonamide (15 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (55 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 19 (16 mg, pale yellow solid). MS (ESI): m / z 280.7 [1 / 2M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.53 (s, 1H), 10.10 (br.s, 1H), 8.89 (s, 1H), 8.09 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 4.44 - 4.34 (m, 4H), 3.07 (s, 3H), 3.05 - 2.95 (m, 2H), 2.86 - 2.77 (m, 2H), 2.28 - 2.21 (m, 2H), 2.17 - 1.95 (m, 6H), 1.66 - 1.44 (m, 4H).

[0356] Example 20 Preparation of Compound 20

[0357] [ka]

[0358] Synthetic Route:

[0359] [ka]

[0360] Manufacturing method: Step 1: Synthesis of compound 20B Methyl 2-fluoro-4-bromobenzoate (1.6 g, 6.87 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (940 mg, 8.24 mmol) and potassium carbonate (2.0 g, 13.7 mmol) were added. The mixture was then stirred at 120 °C under nitrogen gas protection for 16 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (80 mL), and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 20B (2.1 g, yellow oil, 94.3% yield). MS (ESI): m / z 324.0 [M+1] + .

[0361] Step 2: Synthesis of compound 20C Compound 20B (2.0 g, 6.17 mmol) was dissolved in methanol (20 mL), water (20 mL), and tetrahydrofuran (10 mL). Lithium hydroxide monohydrate (260 mg, 6.17 mmol) was added in an ice bath, and the mixture was then reacted at 70°C for 16 hours. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the methanol and tetrahydrofuran. The pH was then adjusted to 5-6 with 1N hydrochloric acid in an ice bath, filtered, and the filter cake was washed with water (50 mL) and dried to give compound 20C (1.5 g, pale yellow solid, 78.4% yield). MS (ESI): m / z 310.0 [M+1]+ .

[0362] Step 3: Synthesis of compound 20D Compound 20C (122 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (125 mg, 0.98 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotary evaporated and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 8-D (100 mg, 0.39 mmol) and N,N-diisopropylethylamine (191 mg, 1.56 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 1 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 20D (120 mg, yellow solid, 55.9% yield).

[0363] Step 3: Synthesis of compound 20 Compound 20D (120 mg, 0.22 mmol) and 2-hydroxy-1-sulfonamide (33 mg, 0.29 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (94 mg, 0.44 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 20 (30 mg, yellow solid). MS (ESI): m / z 295.6 [1 / 2M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.34 (s, 1H), 9.67 (br.s, 1H), 8.69 (s, 1H), 8.05 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.55 - 6.47 (m, 2H), 4.92 (br.s, 1H), 4.38 - 4.29 (m, 4H), 3.71 (t, J = 6.8 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.25 - 3.15 (m, 4H), 2.12 - 1.96 (m, 4H), 1.47 - 1.37 (m, 2H), 0.95 (s, 3H), 0.80 (s, 3H).

[0364] Example 21 Production of Compound 21

[0365]

change

[0366] Synthetic road:

[0367]

change

[0368] Manufacturing method: ステップ1:Synthesis of compound 21B Compound 21A (100 mg, 0.45 mmol) was dissolved in N-methylpyrrolidone (3 mL), N,N-diisopropylethylamine (230 mg, 1.80 mmol), and 4,4-difluoroperidine hydrochloride (114 mg, 0.90 mmol) were added, and the mixture was stirred at 150 °C for 5 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 21B (110 mg, yellow solid, 93.3% yield). MS (ESI): m / z 265.1 [M+1] + .

[0369] Step 2: Synthesis of compound 21C Compound 1E1 (152 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (156 mg, 1.23 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was evaporated to dryness. It was then dissolved in anhydrous tetrahydrofuran (10 mL), and compound 21B (130 mg, 0.49 mmol) and N,N-diisopropylethylamine (191 mg, 1.47 mmol) were added sequentially at room temperature. The reaction solution was then stirred at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 21C (200 mg, yellow solid, 73.1% yield). MS (ESI): m / z 279.4 [1 / 2M+1] + .

[0370] Step 3: Synthesis of compound 21 Compound 21C (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 21 (20 mg, white solid). MS (ESI): m / z 301.3 [1 / 2M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.90 (s, 1H), 10.21 (br.s, 1H), 8.72 (dd, J = 4.2, 1.7 Hz, 1H), 8.24 (dd, J = 8.5, 1.7 Hz, 1H), 8.13 - 8.07 (m, 2H), 7.61 (dd, J = 8.4, 4.1 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.6, 2.1 Hz, 1H), 4.96 (br.s, 1H), 4.23 - 4.16 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 3.04 - 2.97 (m, 4H), 2.28 - 2.06 (m, 5H), 1.93 - 1.58 (m, 3H), 0.41 (s, 4H).

[0371] Example 22 Preparation of Compound 22

[0372] [ka]

[0373] Synthetic Route:

[0374] [ka]

[0375] Manufacturing method: Step 3: Synthesis of compound 22A Compound 18C (550 mg, 2.0 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (352 mg, 3.0 mmol), cesium carbonate (1.32 g, 4.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (99 mg, 0.2 mmol), and tris(dibenzylideneacetone)dipalladium (88 mg, 0.1 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 22A (550 mg, yellow oil, 80% yield). MS (ESI): m / z 353.1 [M+1] + .

[0376] Step 4: Synthesis of Compound 22B Compound 22A (322 mg, 0.9 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 16 hours. TLC showed the reaction was complete, so the reaction solution was stripped under reduced pressure. The residue was dissolved in methanol (2 mL) and water (2 mL), and solid sodium hydroxide (182 mg, 4.5 mmol) was added slowly in an ice bath, followed by stirring at 25°C for 16 hours. TLC showed the reaction was complete, so the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, stripped under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 22B (130 mg, brown oil, 55.6% yield). MS (ESI): m / z 253.1 [M+1] + .

[0377] Step 5: Synthesis of compound 22C Compound 1E1 (120 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (130 mg, 1.0 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (10 mL). Compound 22B (100 mg, 0.4 mmol) and N,N'-diisopropylethylamine (200 mg, 1.6 mmol) were added at room temperature, followed by stirring at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 22C (20 mg, yellow solid, 10% yield). MS (ESI): m / z 544.1 [M+1] + .

[0378] Step 6: Synthesis of Compound 22 Compound 22C (20 mg, 0.04 mmol) and 2-hydroxy-1-sulfonamide (6 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (23 mg, 0.12 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 22 (0.62 mg, pale yellow solid). MS (ESI): m / z 589.2 [M+1] + .

[0379] Example 23 Preparation of Compound 23

[0380] [ka]

[0381] Synthetic Route:

[0382] [ka]

[0383] Manufacturing method: Step 1: Synthesis of compound 23B Compound 23A (500 mg, 1.59 mmol) was added to trifluoroacetic acid (1.5 mL) in an ice bath and stirred for 1.5 hours. When TLC showed the reaction was complete, an ice-water mixture (20 mL) was added to the reaction mixture, which was then stirred at room temperature for 5 minutes. The suspension was filtered, and the filter cake was washed with water until the pH of the filtrate reached 6. The filter cake was collected, dissolved in dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and stripped under reduced pressure to give compound 23B (290 mg, white solid, 84.8% yield).

[0384] Step 2: Synthesis of compound 23D Compound 23B (290 mg, 1.35 mmol) was dissolved in dichloromethane (10 mL), and compound 23C (341 mg, 1.35 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (1 mL x 3). The filter cake was dried to obtain crude compound 23D (500 mg, white solid). MS (ESI): m / z 268.9 [M] + .

[0385] Step 3: Synthesis of compound 23E Crude compound 23D (500 mg) was dissolved in triethyl orthoformate (5 mL) and then stirred at 100° C. for 1 hour. LCMS showed the reaction was complete, and the reaction mixture was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 23E (300 mg, yellow solid). MS (ESI): m / z 278.8 [M+1] + .

[0386] Step 4: Synthesis of compound 23F Compound 23E (300 mg, 1.08 mmol) was dissolved in N-methylpyrrolidone (5 mL), N,N-diisopropylethylamine (230 mg, 4.32 mmol), and 4,4-difluoroperidine hydrochloride (170 mg, 2.16 mmol) were added, and the mixture was stirred at 100 °C under nitrogen gas protection for 16 h. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 23F (220 mg, tan solid, 64.1% yield). MS (ESI): m / z 318.0 [M+1] + .

[0387] Step 5: Synthesis of compound 23G Compound 23F (200 mg, 0.63 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (148 mg, 1.26 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (30 mg, 0.06 mmol), cesium carbonate (411 mg, 1.26 mmol), and tris(dibenzylideneacetone)dipalladium (29 mg, 0.03 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and rotary dried under reduced pressure to give compound 23G (190 mg, yellow solid, 75.3% yield). MS (ESI): m / z 355.2 [M+1] + .

[0388] Step 6: Synthesis of compound 23H Compound 23G (200 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the reaction mixture was concentrated under reduced pressure to give crude compound 23H (200 mg, yellow oil). MS (ESI): m / z 255.1 [M+1] + .

[0389] Step 7: Synthesis of compound 23I Compound 1E1 (182 mg, 0.59 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (188 mg, 1.48 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (10 mL). Compound 23H (150 mg, 0.59 mmol) and N,N'-diisopropylethylamine (305 mg, 2.36 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 23I (100 mg, yellow solid, 31.0% yield). MS (ESI): m / z 273.6 274.4 [1 / 2M+1] + .

[0390] Step 8: Synthesis of Compound 23 Compound 23I (90 mg, 0.16 mmol) and 2-hydroxy-1-sulfonamide (21 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (70 mg, 0.32 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 23 (30 mg, white solid). MS (ESI): m / z 591.4 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.30 (s, 1H), 10.17 (br.s, 1H), 8.97 (s, 1H), 8.50 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.7, 2.1 Hz, 1H), 4.92 (br.s, 1H), 4.42 - 4.36 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.2 Hz, 2H), 3.02 - 2.96 (m, 4H), 2.23 - 2.09 (m, 5H), 1.81 - 1.68 (m, 3H), 0.42 (s, 4H).

[0391] Example 24 Preparation of Compound 24

[0392] [ka]

[0393] Step 1: Synthesis of compound 24B Compound 24A (50 g, 335.6 mmol) was dissolved in ethanol, and hydrazine hydrate (39.5 g, 671.3 mmol, 85% purity) was added, followed by stirring at 90° C. for 12 hours. LCMS showed the reaction was complete, and the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ice-cold ethanol. The filter cake was dried to give crude compound 24B (54 g, yellow solid). MS (ESI): m / z 145.0 [M+1] + .

[0394] Step 2: Synthesis of compound 24C Crude compound 24B (54 g, 373.5 mmol) was dissolved in tetrahydrofuran, and trifluoroacetic anhydride (86.3 g, 410.9 mmol) was added dropwise in an ice bath. The mixture was then stirred in an ice bath for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was stripped under reduced pressure, diluted with water (200 mL), and extracted with dichloromethane (200 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and stripped under reduced pressure to give crude compound 24C (40 g, orange liquid). MS (ESI): m / z 241.0 [M+1] + .

[0395] Step 3: Synthesis of compound 24D Crude compound 24C (40 g, 166.3 mmol) was dissolved in dichloromethane (400 mL), and NBS (86.3 g, 182.9 mmol) was added in portions at -40 °C. The mixture was then allowed to warm to 0 °C within 1 hour. LCMS showed the reaction was complete, and the reaction was quenched with water (200 mL) in an ice bath and extracted with dichloromethane (200 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 24D (15 g, yellow liquid). MS (ESI): m / z 318.8 320.8 [M+1] + .

[0396] Step 4: Synthesis of compound 24E Compound 24D (15 g, 47.0 mmol) was dissolved in ethanol (160 mL), hydrochloric acid (12 mL, 12 mol / L) was added, and the mixture was stirred at 100 °C for 8 hours. LCMS showed the reaction was complete, and the ethanol was removed from the reaction mixture under reduced pressure. The reaction was then quenched with solid sodium bicarbonate until pH = 7, followed by extraction with dichloromethane / methanol (80 mL x 3, 10:1). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 24E (7 g, gray solid). MS (ESI): m / z 222.9 224.9 [M+1] +.

[0397] Step 5: Synthesis of compound 24F Compound 24E (7 g, 31.3 mmol) was dissolved in triethyl orthoformate (70 mL) and stirred at 130 °C for 2 hours. LCMS showed the reaction was complete, so the solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 24F (5.2 g, yellow solid). MS (ESI): m / z 232.8 234.8 [M+1] + .

[0398] Step 6: Synthesis of compound 24G Compound 24F (800 mg, 3.43 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylamine (1.8 g, 13.7 mmol), and 4,4-difluoroperidine hydrochloride (1.1 g, 6.86 mmol) were added, and the mixture was stirred at 60 °C for 4 hours under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 24G (220 mg, reddish-brown solid, 20.2% yield). MS (ESI): m / z 318.0 320.0 [M+1] + .

[0399] Step 7: Synthesis of compound 24H Compound 24G (400 mg, 1.26 mmol) was dissolved in dioxane (10 mL) and tert-butyl carbamate (298 mg, 2.52 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (60 mg, 0.13 mmol), cesium carbonate (823 mg, 2.52 mmol), and tris(dibenzylideneacetone)dipalladium (21 mg, 0.06 mmol) were added. The mixture was then stirred at 110 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 24H (150 mg, brown solid, 24.6% yield). MS (ESI): m / z 355.1 [M+1] + .

[0400] Step 8: Synthesis of compound 24J Compound 24H (100 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the mixture was concentrated under reduced pressure to remove the solvent, diluted with water (20 mL), and then adjusted to pH 7-8 with solid sodium bicarbonate and extracted with ethyl acetate (20 mL x 4). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to give crude compound 24J (100 mg, dark green solid). MS (ESI): m / z 255.1 [M+1] + .

[0401] Step 9: Synthesis of compound 24K Compound 1E1 (122 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (125 mg, 0.98 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (5 mL). Compound 24J (100 mg, 0.39 mmol) and N,N-diisopropylethylamine (152 mg, 1.17 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 2 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 24K (100 mg, yellow solid, purity 53.8%, yield 25.0%). MS (ESI): m / z 273.6 274.4 [M / 2+1] + .

[0402] Step 10: Synthesis of Compound 24 Compound 24K (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (28 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (78 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 24 (40 mg, off-white solid). MS (ESI): m / z 591.1 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.05 (s, 1H), 10.20 (br.s, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 8.7, 2.1 Hz, 1H), 4.91 (br.s, 1H), 4.48 - 4.35 (m, 4H), 3.73 (t, J = 6.5 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 3.00 - 2.93 (m, 4H), 2.22 - 2.07 (m, 5H), 1.81 - 1.56 (m, 3H), 0.38 (s, 4H).

[0403] Example 25 Preparation of Compound 25

[0404] [ka]

[0405] Step 1: Synthesis of compound 25B Compound 25A (5.0 g, 35.1 mmol) was dissolved in glacial acetic acid (50 mL), and N-chlorosuccinimide (5.6 g, 42.1 mmol) was added in portions in an ice bath. The mixture was then stirred at room temperature for 16 h. TLC showed the reaction was complete. The reaction mixture was diluted with water (300 mL), adjusted to pH 7-8 with sodium bicarbonate, and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 25B (3.7 g, pale red solid, 56.9% yield). MS (ESI): m / z 176.9 [M+1] + .

[0406] Step 2: Synthesis of compound 25C Compound 25B (3.5 g, 19.8 mmol) was dissolved in glacial acetic acid (35 mL) and a solution of sodium nitrite (1.5 g, 21.8 mmol) dissolved in water (5 mL) was slowly added dropwise in an ice bath. After the addition, the mixture was stirred at room temperature for 16 h. TLC showed the reaction was complete. The reaction mixture was diluted with water (150 mL), adjusted to pH 7-8 with sodium bicarbonate, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 25C (500 mg, pale red solid, 64.1% yield). MS (ESI): m / z 187.9 [M+1] + .

[0407] Step 3: Synthesis of compound 25D Compound 25C (800 mg, 4.26 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylamine (2.2 g, 17.0 mmol), and 4,4-difluoroperidine hydrochloride (1.3 g, 8.52 mmol) were added, and the mixture was stirred at 80 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 25D (800 mg, tan solid, 62.5% yield). MS (ESI): m / z 273.1 [M+1] + .

[0408] Step 4: Synthesis of compound 25E Compound 25D (1.0 g, 3.49 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Sodium hydride (300 mg, 6.98 mmol) was added in portions in an ice bath and stirred for 30 minutes. Iodomethane (785 mg, 5.24 mmol) was then added dropwise to the reaction mixture. After the addition, the mixture was gradually warmed to room temperature and stirred for 2 hours. TLC showed the reaction was complete. The reaction was gradually quenched with saturated ammonium chloride solution (30 mL) in an ice bath and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 25E (600 mg, brown oil, purity 70.5%, yield 40.2%). MS (ESI): m / z 287.0 [M+1] + .

[0409] Step 5: Synthesis of compound 25F Compound 25E (600 mg, 2.09 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (492 mg, 4.18 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (198 mg, 0.42 mmol), cesium carbonate (1.37 g, 4.18 mmol), and palladium acetate (192 mg, 0.21 mmol) were added. The mixture was then stirred at 110 °C for 16 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 25F (600 mg, yellow solid, 70.2% yield). MS (ESI): m / z 368.2 [M+1] + .

[0410] Step 6: Synthesis of compound 25G Compound 25F (800 mg, 2.18 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the reaction mixture was concentrated under reduced pressure to remove the solvent and obtain crude compound 25G (800 mg, yellow oil). MS (ESI): m / z 268.1 [M+1] + .

