KRAS inhibitor compounds, their pharmaceutical compositions and uses

Abstract

The present invention belongs to the field of pharmaceutical technology and, more specifically, relates to KRAS inhibitor compounds, their pharmaceutical compositions and uses. More specifically, the present invention relates to a compound represented by formula (I), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of a compound represented by formula (I). The compounds and pharmaceutical compositions according to the present invention can be used in the manufacture of drugs for preventing or treating diseases associated with KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutations, particularly in the manufacture of drugs for preventing or treating cancer. JPEG2026514081000140.jpg55170

Description

[Technical Field]

[0001] The present invention relates to the art of pharmaceuticals, and more specifically to compounds capable of inhibiting one or more KRAS mutants, pharmaceutical compositions thereof, and the use of such compounds and pharmaceutical compositions in the manufacture of drugs for preventing or treating KRAS-mediated related diseases. [Background technology]

[0002] The RAS gene is one of the most common mutant genes in cancer (20%–25%). The RAS gene family currently known members include KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for approximately 85%. The KRAS mutation rate reaches as high as 97% in pancreatic ductal adenocarcinoma (PDAC), followed by colorectal cancer, multiple myeloma, and lung cancer at 52%, 42%, and 32%, respectively. The most common sites of mutation in the KRAS gene are codons 12, 13, and 61, and mutation forms include KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12A, KRAS G12V, KRAS G13D, and KRAS Q61H. RAS gene mutations are consistently associated with poor cancer prognosis. KRAS is briefly activated by upstream growth factors or tyrosine kinases (e.g., EGFR), and activated KRAS can activate downstream pathways, including the PI3K-AKT-mTOR signaling pathway which controls cell generation and the RAS-RAF-MEK-ERK signaling pathway which controls cell proliferation. This provides a biological basis for the combined use of many targets.

[0003] In recent years, there has been some progress in drug research and development utilizing the allosteric sites of KRAS G12C mutants. For example, in 2013, a research group reported the discovery of a small molecule inhibitor of KRAS G12C (Nature, 2013, 503, 548-551). In addition, Mirati disclosed a KRAS G12D inhibitor compound in patent WO2021041671 and broad-spectrum KRAS inhibitors (including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, and KRAS Q61H) for the treatment of KRAS-mediated related cancers in patent WO2022132200.

[0004] The frequent discovery of KRAS mutations across various tumor types has made KRAS a highly attractive target for cancer treatment in the pharmaceutical industry, and compounds that inhibit KRAS activity remain highly valuable for research. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2021041671 [Patent Document 2] International Publication No. 2022132200 [Non-patent literature]

[0006] [Non-Patent Document 1] Nature, 2013, 503, 548-551 [Overview of the project]

[0007] The present invention provides a compound capable of inhibiting one or more KRAS mutant forms including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and KRAS Q61H. Also provided are a pharmaceutical composition containing the compound, and the use of the compound and its pharmaceutical composition in the manufacture of a drug for preventing or treating related diseases mediated by KRAS. The drug treats diseases and / or conditions, particularly cancer, by inhibiting KRAS activity.

[0008] In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

Chemical formula

Chemical formula

[0009] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1~4 Alkyl-NR 6 C(=O)R 7 , -C 1~4 Alkyl-NR 6 R 7 , -C 1~4 Alkyl-C(=O)OR 6 , -C 1~4 Alkyl-C(=O)NR 6 R 7 , C 1~6 Alkyl alkyl group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 1~4Alkoxy C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl, (C 7~12 Cycloalkyl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl group, (7-12 member heterocyclyl)-C 1~4 Alkyl, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-OC 1~4 Alkyl, (C 7~12 Cycloalkyl)-OC 1~4 Alkyl alkyl groups, (3-6 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (3-7 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (7-12 member heterocyclyl)-OC 1~4 Alkyl alkyl group, C 1~4 Mercaptoalkyl groups, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkoxy C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl, (C 7~12 Cycloalkyl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl group, (7-12 member heterocyclyl)-C 1~4 Alkyl, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-OC 1~4 Alkyl, (C 7~12 Cycloalkyl)-OC 1~4 Alkyl alkyl groups, (3-6 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (3-7 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (7-12 member heterocyclyl)-OC1~4 Alkyl alkyl group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 Each cycloalkyl group or 3-6 membered heterocyclyl group can independently be any of the following: D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6 , -NR 6 R 7 -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 and C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, where R 6 , R 7 and R 6a Each of these terms has the definition described in the present invention.

[0010] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 -CH2NR 6 C(=O)R 7 -CH2NR 6 R 7 ,-(CH2)2NR 6 R 7 -CH2C(=O)OR 6 , -(CH2)2C(=O)OR 6 , -(CH2)3C(=O)OR 6、-CH2C(=O)NR 6 R 7 、-(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH (CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH 2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2) 2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2 -Cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -(CH2)2-cyclopentyl group, -(CH2)3-cyclopentyl group, -(CH2)2-cyclohexyl group, -CH2-phenyl group, -CH2-imidazolyl group, -CH2-pyrazolyl group, -CH2O-cyclopropyl group, -CH2O-cyclobutyl group, -(CH2)2O-cyclobutyl group, -CH2O-cyclopentyl group, -(CH2)2O-cyclopentyl group, -CH2O-azetidinyl group, -CH2O-oxetanyl group, -CH2O-tetrahydrofuranyl group, -CH2O-pyrrolidinyl group, -CH2O-spiro[2.3]hexyl group, -CH2O-spiro[3.3] heptyl group, -CH2SH, -(CH2)2SH, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, oxetanyl group, tetrahydropyranyl group, azetidinyl group, or pyrrolidinyl group, and the aforementioned -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -(CH2)2-cyclopentyl group, -(CH2)3-cyclopentyl group, -(CH2)2-cyclohexyl group, -CH2-phenyl group, -CH2-imidazolyl group, -CH2-pyrazo The lyl group, -CH2O-cyclopropyl group, -CH2O-cyclobutyl group, -(CH2)2O-cyclobutyl group, -CH2O-cyclopentyl group, -(CH2)2O-cyclopentyl group, -CH2O-azetidinyl group, -CH2O-oxetanyl group, -CH2O-tetrahydrofuranyl group, -CH2O-pyrrolidinyl group, -CH2O-spiro[2.3]hexyl group, -CH2O-spiro[3.3]heptyl group, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, oxetanyl group, tetrahydropyranyl group, azetidinyl group, or pyrrolidinyl group can each be independently and arbitrarily D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 , -NR 6 R 7 -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , substituted with 1, 2, 3 or 4 substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups, where R 6 , R 7 and R 6a Each of these terms has the definition described in the present invention.

[0011] In some embodiments, T is [ka] And, Each R 5 These are independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -C 1~4 Alkylene S(=O)2N(R) 7b )2, C 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 1~4 Alkoxy group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl groups, -NH(C) 1~4 Alkyl), -N(C 1~4 Alkyl)2, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, 6-10 membered aryl group, 5-10 membered heteroaryl group, C 3~6 The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 1~4 Alkoxy group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, -NH(C1~4 Alkyl), -N(C 1~4 Alkyl) 2, 6-10 membered aryl group, 5-10 membered heteroaryl group, C 3~6 Each cycloalkyl group and 3-6 membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. 8 Replaced by, Alternatively, two R atoms bonded to the same carbon atom 5 Together [ka] Forming, Alternatively, two R atoms bonded to the same carbon atom 5 Together with the carbon atoms bonded to them, C 3~6 Forming a cycloalkyl group or a 3-6 membered heterocyclyl group, the C 3~6 Each cycloalkyl group and 3-6 membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. 8 Replaced by, Alternatively, two R atoms bonded to two adjacent atoms 5 Together with the two adjacent atoms bonded to them, C 3~6 Forming a cycloalkyl group or a 3-6 membered heterocyclyl group, the C 3~6 Each cycloalkyl group and 3-6 membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. 8 Replaced by, Each R 8 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Hydroxyalkyl group, C 6~10 Aryl group, 6-10 membered heteroaryl group, -C(=O)OC 1~4 Alkyl group, -C(=O)NHC 1~4 Alkyl group, -C(=O)N(C 1~4 Alkyl)2, R 6h , R 7h and R7k These are, independently, -H, -D, or C 1~4 It is an alkyl group, Here, R 6b , R 6c and R 7b Each of these terms has the definition described in the present invention. In some embodiments, T is [ka] And, Each R 5 These are independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c -CH2S(=O)2N(R 7b )2, -(CH2)2S(=O)2N(R 7b)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3 , -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2C F3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, aziridinyl The group is -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3,-O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2 CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -C H2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N( (CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, - SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, cyclopropyl group The cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group may each be independently and optionally have 1, 2, 3, or 4 R groups. 8 Replaced by, Alternatively, two R atoms bonded to the same carbon atom 5 Together [ka] Forming, Alternatively, two R atoms bonded to the same carbon atom 5These groups, together with the carbon atoms bonded to them, form a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, or morpholinyl group, and the cyclo The ropropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, thioxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group can each be independently and optionally have 1, 2, 3, or 4 R groups. 8 Replaced by, Alternatively, two R atoms bonded to two adjacent atoms 5 These groups, together with two adjacent atoms bonded to them, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyranyl, azilidinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl groups. The cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group may each be independently and optionally have 1, 2, 3, or 4 R groups. 8 Replaced by, Each R 8These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, py The group is a loryl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2 or -C(=O)N(CH3)CH2CH3. R 6h , R 7h and R 7k These are, independently, -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group. Here, R 6b , R 6c and R 7b Each of these terms has the definition described in the present invention.