[0411] Step 7: Synthesis of compound 25H Compound 1E1 (578 mg, 1.87 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (594 mg, 4.68 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 25G (500 mg, 1.87 mmol) and N,N-diisopropylethylamine (966 mg, 7.48 mmol) were added at room temperature, and the reaction solution was stirred at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 25H (400 mg, ochre solid, 36.7% yield). MS (ESI): m / z 280.1 281.1 [M / 2+1] + .

[0412] Step 8: Synthesis of Compound 25 Compound 25H (400 mg, 0.71 mmol) and 2-hydroxy-1-sulfonamide (108 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (14 mg, 0.07 mmol), potassium phosphate (304 mg, 1.42 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 25 (60 mg, pale yellow solid). MS (ESI): m / z 302.7 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.51 (s, 1H), 10.26 (br.s, 1H), 8.24 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 8.6, 2.1 Hz, 1H), 4.95 (s, 1H), 4.33 - 4.24 (m, 4H), 4.14 (s, 3H), 3.76 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.04 - 2.93 (m, 4H), 2.23 - 1.99 (m, 5H), 1.90 - 1.61 (m, 3H), 0.40 (s, 4H).

[0413] Example 26 Preparation of Compound 26

[0414] [ka]

[0415] Manufacturing method: Step 1: Synthesis of compound 26A 2-Fluoro-4-bromobenzoic acid (165 mg, 0.76 mmol) was dissolved in thionyl chloride (4 mL) and stirred at 80 °C for 2 h. TLC showed the reaction was complete, so the reaction solution was rotary evaporated, then dissolved in anhydrous tetrahydrofuran (2 mL), and compound 21B (100 mg, 0.76 mmol) and N,N-diisopropylethylamine (391 mg, 3.04 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 2 h. TLC showed the reaction was complete, so the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 26A (200 mg, yellow solid, purity 85.8%, yield 48.7%). MS (ESI): m / z 465.0 466.9 [M+1] + .

[0416] Step 2: Synthesis of compound 26B Compound 26A (100 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 3-azabicyclo[3.2.1]octane hydrochloride (32 mg, 0.25 mmol) and potassium carbonate (60 mg, 0.42 mmol) were added. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The residue was purified using a silica gel column to give compound 26B (120 mg, yellow solid, 63.1% purity, 63.3% yield). MS (ESI): m / z 278.6 279.7 [M / 2+1] + .

[0417] Step 3: Synthesis of compound 26 Compound 26B (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 26 (27 mg, off-white solid). MS (ESI): m / z 301.1 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.50 (s, 1H), 10.02 (br.s, 1H), 8.71 (dd, J = 4.1, 1.7 Hz, 1H), 8.24 (dd, J = 8.5, 1.7 Hz, 1H), 8.12 (s, 1H), 7.69 - 7.55 (m, 2H), 7.12 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 4.95 (br.s, 1H), 4.20 - 4.10 (m, 4H), 3.76 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 3.09 - 2.98 (m, 2H), 2.79 (d, J = 10.5 Hz, 2H), 2.27 - 2.02 (m, 6H), 1.98 - 1.88 (m, 2H), 1.58 - 1.44 (m, 4H).

[0418] Example 27 Preparation of Compound 27

[0419] [ka]

[0420] Step 1: Synthesis of compound 27B Compound 27A (5 g, 28.7 mmol) was dissolved in acetic acid (50 mL), Raney nickel (2 g) was added, and the mixture was stirred at 55 °C under hydrogen gas (40 psi) protection for 48 hours. LCMS showed the reaction was complete, and the reaction mixture was filtered through diatomaceous earth. The filtrate was stripped under reduced pressure to give crude compound 27B (6 g, brown oil). MS (ESI): m / z 178.0 [M+1] + .

[0421] Step 2: Synthesis of compound 27C Acetic anhydride (25 mL) was added to formic acid (25 mL) and stirred at 50° C. for 2 hours. The solution was then cooled to room temperature, and a solution of compound 27B (6 g) in dichloromethane (50 mL) was added dropwise to the reaction mixture at room temperature, followed by stirring at room temperature for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was stripped under reduced pressure. The residue was quenched with saturated sodium bicarbonate until pH = 7 and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and stripped under reduced pressure to give crude compound 27C (5 g, brown solid). MS (ESI): m / z 205.8 [M+1] + .

[0422] Step 3: Synthesis of compound 27D Crude compound 27C (5 g, 24.3 mmol) was dissolved in acetonitrile (50 mL), and thionyl chloride (4.33 g, 36.4 mmol) was added at room temperature. The mixture was then stirred at 80 °C for 0.5 h. LCMS showed the reaction was complete, and the reaction mixture was stripped under reduced pressure. The residue was quenched with saturated sodium bicarbonate until pH = 7 and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, stripped under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 27D (3.2 g, brown solid). MS (ESI): m / z 187.9 [M+1] + .

[0423] Step 4: Synthesis of compound 27E Compound 27D (270 mg, 1.44 mmol) was dissolved in N-methyl-2-pyrrolidone (6 mL), and 4,4-difluoroperidine hydrochloride (296 mg, 1.87 mmol) and N,N-diisopropylethylamine (558 mg, 4.32 mmol) were added. After the addition, the mixture was stirred at 80 °C for 4 hours under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) at 0 °C and then extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 27E (383 mg, 1.40 mmol, yellow oil, 97.2% yield). MS (ESI): m / z 273.0 [M+1] + .

[0424] Step 5: Synthesis of compound 27F Compound 27E (383 mg, 1.40 mmol) was dissolved in dioxane (7 mL) and tert-butyl carbamate (247 mg, 2.1 mmol), cesium carbonate (1.4 g, 4.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (67 mg, 0.14 mmol), and tris(dibenzylideneacetone)dipalladium (65 mg, 0.07 mmol) were added. The mixture was then stirred at 100 °C for 5 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL × 2). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 27F (220 mg, yellow oil, 44% yield). MS (ESI): m / z 354.2 [M+1] + .

[0425] Step 6: Synthesis of compound 27G Compound 27F (220 mg, 0.62 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 27G (151 mg, yellow oil). MS (ESI): m / z 254.1 [M+1] + .

[0426] Step 7: Synthesis of compound 27H Compound 1E1 (184 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL) and oxalyl chloride (189 mg, 1.5 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (2 mL). Compound 27G (151 mg, 0.6 mmol) and N,N-diisopropylethylamine (309 mg, 2.4 mmol) were added to the reaction solution in an ice bath, followed by stirring at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 27H (98 mg, yellow solid, 30% yield). MS (ESI): m / z 545.2 547.1 [M+1] + .

[0427] Step 8: Synthesis of Compound 27 Compound 27H (98 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (18 mg, 0.11 mmol), potassium phosphate (99 mg, 0.52 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.15 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 27 (6 mg, yellow solid). MS (ESI): m / z 590.2 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.81 (s, 1H), 10.20 (br.s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.7, 2.1 Hz, 1H), 4.94 (br.s, 1H), 4.01 - 3.93 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.01- 2.94 (m, 4H), 2.23 - 2.04 (m, 5H), 1.82 - 1.59 (m, 3H), 0.40 (s, 4H).

[0428] Example 28 Preparation of Compound 28

[0429] [ka]

[0430] Step 1: Synthesis of compound 28B Compound 28A (8.0 g, 38.5 mmol) was dissolved in ethanol (160 mL) and water (30 mL), and iron powder (10.7 g, 192.5 mmol) and concentrated hydrochloric acid (20 mL) were added. The mixture was stirred at 95 °C for 16 hours. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with water (150 mL), adjusted to pH 7 with solid sodium bicarbonate, and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure to give crude compound 28B (10.0 g, yellow solid). MS (ESI): m / z 178.0 [M+1] + .

[0431] Step 2: Synthesis of compound 28C Crude compound 28B (10.0 g, 56.1 mmol) was dissolved in hydrochloric acid (25 mL, 2 mol / L) and water (20 mL). Solid sodium nitrite (3.26 g, 56.1 mmol) was added in portions at 0° C., followed by stirring at 0° C. for 4 hours. TLC showed the reaction was complete. To the reaction mixture was added ice water (150 mL). A solid precipitated, which was filtered. The filter cake was washed twice with water. The filter cake was collected and dried to give crude compound 28C (6.5 g, yellow solid). MS (ESI): m / z 188.9 [M+1] + .

[0432] Step 3: Synthesis of compound 28D Compound 28C (2.0 g, 10.6 mmol) was dissolved in N-methyl-2-pyrrolidone (20 mL), and N,N-diisopropylethylamine (4.1 g, 31.8 mmol) and 4,4-difluoroperidine hydrochloride (2.2 g, 13.8 mmol) were added. The mixture was then stirred at 100 °C for 16 h. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 28D (2.6 g, yellow oil, 89.6% yield). MS (ESI): m / z 274.1 [M+1] + .

[0433] Step 4: Synthesis of compound 28E Compound 28D (1.0 g, 3.7 mmol) was dissolved in tetrahydrofuran (10 mL), and 3,4-dihydro-2H-pyran (615 mg, 7.4 mmol) and p-toluenesulfonic acid monohydrate (69 mg, 0.37 mmol) were added. The mixture was then stirred at room temperature for 5 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give crude compound 28E (1.6 g, yellow solid). MS (ESI): m / z 358.1 [M+1] + .

[0434] Step 5: Synthesis of compound 28F Compound 28E (1.6 g, 4.5 mmol) was dissolved in dioxane (16 mL), and tert-butyl carbamate (787 mg, 6.8 mmol), cesium carbonate (4.38 g, 13.5 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (213 mg, 0.45 mmol), and tris(dibenzylideneacetone)dipalladium (205 mg, 0.23 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 28F (1.7 g, yellow oil, 88% yield). MS (ESI): m / z 439.3 [M+1] + .

[0435] Step 6: Synthesis of compound 28G Compound 28F (1.7 g, 4.0 mmol) was dissolved in toluene (20 mL) and 300-400 mesh silica gel (1.7 g) was added. The mixture was then stirred at 120 °C for 16 h. TLC showed the reaction was complete. The reaction mixture was filtered, the filter cake was washed with dichloromethane / methanol = 5 / 1 (30 mL), and the filtrate was stripped under reduced pressure to give crude compound 28G (860 mg, brown oil). MS (ESI): m / z 339.2 [M+1] + .

[0436] Step 7: Synthesis of compound 28H Compound 28G (860 mg, 2.5 mmol) and compound 1E1 (732 mg, 2.4 mmol) were dissolved in pyridine (8 mL), and phosphorus oxychloride (1.92 g, 12.5 mmol) was added dropwise in an ice bath. The mixture was then stirred at room temperature for 3 hours. TLC showed the reaction was complete, and the reaction solution was evaporated, diluted with ice water (20 mL), and adjusted to pH 5 with 4N hydrochloric acid. The mixture was then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 28H (162 mg, yellow solid, 12% yield). MS (ESI): m / z 273.7 274.8 [(M-84) / 2+1] + .

[0437] Step 8: Synthesis of compound 28I Compound 28H (162 mg, 0.3 mmol) and 2-hydroxy-1-sulfonamide (53 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (37 mg, 0.18 mmol), potassium phosphate (200 mg, 0.87 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.26 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 28I (25 mg, white solid). MS (ESI): m / z 675.2 [M+1] + .

[0438] Step 9: Synthesis of Compound 28 Compound 28I (25 mg) was dissolved in ethanolic hydrochloric acid (2 mL, 4 mol / L) and stirred at 25° C. for 0.5 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure. The residue was purified by HPLC preparative method to give compound 28 (8 mg, white solid). MS (ESI): m / z 591.3 [M+1]+ . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.97 (s, 1H), 10.29 (br.s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.6, 2.1 Hz, 1H), 4.99 (br.s, 1H), 4.50 - 4.28 (m, 4H), 3.76 (t, J = 6.4 Hz, 2H), 3.36 (t, J = 6.4 Hz, 2H), 3.05 - 2.94 (m, 4H), 2.45 - 2.02 (m, 5H), 1.87 - 1.61 (m, 3H), 0.41 (s, 4H).

[0439] Example 29 Preparation of Compound 29

[0440] [ka]

[0441] Step 1: Synthesis of compound 29A Compound 8-A (1.1 g, 3.9 mmol) was dissolved in N-methyl-2-pyrrolidone (12 mL), N,N-diisopropylethylamine (2.06 g, 15.6 mmol) and 2-azaspiro[3.3]heptane hemioxalate (792 mg, 2.7 mmol) were added, and the mixture was stirred at 100 °C for 5 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) at 0 °C and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 29A (1.1 g, yellow oil, 94.8% yield). MS (ESI): m / z 293.0 295.0 [M+1] + .

[0442] Step 2: Synthesis of compound 29B Compound 29A (600 mg, 2.1 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (360 mg, 3.2 mmol), cesium carbonate (1.33 g, 4.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (92 mg, 0.2 mmol), and palladium acetate (24 mg, 0.1 mmol) were added. The mixture was then stirred at 100 °C under nitrogen gas protection for 5 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 29B (550 mg, yellow oil, 80.9% yield). MS (ESI): m / z 330.2 [M+1] + .

[0443] Step 3: Synthesis of compound 29C Compound 29B (550 mg, 1.7 mmol) was dissolved in dichloromethane (7 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 29C (330 mg, brown oil). MS (ESI): m / z 230.1 [M+1] + .

[0444] Step 4: Synthesis of compound 29D Compound 1E1 (440 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (451 mg, 3.5 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 29C (330 mg, 1.4 mmol) and N,N-diisopropylethylamine (737 mg, 5.6 mmol) were added to the reaction solution at room temperature, followed by stirring at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 29D (648 mg, yellow solid, 85.7% yield). MS (ESI): m / z 261.3 262.4 [M / 2+1] + .

[0445] Step 5: Synthesis of compound 29 Compound 29D (120 mg, 0.23 mmol) and 2-hydroxy-1-sulfonamide (37 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (26 mg, 0.13 mmol), potassium phosphate (144 mg, 0.67 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (28 mg, 0.2 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to give compound 29 (5 mg, white solid). MS (ESI): m / z 566.0 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.07 (s, 1H), 10.19 (s, 1H), 8.62 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 1.0 Hz, 1H), 7.49 (d, J = 1.0 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.6, 2.1 Hz, 1H), 4.94 (br.s, 1H), 4.43 - 4.31 (m, 4H), 3.76 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 3.03 - 2.94 (m, 4H), 2.22 (t, J = 7.5 Hz, 5H), 1.93 - 1.69 (m, 5H), 0.43 (s, 4H).

[0446] Example 30 Preparation of Compound 30

[0447] [ka]

[0448] Step 1: Synthesis of compound 30A Compound 8-A (1 g, 3.9 mmol) was dissolved in N-methyl-2-pyrrolidone (12 mL), N,N-diisopropylethylamine (2.06 g, 15.6 mmol) and 3-azabicyclo[3.2.1]octane hydrochloride (1.6 g, 11.7 mmol) were added, and the mixture was stirred at 100 °C for 5 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) at 0 °C and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 30A (260 mg, yellow oil, 24% yield). MS (ESI): m / z 307.0 309.0 [M+1] + .

[0449] Step 2: Synthesis of Compound 30B Compound 30A (260 mg, 0.85 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (148 mg, 1.27 mmol), cesium carbonate (559 mg, 1.7 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (39 mg, 0.09 mmol), and palladium acetate (13 mg, 0.04 mmol) were added. The mixture was then stirred at 100 °C for 5 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 30B (234 mg, yellow oil, 80% yield). MS (ESI): m / z 344.2 [M+1] + .

[0450] Step 3: Synthesis of compound 30C Compound 30B (234 mg, 0.68 mmol) was dissolved in dichloromethane (7 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 30C (164 mg, brown oil). MS (ESI): m / z 244.1 [M+1] + .

[0451] Step 4: Synthesis of compound 30D Compound 1E1 (207 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (214 mg, 1.67 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 30C (164 mg, 0.67 mmol) and N,N-diisopropylethylamine (348 mg, 2.68 mmol) were added to the reaction solution at room temperature, followed by stirring at room temperature for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 30D (132 mg, yellow solid, 37.3% yield). MS (ESI): m / z 268.3 269.0 [M / 2+1] + .

[0452] Step 5: Synthesis of Compound 30 Compound 30D (132 mg, 0.25 mmol) and 2-hydroxy-1-sulfonamide (33 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (26 mg, 0.15 mmol), potassium phosphate (152 mg, 0.73 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.22 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 30 (25 mg, white solid). MS (ESI): m / z 290.7[M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.83 (s, 1H), 10.34 (br.s, 1H), 8.71 (s, 1H), 8.20 - 7.93 (m, 2H), 7.50 (s, 1H), 7.27 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 4.98 (br.s, 1H), 3.76 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.4 Hz, 2H), 3.09 (d, J = 12.6 Hz, 2H), 3.03 - 2.92 (m, 4H), 2.39 - 2.28 (m, 2H), 1.97 - 1.42 (m, 10H), 0.39 (s, 4H).

[0453] Example 31 Preparation of Compound 31

[0454] [ka]

[0455] Step 1: Synthesis of compound 31A Compound 8-A (1.0 g, 3.61 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylamine (930 mg, 7.22 mmol), and 6-aza-spiro[2.5]octane hydrochloride (640 mg, 4.33 mmol) were added, and the mixture was stirred at 100 °C for 16 h. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (70 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography and rotary evaporated under reduced pressure to give compound 31A (1.0 g, pink solid, 86.2% yield). MS (ESI): m / z 307.0 309.0 [M+1] + .