[0012] In some embodiments, ring B is [ka] It is one of the substructures of Each R 2 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR6b C(=O)R 7b , -NR 6b R 7b , C 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 2~4 Hydroxyalkynyl group, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 3~6 The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 2~4 Hydroxyalkynyl group, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~6 It is substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, where R 6b , R 6cand R 7b Each of these terms has the definition described in the present invention.

[0013] Several embodiments, each R 2 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C ≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH 2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl The group is a nyl group, a tetrahydrofuranyl group, a piperidinyl group, or a piperazinyl group, and the groups are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2) 2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group,The pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group and piperazinyl group are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group and piperazinyl group, where R, 6b , R 6c and R 7b Each of these terms has the definition described in the present invention.

[0014] In some embodiments, R 4 It is a 3-6 member heterocyclyl group, [ka] -L-pyrrolidinyl group, -L-piperidinyl group, -L-morpholinyl group, -L-oxetanyl group, -L-oxyranyl group, -L-tetrahydrofuranyl group, -L-octahydroindolidinyl group, -L-cyclopropyl group, -L-cyclopentyl group, -L-octahydropentalenyl group, -L-octahydro-1H-indenyl group, -L-decahydronaphthyl group, -L-pyridyl group, -L-pyrazolyl group, or -L-phenyl group, and each of the 3-6 member heterocyclyl groups, -L-cyclopropyl group, -L-cyclopentyl group, -L-octahydropentalenyl group, -L-octahydro-1H-indenyl group, -L-decahydronaphthyl group, -L-pyridyl group, -L-pyrazolyl group, and -L-phenyl group can each be independently and optionally have 1, 2, 3, or 4 R 9a Replaced by the above [ka] -L-pyrrolidinyl group, -L-piperidinyl group, -L-morpholinyl group, -L-oxetanyl group, -L-oxyranyl group, -L-tetrahydrofuranyl group and -L-octahydroindolidinyl group may each optionally have 1, 2, 3 or 4 R groups. 9b Replaced by, R 9a and R 9b These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, and -NR. 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Haloalkyl group, C 1~4 Haloalkoxy group, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl alkyl group, C 3~6 The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Haloalkyl group, C 1~4 Haloalkoxy group, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl alkyl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1~4 Alkyl and C 1~4Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, or Two R atoms bonded to the same ring carbon atom 9b Together [ka] Forming, L is C 1~4 It is an alkylene group, R 6j and R 7j These are, independently, -H, -D, or C 1~4 It is an alkyl group, Here, R 6d , R 7d , R 6d , R 7e and R 7e Each of these terms has the definition described in the present invention.

[0015] In some embodiments, R 4 These are piperidinyl group, piperazinyl group, pyrrolidinyl group, imidazolidinyl group, [ka] -CH2-pyrrolidinyl group, -CH2-morpholinyl group, -(CH2)2-morpholinyl group, -CH2-oxetanyl group, -CH2-oxyranyl group, -CH2-tetrahydrofuranyl group, -CH2-octahydroindolidinyl group, -CH2-cyclopropyl group, -CH2-cyclopentyl group, -CH2-octahydropentarenyl group, -CH2-octahydro-1H-indenyl group, -CH2-decahydronaphthyl group, -CH2-pyridyl group, -(CH2)2-pyridyl group, -CH2-pyrazolyl group, -(CH2) The group is either a 2-pyrazolyl group or a -CH2-phenyl group, and the piperidinyl group, piperazinyl group, pyrrolidinyl group, imidazolidinyl group, -CH2-cyclopropyl group, -CH2-cyclopentyl group, -CH2-octahydropentarenyl group, -CH2-octahydro-1H-indenyl group, -CH2-decahydronaphthyl group, -CH2-pyridyl group, -(CH2)2-pyridyl group, -CH2-pyrazolyl group, -(CH2)2-pyrazolyl group and -CH2-phenyl group can each be independently and optionally have 1, 2, 3 or 4 R 9a Replaced by the above [ka] -CH2-pyrrolidinyl group, -CH2-morpholinyl group, -(CH2)2-morpholinyl group, -CH2-oxetanyl group, -CH2-oxyranyl group, -CH2-tetrahydrofuranyl group and -CH2-octahydroindolidinyl group may each optionally have 1, 2, 3 or 4 R 9b Replaced by, R 9a and R 9b These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, and -NR. 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy group, -CHF2, -CF3, -OCF3, phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group, or azetidinyl group, and the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy The xy group, -CHF2, phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group, and azetidinyl group are each independently and optionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl group, ethyl group, n-propyl group, and isopropyl group. Or, Two R atoms bonded to the same ring carbon atom 9b Together [ka] Forming, R 6j and R 7j These are, independently, -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group. Here, R 6d , R 7d , R6d , R 7e and R 7e Each of these terms has the definition described in the present invention.

[0016] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e These are, independently, -H, -D, or C 1~4 It is an alkyl group, and the C 1~4 Alkyl groups can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1~4 Alkoxy group, C 6~10 Aryl group, C 3~6 Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, Alternatively, R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~4 Alkyl alkyl group, C 1~4 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkoxy group or C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups, R 6a , R 6c , R 6g and R7g These are, independently, -H, -D, or C 1~4 It is an alkyl group.

[0017] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e Each of these is independently -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group, and the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and t-butyl group are arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , substituted with 1, 2, 3 or 4 substituents selected from methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxyranyl, oxetanyl, azetidinyl and pyrrolidinyl groups, Alternatively, R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7eEach of these groups, together with the same N atom bonded to them, forms pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, or imidazolidine, and each of these pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, and imidazolidine groups is independently and optionally substituted with one, two, three, or four substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methylamino group, dimethylamino group, ethylamino group, cyclopropyl group, cyclopentyl group, pyrrolidinyl group, methoxy group, ethoxy group, isopropoxy group, cyanomethyl group, hydroxymethyl group, hydroxyethyl group, trifluoromethoxy group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, or 1,2-dichloroethyl group. R 6a , R 6c , R 6g and R 7g These are, independently, -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group.

[0018] In some embodiments, the compounds described in the present invention are compounds represented by formula (I-1), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of compounds represented by formula (I-1). [ka] In the formula, R 1 , R 3 , R 4 Y and T each have the definitions described in this invention. R 2a , R 2b and R 2c These are, respectively, R as described in the present invention. 2 It has the same definition as [the other definition]. In another embodiment, the present invention provides a pharmaceutical composition comprising the compound described in the present invention.

[0019] In some embodiments, the pharmaceutical composition described in the present invention further comprises a pharmaceutically acceptable adjuvant.

[0020] In some embodiments, the auxiliary agents described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be in the form of a liquid, solid, semi-solid, gel, or spray.

[0021] In another aspect, the present invention provides the use of the pharmaceutical compositions described in the present invention in the manufacture of drugs for preventing, treating or alleviating diseases associated with KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations.

[0022] In some embodiments, the disease associated with the KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutation described in the present invention is cancer.

[0023] In some embodiments, the cancers described in the present invention include: Cancers of the heart: sarcoma, myxoma, rhabdomyoma, fibroma, lipoma or teratoma; Cancers of the lungs: bronchial cancer, non-small cell lung cancer, small cell lung cancer, alveolar cancer, bronchial adenoma, sarcoma, lymphoma, chondropathic hamartoma, mesothelioma; Cancers of the gastrointestinal tract: esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colorectal cancer; Cancers of the genitourinary tract: kidney cancer, bladder cancer and urethral cancer, prostate cancer, testicular cancer; Cancers of the liver: hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Cancers of the biliary tract: gallbladder cancer, ampulla cancer, bile duct cancer; Cancers of the bones: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma , Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor / chordoma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, giant cell tumor; nervous system cancers: cranial osteoma, brain cancer; gynecological cancers: uterine cancer, vulvar cancer, vaginal cancer, fallopian tube cancer, ovarian cancer, breast cancer; hematological cancers: acute or chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin lymphoma; skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaboshi sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal gland cancers: neuroblastoma.

[0024] In another aspect, the present invention further provides a method for preventing or treating a disease associated with KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition thereof described in the present invention to a patient.

[0025] In another aspect, the present invention further provides the prevention or treatment of diseases associated with KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations using the compounds or pharmaceutical compositions thereof described in the present invention.

[0026] In another aspect, the present invention relates to a method for producing, separating, and purifying compounds represented by formula (I) or (I-1).

[0027] Unless otherwise specified, all stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of the present invention fall within the scope of the present invention.

[0028] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" implies that the substance or composition must conform to chemical or toxicological standards and be relevant to the other components of the preparation and to the mammal for which it is intended to be used.

[0029] The salts of the compounds of the present invention include intermediates for producing or purifying the compounds represented by formula (I) or (I-1), or salts of enantiomers isolated from the compounds represented by formula (I) or (I-1), but are not necessarily pharmaceutically acceptable salts.

[0030] The above description outlines only some aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and in more complete terms below. [Modes for carrying out the invention]

[0031] Definitions and general terms Herein, several embodiments of the present invention are described in detail, illustrated by the accompanying structural and chemical formulas. The present invention is intended to encompass all alternative, modified, and equivalent technical solutions, all of which fall within the scope of the invention as defined in the claims. As will be understood by those skilled in the art, many methods and materials similar or equivalent to those described herein can be used to carry out the present invention. The present invention is not necessarily limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or conflict with this application (including, but not limited to, defined terms, application of terms, and described techniques), this application shall prevail.

[0032] To further understand the present invention, several features have been described in many independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the present invention have been described in a single embodiment, but may also be provided individually or in any suitable subcombination.

[0033] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as those commonly understood by those skilled in the art to which this invention pertains. All patents and published works relating to this invention are incorporated herein by reference.

[0034] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. The test subjects may also be, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0035] As used in the present invention, the term "patient" refers to a human being (including adults and children) or another animal. In some embodiments, "patient" refers to a human being.

[0036] The term "includes" is an open expression, meaning it includes the content explicitly stated in this invention, but does not exclude the content of other embodiments.

[0037] A "stereoisomer" refers to a compound that has the same chemical structure but differs in the spatial arrangement of its atoms or groups. Stereoiomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise specified in other embodiments, all stereoisomers or mixtures of stereoisomers of the structural formulas described in this invention fall within the scope of this invention. Furthermore, unless otherwise specified in other embodiments, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0038] When used in this invention, the definitions and rules of stereochemistry generally follow those of SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994.

[0039] The resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers by, for example, chromatography and / or fractional crystallization, depending on the differences in the physical and chemical properties of the components.

[0040] The term "tautomer" or "tautomer form" refers to structural isomers that have different energies and can be converted to each other by a low-energy barrier. When tautomerism is possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversion by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion by rearrangement of several bond-forming electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypentane-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A concrete example of phenol-ketototherapeutic activity is the interconversion of tautomers of pyridine-4-ol and pyridine-4(1H)-one. Unless otherwise noted, all tautomers of the compounds of the present invention fall within the scope of the present invention.

[0041] As described in the present invention, the compounds of the present invention may be independently and optionally substituted with one or more substituents, for example, the compounds of the previous general formula, or the special examples, subclasses, and compounds included in the present invention in the examples. To be understood, the two terms “independently and optionally substituted” or “optionally substituted” can be used interchangeably with the terms “substituted or unsubstituted.” Generally, the term “substituted” means that one or more hydrogen atoms in a given structure are replaced by specific substituents. Unless otherwise expressly stated in other embodiments, any substituent may be substituted at each substitutedable position of the group. If one or more positions in a given structural formula are substituted with one or more substituents selected from specific groups, the substituents may be the same or different at each position.

[0042] Furthermore, it should be explained that, unless otherwise explicitly stated, when used in this invention, the explanatory phrases "each... independently...", "each independently...", and "...independently..." are interchangeable and should all be understood in a broad sense. They can express that specific choices represented by the same symbols do not influence each other under different bases, and they can also express that specific choices represented by the same symbols do not influence each other under the same base.

[0043] In each part of this specification, substituents of the compounds disclosed herein are disclosed according to the type or range of the group. As particularly noted, the present invention includes each independent secondary combination of each member of these types and ranges of groups. For example, "C 1~6 The term "alkyl group" refers in particular to the independently disclosed methyl group, ethyl group, C3 alkyl group, C4 alkyl group, C5 alkyl group, and C6 alkyl group.

[0044] Each part of the present invention describes the bonding substituents. Where the structure clearly requires a bonding group, the Markush variables listed for that group should be understood as the bonding group. For example, when the structure requires a bonding group and “alkyl group” or “aryl group” is listed in the definition of the Markush group for that variable, the “alkyl group” or “aryl group” represents the bonded alkylene group or arylene group, respectively.

[0045] The term "alkyl group" refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, and the alkyl group may optionally be substituted with one or more substituents as described in the present invention. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, C 1~6 Represented by an alkyl group, in another embodiment, the alkyl group contains 1 to 4 carbon atoms, C 1~4 Represented by an alkyl group, in further embodiments the alkyl group contains 1 to 3 carbon atoms, C 1~3It is represented by an alkyl group. Examples of alkyl groups include methyl group (Me, -CH3), ethyl group (Et, -CH2CH3), n-propyl group (n-Pr, -CH2CH2CH3), isopropyl group (i-Pr, -CH(CH3)2), n-butyl group (n-Bu, -CH2CH2CH2CH3), isobutyl group (i-Bu, -CH2CH(CH3)2), s-butyl group (s-Bu, -CH(CH3)CH2CH3), and t-butyl group (t-Bu, -C( CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2C H(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl group (- Examples include, but are not limited to, CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, etc.

[0046] The term "alkylene group" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon. In some embodiments, the alkylene group contains 1 to 6 carbon atoms. 1~6 Represented by an alkylene group, in some other embodiments, the alkylene group contains 1 to 4 carbon atoms, C 1~4Represented by an alkylene group, in some other embodiments, the alkylene group contains 1 to 3 carbon atoms, C 1~3 Represented by an alkylene group, in some other embodiments, the alkylene group contains 1-2 carbon atoms, C 1~2 It is represented by an alkylene group. Examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, and -CH(CH3)CH2-.

[0047] The term "alkenyl group" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, having at least one unsaturated site, i.e., one carbon-carbon sp² 2 The alkenyl group has a double bond, and the above alkenyl group may optionally be substituted with one or more substituents as described in the present invention, which include a "cis" and "trans" configuration or an "E" and "Z" configuration. In one embodiment, the alkenyl group contains 2 to 6 carbon atoms, C 2~6 Represented by an alkenyl group, in another embodiment, the alkenyl group contains 2 to 4 carbon atoms, C 2~4 It is represented by an alkenyl group. Examples of alkenyl groups include, but are not limited to, the vinyl group (-CH=CH2), the allyl group (-CH2CH=CH2), and the 1-propenyl group (i.e., the propenyl group, -CH=CH-CH3).