[0456] Step 2: Synthesis of compound 31B Compound 31A (500 mg, 1.63 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (382 mg, 3.26 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (156 mg, 0.33 mmol), cesium carbonate (1.06 mg, 3.26 mmol), and palladium acetate (37 mg, 0.16 mmol) were added. The mixture was then reacted at 100 °C for 16 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 31B (400 mg, yellow solid, 71.6% yield). MS (ESI): m / z 344.1[M+1] + .

[0457] Step 3: Synthesis of compound 31C Compound 31B (100 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.4 mL) was added, and the mixture was stirred at room temperature for 16 hours. TLC showed the reaction was complete, and the mixture was concentrated under reduced pressure to remove the solvent and obtain crude compound 31C (100 mg, yellow oil). MS (ESI): m / z 244.1 [M+1] + .

[0458] Step 4: Synthesis of compound 31D Compound 1E1 (89 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL) and oxalyl chloride (91 mg, 0.73 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. It was then dissolved in anhydrous tetrahydrofuran (5 mL). A mixture of compound 31C (70 mg, 0.29 mmol) and N,N-diisopropylethylamine (148 mg, 1.16 mmol) in tetrahydrofuran was added at room temperature, and the reaction solution was stirred at 50 °C for 2 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified using a silica gel column to give compound 31D (80 mg, yellow solid, purity 65.8%, yield 31.7%). MS (ESI): m / z 268.1 269.1 [M / 2+1] + .

[0459] Step 5: Synthesis of Compound 31 Compound 31D (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 31 (15 mg, off-white solid). MS (ESI): m / z 290.7[M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.77 (s, 1H), 10.19 (br.s, 1H), 8.74 (s, 1H), 8.14 - 7.93 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.6, 2.1 Hz, 1H), 4.94 (br.s, 1H), 4.40 - 4.29 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.02 - 2.93 (m, 4H), 1.91 - 1.40 (m, 8H), 0.39 (s, 4H), 0.36 (s, 4H).

[0460] Example 32 Preparation of Compound 32

[0461] [ka]

[0462] Step 1: Synthesis of compound 32 Compound 21C (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (78 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 32 (30 mg, white solid). MS (ESI): m / z 286.2 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.90 (s, 1H), 10.25 (s, 1H), 8.72 (dd, J = 4.1, 1.7 Hz, 1H), 8.24 (dd, J = 8.5, 1.7 Hz, 1H), 8.17 - 8.04 (m, 2H), 7.61 (dd, J = 8.4, 4.1 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.6, 2.1 Hz, 1H), 4.24 - 4.16 (m, 4H), 3.13 (s, 3H), 3.05 - 2.96 (m, 4H), 2.27 - 2.07 (m, 5H), 1.86 - 1.61 (m, 3H), 0.40 (s, 4H).

[0463] Example 33 Preparation of Compound 33

[0464] [ka]

[0465] Step 3: Synthesis of compound 33 Compound 26B (800 mg, 0.14 mmol) and methanesulfonamide (17 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (61 mg, 0.28 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (8 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to give compound 33 (15 mg, white solid). MS (ESI): m / z 286.2 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.49 (s, 1H), 10.04 (s, 1H), 8.71 (dd, J = 4.1, 1.7 Hz, 1H), 8.25 (dd, J = 8.5, 1.8 Hz, 1H), 8.12 (s, 1H), 7.71 - 7.54 (m, 2H), 7.11 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.4, 2.0 Hz, 1H), 4.21 - 4.10 (m, 4H), 3.07 (s, 3H), 3.06 - 3.01 (m, 2H), 2.80 (d, J = 10.5 Hz, 2H), 2.27 - 2.03 (m, 6H), 1.93 (d, J = 7.6 Hz, 2H), 1.58 - 1.44 (m, 4H).

[0466] Example 34 Preparation of Compound 34

[0467] [ka]

[0468] Step 1: Synthesis of compound 34A Compound 8-A (20 g, 72.2 mmol) was dissolved in acetonitrile (180 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (28.1 g, 79.4 mmol) was added at room temperature. The mixture was then stirred at 80 °C for 5 hours. LCMS showed the reaction was complete, and the reaction mixture was desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was purified by reverse-phase column chromatography to give 34A (3.1 g, yellow solid, 14.5% yield). MS (ESI): m / z 295.8 [M+1] + .

[0469] Step 2: Synthesis of compound 34B Compound 34A (1.0 g, 3.39 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylamine (884 mg, 6.78 mmol) and 4,4-difluoroperidine hydrochloride (650 mg, 4.07 mmol) were added, and the mixture was stirred at 100 °C for 16 h. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (80 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 34B (1.0 g, pale yellow solid, purity 73.5%, yield 64.7%). MS (ESI): m / z 335.0 337.0 [M+1] + .

[0470] Step 3: Synthesis of compound 34C Compound 34B (400 mg, 1.19 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (280 mg, 2.38 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol), cesium carbonate (340 mg, 2.38 mmol), and palladium acetate (13 mg, 0.06 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. When TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 34C (300 mg, off-white solid, purity 75.2%, yield 50.9%). MS (ESI): m / z 372.1 [M+1] + .

[0471] Step 4: Synthesis of compound 34D Compound 34C (300 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the mixture was concentrated under reduced pressure to remove the solvent and obtain crude compound 34D (300 mg, yellow oil). MS (ESI): m / z 272.1 [M+1] + .

[0472] Step 5: Synthesis of Compound 34E Compound 1E1 (228 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (234 mg, 1.85 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. The residue was dissolved in anhydrous tetrahydrofuran (5 mL). A mixture of compound 34D (200 mg, 0.74 mmol) and N,N-diisopropylethylamine (381 mg, 2.96 mmol) was added at room temperature, followed by stirring at 50 °C for 2 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified using a silica gel column to give compound 34E (200 mg, pale yellow solid, purity 65.8%, yield 31.7%). MS (ESI): m / z 282.8 283.9 [M / 2+1] + .

[0473] Step 6: Synthesis of compound 34 Compound 34E (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (75 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. LCMS showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 34 (40 mg, pale yellow solid). MS (ESI): m / z 304.5 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 13.03 (s, 1H), 10.30 (br.s, 1H), 8.43 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.6, 2.1 Hz, 1H), 4.95 (br.s, 1H), 4.46 - 4.36 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 3.03 - 2.94 (m, 4H), 2.21 - 2.02 (m, 5H), 1.85 - 1.61 (m, 3H), 0.41 (s, 4H).

[0474] Example 35 Preparation of Compound 35

[0475] [ka]

[0476] Manufacturing method: Step 1: Synthesis of compound 35B Compound 42B (1 g, 2.26 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cuprous iodide (2.15 g, 11.3 mmol), cesium fluoride (1.03 g, 6.78 mmol), and (trifluoromethyl)trimethylsilane (963 mg, 6.78 mmol) were added. The mixture was then stirred at 95 °C for 12 hours under nitrogen gas protection. LCMS showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 35B (110 mg, yellow solid, 12.6% yield). MS (ESI): m / z 384.9 387.0 [M+1] + .

[0477] Step 2: Synthesis of compound 35C Compound 35B (110 mg, 0.29 mmol) was dissolved in dioxane (6 mL), and tert-butyl carbamate (55 mg, 0.44 mmol), cesium carbonate (187 g, 0.58 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14 mg, 0.03 mmol), and palladium acetate (4 mg, 0.02 mmol) were added. The mixture was then stirred under nitrogen atmosphere at 100 °C for 5 h. After TLC showed the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 35C (69 mg, yellow oil, 55.1% yield). MS (ESI): m / z 422.1 [M+1] + .

[0478] Step 4: Synthesis of compound 35D Compound 35C (69 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. After the addition, the mixture was stirred at 25° C. for 2 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 35D (50 mg, brown oil). MS (ESI): m / z 322.1 [M+1] + .

[0479] Step 4: Synthesis of compound 35E Compound 1E1 (48 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) and oxalyl chloride (49 mg, 0.4 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, so the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (2 mL). Compound 35D (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (80 mg, 0.64 mmol) were added at room temperature, followed by stirring at room temperature for 1 hour. TLC showed the reaction was complete, so the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified on a silica gel column to give compound 35E (50 mg, yellow solid, 50% yield).

[0480] Step 5: Synthesis of Compound 35 Compound 35E (50 mg, 0.08 mmol) and 2-hydroxy-1-sulfonamide (13 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (9 mg, 0.05 mmol), potassium phosphate (50 mg, 0.23 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 35 (15 mg, white solid). MS (ESI): m / z 329.7 [M / 2+1] + 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 13.22 (s, 1H), 10.27 (br.s, 1H), 8.80 (s, 1H), 8.21 - 8.01 (m, 2H), 7.29 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 4.95 (br.s, 1H), 4.41 - 4.33 (m, 4H), 3.76 (t, J = 6.4 Hz, 2H), 3.36 (t, J = 6.4 Hz, 2H), 3.05 - 2.92 (m, 4H), 2.28 - 2.04 (m, 5H), 1.87 - 1.59 (m, 3H), 0.41 (s, 4H).

[0481] Example 36 Preparation of Compound 36

[0482] [ka]

[0483] Manufacturing method: Step 1: Synthesis of compound 36B Compound 36A (1.0 g, 3.95 mmol) was dissolved in N,N-dimethylacetamide (10 mL), 3-bromo-1,1,1-trifluoroacetone (1.9 g, 9.88 mmol) was added, and the mixture was stirred at 90 °C for 16 hours. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give crude compound 36B (600 mg, brown oil). MS (ESI): m / z 345.8 [M+1] + .

[0484] Step 2: Synthesis of compound 36C Compound 36B (600 mg, 1.74 mmol) was dissolved in N-methylpyrrolidone (10 mL), N,N-diisopropylethylamine (451 mg, 3.48 mmol), and 4,4-difluoroperidine hydrochloride (332 mg, 2.09 mmol) were added, and the mixture was stirred at 100 °C for 4 hours. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 36C (400 mg, pale yellow solid, 71.8% purity, 42.9% yield). MS (ESI): m / z 385.0 387.0 [M+1] + .

[0485] Step 3: Synthesis of compound 36D Compound 36C (200 mg, 0.52 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (122 mg, 1.04 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol), cesium carbonate (340 mg, 1.04 mmol), and palladium acetate (6 mg, 0.03 mmol) were added. The mixture was then stirred at 100 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 36D (160 mg, yellow solid, purity 81.4%, yield 59.5%). MS (ESI): m / z 366.1 [M-55] + .

[0486] Step 4: Synthesis of compound 36E Compound 36D (180 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the mixture was concentrated under reduced pressure to remove the solvent, yielding crude compound 36E (180 mg, yellow oil). MS (ESI): m / z 322.1 [M+1] + .

[0487] Step 5: Synthesis of compound 36F Compound 1E1 (135 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (139 mg, 1.10 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (5 mL). Compound 36E (140 mg, 0.44 mmol) and N,N-diisopropylethylamine (225 mg, 1.76 mmol) were added at room temperature, followed by stirring at 50 °C for 2 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified on a silica gel column to give compound 36F (200 mg, pale yellow solid, purity 81.3%, yield 60.8%). MS (ESI): m / z 307.1 308.2 [M / 2+1] + .

[0488] Step 6: Synthesis of Compound 36 Compound 36F (100 mg, 0.16 mmol) and 2-hydroxy-1-sulfonamide (25 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (69 mg, 0.32 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 36 (38 mg, pale yellow solid). MS (ESI): m / z 329.7 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.03 (s, 1H), 10.21 (br.s, 1H), 8.88 (s, 1H), 8.71 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.15 (dd, J = 8.6, 2.1 Hz, 1H), 4.95 (br.s, 1H), 4.44 - 4.32 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.36 (t, J = 6.4 Hz, 2H), 3.03 - 2.92 (m, 4H), 2.29 - 1.99 (m, 5H), 1.83 - 1.58 (m, 3H), 0.41 (s, 4H).

[0489] Example 37 Preparation of Compound 37

[0490] [ka]

[0491] Manufacturing method: Step 1: Synthesis of compound 37B Compound 37A (900 mg, 4.1 mmol) was dissolved in methanol (10 mL) and thionyl chloride (974 mg, 8.2 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 12 hours. TLC showed the reaction was complete, and the reaction mixture was rotary evaporated. The residue was adjusted to pH 7 with saturated sodium bicarbonate and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 37B (300 mg, off-white solid).

[0492] Step 2: Synthesis of compound 37C Crude compound 37B (900 mg, 3.8 mmol) was dissolved in N-methylpyrrolidone (10 mL), and 6-aza-spiro[2.5]octane hydrochloride (681 g, 4.6 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.4 mmol) were added. The mixture was then stirred at 120 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (60 mL) in an ice bath and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 37C (1.4 g, yellow solid). MS (ESI): 325.0 327.0 m / z [M+1] + .

[0493] Step 3: Synthesis of compound 37D Compound 37C (1.34 g, 4.1 mmol) was dissolved in methanol (5 mL) and water (5 mL), and sodium hydroxide (330 mg, 8.2 mmol) was added. The mixture was then stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction mixture was adjusted to pH 6 with hydrochloric acid solution (1 mol / L) in an ice bath and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 37D (1 g, off-white solid). MS (ESI): 311.0 313.0 m / z [M+1] + .

[0494] Step 4: Synthesis of compound 37E Compound 37D (372 mg, 1.18 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (378 mg, 2.96 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (8 mL). A mixture of compound 8-D (300 mg, 1.18 mmol) and N,N-diisopropylethylamine (462 mg, 4.72 mmol) was added at room temperature, and the reaction solution was stirred at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 37E (300 mg, ochre solid, purity 77.5%, yield 24.0%). MS (ESI): 273.6 274.5 m / z [M / 2+1] + .

[0495] Step 5: Synthesis of Compound 37 Compound 37E (5 mg, 0.009 mmol) and 2-hydroxy-1-sulfonamide (1.4 mg, 0.011 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and cuprous iodide (0.2 mg, 0.001 mmol), cesium carbonate (3.9 mg, 0.018 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.3 mg, 0.002 mmol) were added sequentially. The mixture was then stirred at 120 °C under nitrogen gas protection for 2 h. TLC showed the reaction was complete. The combined reaction mixtures were filtered, and the filtrate was further evaporated under reduced pressure. The residue was purified by preparative HPLC to give compound 37 (8 mg, yellow solid, formate salt). MS (ESI): 591.1 m / z [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 11.38 (s, 1H), 10.37 (s, 1H), 8.80 (s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.60 - 7.47 (m, 2H), 4.99 (br.s, 1H), 4.51 - 4.28 (m, 4H), 3.78 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.2 Hz, 2H), 3.09 - 2.99 (m, 4H), 2.22 - 1.97 (m, 5H), 1.80 - 1.58 (m, 4H), 0.36 (s, 4H).

[0496] Example 38 Preparation of Compound 38

[0497] [ka]

[0498] Step 1: Synthesis of compound 38B Compound 38A (5 g, 24.3 mmol) was dissolved in a 33% hydrobromic acid / acetic acid solution (40 mL) and then stirred at 60 °C for 5 hours. LCMS showed the reaction was complete, and the reaction solution was diluted with water (60 mL) in an ice bath and then stirred in an ice bath for 10 minutes. The suspension was filtered, and the filter cake was washed with ice water (10 mL x 2). The filter cake was dissolved in ethyl acetate (60 mL) and water (30 mL) and then neutralized with aqueous sodium hydroxide (1 mol / L) until pH = 7. The aqueous phase was extracted with ethyl acetate (60 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 38B (2.5 g, off-white solid). MS (ESI): m / z 295.9 [M+1] + .

[0499] Step 2: Synthesis of compound 38C Compound 38B (2 g, 6.78 mmol) was dissolved in N-methylpyrrolidone (20 mL), and 6-aza-spiro[2.5]octane hydrochloride (1.2 g, 8.14 mmol) and N,N-diisopropylethylamine (3.6 mL, 20.3 mmol) were added. The mixture was then stirred at 120 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (60 mL) in an ice bath and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 38C (1.1 g, off-white solid). MS (ESI): m / z 325.0 327.0 [M+1] + .

[0500] Step 3: Synthesis of compound 38D Compound 38C (1.1 g, 3.4 mmol) was dissolved in methanol (5 mL) and water (5 mL), and sodium hydroxide (271 mg, 6.8 mmol) was added. The mixture was then stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction mixture was adjusted to pH 6 with hydrochloric acid solution (1 mol / L) in an ice bath and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 38D (800 mg, white solid). MS (ESI): m / z 311.0 313.0 [M+1] + .

[0501] Step 4: Synthesis of compound 38E Compound 38D (100 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL) and oxalyl chloride (102 mg, 0.8 mmol) and one drop of N,N-dimethylformamide were added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (2 mL). Compound 8-D (81 mg, 0.32 mmol) and N,N-diisopropylethylamine (165 mg, 1.28 mmol) were added at room temperature, followed by stirring at room temperature for 1 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 38E (130 mg, yellow solid, 75% yield). MS (ESI): m / z 273.6 274.5 [M / 2+1] + .

[0502] Step 5: Synthesis of compound 38 Compound 38E (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (21 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (14 mg, 0.08 mmol), potassium phosphate (77 mg, 0.38 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.11 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 38 (5 mg, white solid, formate salt). MS (ESI): m / z 591.3 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.80 (br.s, 1H), 8.72 (s, 1H), 8.05 (s, 1H), 7.52 (d, J = 1.1 Hz, 1H), 6.69 (s, 1H), 4.83 (br.s, 1H), 4.42 - 4.31 (m, 4H), 3.73 (t, J = 6.8 Hz, 2H), 3.52 - 3.34 (m, 2H), 3.01 - 2.99 (m, 5H), 2.16 - 2.00 (m, 5H), 1.64 - 1.51 (m, 4H), 0.31 (s, 4H).