[0048] The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, having at least one unsaturated site, i.e., one carbon-carbon sp triple bond, and the alkynyl group may optionally be substituted with one or more substituents as described in the present invention. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms, C 2~6 Represented by an alkynyl group, in another embodiment, the alkynyl group contains 2 to 4 carbon atoms, C 2~4 It is represented by an alkynyl group. Examples of alkynyl groups include, but are not limited to, the ethynyl group (-C≡CH), the propargyl group (-CH2C≡CH), and the 1-propynyl group (-C≡C-CH3).

[0049] The term "cyanoalkyl group" refers to an alkyl group substituted with one or more cyano groups, where the cyano group and alkyl group have the definitions described in this invention. In some embodiments, "cyanoalkyl group" refers to an alkyl group substituted with one cyano group. In some embodiments, "cyanoalkyl group" refers to a C 1~6 Cyanoalkyl groups, i.e., C substituted with one or more cyano groups 1~6 It is an alkyl group. In some preferred embodiments, C 1~6 A cyanoalkyl group is a C molecule substituted with one cyano group. 1~6 It is an alkyl group. In some other embodiments, “cyanoalkyl group” is C 1~4 Cyanoalkyl groups, i.e., C substituted with one or more cyano groups 1~4 It is an alkyl group. Examples of cyanoalkyl groups include, but are not limited to, -CH2CN, -CH2CH2CH2CH2CN, -CH2CH2CN, -CH2CH(CN)CH2CH2CN, and -CH2CH(CN)CH2CH(CH3)CN.

[0050] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups, where the alkyl group and hydroxyl group have the definitions described in this invention. In some embodiments, a hydroxyalkyl group refers to an alkyl group substituted with one, two, three, or four hydroxyl groups. In some embodiments, a hydroxyalkyl group refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, a hydroxyalkyl group refers to a C 1~6 It represents a hydroxyalkyl group, that is, C 1~6 This means that the alkyl group is substituted with one or more hydroxyl groups, preferably C 1~6 Hydroxyalkyl groups are C 1~6 The alkyl group represents an alkyl group substituted with one hydroxyl group. In some embodiments, the hydroxyalkyl group is C 1~4 Represents a hydroxyalkyl group. In some embodiments, the hydroxyalkyl group is C 1~3This represents a hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, and -CH2CH(OH)CH2CH(CH3)OH.

[0051] The term "haloalkyl group" means that an alkyl group is substituted with one or more halogen atoms, and the alkyl group and halogen have the definitions described in this invention. In some embodiments, the haloalkyl group is C 1~6 It is a haloalkyl group, C 1~6 This means that the alkyl group is substituted with one or more halogen atoms, and in some other embodiments, the haloalkyl group is C 1~4 It is a haloalkyl group, C 1~4 This means that the alkyl group is substituted with one or more halogen atoms, and in some other embodiments, the haloalkyl group is C 1~3 It is a haloalkyl group, C 1~3 This means that the alkyl group is substituted with one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, and 1,1-dibromoethyl.

[0052] The term "haloalkenyl group" means that an alkenyl group is substituted with one or more halogen atoms, and the alkenyl group has the definition described in this invention. In some embodiments, the haloalkenyl group is C 2~6 It is a haloalkenyl group, C 2~6 This means that the alkenyl group is substituted with one or more halogen atoms, and in some other embodiments, the haloalkenyl group is C 2~4 It is a haloalkenyl group, C2~4 This means that the alkenyl group is substituted with one or more halogen atoms. Examples of such groups include, but are not limited to, 1-chlorovinyl (-CCl=CH2), 2-fluorovinyl (-CH=CHF), 1-fluoroallyl (-CHFCH=CH2), 3-fluoropropenyl (i.e., -CH=CH-CH2F), and 3,3-difluoropropenyl (i.e., -CH=CH-CHF2).

[0053] The term "haloalkynyl group" means that an alkynyl group is substituted with one or more halogen atoms, and the alkynyl group has the definition described in this invention. In some embodiments, the haloalkynyl group is C 2~6 It is a haloalkynyl group, C 2~6 This means that the alkynyl group is substituted with one or more halogen atoms, and in some other embodiments, the haloalkynyl group is C 2~4 It is a haloalkynyl group, C 2~4 This means that the alkynyl group is substituted with one or more halogen atoms. Examples of such groups include, but are not limited to, the 2-chloroethynyl group (-C≡CCl), the 1-chloropropargyl group (-CHClC≡CH), and the 3-chloropropynyl group (-C≡C-CH2Cl).

[0054] The term "alkoxyalkyl group" refers to an alkyl group substituted with one or more alkoxy groups, and the alkoxy group and alkyl group have the definitions described in this invention. In some embodiments, the alkoxyalkyl group is C 1~6 Alkoxy C 1~6 Representing an alkyl group, in some other embodiments, the alkoxyalkyl group is C 1~4 Alkoxy C 1~4 Representing an alkyl group, in some other embodiments, the alkoxyalkyl group is C 1~4 Alkoxy C 1~3 Represents an alkyl group, and in some embodiments, the alkoxyalkyl group is C 1~3 Alkoxy C 1~3This represents an alkyl group. Examples of alkoxy groups include, but are not limited to, methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, methoxyethyl group, methoxy n-propyl group, methoxyisopropyl group, ethoxyethyl group, ethoxy n-propyl group, ethoxyisopropyl group, n-propoxyethyl group, isopropoxyethyl group, n-propoxy n-propyl group, n-propoxyisopropyl group, isopropoxy n-propyl group, and isopropoxyisopropyl group.

[0055] The term "carboxyalkyl group" refers to an alkyl group substituted with one or more carboxyl groups, where the carboxyl group and alkyl group have the definitions described in this invention. In some embodiments, the carboxyalkyl group is C 1~6 A carboxyalkyl group, which is a C atom substituted with one or more carboxyl groups. 1~6 Representing an alkyl group, in some other embodiments, the carboxyalkyl group is C 1~4 A carboxyalkyl group, which is a C atom substituted with one or more carboxyl groups. 1~4 Representing an alkyl group, in some other embodiments, the carboxyalkyl group is C 1~3 A carboxyalkyl group, which is a C atom substituted with one or more carboxyl groups. 1~3 This represents an alkyl group. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH2COOH), 2-carboxyethyl (-(CH2)2COOH), and 3-carboxypropyl (-(CH2)3COOH).

[0056] The term "alkylamino group" refers to an amino group substituted with one or two alkyl groups, and includes "N-alkylamino group" and "N,N-dialkylamino," where the alkyl group and amino group have the meanings described in this invention. In some embodiments, the alkylamino group is C 1~6 An alkylamino group is represented, which is an alkylamino group containing 1 to 6 carbon atoms, and in some other embodiments, the alkylamino group is C 1~4This represents an alkylamino group, which is an alkylamino group containing 1 to 4 carbon atoms. 1~3 This represents an alkylamino group, which contains 1 to 3 carbon atoms. A suitable alkylamino group may be a monoalkylamino group or a dialkylamino group. Examples of such groups include, but are not limited to, N-methylamino group (methylamino group, -NHCH3), N-ethylamino group (ethylamino group, -NHCH2CH3), N,N-dimethylamino group (dimethylamino group, -N(CH3)2), and N,N-diethylamino group (diethylamino, -N(CH2CH3)2).

[0057] The term "mercaptoalkyl group" refers to an alkyl group substituted with one or more mercapto groups, where the alkyl group has the definition described in this invention. In some embodiments, the mercaptoalkyl group is C 1~6 Represents a mercaptoalkyl group, where C is substituted with one or more mercapto groups. 1~6 It is an alkyl group, preferably C 1~6 A mercaptoalkyl group is a C molecule substituted with one mercapto group. 1~6 It is an alkyl group. In some other embodiments, the mercaptoalkyl group is C 1~4 Represents a mercaptoalkyl group. In some other embodiments, the mercaptoalkyl group is C 1~3 This represents a mercaptoalkyl group. Examples of mercaptoalkyl groups include, but are not limited to, mercaptomethyl (-CH2SH), 2-mercaptoethyl (-(CH2)2SH), 3-mercaptopropyl (-(CH2)3SH), and 2,3-dimercaptopropyl (-CH2CH(SH)CH2(SH)).