[0503] Example 39 Preparation of Compound 39

[0504] [ka]

[0505] Step 1: Synthesis of compound 39B Compound 39A (500 mg, 2.50 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (508 mg, 5.00 mmol), and 4,4-difluoroperidine hydrochloride (476 mg, 3.00 mmol) were added, and the mixture was stirred at room temperature for 16 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 39B (1 g, yellow solid). MS (ESI): m / z 285.0 [M+1] + .

[0506] Step 2: Synthesis of compound 39C Compound 39B (400 mg, 1.41 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (330 mg, 2.82 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (63 mg, 0.14 mmol), cesium carbonate (918 mg, 2.82 mmol), and palladium acetate (16 mg, 0.07 mmol) were added. The mixture was then stirred at 100 °C under nitrogen gas protection for 16 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 39C (400 mg, orange-yellow solid, 75.7% yield). MS (ESI): m / z 366.1 [M+1] + .

[0507] Step 3: Synthesis of compound 39D Compound 39C (300 mg, 0.82 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the mixture was concentrated under reduced pressure to remove the solvent, diluted with water (20 mL), and then adjusted to pH 7-8 with solid sodium bicarbonate and extracted with ethyl acetate (20 mL x 4). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to give crude compound 39D (180 mg, reddish-brown solid). MS (ESI): m / z 266.0 [M+1] + .

[0508] Step 4: Synthesis of compound 39E Compound 1E1 (211 mg, 0.68 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (215 mg, 1.70 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, so the reaction solution was rotary evaporated, then dissolved in anhydrous tetrahydrofuran (5 mL), and compound 39D (180 mg, 0.68 mmol) and N,N-diisopropylethylamine (350 mg, 2.04 mmol) were added sequentially at room temperature, followed by stirring at 50 °C for 2 hours. TLC showed the reaction was complete, so the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain crude compound 39E (200 mg, reddish-brown solid).

[0509] Step 5: Synthesis of compound 39 Compound 39E (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 39 (8 mg, yellow solid). MS (ESI): m / z 301.7 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.10 (s, 1H), 10.27 (br.s, 1H), 8.93 (d, J = 1.9 Hz, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.20 - 8.05 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.7, 2.1 Hz, 1H), 4.99 (br.s, 1H), 4.28 - 4.20 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 3.06 - 2.97(m, 4H), 2.31 - 2.05 (m, 5H), 1.75 (s, 3H), 0.41 (s, 4H).

[0510] Example 40 Preparation of Compound 40

[0511] [ka]

[0512] Step 1: Synthesis of compound 40B Compound 40A (550 mg, 2.7 mmol) was dissolved in N-methyl-2-pyrrolidone (7 mL), and N,N-diisopropylethylamine (1.06 g, 8.1 mmol) and 4,4-difluoroperidine hydrochloride (561 mg, 3.5 mmol) were added. The mixture was then stirred at 80 °C for 5 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) at 0 °C and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give crude compound 40B (990 mg, yellow oil). MS (ESI): m / z 284.1 286.1 [M+1] + .

[0513] Step 2: Synthesis of compound 40C Crude compound 40B (990 mg, 3.5 mmol) was dissolved in dioxane (12 mL) and tert-butyl carbamate (616 mg, 5.3 mmol), cesium carbonate (2.3 mg, 7.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (165 mg, 0.35 mmol), and tris(dibenzylideneacetone)dipalladium (165 mg, 0.18 mmol) were added. The mixture was then stirred at 100 °C for 5 h under nitrogen gas protection. TLC showed the reaction was complete. The mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give crude compound 40C (1.4 g, yellow oil). MS (ESI): m / z 365.2 [M+1] + .

[0514] Step 3: Synthesis of compound 40D Compound 40C (500 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25° C. for 2 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 40D (400 mg, brown oil). MS (ESI): m / z 265.1 [M+1] + .

[0515] Step 4: Synthesis of compound 40E Compound 1E1 (468 mg, 1.5 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (480 mg, 3.8 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete. The reaction solution was rotovapped, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 40D (400 mg, 1.5 mmol) and N,N-diisopropylethylamine (781 mg, 6.0 mmol) were then added to the reaction solution, followed by stirring at 65 °C for 16 h. TLC showed the reaction was complete. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 40E (280 mg, yellow solid, 33.3% yield). MS (ESI): 278.6 279.6 [M / 2+1] + .

[0516] Step 5: Synthesis of compound 40 Compound 40E (280 mg, 0.5 mmol) and 2-hydroxy-1-sulfonamide (84 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (57 mg, 0.3 mmol), potassium phosphate (308 mg, 1.45 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (60 mg, 0.43 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 40 (41 mg, yellow solid). MS (ESI): m / z 601.2 [M+1] + 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.30 (s, 1H), 10.06 (br.s, 1H), 8.95 (dd, J = 4.2, 1.6 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.4, 4.3 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.15 (dd, J = 8.6, 2.1 Hz, 1H), 4.98 (br.s, 1H), 3.77 (t, J = 6.4 Hz, 2H), 3.61 - 3.51 (m, 4H), 3.37 (t, J = 6.4 Hz, 2H), 3.01 (d, J = 6.4 Hz, 4H), 2.25 (d, J = 16.0 Hz, 5H), 1.94 - 1.74 (m, 3H), 0.40 (s, 4H).

[0517] Example 41 Preparation of Compound 42

[0518] [ka]

[0519] Step 1: Synthesis of compound 42A Compound 8-A (5 g, 18.1 mmol) was dissolved in DMF (40 mL), N-iodosuccinimide (4.47 g, 19.9 mmol) was added, and the mixture was stirred at 60 °C for 3 hours. LCMS showed the reaction was complete, so the reaction mixture was cooled to room temperature, quenched with saturated sodium thiosulfate solution (80 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 42A (6.8 g, yellow solid, 93.5% yield). MS (ESI): m / z 403.7 [M+1] + .

[0520] Step 2: Synthesis of compound 42B Compound 42A (1 g, 2.5 mmol) was dissolved in N-methylpyrrolidone (40 mL), and 4,4-difluoroperidine hydrochloride (430 mg, 2.7 mmol) was added. The mixture was then stirred at 100 °C for 3 hours. LCMS showed the reaction was complete, so the reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and rotary evaporated under reduced pressure to give compound 42B (900 mg, off-white solid, 81.8% yield). MS (ESI): m / z 442.9 444.9 [M+1] + .

[0521] Step 3: Synthesis of compound 42C Compound 42B (3.5 g, 7.9 mmol) was dissolved in dioxane (40 mL) and water (4 mL), and trimethylboroxine (6.8 mL, 23.7 mmol, 3.5 mol / L tetrahydrofuran solution), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (320 mg, 0.4 mmol), and potassium carbonate (2.18 g, 15.8 mmol) were added. The mixture was then stirred at 75 °C under nitrogen gas protection for 3 h. LCMS showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by reverse phase chromatography to give compound 42C (290 mg, off-white solid, 11.1% yield). MS (ESI): m / z 331.0 333.0 [M+1] + .

[0522] Step 4: Synthesis of compound 42D Compound 42C (280 mg, 0.85 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (200 mg, 1.70 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (40 mg, 0.09 mmol), cesium carbonate (553 mg, 1.70 mmol), and tris(dibenzylideneacetone)dipalladium (40 mg, 0.04 mmol) were added. The mixture was then reacted at 110 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography and rotary evaporated under reduced pressure to give compound 42D (250 mg, yellow solid, purity 94.1%, yield 75.7%). MS (ESI): m / z 368.2 [M+1] + .

[0523] Step 5: Synthesis of compound 42E Compound 42D (250 mg, 0.68 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete, and the mixture was concentrated under reduced pressure to remove the solvent, yielding crude compound 42E (250 mg, yellow oil). MS (ESI): m / z 268.1 [M+1] + .

[0524] Step 5: Synthesis of compound 42F Compound 1E1 (208 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (218 mg, 1.68 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 42E (180 mg, 0.67 mmol) and N,N-diisopropylethylamine (350 mg, 2.68 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 42F (110 mg, yellow solid, purity 63.2%, yield 18.5%). MS (ESI): m / z 280.1 281.1 [M / 2+1] + .

[0525] Step 3: Synthesis of compound 42 Compound 42F (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.44 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 42 (20 mg, white solid). MS (ESI): m / z 604.3 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ 12.90 (s, 1H), 10.21 (br.s, 1H), 8.50 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.7, 2.1 Hz, 1H), 4.97 (br.s, 1H), 4.49 - 4.33 (m, 4H), 3.76 (t, J = 6.5 Hz, 2H), 3.36 (t, J = 6.4 Hz, 2H), 3.05 - 2.94 (m, 4H), 2.42 (s, 3H), 2.21 - 1.98 (m, 5H), 1.87 - 1.61 (m, 3H), 0.40 (s, 4H).

[0526] Example 42 Preparation of Compound 43

[0527] [ka]

[0528] Step 1: Synthesis of compound 43B Compound 43A (2.0 g, 9.17 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 6-aza-spiro[2.5]octane hydrochloride (1.6 g, 11.0 mmol) and N,N-diisopropylethylamine (3.4 g, 22.9 mmol) were added. The mixture was then stirred at room temperature under nitrogen gas protection for 16 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 43B (2.8 g, white solid, 97.7% yield). MS (ESI): m / z 308.9 311.0 [M+1] + .

[0529] Step 2: Synthesis of compound 43C Compound 43B (2.9 g, 9.38 mmol) was dissolved in N-methylpyrrolidone (30 mL), 4-methoxybenzylamine (1.6 g, 11.3 mmol) and N,N-diisopropylethylamine (2.4 g, 18.8 mmol) were added, and the mixture was stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 43C (3.7 g, yellow oily solid, 83.0% yield).

[0530] Step 3: Synthesis of compound 43D Compound 43C (3.7 g, 8.68 mmol) was dissolved in trifluoroacetic acid (20 mL), trifluoromethanesulfonic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. When TLC showed the reaction was complete, the reaction mixture was diluted with water (100 mL), adjusted to pH 7-8 with solid sodium bicarbonate, and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 43D (2.0 g, yellow oil, 73.0% yield). MS (ESI): m / z 306.1-308.0 [M+1] + .

[0531] Step 4: Synthesis of compound 43E Compound 43D (500 mg, 1.63 mmol) was dissolved in triethyl orthoformate (5 mL), acetic anhydride (167 mg, 1.39 mmol) was added, and the mixture was stirred at 145° C. for 3 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure to give crude compound 43E (500 mg, brown solid). MS (ESI): m / z 362.1 364.0 [M+1] + .

[0532] Step 5: Synthesis of compound 43F Compound 43E (500 mg, 1.38 mmol) and compound 8-D (350 mg, 1.38 mmol) were dissolved in glacial acetic acid (5 mL) and then stirred at 125 °C for 1 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (50 mL), adjusted to pH 7-8 with solid sodium bicarbonate, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 43F (200 mg, yellow solid, 83.2% purity, 21.2% yield). MS (ESI): m / z 285.1 286.2 [M / 2+1] + .

[0533] Step 6: Synthesis of compound 43 Compound 43F (200 mg, 0.35 mmol) and 2-hydroxy-1-sulfonamide (53 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (149 mg, 0.70 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120 °C for 16 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 43 (30 mg, yellow solid). MS (ESI): m / z 614.2. [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.88 (s, 1H), 10.30 (br.s, 1H), 9.21 (s, 1H), 8.60 (s, 1H), 8.13 (d, J = 1.1 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 2H), 5.03 (br.s, 1H), 4.51 - 4.39 (m, 4H), 3.78 (t, J = 6.4 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 3.20 (d, J = 10.9 Hz, 2H), 2.86 (t, J = 11.4 Hz, 2H), 2.64 - 2.53 (m, 2H), 2.22 - 2.06 (m, 4H), 1.04 (d, J = 12.9 Hz, 2H), 0.52 - 0.37 (m, 4H).

[0534] Example 43 Preparation of Compound 44

[0535] [ka]

[0536] Step 1: Synthesis of compound 44A Compound 3A (500 mg, 1.17 mmol) was dissolved in N-methyl-2-pyrrolidone (6 mL), and potassium carbonate (325 mg, 2.34 mmol) and isoindoline (220 mg, 1.4 mmol) were added. The mixture was then stirred at 120 °C for 16 hours under nitrogen gas protection. TLC showed the reaction was complete. Water (30 mL) was added to the reaction mixture at 0 °C, and the mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give crude compound 44A (330 mg, 0.62 mmol, tan oil). MS (ESI): 264.6 265.6 [M / 2+1] + .

[0537] Step 2: Synthesis of compound 44 Compound 44A (330 mg, 0.62 mmol) and 2-hydroxy-1-sulfonamide (99 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (71 mg, 0.4 mmol), potassium phosphate (385 mg, 1.8 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (77 mg, 0.53 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 44 (25 mg, yellow solid). MS (ESI): m / z 573.1 [M+1] + 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 11.15 (s, 1H), 9.93 (s, 1H), 7.51 - 7.19 (m, 6H), 6.90 (s, 1H), 6.72 (d, J = 8.5 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.59 (s, 4H), 3.83 - 3.67 (m, 6H), 3.33 (t, J = 5.6 Hz, 2H), 2.30 (s, 3H), 1.98 - 1.83 (m, 4H).

[0538] Example 44 Preparation of Compound 45

[0539] [ka]

[0540] Manufacturing method: Step 1: Synthesis of compound 45 Compound 15G (400 mg, 0.71 mmol) and methanesulfonamide (79 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (8 mL), and cuprous iodide (13 mg, 0.07 mmol), potassium phosphate (295 mg, 1.42 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 45 (150 mg, off-white solid). MS (ESI): m / z 288.5 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.92 (s, 1H), 10.25 (s, 1H), 8.30 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 5.4 Hz, 1H), 7.51 (d, J = 5.5 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.6, 2.1 Hz, 1H), 3.86 - 3.76 (m, 4H), 3.12 (s, 3H), 3.04 - 2.95 (m, 4H), 2.27 - 2.05 (m, 5H), 1.89 - 1.64 (m, 3H), 0.39 (s, 4H).

[0541] Example 45 Preparation of Compound 46

[0542] [ka]

[0543] Step 5: Synthesis of compound 46 Compound 34E (600 mg, 1.07 mmol) and methanesulfonamide (132 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (120 mg, 0.64 mmol), potassium phosphate (654 mg, 3.1 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (132 mg, 0.92 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 46 (101 mg, off-white solid). MS (ESI): m / z 289.7 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 10.27 (s, 1H), 8.43 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.6, 2.1 Hz, 1H), 4.41 (s, 4H), 3.13 (s, 3H), 2.99 (s, 4H), 2.23 - 1.99 (m, 5H), 1.73 (s, 3H), 0.41 (s, 4H).

[0544] Example 46 Preparation of Compound 47

[0545] [ka]

[0546] Step 1: Synthesis of compound 47 Compound 22F (200 mg, 0.4 mmol) and methanesulfonamide (45 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (42 mg, 0.24 mmol), potassium phosphate (226 mg, 1.16 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (45 mg, 0.34 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 47 (81 mg, yellow solid). MS (ESI): m / z 559.1 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.69 (s, 1H), 11.34 (s, 1H), 10.19 (s, 1H), 8.15 - 8.04 (m, 2H), 7.46 (t, J = 2.8 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 8.6, 2.1 Hz, 1H), 6.50 - 6.43 (m, 1H), 3.59 - 3.51 (m, 4H), 3.11 (s, 3H), 3.04 - 2.95 (m, 4H), 2.29 - 2.10 (m, 5H), 1.94 - 1.59 (m, 3H), 0.39 (s, 4H).

[0547] Example 47 Preparation of Compound 48

[0548] [ka]

[0549] Manufacturing method: Step 1: Synthesis of compound 48 Compound 25H (400 mg, 0.71 mmol) and methanesulfonamide (82 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (8 mL), and cuprous iodide (14 mg, 0.07 mmol), potassium phosphate (304 mg, 1.42 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 48 (180 mg, off-white solid). MS (ESI): m / z 287.7 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 12.52 (s, 1H), 10.24 (br.s, 1H), 8.24 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 4.34 - 4.23 (m, 4H), 4.14 (s, 3H), 3.10 (s, 3H), 3.03 - 2.96 (m, 4H), 2.19 - 1.98 (m, 5H), 1.89 - 1.58 (m, 3H), 0.40 (s, 4H).

[0550] Example 48 Preparation of Compound 49

[0551] [ka]

[0552] Step 1: Synthesis of compound 49-2 Compound 49-1 (50 g, 232.2 mmol) was dissolved in diethylene glycol (600 mL), and potassium hydroxide (59.8 g, 1.07 mol) and hydrazine hydrate (62.9 g, 1.07 mol) were added in an ice bath, followed by stirring at 180 °C for 5 h. LCMS showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (500 mL), and extracted with methyl tert-butyl ether (500 mL × 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude compound 49-2 (50 g, pale yellow oil). MS (ESI): m / z 202.2 [M+1] + .

[0553] Step 2: Synthesis of compound 49-3 Crude compound 49-2 (50 g, 248.4 mmol) was added to ethyl acetate hydrochloride (200 mL, 4 mol / L) in an ice bath, and then methanol (200 mL) was added. The mixture was then stirred at 45 °C for 96 h under hydrogen balloon protection. LCMS showed the reaction was complete, and the reaction mixture was filtered through diatomaceous earth. The filtrate was further evaporated under reduced pressure to give crude compound 49-3 (20 g, pale yellow solid).

[0554] Step 3: Synthesis of compound 49-4 Compound 6D (20 g, 85.8 mmol) was dissolved in N-methylpyrrolidone (200 mL), and compound 49-3 (40 g, 257 mmol) and potassium carbonate (71 g, 515 mmol) were added. The mixture was then stirred at 120 °C for 16 h. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (1000 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 49-4 (20 g, pale yellow oil, purity 80.2%, yield 57.6%). MS (ESI): m / z 324.0 326.0 [M+1] + .

[0555] Step 4: Synthesis of compound 49A Compound 49-4 (20 g, 61.7 mmol) was dissolved in methanol (150 mL), water (150 mL), and tetrahydrofuran (150 mL). Lithium hydroxide monohydrate (5.2 g, 123 mmol) was added in an ice bath and the mixture was stirred at 50 °C for 16 h. TLC showed the reaction was complete. The reaction mixture was then evaporated under reduced pressure to remove the methanol and tetrahydrofuran. 1N hydrochloric acid was then added to adjust the pH to 5-6. A white solid precipitated, which was filtered. The filter cake was washed with water (200 mL). The filter cake was collected and dried to give compound 49A (17.5 g, white solid, 90.8% purity, 83.0% yield). MS (ESI): m / z 310.0 312.0 [M+1] + . 1 H NMR (300 MHz, Chloroform-d) δ(ppm) 8.16 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.4, 1.8 Hz, 1H), 3.08 - 3.01 (m, 2H), 2.95 - 2.89 (m, 2H), 2.44 - 2.37 (m, 2H), 1.99 - 1.80 (m, 5H), 1.71 - 1.69 (m, 1H).

[0556] Step 5: Synthesis of compound 49B Compound 49A (1.0 g, 3.27 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (1.0 g, 8.18 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 15F (880 mg, 1.80 mmol) and N,N-diisopropylethylamine (1.7 g, 13.1 mmol) was added at room temperature, and the reaction solution was stirred at 50 °C for 1 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 49B (1.2 g, yellow solid, purity 70.2%, yield 45.9%). MS (ESI): m / z 281.0 282.3 [M / 2+1] + .

[0557] Step 6: Synthesis of compound 49 Compound 49B (100 mg, 0.18 mmol) and methanesulfonamide (20 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 49 (30 mg, off-white solid). MS (ESI): m / z 288.7 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.57 (s, 1H), 10.04 (s, 1H), 8.32 (s, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.4, 2.0 Hz, 1H), 3.81 - 3.70 (m, 4H), 3.09 - 2.96 (m, 5H), 2.80 (d, J = 10.6 Hz, 2H), 2.29 - 2.02 (m, 6H), 1.98 - 1.88 (m, 2H), 1.62 - 1.43 (m, 4H).

[0558] Example 49 Preparation of Compound 50

[0559] [ka]

[0560] Manufacturing method: Step 1: Synthesis of Compound 50 Compound 49B (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 50 (30 mg, off-white solid). MS (ESI): m / z 303.6 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.58 (s, 1H), 10.02 (br.s, 1H), 8.32 (s, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 5.4 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.4, 1.9 Hz, 1H), 4.95 (br.s, 1H), 3.78 -3.73 (m, 6H), 3.31 (t, J = 6.7 Hz, 2H), 3.06 - 2.98 (m, 2H), 2.79 (d, J = 10.6 Hz, 2H), 2.25 - 2.06 (m, 6H), 1.98 - 1.89 (m, 2H), 1.58 - 1.45 (m, 4H).

[0561] Example 50 Preparation of Compound 51

[0562] [ka]

[0563] Step 1: Synthesis of compound 51 Compound 51A (180 mg, 0.3 mmol) and 2-hydroxy-1-sulfonamide (54 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (36 mg, 0.18 mmol), potassium phosphate (198 mg, 0.87 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (42 mg, 0.26 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. LCMS showed the reaction was complete, and the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 51 (50 mg, yellow solid). MS (ESI): m / z 304.7 [M / 2+1] + .1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.65 (s, 1H), 10.05 (br.s, 1H), 8.51 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.5, 2.0 Hz, 1H), 4.95 (br.s, 1H), 4.44 - 4.31 (m, 4H), 3.75 (t, J = 6.6 Hz, 2H), 3.32 (t, J = 6.6 Hz, 2H), 3.03 - 2.94 (m, 2H), 2.80 (d, J = 10.5 Hz, 2H), 2.31 - 2.22 (m, 2H), 2.16 - 1.95 (m, 6H), 1.66 - 1.47 (m, 4H).

[0564] Example 51 Production of Compound 52

[0565]

change

[0566] ステップ1:Synthesis of compound 51A Compound 49A (456 mg, 1.5 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (468 mg, 3.8 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete. The reaction solution was then rotary evaporated, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 34D (400 mg, 1.5 mmol) and N,N-diisopropylethylamine (761 mg, 6.0 mmol) were added at room temperature, and the reaction solution was then stirred at 25 °C for 2 hours. TLC showed the reaction was complete. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 51A (725 mg, yellow solid, 86.6% yield). MS (ESI): m / z 563.1 565.1 [M+1] + .

[0567] Step 2: Synthesis of Compound 52 Compound 51A (180 mg, 0.3 mmol) and methanesulfonamide (42 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (36 mg, 0.18 mmol), potassium phosphate (198 mg, 0.87 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (42 mg, 0.26 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 52 (60 mg, yellow solid). MS (ESI): m / z 289.5 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.64 (s, 1H), 10.08 (s, 1H), 8.51 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 4.43 - 4.32 (m, 4H), 3.08 (s, 3H), 2.99 (dd, J = 10.5, 3.6 Hz, 2H), 2.86 - 2.76 (m, 2H), 2.30 - 2.21 (m, 2H), 2.14 - 1.95 (m, 6H), 1.65 - 1.45 (m, 4H).

[0568] Example 52 Preparation of Compound 53

[0569] [ka]

[0570] Step 1: Synthesis of compound 53A Compound 49A (438 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (450 mg, 3.55 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. It was then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 23H (360 mg, 1.42 mmol) and N,N-diisopropylethylamine (731 mg, 5.68 mmol) was added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 53A (350 mg, yellow solid, 45.2% yield). MS (ESI): m / z 546.1 548.1 [M+1] + .

[0571] Step 2: Synthesis of compound 53 Compound 53A (150 mg, 0.27 mmol) and methanesulfonamide (31 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (5 mg, 0.03 mmol), potassium phosphate (116 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 53 (30 mg, off-white solid). MS (ESI): m / z 561.2 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.92 (s, 1H), 10.09 (br.s, 1H), 9.04 (s, 1H), 8.50 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.06 - 6.96 (m, 1H), 4.39 - 4.32 (m, 4H), 3.08 (s, 3H), 3.02 - 2.96 (m, 2H), 2.82 (d, J = 10.7 Hz, 2H), 2.29 - 2.22 (m, 2H), 2.20 - 1.94 (m, 6H), 1.63 - 1.50 (m, 4H).

[0572] Example 53 Preparation of Compound 54

[0573] [ka]

[0574] Step 1: Synthesis of compound 54 Compound 53A (150 mg, 0.27 mmol) and 2-hydroxy-1-sulfonamide (41 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (5 mg, 0.03 mmol), potassium phosphate (116 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 54 (30 mg, off-white solid). MS (ESI): m / z 591.2 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.92 (s, 1H), 10.06 (br.s, 1H), 9.04 (s, 1H), 8.50 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 4.95 (br.s, 1H), 4.42 - 4.28 (m, 4H), 3.75 (t, J = 6.5 Hz, 2H), 3.32 (t, J = 6.5 Hz, 2H), 3.03 - 2.92 (m, 2H), 2.82 (d, J = 10.6 Hz, 2H), 2.29 - 2.21 (m, 2H), 2.20 - 1.92 (m, 6H), 1.66 - 1.46 (m, 4H).

[0575] Example 54 Preparation of Compound 55

[0576] [ka]

[0577] Step 1: Synthesis of compound 55 Compound 55A (150 mg, 0.27 mmol) and 2-hydroxy-1-sulfonamide (40 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (4 mg, 0.03 mmol), potassium phosphate (114 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 55 (30 mg, off-white solid). MS (ESI): m / z 302.7 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.04 (s, 1H), 9.94 (br.s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 8.4, 2.0 Hz, 1H), 4.91 (br.s, 1H), 4.25 - 4.17 (m, 4H), 4.11 (s, 3H), 3.72 (t, J = 6.6 Hz, 2H), 3.27 (t, J = 6.7 Hz, 2H), 3.04 - 2.95 (m, 2H), 2.74 (d, J = 10.6 Hz, 2H), 2.22 - 2.16 (m, 2H), 2.09 - 1.89 (m, 6H), 1.53 - 1.41 (m, 4H).

[0578] Example 55 Preparation of Compound 56

[0579] [ka]

[0580] Step 1: Synthesis of compound 55A Compound 49A (556 mg, 1.80 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (570 mg, 4.50 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped. It was then dissolved in anhydrous tetrahydrofuran (10 mL) and a mixture of compound 25G (480 mg, 1.80 mmol) and N,N-diisopropylethylamine (928 mg, 7.20 mmol) was added sequentially at room temperature. The reaction solution was then stirred at 50 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 55A (350 mg, yellow solid, 34.8% yield). MS (ESI): m / z 559.2 561.2 [M+1] + .

[0581] Step 2: Synthesis of compound 56 Compound 55A (150 mg, 0.27 mmol) and methanesulfonamide (31 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (4 mg, 0.03 mmol), potassium phosphate (114 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 56 (30 mg, off-white solid). MS (ESI): m / z 287.6 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.03 (s, 1H), 9.97 (br.s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 8.4, 2.0 Hz, 1H), 4.24 - 4.18 (m, 4H), 4.11 (s, 3H), 3.04 - 2.96 (m, 5H), 2.75 (d, J = 10.5 Hz, 2H), 2.22 - 2.15 (m, 2H), 2.07 - 1.89 (m, 6H), 1.56 - 1.42 (m, 4H).

[0582] Example 56 Preparation of Compound 57

[0583] [ka]

[0584] Step 1: Synthesis of compound 57 Compound 23I (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (78 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.36 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 57 (30 mg, off-white solid). MS (ESI): m / z 281.2 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.28 (s, 1H), 10.29 (s, 1H), 8.95 (s, 1H), 8.49 (s, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.15 (dd, J = 8.6, 2.1 Hz, 1H), 4.43 - 4.32 (m, 4H), 3.13 (s, 3H), 3.06 - 2.93 (m, 4H), 2.35 - 1.43 (m, 8H), 0.41 (s, 4H).

[0585] Example 57 Preparation of Compound 58

[0586] [ka]

[0587] Step 1: Synthesis of compound 58 Compound 27H (200 mg, 0.37 mmol) and methanesulfonamide (42 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (156 mg, 0.74 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 58 (30 mg, off-white solid). MS (ESI): m / z 560.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 12.81 (s, 1H), 10.24 (s, 1H), 8.71 (d, J = 0.8 Hz, 1H), 8.53 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.6, 2.1 Hz, 1H), 4.03 - 3.92 (m, 4H), 3.12 (s, 3H), 3.03 - 2.94 (m, 4H), 2.28 - 1.53 (m, 8H), 0.40 (s, 4H).

[0588] Example 58 Preparation of Compound 59

[0589] [ka]

[0590] Step 1: Synthesis of compound 59A Compound 49A (525 mg, 1.70 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (540 mg, 4.25 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotovapped. It was then dissolved in anhydrous tetrahydrofuran (10 mL) and a mixture of compound 27G (430 mg, 1.70 mmol) and N,N-diisopropylethylamine (877 mg, 6.80 mmol) was added sequentially at room temperature. The reaction solution was then stirred at 50 °C for 1 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 59A (450 mg, yellow solid, purity 75.1%, yield 36.5%). MS (ESI): m / z 273.1 273.9 [M / 2+1] + .

[0591] Step 2: Synthesis of compound 59 Compound 59A (200 mg, 0.37 mmol) and 2-hydroxy-1-sulfonamide (55 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (156 mg, 0.74 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 59 (30 mg, off-white solid). 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.45 (s, 1H), 10.02 (br.s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.4, 2.0 Hz, 1H), 4.94 (br.s, 1H), 3.98 - 3.87 (m, 4H), 3.75 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 3.04 -2.94 (m, 2H), 2.79 (d, J = 10.6 Hz, 2H), 2.28 - 2.20 (m, 2H), 2.16 - 1.93 (m, 6H), 1.64 - 1.47 (m, 4H).

[0592] Example 59 Preparation of Compound 60

[0593] [ka]

[0594] Step 1: Synthesis of compound 60 Compound 59A (200 mg, 0.37 mmol) and methanesulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (156 mg, 0.74 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 60 (20 mg, off-white solid). MS (ESI): m / z 560.3 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.45 (s, 1H), 10.05 (br.s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.5, 2.0 Hz, 1H), 3.98 - 3.88 (m, 4H), 3.07 (s, 3H), 2.99 (dd, J = 10.7, 3.7 Hz, 2H), 2.80 (d, J = 10.6 Hz, 2H), 2.28 - 2.21 (m, 2H), 2.18 - 1.90 (m, 6H), 1.66 - 1.44 (m, 4H).

[0595] Example 60 Preparation of Compound 61

[0596] [ka]

[0597] Step 1: Synthesis of compound 61 Compound 24K (150 mg, 0.28 mmol) and methanesulfonamide (35 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (32 mg, 0.17 mmol), potassium phosphate (170 mg, 0.81 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.24 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated brine (8 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 61 (30 mg, yellow solid). MS (ESI): m / z 561.2 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 13.08 (s, 1H), 10.27 (s, 1H), 9.37 (s, 1H), 8.79 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.15 (dd, J = 8.7, 2.1 Hz, 1H), 4.54 - 4.38 (m, 4H), 3.13 (s, 3H), 3.04 - 2.94 (m, 4H), 2.27 - 2.06 (m, 5H), 1.87 - 1.62 (m, 3H), 0.41 (s, 4H).

[0598] Example 61 Preparation of Compound 62

[0599] [ka]

[0600] Step 1: Synthesis of compound 62A Compound 49A (800 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (821 mg, 6.5 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 22E (652 mg, 2.6 mmol) and N,N-diisopropylethylamine (1.33 g, 10.4 mmol) were added at room temperature, followed by stirring at 25 °C for 1 hour. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 62A (980 mg, 1.8 mmol, yellow solid, 69% yield). MS (ESI): m / z 272.6 273.4[M / 2+1] + .

[0601] Step 2: Synthesis of compound 62 Compound 62A (200 mg, 0.36 mmol) and 2-hydroxy-1-sulfonamide (60 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (42 mg, 0.22 mmol), potassium phosphate (226 mg, 1.01 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (44 mg, 0.31 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 62 (52.7 mg, yellow solid). MS (ESI): m / z 589.1 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 11.32 (s, 1H), 10.37 (s, 1H), 10.01 (s, 1H), 8.09 (s, 1H), 7.72 (dd, J = 8.4, 1.4 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.5, 2.0 Hz, 1H), 6.46 (dd, J = 3.0, 1.6 Hz, 1H), 4.94 (br.s, 1H), 3.74 (t, J = 6.6 Hz, 2H), 3.52 - 3.44 (m, 4H), 3.31 (t, J = 6.7 Hz, 2H), 3.05 - 2.96 (m, 2H), 2.79 (d, J = 10.5 Hz, 2H), 2.26 - 2.08 (m, 6H), 2.02 - 1.94 (m, 2H), 1.59 - 1.44 (m, 4H).

[0602] Example 62 Production of Compound 63

[0603]

change

[0604] ステップ1:Synthesis of compound 63 Compound 62A (200 mg, 0.36 mmol) and methanesulfonamide (46 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (42 mg, 0.22 mmol), potassium phosphate (226 mg, 1.01 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (44 mg, 0.31 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 63 (61.3 mg, yellow solid). MS (ESI): m / z 559.2 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 11.32 (s, 1H), 10.37 (s, 1H), 10.03 (s, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.4, 2.0 Hz, 1H), 6.46 (s, 1H), 3.52 - 3.48 (m, 4H), 3.07 (s, J = 1.8 Hz, 3H), 3.06 -2.97 (m, 2H), 2.80 (d, J = 10.5 Hz, 2H), 2.25 - 2.10 (m, 6H), 2.03 - 1.93 (m, 2H), 1.59 - 1.44 (m, 4H).

[0605] Example 63 Preparation of Compound 64

[0606] [ka]

[0607] Step 1: Synthesis of compound 64A Compound 49A (729 mg, 2.4 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (750 mg, 6 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, so the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 24J (600 mg, 2.4 mmol) and N,N-diisopropylethylamine (1.2 g, 9.6 mmol) were added at room temperature, followed by stirring at room temperature for 1 hour. TLC showed the reaction was complete, so the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give compound 64A (573 mg, yellow solid, 45.8% yield). MS (ESI): m / z 273.6 274.5 [M / 2+1] + .