[0058] The term "alkoxy group" means that an alkyl group is bonded to the rest of the molecule by an oxygen atom, and the alkyl group has the meaning described in this invention. Unless otherwise described in detail, the above alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, C 1~6An alkoxy group is represented, and in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, C 1~4 Representing an alkoxy group, in another embodiment, the alkoxy group contains 1 to 3 carbon atoms, C 1~3 This represents an alkoxy group. The above alkoxy group may optionally be substituted with one or more substituents as described in the present invention. Examples of alkoxy groups include methoxy group (MeO, -OCH3), ethoxy group (EtO, -OCH2CH3), 1-propoxy group (n-PrO, n-propoxy group, -OCH2CH2CH3), 2-propoxy group (i-PrO, i-propoxy group, -OCH(CH3)2), 1-butoxy group (n-BuO, n-butoxy group, -OCH2CH2CH2CH3), 2-methyl-l-propoxy group (i-BuO, i-butoxy group, -OCH2CH(CH3)2), 2-butoxy group (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), and 2-methyl-2-propoxy group (t- Examples include, but are not limited to, BuO, t-butoxy group (-OC(CH3)3), 1-pentoxy group (n-pentoxy group, -OCH2CH2CH2CH2CH3), 2-pentoxy group (-OCH(CH3)CH2CH2CH3), 3-pentoxy group (-OCH(CH2CH3)2), 2-methyl-2-butoxy group (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy group (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy group (-OCH2CH2CH(CH3)2), and 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3).

[0059] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, and the alkoxy group and halogen have the definitions described in this invention. In some embodiments, the haloalkoxy group is a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1~6 Representing a haloalkoxy group, in some other embodiments, the haloalkoxy group is a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1~4 Representing a haloalkoxy group, in some other embodiments, the haloalkoxy group is a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C1~3 This represents a haloalkoxy group. Examples of haloalkoxy groups include, but are not limited to, the trifluoromethoxy group (-OCF3), the monofluoromethoxy group (-OCH2F), and the 2-fluoroethoxy group (-OCH2CH2F).

[0060] The terms "carbocyclic ring" or "carbocyclic group" refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbocyclic system containing 3 to 12 ring atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced with -C(=O)- (or -(CO)-). In one embodiment, the carbocyclic group contains 3 to 6 ring carbon atoms, C 3~6 Represented as a carbocyclic group, in some other embodiments, the carbocyclic group is a saturated ring containing 3 to 6 ring carbon atoms, C 3~6 Represented by a cycloalkyl group, in some other embodiments, the above C 3~6 A cycloalkyl group is a saturated monocycle. In one embodiment, the carbocyclic group contains 7 to 12 ring carbon atoms, C 7~12 Represented as a carbocyclic group, in some other embodiments, the carbocyclic group is a saturated ring containing 7 to 12 ring carbon atoms, C 7~12 It is represented by a cycloalkyl group. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, and octahydropentarenyl groups. Examples of carbocyclic groups in which the -CH2- group can be replaced by -C(=O)- include, but are not limited to, cyclopentanone and cyclobutanone.

[0061] The term "cycloalkyl group" refers to a monovalent saturated monocyclic or bicyclic carbocyclic system of 3 to 12 carbon atoms, where the -CH2- group in the carbocyclic may optionally be replaced with -C(=O)- (or -(CO)-). In some embodiments, the cycloalkyl group contains 3 to 12 ring carbon atoms, i.e., C 3~12 It is a cycloalkyl group. In some other embodiments, the cycloalkyl group contains 3 to 10 ring carbon atoms, i.e., C3~10 It is a cycloalkyl group. In some other embodiments, the cycloalkyl group comprises 7 to 12 ring carbon atoms, i.e., C 7~12 It is a cycloalkyl group. In some other embodiments, the above C 7~12 Cycloalkyl groups are bicyclic. In some other embodiments, the cycloalkyl group contains 7 to 10 ring carbon atoms, i.e., C 7~10 It is a cycloalkyl group. In some other embodiments, the above C 7~10 Cycloalkyl groups are bicyclic. In some other embodiments, cycloalkyl groups contain 3 to 6 ring carbon atoms, i.e., C 3~6 It is a cycloalkyl group. In some other embodiments, the above C 3~6 Cycloalkyl groups are monocyclic. In some other embodiments, cycloalkyl groups contain 3 to 5 ring carbon atoms, i.e., C 3~5 It is a cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, the cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, octahydro-1H-indenyl group, and octahydropentarenyl group. Examples of carbocyclic groups in which the -CH2- group can be replaced with -C(=O)- include, but are not limited to, cyclopentanone and cyclobutanone.

[0062] The terms “heterocycle” and “heterocyclyl group” refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring atoms, where at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms, and the heterocycle or heterocyclyl group is non-aromatic and does not contain any aromatic rings. A heterocycle is represented as a monovalent heterocyclyl group when it is bonded to another part of the molecule via one bonding site. Unless otherwise stated, the heterocyclyl group may be carbon-based or nitrogen-based, and the -CH2- group may optionally be replaced with -C(O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclyl group consists of 3 to 12 atoms and represents a 3 to 12-membered heterocycle or 3 to 12-membered heterocyclyl group. In some embodiments, the heterocycle or heterocyclyl group is composed of 3 to 10 atoms and represents a 3 to 10-membered heterocycle or heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group is composed of 3 to 9 atoms and represents a 3 to 9-membered heterocycle or heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group is composed of 5 to 9 atoms and represents a 5 to 9-membered heterocycle or heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group is composed of 3 to 7 atoms and represents a 3 to 7-membered heterocycle or heterocyclyl group. In some other embodiments, the 3 to 7-membered heterocycle or 3 to 7-membered heterocyclyl group is a 3 to 7-membered monocyclic heterocycle or a 3 to 7-membered monocyclic heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group consists of 3 to 6 atoms and represents a 3 to 6-membered heterocycle or heterocyclyl group. In some other embodiments, the 3 to 6-membered heterocycle or heterocyclyl group is a 3 to 6-membered monocyclic heterocycle or monocyclic heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group consists of 7 to 12 atoms and represents a 7 to 12-membered heterocycle or heterocyclyl group.In some other embodiments, the 7-12 membered heterocycle or 7-12 membered heterocyclyl group is a 7-12 membered bicyclic heterocycle or 7-12 membered bicyclic heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group is composed of 7-10 atoms and represents a 7-10 membered heterocycle or 7-10 membered heterocyclyl group. In some other embodiments, the 7-10 membered heterocycle or 7-10 membered heterocyclyl group is a 7-10 membered bicyclic heterocycle or 7-10 membered bicyclic heterocyclyl group. In some other embodiments, the heterocycle or heterocyclyl group is composed of 5-6 atoms and represents a 5-6 membered heterocycle or 5-6 membered heterocyclyl group. Examples of the above heterocycles include, but are not limited to, ethylene oxide, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octane. The above heterocyclyl groups include, but are not limited to, oxyranyl groups, azilidinyl groups, azetidinyl groups, oxetanyl groups, thioxetanyl groups, pyrrolidinyl groups, tetrahydrofuranyl groups, tetrahydrothienyl groups, thiazolidinyl groups, pyrazolidinyl groups, pyrazolinyl groups, oxazolidinyl groups, imidazolidinyl groups, piperidinyl groups, piperazinyl groups, or morpholinyl groups.

[0063] The term "aryl group" refers to a monovalent monocyclic, bicyclic, or tricyclic carbocyclic system containing 6 to 14 ring atoms, 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, and each ring system contains a ring consisting of 3 to 7 atoms. In some embodiments, the aryl group contains 6 to 12 ring atoms, and C 6~12 It is represented by an aryl group or a 6-12 membered aryl group. In some embodiments, the aryl group contains 6-10 ring atoms and C 6~10It is represented by an aryl group or a 6- to 10-membered aryl group. Examples of aryl groups include the phenyl group, naphthyl group, 1,2,3,4-tetrahydronaphthyl group, or anthracene.