[0608] Step 2: Synthesis of compound 64 Compound 64A (180 mg, 0.33 mmol) and 2-hydroxy-1-sulfonamide (54 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (376 mg, 0.20 mmol), potassium phosphate (203 mg, 0.96 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.28 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 64 (30.1 mg, yellow solid). MS (ESI): m / z 591.3 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.67 (s, 1H), 10.05 (br.s, 1H), 9.37 (d, J = 1.2 Hz, 1H), 8.86 (d, J = 1.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.95 (br.s, 1H), 4.50 - 4.31 (m, 4H), 3.75 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 7.1 Hz, 2H), 2.98 (d, J = 10.5 Hz, 2H), 2.80 (d, J = 10.5 Hz, 2H), 2.28 - 2.06 (m, 6H), 1.99 - 1.90 (m, 2H), 1.65 - 1.44 (m, 4H).

[0609] Example 64 Preparation of Compound 65

[0610] [ka]

[0611] Step 1: Synthesis of compound 65 Compound 64A (180 mg, 0.33 mmol) and methanesulfonamide (41 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (376 mg, 0.20 mmol), potassium phosphate (203 mg, 0.96 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.28 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 65 (37.7 mg, yellow solid). MS (ESI): m / z 561.2 [M+1] +. 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 10.66 (s, 1H), 10.08 (br.s, 1H), 9.37 (d, J = 1.3 Hz, 1H), 8.86 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 4.50 - 4.33 (m, 4H), 3.07 (s, 3H), 2.99 (d, J = 10.6 Hz, 2H), 2.81 (d, J = 10.6 Hz, 2H), 2.27 - 2.06 (m, 6H), 2.00 - 1.91 (m, 2H), 1.65 - 1.44 (m, 4H).

[0612] Example 65 Preparation of Compound 66

[0613] [ka]

[0614] Manufacturing method: Step 1: Synthesis of compound 66B Compound 66A (180 mg, 0.29 mmol) and methanesulfonamide (35 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (33 mg, 0.17 mmol), potassium phosphate (176 mg, 0.84 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.25 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 66B (120 mg, yellow solid, 65% yield). MS (ESI): m / z 281.1[M-THP / 2+1] + .

[0615] Step 2: Synthesis of compound 66 Compound 66B (120 mg, 0.19 mmol) was dissolved in a solution of hydrochloric acid and ethyl acetate (3 mL) and then stirred at room temperature for 0.5 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure. The residue was purified by HPLC preparative method to give compound 66 (42.1 mg, white solid). MS (ESI): m / z 281.1 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 15.73 (s, 1H), 10.47 (s, 1H), 10.07 (br.s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.4, 2.1 Hz, 1H), 4.42 - 4.27 (m, 4H), 3.10 - 2.97 (m, 5H), 2.79 (d, J = 10.6 Hz, 2H), 2.27 - 2.17 (m, 2H), 2.14 - 2.00 (m, 4H), 1.97 - 1.90 (m, 2H), 1.61 - 1.43 (m, 4H).

[0616] Example 66 Preparation of Compound 67

[0617] [ka]

[0618] Step 1: Synthesis of compound 66A Compound 49A (457 mg, 1.5 mmol) and compound 28G (625 mg, 1.8 mmol) were dissolved in pyridine (10 mL), and phosphorus oxychloride (1.4 mg, 9 mmol) was added dropwise in an ice bath. The mixture was then stirred at room temperature for 3 hours. TLC showed the reaction was complete, and the reaction mixture was adjusted to pH 6 with 1N hydrochloric acid in an ice bath, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified using a silica gel column to give compound 66A (360 mg, yellow solid, 38% yield). MS (ESI): m / z 273.6 274.3 [M-THP / 2+1] + .

[0619] Step 2: Synthesis of compound 67A Compound 66A (180 mg, 0.29 mmol) and 2-hydroxy-1-sulfonamide (46 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (33 mg, 0.17 mmol), potassium phosphate (176 mg, 0.84 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.25 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 67A (180 mg, yellow solid, 89.6% yield). MS (ESI): m / z 296.2[M-THP / 2+1] + .

[0620] Step 3: Synthesis of compound 67 Compound 67A (180 mg, 0.26 mmol) was dissolved in ethanolic hydrochloric acid (3 mL) and stirred at room temperature for 0.5 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure. The residue was purified by HPLC preparative chromatography to give compound 67 (47.5 mg, white solid). MS (ESI): m / z 296.2 [M / 2+1]+ , 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 15.59 (br.s, 1H), 10.48 (s, 1H), 10.03 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H), 7.02 - 6.90 (m, 1H), 4.95 (br.s, 1H), 4.42 - 4.31 (m, 4H), 3.74 (d, J = 6.7 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 3.01 (d, J = 9.9 Hz, 2H), 2.78 (d, J = 10.5 Hz, 2H), 2.29 - 2.18 (m, 2H), 2.15 - 2.01 (m, 4H), 1.98 - 1.89 (m, 2H), 1.61 - 1.40 (m, 4H).

[0621] Example 67 Production of Compound 68

[0622]

change

[0623] ステップ1: Synthesis of compound 68A Compound 28H (200 mg, 0.32 mmol) and methanesulfonamide (39 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (4 mL), and cuprous iodide (36 mg, 0.19 mmol), potassium phosphate (195 mg, 0.93 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (39 mg, 0.28 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 68A (144 mg, yellow solid, 68.7% yield). MS (ESI): m / z 281.2 [M-THP / 2+1] + .

[0624] Step 2: Synthesis of compound 68 Compound 68A (144 mg, 0.22 mmol) was dissolved in a solution of hydrochloric acid and ethyl acetate (3 mL). The mixture was stirred at room temperature for 0.5 hours. TLC showed the reaction was complete, and the solvent was removed under reduced pressure. The residue was purified by HPLC to give compound 68 (50.6 mg, white solid). MS (ESI): m / z 281.2 [M / 2+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 15.60 (br.s, 1H), 12.99 (s, 1H), 10.27 (br.s, 1H), 8.10 (dd, J = 8.7, 1.4 Hz, 1H), 7.85 (d, J = 1.4 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.7, 2.0 Hz, 1H), 4.49 - 4.32 (m, 4H), 3.12 (s, 3H), 3.05 - 2.94 (m, 4H), 2.29 - 2.02 (m, 5H), 1.91 - 1.55 (m, 3H), 0.40 (s, 4H).

[0625] Example 68 Preparation of Compound 69

[0626] [ka]

[0627] Step 1: Synthesis of compound 69A Compound 49A (646 mg, 2.09 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (664 mg, 5.23 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 min. TLC showed the reaction was complete, and the reaction solution was rotovapped and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 41C (780 mg, 2.09 mmol) and N,N-diisopropylethylamine (1.1 g, 8.36 mmol) was added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 1 h. TLC showed the reaction was complete, and the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified using a silica gel column to give compound 69A (800 mg, yellow solid, purity 81.2%, yield 46.7%). MS (ESI): m / z 332.9 334.2 [M / 2+1] + .

[0628] Step 2: Synthesis of compound 69B Compound 69A (200 mg, 0.30 mmol) and methanesulfonamide (34 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (6 mg, 0.03 mmol), potassium phosphate (128 mg, 0.60 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (9 mg, 0.06 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 69B (100 mg, yellow oil, purity 93.7%, yield 45.9%). MS (ESI): m / z 340.7[M / 2+1] + .

[0629] Step 3: Synthesis of compound 69 Compound 69B (100 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (2 mL), trifluoromethanesulfonic acid (0.2 mL) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction mixture was diluted with water (20 mL), adjusted to pH 8 with solid sodium bicarbonate, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 69 (20 mg, off-white solid). MS (ESI): m / z 560.2 [M+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.94 (s, 1H), 10.31 - 9.98 (m, 2H), 8.22 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.97 (dd, J = 8.4, 1.9 Hz, 1H), 4.32 - 3.79 (m, 4H), 3.08 - 2.98 (m, 5H), 2.79 (d, J = 10.5 Hz, 2H), 2.27 - 2.19 (m, 2H), 2.17 - 1.93 (m, 6H), 1.58 - 1.45 (m, 4H).

[0630] Example 69 Preparation of Compound 70

[0631] [ka]

[0632] Step 1: Synthesis of compound 70 Compound 39E (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by HPLC to give compound 70 (8 mg, yellow solid). MS (ESI): m / z 286.6 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 13.09 (s, 1H), 10.30 (s, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.22 - 8.06 (m, 2H), 7.27 (d, J = 2.1 Hz, 1H), 7.20 - 7.05 (m, 1H), 4.28 - 4.16 (m, 4H), 3.13 (s, 3H), 3.06 - 2.98 (m, 4H), 2.33 - 1.56 (m, 8H), 0.41 (s, 4H).

[0633] Example 70 Preparation of Compound 71

[0634] [ka]

[0635] Step 1: Synthesis of compound 71A Compound 69A (200 mg, 0.30 mmol) and 2-hydroxy-1-sulfonamide (45 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (6 mg, 0.03 mmol), potassium phosphate (128 mg, 0.60 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (9 mg, 0.06 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified using a silica gel column to give compound 71A (100 mg, yellow oil, purity 88.5%, yield 41.5%). MS (ESI): m / z 355.7 [M / 2+1] + .

[0636] Step 3: Synthesis of compound 71 Compound 71A (100 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (0.2 mL) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL), adjusted to pH 8 with solid sodium bicarbonate, and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to give the crude compound, which was then purified by preparative thin-layer chromatography to give compound 71 (30 mg, off-white solid).

[0637] MS (ESI): m / z 590.3 [M+1] + . 1 H NMR (300 MHz, DMSO-d6) δ(ppm) 14.20 - 13.23 (m, 1H), 10.51 - 9.92 (m, 2H), 8.32 -7.79 (m, 2H), 7.72 - 7.61 (m, 1H), 7.11 (s, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.35 - 4.19 (m, 2H), 3.83 - 3.60 (m, 4H), 3.31 (t, J = 5.7 Hz, 2H), 3.08 - 2.96 (m, 2H), 2.82 - 2.73 (m, 2H), 2.26 - 1.93 (m, 8H), 1.61 - 1.44 (m, 4H).

[0638] Example 71 Preparation of Compound 72

[0639] [ka]

[0640] Step 1: Synthesis of compound 72A Compound 49A (408 mg, 1.32 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (420 mg, 3.30 mmol) was added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. TLC showed the reaction was complete, and the reaction solution was rotary evaporated and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 39D (350 mg, 1.32 mmol) and N,N-diisopropylethylamine (512 mg, 3.96 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50 °C for 16 hours. TLC showed the reaction was complete, and the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound 72A (200 mg, reddish-brown solid, 27.2% yield). MS (ESI): m / z 279.2 280.2 [M / 2+1] + .

[0641] Step 2: Synthesis of compound 72 Compound 72A (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cuprous iodide (3 mg, 0.04 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by high-performance liquid chromatography to give compound 72 (8 mg, orange-yellow solid). MS (ESI): m / z 286.6 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.65 (s, 1H), 10.07 (br.s, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.09 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.22 - 4.14 (m, 4H), 3.08 - 2.99 (m, 5H), 2.85 - 2.77 (m, 2H), 2.26 - 2.05 (m, 6H), 1.97 - 1.86 (m, 2H), 1.58 - 1.43 (m, 4H).

[0642] Example 72 Preparation of Compound 73

[0643] [ka]

[0644] Compound 72A (200 mg, 0.36 mmol) and 2-hydroxyethane-1-sulfonamide (54 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (6 mL), and cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (153 mg, 0.72 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.08 mmol) were added sequentially. The mixture was then stirred at 120 °C for 2 h under nitrogen gas protection. TLC showed the reaction was complete, and the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative chromatography to give compound 73 (55 mg, orange-yellow solid). MS (ESI): m / z 301.7 [M / 2+1] + . 1H NMR (300 MHz, DMSO-d6) δ(ppm) 10.64 (s, 1...

Claims

1. A nitrogen-containing compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, 【Chemical 1】 Among them, R ｘ represents a 3- to 6-membered monocyclic cycloalkyl group, a 5- to 6-membered monocyclic heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－１ a 5- to 6-membered monocyclic heterocycloalkyl group substituted with one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R ｘ－３ a 7- to 9-membered spiroheterocycloalkyl group substituted with one or more R ｘ－４ and the "5- to 6-membered monocyclic heterocycloalkyl group", the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiro heterocycloalkyl group", the "one or more R ｘ－１ "a 5- to 6-membered monocyclic heterocycloalkyl group substituted with one or more R ｘ－２ "6- to 9-membered bridged heterocycloalkyl group substituted with" and "one or more R ｘ－３ In the "7- to 9-membered spiroheterocycloalkyl group substituted with one or more R", the heteroatoms independently consist of one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two selected from N, O and S, and the "5- to 6-membered monocyclic heterocycloalkyl group", the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiroheterocycloalkyl group", the "one or more R ｘ－１ "a 5- to 6-membered monocyclic heterocycloalkyl group substituted with one or more R ｘ－２ "6- to 9-membered bridged heterocycloalkyl group substituted with" and "one or more R ｘ－３ "7-9 membered spiroheterocycloalkyl group substituted with" is linked to ring A via the N atom, Each R ｘ－１ , R ｘ－２ , R ｘ－３ and R ｘ－４ are each independently a halogen, R Ｎ－１０ｋ , R Ｎ－１０ｌ , C １－６ alkyl group, C substituted with one or more halogens １－６ alkyl group, -OR Ｎ－ａ , C substituted with one or more halogens １－６ Alkoxy group, CN, -NR Ｎ－ａ R Ｎ－ａ or oxo, R １ is -L-R １－１ and L is *-NHSO ２ -, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SO ２ NH- or -SO ２ -, and * represents one end connected to ring A, R １－１ is C １－６ an alkyl group, a 3- to 6-membered monocyclic cycloalkyl group, a 4- to 8-membered monocyclic heterocycloalkyl group, one or more R ａ C substituted with １－６ an alkyl group or one or more R ｂ In the 4- to 8-membered monocyclic heterocycloalkyl group, the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R ａ are each independently a hydroxy group, a halogen, or —NH(R ａ－１ ) and R ａ－１ is C １－６ is an alkyl group, Each R ｂ are each independently C １－６ C substituted with alkyl groups or one or more hydroxy groups １－６ is an alkyl group, G is C(R １０ ) or N, and R １０ is H, halogen, C １－６ alkyl group, C substituted with one or more halogens １－６ Alkyl group, —OH, —O—R Ｎ－８ａ Or -O-R Ｎ－８ｂ and M is a phenyl group, a naphthyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, one or more R ２ a 6-membered heteroaryl group substituted with one or more R ３ a 9- to 10-membered heteroaryl group substituted with one or more R ４ a 6-membered heterocycloalkenyl group substituted with one or more R ５ a phenyl group substituted with one or more R ５ or a naphthyl group substituted with one or more R ６ and the "5-membered heteroaryl group", "6-membered heteroaryl group", "9- to 10-membered heteroaryl group", "6-membered heterocycloalkenyl group", "one or more R ２ "a 6-membered heteroaryl group substituted with ", "one or more R ３ "a 9- to 10-membered heteroaryl group substituted with one or more R ４ "a 6-membered heterocycloalkenyl group substituted with one or more R ６ In the "5-membered heteroaryl group substituted with" the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R ２ , R ３ , R ４ , R ５ and R ６ are each independently oxo, halogen, R Ｎ－４ａ , R Ｎ－４ｂ , C １－６ alkyl group, C substituted with one or more halogens １－６ Alkyl group, cyano group, C １－６ Alkoxy group, —O—R Ｎ－６ａ or -Y-R Ｎ－１３ and R Ｎ－６ａ is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; Y is -C １－６ Alkyl-, -N(C １－６ alkyl)-C １－６ Alkyl-, —C(═O)NR Ｎ－ａ R Ｎ－ａ (C １－６ alkyl), —O—, —O—C １－６ Alkyl-, S, S=O, S(=O) ２ , -S(=O)(=NR Ｎ－１３ )- or -S(=O)(=NH)-, R Ｎ－１３ is R Ｎ－１３ａ or R Ｎ－１３ｂ and Each R Ｎ－４ａ , R Ｎ－８ａ , R Ｎ－１０ｋ and R Ｎ－１３ａ are each independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which may be substituted or unsubstituted by halogen, C １－６ alkyl group, C substituted with one or more halogens １－６ alkyl group, -OR Ｎ－ａ , C substituted with one or more halogens １－６ Alkoxy group, CN, —C(═O)R Ｎ－ｂ , -C(=O)OR Ｎ－ａ , —C(═O)NR Ｎ－ａ R Ｎ－ａ , -C(=NR Ｎ－ａ ) NR Ｎ－ａ R Ｎ－ａ , —OC(═O)R Ｎ－ｂ , -OC(=O)NR Ｎ－ａ R Ｎ－ａ , -OC １－６ Alkyl NR Ｎ－ａ R Ｎ－ａ , -OC １－６ Alkyl OR Ｎ－ａ , -SR Ｎ－ａ , -S(=O)R Ｎ－ｂ , -S(=O) ２ R Ｎ－ｂ , -S(=O) ２ NR Ｎ－ａ R Ｎ－ａ , -NR Ｎ－ａ R Ｎ－ａ , -N(R Ｎ－ａ ) C(=O)R Ｎ－ｂ , -N(R Ｎ－ａ ) C(=O) OR Ｎ－ｂ , -N(R Ｎ－ａ )C(=O)NR Ｎ－ａ R Ｎ－ａ , -N(R Ｎ－ａ ) C(=NR Ｎ－ａ ) NR Ｎ－ａ R Ｎ－ａ , -N(R Ｎ－ａ ) S(=O) ２ R Ｎ－ｂ , -N(R Ｎ－ａ ) S(=O) ２ NR Ｎ－ａ R Ｎ－ａ , -NR Ｎ－ａ C １－６ Alkyl NR Ｎ－ａ R Ｎ－ａ , -NR Ｎ－ａ C １－６ Alkyl OR Ｎ－ａ , -C １－６ Alkyl NR Ｎ－ａ R Ｎ－ａ , -C １－６ Alkyl OR Ｎ－ａ , -C １－６ AlkylN(R Ｎ－ａ ) C(=O)R Ｎ－ｂ , -C １－６ AlkylOC(=O)R Ｎ－ｂ , -C １－６ AlkylC(=O)NR Ｎ－ａ R Ｎ－ａ , -C １－６ AlkylC(=O)OR Ｎ－ａ , R Ｎ－１４ and oxo; Each R Ｎ－４ｂ , R Ｎ－８ｂ , R Ｎ－１０ｌ and R Ｎ－１３ｂ are each independently a halogen, —OR Ｎ－ａ , C substituted with one or more halogens １－６ C substituted with 0, 1, 2, 3, 4 or 5 groups selected from alkoxy groups and CN １－６ is an alkyl group, Each R Ｎ－１４ are each independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which may further contain halogen, C １－６ alkyl group, C substituted with one or more halogens １－６ alkyl group, -OR Ｎ－ａ , C substituted with one or more halogens １－６ Alkoxy group, CN, —C(═O)R Ｎ－ｂ , -C(=O)OR Ｎ－ａ , —C(═O)NR Ｎ－ａ R Ｎ－ａ , -C(=NR Ｎ－ａ ) NR Ｎ－ａ R Ｎ－ａ , —OC(═O)R Ｎ－ｂ , -OC(=O)NR Ｎ－ａ R Ｎ－ａ , -OC １－６ Alkyl NR Ｎ－ａ R Ｎ－ａ , -OC １－６ Alkyl OR Ｎ－ａ , -SR Ｎ－ａ , -S(=O)R Ｎ－ｂ , -S(=O) ２ R Ｎ－ｂ , -S(=O) ２ NR Ｎ－ａ R Ｎ－ａ , -NR Ｎ－ａ R Ｎ－ａ , -N(R Ｎ－ａ ) C(=O)R Ｎ－ｂ , -N(R Ｎ－ａ ) C(=O) OR Ｎ－ｂ , -N(R Ｎ－ａ )C(=O)NR Ｎ－ａ R Ｎ－ａ , -N(R Ｎ－ａ ) C(=NR Ｎ－ａ ) NR Ｎ－ａ R Ｎ－ａ , -N(R Ｎ－ａ ) S(=O) ２ R Ｎ－ｂ , -N(R Ｎ－ａ ) S(=O) ２ NR Ｎ－ａ R Ｎ－ａ , -NR Ｎ－ａ C １－６ Alkyl NR Ｎ－ａ R Ｎ－ａ , -NR Ｎ－ａ C １－６ Alkyl OR Ｎ－ａ , -C １－６ Alkyl NR Ｎ－ａ R Ｎ－ａ , -C １－６ Alkyl OR Ｎ－ａ , -C １－６ AlkylN(R Ｎ－ａ ) C(=O)R Ｎ－ｂ , -C １－６ AlkylOC(=O)R Ｎ－ｂ , -C １－６ AlkylC(=O)NR Ｎ－ａ R Ｎ－ａ , -C １－６ AlkylC(=O)OR Ｎ－ａ and oxo; Each R Ｎ－ａ are each independently H or R Ｎ－ｂ and Each R Ｎ－ｂ are each independently C １－６ an alkyl group, a phenyl group, or a benzyl group, １－６ The alkyl group may be a halogen, —OH, —OC １－６ Alkyl group, —NH ２ , -NHC １－６ Alkyl group, —OC(═O)C １－６ Alkyl group or -N(C １－６ alkyl) C １－６ and the phenyl or benzyl group is substituted with 0, 1, 2 or 3 substituents selected from alkyl groups, halogen, C １－６ alkyl group, C substituted with one or more halogens １－６ Alkyl group, —OH, —OC １－６ Alkyl group, —NH ２ , -NHC １－６ Alkyl group, —OC(═O)C １－６ Alkyl group or -N(C １－６ alkyl) C １－６ substituted with 0, 1, 2 or 3 substituents selected from alkyl groups; W and X ２ The definition of may be written in one of the following forms: Technical proposal 1: W is *-CONR Ｗ - and X ２ is R Ｗ－１ where * represents one end connected to ring A; Technical proposal 2: W is *-NR Ｗ CO-, and X ２ is R Ｗ－１ where * represents one end connected to ring A; Technical proposal 3: W is *-C (=X １ ) NR Ｗ - and X １ , X ２ and together with the C atom therebetween form a 6-membered heteroaryl group, in which the heteroatom is one, two or three kinds selected from N, O and S, the number of heteroatoms is 1, 2 or 3, and * represents one end linked to ring A, R Ｗ is H, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, R Ｗ－１ is H, halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, And the compound represented by the above formula I can be prepared by the following conditions: Condition 1: R ｘ is a 6- to 9-membered bridged heterocycloalkyl group or one or more R ｘ－２ is a 6- to 9-membered bridged heterocycloalkyl group substituted with Condition 2: M is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R ５ a naphthyl group substituted with one or more R ６ a 5-membered heteroaryl group substituted with one or more R ３ or one or more R ４ is a 6-membered heterocycloalkenyl group substituted with Condition 3: W is *-C (=X １ ) NR Ｗ - and X １ , X ２ and form a 6-membered heteroaryl group together with the C atom therebetween, A nitrogen-containing compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

2. A nitrogen-containing compound of formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: 【Chemistry 2】 Among them, R ｘ represents a 3- to 6-membered monocyclic cycloalkyl group, a 5- to 6-membered monocyclic heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－１ a 5- to 6-membered monocyclic heterocycloalkyl group substituted with one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R ｘ－３ a 7- to 9-membered spiroheterocycloalkyl group substituted with one or more R ｘ－４ and the "5- to 6-membered monocyclic heterocycloalkyl group", the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiro heterocycloalkyl group", the "one or more R ｘ－１ "a 5- to 6-membered monocyclic heterocycloalkyl group substituted with one or more R ｘ－２ "6- to 9-membered bridged heterocycloalkyl group substituted with" and "one or more R ｘ－３ In the "7- to 9-membered spiroheterocycloalkyl group substituted with one or more R", the heteroatoms independently consist of one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two selected from N, O and S, and the "5- to 6-membered monocyclic heterocycloalkyl group", the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiroheterocycloalkyl group", the "one or more R ｘ－１ "a 5- to 6-membered monocyclic heterocycloalkyl group substituted with one or more R ｘ－２ "6- to 9-membered bridged heterocycloalkyl group substituted with" and "one or more R ｘ－３ "7-9 membered spiroheterocycloalkyl group substituted with" is linked to ring A via the N atom, Each R ｘ－１ , R ｘ－２ , R ｘ－３ and R ｘ－４ are each independently a halogen, C １－６ Alkyl group, C １－６ Alkoxy group, C substituted with one or more halogens １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkoxy group, R １ is -L-R １－１ and L is *-NHSO ２ -, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SO ２ NH- or -SO ２ -, and * represents one end connected to ring A, R １－１ is C １－６ an alkyl group, a 3- to 6-membered monocyclic cycloalkyl group, a 4- to 8-membered monocyclic heterocycloalkyl group, one or more R ａ C substituted with １－６ an alkyl group or one or more R ｂ In the 4- to 8-membered monocyclic heterocycloalkyl group, the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R ａ are each independently a hydroxy group, a halogen, or —NH(R ａ－１ ) and R ａ－１ is C １－６ is an alkyl group, Each R ｂ are each independently C １－６ alkyl group, C substituted with one or more hydroxy groups １－６ is an alkyl group, B is a phenyl group, a naphthyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, one or more R ２ a 6-membered heteroaryl group substituted with one or more R ３ a 9- to 10-membered heteroaryl group substituted with one or more R ４ a 6-membered heterocycloalkenyl group substituted with one or more R ５ a phenyl group substituted with one or more R ５ or a naphthyl group substituted with one or more R ６ and the "5-membered heteroaryl group", "6-membered heteroaryl group", "9- to 10-membered heteroaryl group", "6-membered heterocycloalkenyl group", "one or more R ２ "a 6-membered heteroaryl group substituted with ", "one or more R ３ "a 9- to 10-membered heteroaryl group substituted with one or more R ４ "a 6-membered heterocycloalkenyl group substituted with one or more R ６ In the "5-membered heteroaryl group substituted with" the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R ２ , R ３ , R ４ , R ５ , R ６ are each independently a halogen, a cyano group, an oxo group (=O), C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, one or more R ２－１ a 3- to 10-membered cycloalkyl group substituted with one or more R ２－２ or one or more R ２－３ and the "5- to 10-membered heteroaryl group", "4- to 10-membered heterocycloalkyl group", "one or more R ２－２ "a 4- to 10-membered heterocycloalkyl group substituted with one or more R ２－３ In the "5- to 10-membered heteroaryl group substituted with" the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R ２－１ , R ２－２ and R ２－３ are each independently a halogen, C １－６ Alkyl group, oxo group, CN, hydroxy group, 3- to 6-membered monocyclic cycloalkyl group, C substituted with one or more halogens １－６ alkyl group, C substituted with one or more halogens １－６ an alkoxy group, a 3- to 6-membered monocyclic cycloalkyl group substituted with one or more halogen atoms, or C １－６ is an alkoxy group, W and X ２ The definition of may be written in one of the following forms: (1) W is *-CONR Ｗ - and X ２ is R Ｗ－１ where * represents one end connected to ring A; (2) W is *-NR Ｗ CO-, and X ２ is R Ｗ－１ where * represents one end connected to ring A; (3) W is *-C (=X １ ) NR Ｗ - and X １ , X ２ and together with the C atom therebetween form a 6-membered heteroaryl group, in which the heteroatom is one, two or three kinds selected from N, O and S, the number of heteroatoms is 1, 2 or 3, and * represents one end connected to ring A, R Ｗ is H, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, R Ｗ－１ is H, halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, G is C(R １０ ) or N, R １０ is H, halogen, C １－６ C substituted with an alkyl group, a hydroxy group, or one or more halogens １－６ is an alkyl group, And the compound represented by the formula II can be prepared by the following conditions: (1) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group or one or more R ｘ－２ is a 6- to 9-membered bridged heterocycloalkyl group substituted with (2) B is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R ５ a naphthyl group substituted with one or more R ６ a 5-membered heteroaryl group substituted with one or more R ３ or one or more R ４ is a 6-membered heterocycloalkenyl group substituted with (3) W is *-C (=X １ ) NR Ｗ - and X １ , X ２ and form a 6-membered heteroaryl group together with the C atom therebetween, A nitrogen-containing compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

3. The nitrogen-containing compound represented by formula II is any one of the following technical solutions: Technical proposal 1: R ｘ represents a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－２ and the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiro heterocycloalkyl group" and the "one or more R ｘ－２ In the "6- to 9-membered bridged heterocycloalkyl group substituted with one or more R", the heteroatoms are independently one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two selected from N, O and S, and the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiro heterocycloalkyl group" and the "one or more R ｘ－２ "6-9 membered bridged heterocycloalkyl group substituted with" is linked to ring A via the N atom, Each R ｘ－２ are each independently C １－６ is an alkyl group, R １ is -L-R １－１ and L is *-NHSO ２ -, and * represents one end connected to ring A, R １－１ is C １－６ an alkyl group, one or more R ａ C substituted with １－６ an alkyl group or one or more R ｂ is a 3- to 6-membered monocyclic cycloalkyl group substituted with Each R ａ are each independently a hydroxy group, Each R ｂ are each independently C １－６ is an alkyl group, B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, one or more R ２ a 6-membered heteroaryl group substituted with one or more R ３ and the "5-membered heteroaryl group", "9- to 10-membered heteroaryl group", "one or more R ２ "a 6-membered heteroaryl group substituted with one or more R ３ In the "9- to 10-membered heteroaryl group substituted with" the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R ２ are each independently C １－６ is an alkyl group, Each R ３ are each independently a halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, one or more R ２－１ or one or more R ２－２ and the "4- to 10-membered heterocycloalkyl group" or "one or more R ２－２ In the "4- to 10-membered heterocycloalkyl group substituted with", the heteroatoms are independently one, two or three types selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, Each R ２－１ , R ２－２ and R ２－３ are each independently a halogen; W and X ２ The definition of may be written in one of the following forms: (1) W is *-CONR Ｗ - and X ２ is R Ｗ－１ where * represents one end connected to ring A; (2) W is *-C (=X １ ) NR Ｗ - and X １ , X ２ and together with the C atom therebetween form a 6-membered heteroaryl group, in which the heteroatom is one, two or three kinds selected from N, O and S, the number of heteroatoms is 1, 2 or 3, and * represents one end linked to ring A, R Ｗ is H and R Ｗ－１ is H, G is C(R １０ ) or N, R １０ is H, And the compound represented by the formula II can be prepared by the following conditions: (1) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group or one or more R ｘ－２ is a 6- to 9-membered bridged heterocycloalkyl group substituted with (2) B is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R ５ a naphthyl group substituted with one or more R ６ a 5-membered heteroaryl group substituted with one or more R ３ or one or more R ４ is a 6-membered heterocycloalkenyl group substituted with (3) W is *-C (=X １ ) NR Ｗ - and X １ , X ２ and form a 6-membered heteroaryl group together with the C atom therebetween, Technical proposal 2: R ｘ represents a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－２ and the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiro heterocycloalkyl group" and the "one or more R ｘ－２ In the "6- to 9-membered bridged heterocycloalkyl group substituted with one or more R", the heteroatoms are independently one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two selected from N, O and S, and the "6- to 9-membered bridged heterocycloalkyl group", the "7- to 9-membered spiro heterocycloalkyl group" and the "one or more R ｘ－２ "6-9 membered bridged heterocycloalkyl group substituted with" is linked to ring A via the N atom, Each R ｘ－２ are each independently C １－６ is an alkyl group, R １ is -L-R １－１ and L is *-NHSO ２ -, and * represents one end connected to ring A, R １－１ is C １－６ an alkyl group, one or more R ａ C substituted with １－６ an alkyl group or one or more R ｂ is a 3- to 6-membered monocyclic cycloalkyl group substituted with Each R ａ are each independently a hydroxy group, Each R ｂ are each independently C １－６ is an alkyl group, B is a 9- to 10-membered heteroaryl group, one or more R ２ a 6-membered heteroaryl group substituted with one or more R ３ and the "5-membered heteroaryl group", "9- to 10-membered heteroaryl group", "one or more R ２ "a 6-membered heteroaryl group substituted with one or more R ３ In the "9- to 10-membered heteroaryl group substituted with," the heteroatoms are independently one, two or three selected from N, O and S, the number of heteroatoms is independently 1, 2, 3 or 4, when the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group and has two heteroatoms, the heteroatoms are independently one or two selected from N or O, when the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group and has three heteroatoms, the heteroatom is N, when the 9- to 10-membered heteroaryl group is a 10-membered heteroaryl group and has N heteroatom, the heteroatoms are located on different rings, B is one or more R ２ When R is a 6-membered heteroaryl group substituted with ｘ is an 8- to 9-membered bridged heterocycloalkyl group, and in the "8- to 9-membered bridged heterocycloalkyl group", the heteroatoms independently consist of one N atom and 0, 1 or 2 X atoms, and the X atoms are independently one or two types selected from N, O and S, and the "8- to 9-membered bridged heterocycloalkyl group" is linked to ring A via an N atom, Each R ２ are each independently C １－６ is an alkyl group, Each R ３ are each independently a halogen or C １－６ is an alkyl group, U is a 4- to 10-membered heterocycloalkyl group or one or more R ２－２ and the "4- to 10-membered heterocycloalkyl group" or "one or more R ２－２ In the "4- to 10-membered heterocycloalkyl group substituted with," the heteroatoms are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 2, 3 or 4; Each R ２－２ are each independently a halogen; W is *-CONR Ｗ - and X ２ is R Ｗ－１ where * represents one end connected to ring A; R Ｗ is H and R Ｗ－１ is H, G is C(R １０ ) or N, R １０ is H, And the compound represented by the formula II can be prepared by the following conditions: (1) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group or one or more R ｘ－２ is a 6- to 9-membered bridged heterocycloalkyl group substituted with (2) B is a 9- to 10-membered heteroaryl group, one or more R ３ is a 9- to 10-membered heteroaryl group substituted with Technical proposal 3: R ｘ is a 6- to 9-membered bridged heterocycloalkyl group, one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group or a 7- to 9-membered spiro heterocycloalkyl group substituted with Each R ｘ－２ are each independently C １－６ is an alkyl group, R １ is -L-R １－１ and L is *-NHSO ２ - and R １－１ is C １－６ an alkyl group, one or more R ａ C substituted with １－６ an alkyl group or one or more R ｂ is a 3- to 6-membered monocyclic cycloalkyl group substituted with R ａ is a hydroxy group, Each R ｂ are each independently C １－６ is an alkyl group, B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, one or more R ２ or one or more R ３ is a 9- to 10-membered heteroaryl group substituted with Each R ２ are each independently C １－６ is an alkyl group, Each R ３ are each independently C １－６ is an alkyl group, U is a 4- to 10-membered heterocycloalkyl group, one or more R ２－１ or one or more R ２－２ is a 4- to 10-membered heterocycloalkyl group substituted with Each R ２－１ are each independently a halogen; Each R ２－２ are each independently a halogen; W is *-CONH-, and X ２ is H, And the compound represented by the formula II can be prepared by the following conditions: (1) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group; (2) B is a 5-membered heteroaryl group, a naphthyl group, a 9- to 10-membered heteroaryl group, or one or more R ５ or a naphthyl group substituted with one or more R ３ is a 9- to 10-membered heteroaryl group substituted with A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