[0064] The terms “heteroaryl group” or “heteroaryl ring” refer to a monovalent monocyclic, bicyclic, or tricyclic system containing 5 to 14 ring atoms, 5 to 12 ring atoms, 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic, and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl groups are usually bonded to the parent molecule via the aromatic ring of the heteroaryl group, although this is not mandatory. If a -CH2- group is present on the heteroaryl group, the -CH2- group may optionally be replaced with -C(=O)-. Unless otherwise stated, the heteroaryl group may be bonded to the rest of the molecule (e.g., the host structure in the general formula) via any reasonable site (which may be C or N). The term “heteroaryl” can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound.” In some embodiments, the heteroaryl group is a heteroaryl group containing 5 to 12 ring atoms and is represented as a 5 to 12-membered heteroaryl group; in some other embodiments, the heteroaryl group is a heteroaryl group containing 5 to 10 ring atoms and is represented as a 5 to 10-membered heteroaryl group; and in some other embodiments, the heteroaryl group is a heteroaryl group containing 5 to 6 ring atoms and is represented as a 5 to 6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, the furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, and benzopyrrolyl group.

[0065] The term "alkylthio group" means that an alkyl group is bonded to the rest of the molecule by a sulfur atom, and the alkyl group has the definition described in this invention. In some embodiments, the alkylthio group is C 1~6 The alkylthio group is an alkylthio group containing 1 to 6 carbon atoms, and in some other embodiments, the alkylthio group is C 1~4 The alkylthio group is an alkylthio group containing 1 to 4 carbon atoms, and in some other embodiments, the alkylthio group is C 1~3 This refers to an alkylthio group, specifically one containing 1 to 3 carbon atoms. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH3) and ethylthio (-SCH2CH3).

[0066] The term "haloalkylthio group" refers to an alkylthio group substituted with one or more halogen atoms, and the alkylthio group has the definition described in this invention. In some embodiments, the haloalkylthio group is C 1~6 A haloalkylthio group, substituted with one or more halogen atoms. 1~6 Represents an alkylthio group, and in some other embodiments, the haloalkylthio group is C 1~4 A haloalkylthio group, substituted with one or more halogen atoms. 1~4 Represents an alkylthio group, and in some other embodiments, the haloalkylthio group is C 1~3 A haloalkylthio group, substituted with one or more halogen atoms. 1~3 This represents an alkylthio group. The definition of a haloalkylthio group includes, but is not limited to, trifluoromethylthio group (-SCF3), 2,2,2-trifluoroethylthio group (-SCH2CF3), monofluoromethylthio group (-SCH2F), etc.

[0067] The term "arylalkyl group" refers to an alkyl group substituted with one aryl group, and the aryl group and alkyl group have the definitions described in this invention. In some embodiments, the arylalkyl group is (C 6~10 Ariel)-C1~6 Alkyl or (6-10 member aryl)-C 1~6 It is an alkyl group, and in some other embodiments, the arylalkyl group is (C 6~10 Ariel)-C 1~4 Alkyl or (6-10 member aryl)-C 1~4 It is an alkyl group, and in some other embodiments, the arylalkyl group is (C 6~10 Ariel)-C 1~3 Alkyl or (6-10 member aryl)-C 1~3 The alkyl group is, in some other embodiments, the arylalkyl group is phenyl C 1~6 The alkyl group is, in some other embodiments, the arylalkyl group is phenyl C 1~4 The alkyl group is, in some other embodiments, the arylalkyl group is phenyl C 1~3 It is an alkyl group. Examples of arylalkyl groups include, but are not limited to, phenylmethyl, phenylethyl, and naphthylmethyl groups.

[0068] The term "heteroarylalkyl group" refers to an alkyl group substituted with one heteroaryl group, and the heteroaryl group and alkyl group have the definitions described in this invention. In some embodiments, the heteroarylalkyl group is (5-12 member heteroaryl)-C 1~6 The alkyl group is, in some other embodiments, the heteroarylalkyl group is (5-12 member heteroaryl)-C 1~4 The alkyl group is, in some other embodiments, the heteroarylalkyl group is (5-12 member heteroaryl)-C 1~3 It is an alkyl group, and in some other embodiments, the heteroarylalkyl group is (5-6 member heteroaryl)-C 1~6 It is an alkyl group, and in some other embodiments, the heteroarylalkyl group is (5-6 member heteroaryl)-C 1~4 It is an alkyl group, and in some other embodiments, the heteroarylalkyl group is (5-6 member heteroaryl)-C 1~3It is an alkyl group. Examples of heteroarylalkyl groups include, but are not limited to, pyrimidinylmethyl, pyridylmethyl, pyridylethyl, and pyrazolylmethyl groups.

[0069] The term "heterocyclylalkyl group" refers to an alkyl group substituted with one heterocyclyl group, and the heterocyclyl group and alkyl group have the definitions set forth in this invention. In some embodiments, the heterocyclyl alkyl group is (3-6 member heterocyclyl)-C 1~6 It is an alkyl group, and in some other embodiments, the heterocyclylalkyl group is (3-6 membered heterocyclyl)-C 1~4 It is an alkyl group, and in some other embodiments, the heterocyclylalkyl group is (3-6 membered heterocyclyl)-C 1~4 It is an alkyl group, and in some other embodiments, the heterocyclylalkyl group is (3-6 membered heterocyclyl)-C 1~3 It is an alkyl group. Examples of heterocyclylalkyl groups include, but are not limited to, piperidinylmethyl, piperidinylethyl, and pyrrolidinylmethyl groups.

[0070] The term "cycloalkylalkyl group" refers to an alkyl group substituted with one cycloalkyl group. In some embodiments, the cycloalkyl alkyl group is (C 3~6 Cycloalkyl)-C 1~6 It is an alkyl group, and in some other embodiments, a cycloalkylalkyl group is (C 3~6 Cycloalkyl)-C 1~4 It is an alkyl group, and in some other embodiments, a cycloalkylalkyl group is (C 3~6 Cycloalkyl)-C 1~3 It is an alkyl group. Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclohexylethyl groups.

[0071] The term "cycloalkyl-O-alkyl group" refers to an alkyl group substituted with one cycloalkyloxy (cycloalkyl-O-). In some embodiments, the cycloalkyl-O-alkyl group is (C 3~12 Cycloalkyl)-OC 1~6 It is an alkyl group, and in some other embodiments, the cycloalkyl-O-alkyl group is (C 3~6 Cycloalkyl)-OC 1~6 It is an alkyl group, and in some other embodiments, the cycloalkyl-O-alkyl group is (C 3~6 Cycloalkyl)-OC 1~4 It is an alkyl group, and in some other embodiments, the cycloalkyl-O-alkyl group is (C 3~6 Cycloalkyl)-OC 1~3 Examples of alkyl groups, specifically cycloalkyl-O-alkyl groups, include, but are not limited to, -CH2O-cyclopropyl group, -CH2O-cyclobutyl group, -(CH2)2O-cyclobutyl group, -CH2O-cyclopentyl group, and -(CH2)2O-cyclopentyl group.

[0072] The term "heterocyclyl-O-alkyl group" refers to an alkyl group substituted with one heterocyclyloxy (heterocyclyl-O-). In some embodiments, the heterocyclyl-O-alkyl group is (3-12 member heterocyclyl)-OC 1~6 It is an alkyl group, and in some other embodiments, the heterocyclyl-O-alkyl group is (3-6 membered heterocyclyl)-OC 1~4 It is an alkyl group, and in some other embodiments, the heterocyclyl-O-alkyl group is (7-12 member heterocyclyl)-OC 1~4 It is an alkyl group, and in some other embodiments, the heterocyclyl-O-alkyl group is (3-6 membered heterocyclyl)-OC 1~3It is an alkyl group. Examples of heterocyclyl-O-alkyl groups include, but are not limited to, the -CH2O-azetidinyl group, -CH2O-azetidinyl group, -CH2O-oxetanyl group, -CH2O-tetrahydrofuranyl group, -CH2O-spiro[2,3]hexyl group, and -CH2O-spiro[3,3]heptyl-.

[0073] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0074] The term "Oxo" represents =O.

[0075] The term "cyano" represents -CN or -C≡N.

[0076] The term "mercapto" represents -SH.

[0077] The term "hydroxyl" represents -OH.

[0078] The term "carboxyl" represents -C(=O)OH.

[0079] The term "amino" represents -NH2.

[0080] The terms "consisting of j to k atoms" or "j to k members" mean that the cyclic group consists of j to k ring atoms, where the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P, where j and k are independently any non-zero natural numbers, k > j, and "j to k" includes j, k, and any natural numbers between them. For example, "consisting of 3 to 8 atoms" or "3 to 8 members", "consisting of 3 to 6 atoms" or "3 to 6 members", "consisting of 5 to 10 atoms" or "5 to 10 members" or "consisting of 5 to 6 atoms" or "5 to 6 members" means that the cyclic group consists of 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8), 3 to 6 (i.e., 3, 4, 5, or 6), 5 to 10 (i.e., 5, 6, 7, 8, 9, or 10), or 5 to 6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P.

[0081] As described in the present invention, substituent (R) q A ring system formed by a single bond connecting to a central ring means that the q substituents R can be substituted at any substitutable or any reasonable position on the ring where they are located. For example, formula a is a naphthalene ring with n R 2 This means that it can be substituted, and if n is greater than 1, each R 2 These can be independently selected from the same or different substituents.

[0082] [ka]

[0083] As used in the present invention, the term "prodrug" means that one compound is converted in the body to a compound represented by formula (I) or (I-1). Such conversion is influenced by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compounds of the present invention may be esters, and esters that can be prodrugs in the prior invention include phenyl esters and aliphatic (C) esters. 1~24These include esters, acyloxymethyl esters, carbonate esters, carbamic acid esters, and amino acid esters. For example, one compound of the present invention contains hydroxyl, which can be acylated to obtain a prodrug compound. Other prodrug forms contain phosphate esters, for example, these phosphate ester compounds can be obtained by phosphorylation of hydroxyl in the parent compound.

[0084] A "metabolite" is a product obtained in the body through metabolic action of a specific compound or its salt. The metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using test methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, and enzymatic degradation of the administered compound. Accordingly, the present invention includes metabolites of a compound, and includes metabolites produced by contacting the compound of the present invention with a mammal for a certain period of time.

[0085] In the context of the present invention, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art and are described, for example, in the literature: SMBerge et al., "Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19." Salts formed by pharmaceutically acceptable, non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with an amino group, such as hydrochloride, hydrobromide, phosphate, sulfate, and perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, and malonate, or these salts may be obtained by other methods described in books, such as ion exchange. The present invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble, oil-soluble, or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include amine cations formed with suitable, non-toxic ammonium, quaternary ammonium salts and anti-equilibrium ions, such as halides, hydroxides, carboxylates, sulfides, phosphorides, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0086] In this invention, "solvate" refers to an aggregate formed by one or more solvent molecules and the compound of the present invention. The solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol, or mixtures thereof. The term "hydrate" refers to an aggregate formed by a solvent molecule with water.

[0087] The term "hydrate" can be used when the solvent is water. In one embodiment, one compound molecule of the present invention can bind with one water molecule, for example, a monohydrate; in another embodiment, one compound molecule of the present invention can bind with more than one water molecule, for example, a dihydrate; and in yet another embodiment, one compound molecule of the present invention can bind with fewer than one water molecule, for example, a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological efficacy of the unhydrated form of the above compound.

[0088] As used in the present invention, the term “to treat” any disease or condition means, in some embodiments, to improve the disease or condition (i.e., to alleviate, prevent or reduce the progression of the disease or at least one of its clinical symptoms). In some other embodiments, “treatment” means to alleviate or improve at least one physical parameter, including a physical parameter that may not be perceived by the patient. In some other embodiments, “treatment” means to adjust the disease or condition physically (e.g., a stable, perceptible symptom) or physiologically (e.g., a stable physical parameter) or both. In some other embodiments, “treatment” means to prevent or delay the onset, occurrence or exacerbation of the disease or condition.

[0089] The terms “prevention” or “prevention” mean reducing the risk of developing a disease or disorder (i.e., stopping the progression of at least one clinical symptom of a disease in a subject who is likely to face such a disease or has a prior predisposition to face such a disease, but has not yet experienced or manifested any symptoms of the disease).

[0090] The term "therapeutic dose" refers to the amount of a compound that, when administered to a subject to treat a disease, is effective in treating that disease. The therapeutic dose can vary depending on the compound, the disease and its severity, as well as the conditions of the subject being treated, such as age, weight, and sex.

[0091] Unless otherwise stated, all suitable isotopic changes, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention fall within the scope of the present invention.

[0092] If the stereochemistry of any particular chiral atom is not shown in a structure disclosed in this invention, all stereoisomers of the structure are considered within this invention and are included in the invention as compounds disclosed in this invention. If the stereochemistry is shown by a solid wedge or dashed line indicating a specific configuration, the stereoisomers of the structure are clearly defined.

[0093] The nitrogen oxides of the compounds of the present invention are also included in the scope of the present invention. The nitrogen oxides of the compounds of the present invention can be produced by oxidizing a corresponding nitrogen-containing basic substance with a conventional oxidizing agent (e.g., hydrogen peroxide) at a raised temperature, for example, in the presence of an acid such as acetic acid, or by reacting it with a peracid in a suitable solvent, for example, by reacting it with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or by reacting it with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0094] The compound represented by formula (I) or (I-1) may exist in the form of a salt.

[0095] Any structural formula shown in this invention is intended to represent both the isotope-unenriched and isotope-enriched forms of these compounds. The isotope-enriched compounds have the structure shown by the general formulas presented in this invention, except that one or more atoms are substituted with atoms having selected atomic weights or mass numbers. Exemplary isotopes that can be introduced into the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P,32 P, 35 S, 36 Cl and 125 Includes I.

[0096] Description of the compound of the present invention The present invention provides compounds or pharmaceutical compositions thereof that function as KRAS inhibitors, particularly KRAS12D inhibitors. The present invention further relates to the use of such compounds or pharmaceutical compositions thereof in the manufacture of drugs that treat diseases and / or symptoms by inhibiting KRAS activity.

[0097] The excellent properties of the compounds of the present invention, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerance.

[0098] In one embodiment, the present invention provides a compound represented by formula (I), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of a compound represented by formula (I). [ka] In the formula, R 1 , R 2 , R 3 , R 4 Y, T, ring B, and n each have the definitions described in this invention.

[0099] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R7 -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1~6 Alkyl-NR 6 C(=O)R 7 , -C 1~6 Alkyl-NR 6 R 7 , -C 1~6 Alkyl-C(=O)OR 6 , -C 1~6 Alkyl-C(=O)NR 6 R 7 , C 1~6 Alkyl alkyl group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy C 1~6 Alkyl, (C 3~12 Cycloalkyl)-C 1~6 Alkyl group, (3-12 member heterocyclyl)-C 1~6 Alkyl, (C 6~10 Ariel)-C 1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6 Alkyl, (C 3~12 Cycloalkyl)-OC 1~6 Alkyl alkyl groups, (3-12 member heterocyclyl)-OC 1~6 Alkyl alkyl group, C 1~6 Mercaptoalkyl groups, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 3~12 The above C is a cycloalkyl group or a 3-12 membered heterocyclyl group. 1~6 Alkoxy C 1~6 Alkyl, (C 3~12 Cycloalkyl)-C 1~6 Alkyl group, (3-12 member heterocyclyl)-C 1~6 Alkyl, (C 6~10 Ariel)-C 1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6An alkyl group, (C 3~12 ycloalkyl)-O-C 1~6 an alkyl group, (3- to 12-membered heterocyclyl)-O-C 1~6 an alkyl group, C 6~12 an aryl group, a 5- to 12-membered heteroaryl group, C 3~12 The cycloalkyl group and the 3- to 12-membered heterocyclyl group are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 and C 1~6 an alkyl group, where R 6 , R 7 and R 6a each have the definitions described in the present invention.