4. R ｘ is a 6- to 9-membered bridged heterocycloalkyl group, one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group or a 7- to 9-membered spiro heterocycloalkyl group substituted with Each R ｘ－２ are each independently C １－６ is an alkyl group, R １ is -L-R １－１ and L is *-NHSO ２ - and R １－１ is C １－６ an alkyl group, one or more R ａ C substituted with １－６ an alkyl group or one or more R ｂ is a 3- to 6-membered monocyclic cycloalkyl group substituted with R ａ is a hydroxy group, Each R ｂ are each independently C １－６ is an alkyl group, B is a naphthyl group, a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, one or more R ５ a naphthyl group substituted with one or more R ２ or one or more R ３ is a 9- to 10-membered heteroaryl group substituted with Each R ２ are each independently C １－６ is an alkyl group, Each R ３ are each independently C １－６ is an alkyl group, U is a 4- to 10-membered heterocycloalkyl group, one or more R ２－１ or one or more R ２－２ is a 4- to 10-membered heterocycloalkyl group substituted with Each R ２－１ are each independently a halogen; Each R ２－２ are each independently a halogen; W is *-CONH-, and X ２ is H, And the compound represented by the formula II can be prepared by the following conditions: (1) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group; (2) B is a 5-membered heteroaryl group, a naphthyl group, a 9- to 10-membered heteroaryl group, or one or more R ５ or a naphthyl group substituted with one or more R ３ is a 9- to 10-membered heteroaryl group substituted with A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

5. The following conditions are met: (1) R ｘ represents a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R ｘ－３ is a 7-9 membered spiroheterocycloalkyl group substituted with (2) Each R ｘ－１ , R ｘ－２ , R ｘ－３ and R ｘ－４ are each independently a halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, (3) L is *-NHSO ２ -is, (4) R １－１ is C １－６ an alkyl group, a 3- to 6-membered monocyclic cycloalkyl group, one or more R ｂ a 3- to 6-membered monocyclic cycloalkyl group substituted with one or more R ａ C substituted with １－６ is an alkyl group, (5) R ａ is a hydroxy group, (6) Each R ｂ are each independently C １－６ is an alkyl group, (7) B is a phenyl group, a naphthyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, or one or more R ５ a naphthyl group substituted with one or more R ２ a 6-membered heteroaryl group substituted with one or more R ３ or one or more R ４ is a 6-membered heterocycloalkenyl group substituted with (8) Each R ２ , R ３ , R ４ , R ５ , R ６ are each independently a halogen, an oxo group, or C １－６ is an alkyl group, (9) U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, or one or more R ２－１ or one or more R ２－２ is a 4- to 10-membered heterocycloalkyl group substituted with (10) Each R ２－１ , R ２－２ and R ２－３ are each independently a halogen, C １－６ Alkyl group, hydroxy group, C １－６ C substituted with an alkoxy group or one or more halogens １－６ is an alkyl group, (11) G is C(R １０ ) (12) R １０ is H, halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, (13) W is *-CONR Ｗ - and X ２ is R Ｗ－１ and R Ｗ－１ is H or halogen, and R Ｗ is H; A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

6. The following conditions are met: (1) R ｘ represents a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－２ is a 6- to 9-membered bridged heterocycloalkyl group substituted with Each R ｘ－２ are each independently C １－６ is an alkyl group, (2) Each R ｘ－１ , R ｘ－２ , R ｘ－３ and R ｘ－４ are each independently C １－６ is an alkyl group, (3) L is *-NHSO ２ - or -NH-; (4) B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R ２ a 6-membered heteroaryl group substituted with one or more R ３ is a 9- to 10-membered heteroaryl group substituted with Preferably, B is a 9- to 10-membered heteroaryl group, one or more R ３ is a 9-10 membered heteroaryl group substituted with (5) B is one or more R ２ When R is a 6-membered heteroaryl group substituted with ｘ is an 8-9 membered bridged heterocycloalkyl group; (6) Each R ２ , R ３ , R ４ , R ５ , R ６ are each independently a halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, Each R ２ are each independently preferably C １－６ is an alkyl group, and each R ３ are each independently preferably halogen or C １－６ is an alkyl group, (7) U is a 4- to 10-membered heterocycloalkyl group or one or more R ２－２ is a 4- to 10-membered heterocycloalkyl group substituted with Each R ２－２ are each independently a halogen; (8) G is C(R １０ ) or N, and R １０ is H, (9) R Ｗ is H, (10) R Ｗ－１ is H; A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

7. The following conditions are met: (1) In B, the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group, the number of heteroatoms is two, and the heteroatoms are one or two types independently selected from N and O; Alternatively, in B, the 9- to 10-membered heteroaryl group is a 9-membered heteroaryl group, the number of heteroatoms is 3, and the heteroatom is N; Alternatively, in B, the 9- to 10-membered heteroaryl group is a 10-membered heteroaryl group, the heteroatom is N, the number of heteroatoms is 2, and the heteroatoms are located in different rings. (2) B is a 9- to 10-membered heteroaryl group, one or more R ２ or one or more R ３ is a 9- to 10-membered heteroaryl group substituted with Each R ２ are each independently C １－６ is an alkyl group, Each R ３ are each independently a halogen or C １－６ is an alkyl group, (3) In U, the 4- to 10-membered heterocycloalkyl group is a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, or a 7- to 9-membered spiroheterocycloalkyl group. (4) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group or one or more R ｘ－２ is a 6- to 9-membered bridged heterocycloalkyl group substituted with (5) R １－１ In the above, １－６ the alkyl group is an ethyl group or an isopropyl group; A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

8. The following conditions are met: (1) R ｘ is one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, or a 7- to 9-membered spiroheterocycloalkyl group substituted by (2) Each R ｘ－１ , R ｘ－２ , R ｘ－３ and R ｘ－４ are each independently a halogen or C １－６ is an alkyl group, preferably C １－３ alkyl group, F, Cl or Br; (3) R １－１ is C １－３ an alkyl group, one or more R ａ C substituted with １－３ an alkyl group or one or more R ｂ is a 3- to 6-membered monocyclic cycloalkyl group substituted with (4) B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R ２ or one or more R ３ is a 9- to 10-membered heteroaryl group substituted with, preferably a 9- to 10-membered heteroaryl group or one or more R ３ is a 9-10 membered heteroaryl group substituted with (5) Each R ２ , R ３ , R ４ , R ５ , R ６ are each independently C １－３ is an alkyl group, (6) U is a 4- to 9-membered heterocycloalkyl group, one or more R ２－１ or one or more R ２－２ is a 4- to 9-membered heterocycloalkyl group substituted with, preferably a 4- to 9-membered heterocycloalkyl group or one or more R ２－２ is a 4- to 9-membered heterocycloalkyl group substituted with (7) Each R ２－１ , R ２－２ and R ２－３ are each independently a halogen, preferably F, Cl or Br; (8) W is *-CONR Ｗ - and X ２ is R Ｗ－１ and R Ｗ－１ is H and R Ｗ is H; A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

9. The following conditions are met: (1) R ｘ represents a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiro heterocycloalkyl group, one or more R ｘ－２ a 6- to 9-membered bridged heterocycloalkyl group substituted with one or more R ｘ－３ is a 7-9 membered spiroheterocycloalkyl group substituted with Each R ｘ－１ , R ｘ－２ , R ｘ－３ and R ｘ－４ are each independently a halogen, C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, preferably a halogen or C １－６ alkyl group, more preferably C １－３ alkyl group, F, Cl or Br; (2) R １－１ is C １－６ an alkyl group, one or more R ｂ a 3- to 6-membered monocyclic cycloalkyl group substituted with one or more R ａ C substituted with １－６ is an alkyl group, R ａ is a hydroxy group, Each R ｂ are each independently C １－６ is an alkyl group, (3) B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, or one or more R ２ or one or more R ３ is a 9- to 10-membered heteroaryl group substituted with Each R ２ , R ３ are each independently a halogen or C １－６ is an alkyl group, (4) U is a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, or one or more R ２－１ or one or more R ２－２ is a 4- to 10-membered heterocycloalkyl group substituted with Each R ２－１ and R ２－２ are each independently a halogen, C １－６ Alkyl group, hydroxy group, C １－６ C substituted with an alkoxy group or one or more halogens １－６ an alkyl group, preferably F, Cl or Br; (5) G is C(R １０ ) and R １０ is H, (6) The compound represented by formula II is (a) R ｘ is a 6- to 9-membered bridged heterocycloalkyl group; (b) B is a 5-membered heteroaryl group, a 9- to 10-membered heteroaryl group, a 6-membered heterocycloalkenyl group, one or more R ４ a 6-membered heterocycloalkenyl group substituted with one or more R ３ is a 9- to 10-membered heteroaryl group substituted with, preferably a 9- to 10-membered heteroaryl group or one or more R ３ and (b) satisfy one or more of the following conditions: A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

10. The nitrogen-containing compound represented by formula II is 【Chemistry 3】 and Each V １ are each independently C or N; V ２ is N or C-R １１ is preferably N, D is a partially saturated or unsaturated 5- to 6-membered carbocyclic ring or a partially saturated or unsaturated 5- to 6-membered heterocyclic ring, and the 5- to 6-membered carbocyclic ring or the 5- to 6-membered heterocyclic ring may optionally contain 0, 1, 2, or 3 R １１ In the "5- to 6-membered heterocycle", the heteroatom is N, O, or S, and the number of heteroatoms is independently 1, 2, 3, or 4; R １１ is hydrogen, halogen, cyano group, C １－６ Alkyl group, C １－６ C substituted with an alkoxy group or one or more halogens １－６ is an alkyl group, A nitrogen-containing compound of formula II according to claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

11. The following conditions are met: (1) The "6- to 9-membered bridged heterocycloalkyl group" is a 6- to 9-membered bridged heterocycloalkyl group each independently containing one or two heteroatoms, and is preferably any one of the following fragments: 【Chemistry 4】 That is, (2) In one embodiment, the "9- to 10-membered heteroaryl group" is independently any one of the following fragments: 【Chemistry 5】 【change】 That is, (3) The "4- to 10-membered heterocycloalkyl group" is each independently a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 8-membered spiroheterocycloalkyl group, or a 7- to 9-membered bridged heterocycloalkyl group, preferably 【Chemistry 6】 That is, (4) R ｘ is one of the following fragments: 【Chemistry 7】 That is, (5) In one embodiment, B is any one of the following fragments (in the fragments below, the dashed line on the left represents the bond connected to U): 【Chemistry 8】 【change】 That is, (6) U is any one of the following fragments: 【Chemistry 9】 and A nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

12. The following conditions are met: (1) The "5- to 6-membered monocyclic heterocycloalkyl group" is a 5- to 6-membered heterocycloalkyl group each independently containing one or two heteroatoms. (2) The "6- to 9-membered bridged heterocycloalkyl group" is a 6- to 9-membered bridged heterocycloalkyl group each independently containing one or two heteroatoms. (3) The "7- to 9-membered spiroheterocycloalkyl group" is a 7- to 9-membered spiroheterocycloalkyl group each independently containing 1 or 2 heteroatoms. (4) The "halogen" is independently fluorine, chlorine, bromine, or iodine. (5) The above “C １－６ "alkyl group" is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group; (6) The "3- to 6-membered monocyclic cycloalkyl group" is each independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. (7) The above “C １－６ "alkoxy group" is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, or a tert-butoxy group; (8) The "4- to 8-membered monocyclic heterocycloalkyl group" is a "4- to 8-membered monocyclic heterocycloalkyl group" containing one O atom. (9) The 5-membered heteroaryl groups are each independently a 5-membered heteroaryl group in which "the heteroatom is one or two selected from N and S." (10) The "6-membered heteroaryl group" is independently any one of the following fragments: 【Chemistry 10】 That is, (11) The "9- to 10-membered heteroaryl group" is independently any one of the following fragments: 【Chemistry 11】 That is, (12) The "6-membered heterocycloalkenyl group" is a 6-membered heterocycloalkenyl group having 1 or 2 heteroatoms, each of which is independently a N heteroatom. (13) The "3- to 10-membered cycloalkyl group" is a 3- to 6-membered monocyclic cycloalkyl group or a 6- to 8-membered spirocycloalkyl group. (14) The "4- to 10-membered heterocycloalkyl group" is a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 8-membered spiroheterocycloalkyl group, or a 7- to 9-membered bridged heterocycloalkyl group. (15) The "6- to 10-membered aryl group" is a phenyl group. (16) The "5- to 10-membered heteroaryl group" is a 5- to 6-membered heteroaryl group having one or two heteroatoms, wherein the heteroatom is N. (17) W is *-C(X １ ) NR Ｗ - and X １ , X ２ and when forming a 6-membered heteroaryl group together with a C atom therebetween, the heteroatom in the "6-membered heteroaryl group" is N, and the number of heteroatoms is 1 or 2. A nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

13. The following conditions are met: (1) The "5- to 6-membered monocyclic heterocycloalkyl group" is independently 【Chemistry 12】 That is, (2) The "6- to 9-membered bridged heterocycloalkyl group" is independently 【Chemistry 13】 That is, (3) The "7- to 9-membered spiro heterocycloalkyl group" is independently any one of the following fragments: 【Chemistry 14】 That is, (4) The "halogen" is fluorine. (5) The above “C １－６ "alkyl groups" are each independently a methyl group or an ethyl group; (6) The "3- to 6-membered monocyclic cycloalkyl group" is a cyclopropyl group. (7) The above “C １－６ "alkoxy groups" are each independently a methoxy group or an ethoxy group; (8) The "4- to 8-membered monocyclic heterocycloalkyl group" is 【Chemistry 15】 That is, (9) The "5-membered heteroaryl group" is independently any one of the following fragments: 【Chemistry 16】 That is, (10) The "6-membered heteroaryl group" is independently linked to U via the dashed line on the left side. 【Chemistry 17】 That is, (11) The "9- to 10-membered heteroaryl group" is independently linked to U via the dashed line on the left side. 【Chemistry 18】 That is, (12) The "6-membered heterocycloalkenyl group" is independently any one of the following fragments: 【Chemistry 19】 That is, (13) The "3- to 10-membered cycloalkyl group" is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, 【Chemistry 20】 That is, (14) The "4- to 10-membered heterocycloalkyl group" is each independently a 4- to 6-membered monocyclic heterocycloalkyl group, a 6- to 8-membered spiroheterocycloalkyl group, or a 7- to 9-membered bridged heterocycloalkyl group, preferably 【Chemical 21】 That is, (15) The "5- to 10-membered heteroaryl group" is 【Chemical 22】 and A nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

14. The following conditions: (1) The "6- to 9-membered bridged heterocycloalkyl group" is independently 【Chemical 23】 That is, (2) The "7- to 9-membered spiroheterocycloalkyl group" is 【Chemistry 24】 That is, (3) The "5-membered heteroaryl group" is 【Chemistry 25】 For example, the dashed line on the right connects to U. 【Chemical 26】 That is, (4) The "6-membered heteroaryl group" is linked to U via the dashed line on the left side. 【Chemical 27】 That is, (5) The "9- to 10-membered heteroaryl group" is independently linked to U via the dashed line on the left side. 【Chemical Formula 28】 That is, (6) The "6-membered heterocycloalkenyl group" is linked to U via the dashed line on the left. 【Chemical 29】 That is, (7) The "3 to 10-membered cycloalkyl group" is 【Chemistry 30】 That is, (8) The "4- to 10-membered heterocycloalkyl group" is independently 【Chemical 31】 and A nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

15. The following conditions: (1) R ｘ is one of the following fragments: 【Chemical Formula 32】 That is, (2) R １ is one of the following fragments: 【Chemical 33】 That is, (3) B is any one of the following fragments: 【Chemical 34】 That is, (4) U is any one of the following fragments: 【Chemical 35】 and A nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

16. The following conditions: (1) R ｘ teeth, 【Chemical 36】 That is, (2) R １ teeth, 【Chemical 37】 That is, (3) B is 【Chemical Formula 38】 That is, (4) U is 【Chemical Formula 39】 and A nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

17. A nitrogen-containing compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotopically labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing compound is 【Chemistry 40】 【change】 【change】 【change】 【change】 【change】 【change】 is any one of the compounds a nitrogen-containing compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof,

18. 1. A pharmaceutical composition comprising: (1) A nitrogen-containing compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; a nitrogen-containing compound represented by formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; or a nitrogen-containing compound according to claim 17, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; (2) A pharmaceutical composition containing a pharmaceutically acceptable additive.

19. Use of a nitrogen-containing compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, a nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a nitrogen-containing compound according to claim 17, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in the manufacture of a KIF18A inhibitor.

20. In the manufacture of a drug, a nitrogen-containing compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, a nitrogen-containing compound represented by formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof 18. An application of the nitrogen-containing compound according to claim 17, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotopically labeled derivative, its solvate or its solvate of a pharmaceutically acceptable salt, wherein the drug is used to treat a disease associated with the KIF18A protein mechanism of action, such as cancer, and for example a cancer associated with the KIF18A protein mechanism of action, preferably the cancer is ovarian cancer, colon cancer or ductal carcinoma.

21. 17. Use of a nitrogen-containing compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a nitrogen-containing compound of formula II according to claim 2 or 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a nitrogen-containing compound according to claim 17, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, wherein the medicament is used to treat cancer, preferably, the cancer is ovarian cancer, colon cancer, or ductal carcinoma.

Images