[0100] In some embodiments, T is

Chemical formula

Chemical formula

Chemical formula

[0101] Several embodiments, each R 5 These are independently H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -C 1~4 Alkylene-S(=O)2N(R) 7b )2, C 1~6 Alkyl alkyl group, C 1~6 Alkylthio group, C 1~6 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl groups, -NH(C) 1~6 Alkyl), -N(C 1~6 Alkyl)2, C 2~6 Haloalkenyl group, C 2~6 Haloalkynyl group, C 1~6 Haloalkoxy group, C 1~6 Haloalkylthio group, C 6~10 Aryl group, 5-10 membered heteroaryl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~6 Alkyl alkyl group, C 1~6 Alkylthio group, C 1~6 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NH(C 1~6 Alkyl), -N(C1~6 (alkyl)2, C 6~10 an aryl group, a 5- to 10-membered heteroaryl group, C 3~6 The cycloalkyl group and the 3- to 6-membered heterocyclyl group are each independently optionally substituted with 1, 2, 3 or 4 R 8 where R 6b , R 7c , R 6c and R 8 each have the definitions described in the present invention.

[0102] In some embodiments, two R 5 bonded to the same carbon atom together form

Chemical formula

[0103] In some embodiments, two R 5 bonded to the same carbon atom together with the carbon atom to which they are bonded form a C 3~6 cycloalkyl group or a 3- to 6-membered heterocyclyl group, and the C 3~6 cycloalkyl group and the 3- to 6-membered heterocyclyl group are each independently optionally substituted with 1, 2, 3 or 4 R 8 where R 8 has the definition described in the present invention, In some embodiments, two R 5 bonded to two adjacent atoms together with the two adjacent atoms to which they are bonded form a C 3~6 cycloalkyl group or a 3- to 6-membered heterocyclyl group, and the C 3~6 cycloalkyl group and the 3- to 6-membered heterocyclyl group are each independently optionally substituted with 1, 2, 3 or 4 R 8 where R 8 has the definition described in the present invention.

[0104] Several embodiments, each R 8 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 1~6 Hydroxyalkyl group, C 6~10 Aryl group, 6-10 membered heteroaryl group, -C(=O)OC 1~6 Alkyl group, -C(=O)NHC 1~6 Alkyl group, -C(=O)N(C 1~6 It is alkyl(2).

[0105] In some embodiments, ring B is C 6~12 It is an aryl group or a 5-12 membered heteroaryl group.

[0106] Several embodiments, each R 2 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1~6 Alkyl alkyl group, C 1~6 Alkylthio group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 2~6 Hydroxyalkynyl group, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl group, C 2~6 Haloalkenyl group, C 2~6 Haloalkynyl group, C 1~6 Haloalkoxy group, C 1~6 Haloalkylthio group, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 3~6The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~6 Alkyl alkyl group, C 1~6 Alkylthio group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 2~6 Hydroxyalkynyl group, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl group, C 2~6 Haloalkenyl group, C 2~6 Haloalkynyl group, C 1~6 Haloalkoxy group, C 1~6 Haloalkylthio group, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~6 It is substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, where R 6b , R 7b and R 6c Each of these terms has the definition described in the present invention.

[0107] In some embodiments, R 3 -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, or C 1~4 It is a haloalkyl group.

[0108] In some embodiments, Y is a bond, O, or S.

[0109] In some embodiments, R 4 These are 3-10 member heterocyclyl groups, -L-(3-12 member heterocyclyl), -L-(C 3~12Cycloalkyl), -L-(5-12 member heteroaryl), or -L-(C 6~10 It is an aryl group, and the above 3-10 member heterocyclyl group, -L-(C 3~12 Cycloalkyl, -L-(5-12 member heteroaryl), and -L-(C 6~10 Each of the R's (aryls) can be any one, two, three, or four R's, independently of each other. 9a Substituted with, the above -L- (3-12 member heterocyclil) is optionally 1, 2, 3 or 4 R 9b It is replaced by, here, L, R 9a and R 9b Each of these terms has the definition described in the present invention.

[0110] In some embodiments, L is C 1~6 It is an alkylene group.

[0111] In some embodiments, R 9a -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, C 1~6 Haloalkoxy group, (C 6~10 Ariel)-C 1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6 Alkyl group, (3-6 member heterocyclyl)-C 1~6 Alkyl, (C 3~6 Cycloalkyl)-C 1~6 Alkyl alkyl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, C 1~6 Haloalkoxy group, (C 6~10Ariel)-C 1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6 Alkyl group, (3-6 member heterocyclyl)-C 1~6 Alkyl, (C 3~6 Cycloalkyl)-C 1~6 Alkyl alkyl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1~6 Alkyl and C 1~6 Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, where R 6d and R 7d Each of these terms has the definition described in the present invention.

[0112] In some embodiments, R 9b -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, C 1~6 Haloalkoxy group, (C 6~10 Ariel)-C 1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6 Alkyl group, (3-6 member heterocyclyl)-C 1~6 Alkyl, (C 3~6 Cycloalkyl)-C 1~6 Alkyl alkyl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, C 1~6 Haloalkoxy group, (C 6~10Ariel)-C 1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6 Alkyl group, (3-6 member heterocyclyl)-C 1~6 Alkyl, (C 3~6 Cycloalkyl)-C 1~6 Alkyl alkyl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1~6 Alkyl and C 1~6 Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, where R 6d and R 7d Each of these terms has the definition described in the present invention.

[0113] In some embodiments, two R atoms bonded to the same ring carbon atom 9b Together [ka] Forms R 6j and R 7j Each of these terms has the definition described in the present invention.

[0114] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e These are, independently, -H, -D, or C 1~6 It is an alkyl group, and the above C 1~6 Alkyl groups can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1~6 Alkoxy group, C 6~12 Aryl group, C 3~6Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, In some embodiments, R 6 and R 7 Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the above 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~6 Alkyl alkyl group, C 1~6 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkoxy group or C 1~6 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0115] In some embodiments, R 6b and R 7b Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the above 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~6 Alkyl alkyl group, C 1~6 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkoxy group or C 1~6 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0116] In some embodiments, R 6d and R 7d Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the above 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~6Alkyl alkyl group, C 1~6 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkoxy group or C 1~6 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0117] In some embodiments, R 6e and R 7e Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the above 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~6 Alkyl alkyl group, C 1~6 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkoxy group and C 1~6 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0118] In some embodiments, R 6a , R 6c , R 6g , R 7g , R 6h , R 7h , R 7k , R 6j and R 7j These are, independently, -H, -D, or C 1~6 It is an alkyl group, In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.

[0119] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a-C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1~4 Alkyl-NR 6 C(=O)R 7 , -C 1~4 Alkyl-NR 6 R 7 , -C 1~4 Alkyl-C(=O)OR 6 , -C 1~4 Alkyl-C(=O)NR 6 R 7 , C 1~6 Alkyl alkyl group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 1~4 Alkoxy C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl, (C 7~12 Cycloalkyl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl group, (7-12 member heterocyclyl)-C 1~4 Alkyl, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-OC 1~4 Alkyl, (C 7~12 Cycloalkyl)-OC 1~4 Alkyl alkyl groups, (3-6 member heterocyclyl)-OC 1~6Alkyl alkyl groups, (3-7 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (7-12 member heterocyclyl)-OC 1~4 Alkyl alkyl group, C 1~4 Mercaptoalkyl groups, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkoxy C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl, (C 7~12 Cycloalkyl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl group, (7-12 member heterocyclyl)-C 1~4 Alkyl, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-OC 1~4 Alkyl, (C 7~12 Cycloalkyl)-OC 1~4 Alkyl alkyl groups, (3-6 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (3-7 member heterocyclyl)-OC 1~6 Alkyl alkyl groups, (7-12 member heterocyclyl)-OC 1~4 Alkyl alkyl group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 Each cycloalkyl group or 3-6 membered heterocyclyl group can independently be any of the following: D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6 , -NR 6 R 7 -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 and C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, where R 6 , R 7 and R 6a Each of these terms has the definition described in the present invention.

[0120] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 -CH2NR 6 C(=O)R 7 -CH2NR 6 R 7 ,-(CH2)2NR 6 R 7 -CH2C(=O)OR 6 , -(CH2)2C(=O)OR 6 , -(CH2)3C(=O)OR 6 -CH2C(=O)NR 6 R 7 -(CH2)2C(=O)NR 6 R 7 -(CH2)3C(=O)NR 6 R 7, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH (CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH 2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2) 2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2 -Cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -(CH2)2-cyclopentyl group, -(CH2)3-cyclopentyl group, -(CH2)2-cyclohexyl group, -CH2-phenyl group, -CH2-imidazolyl group, -CH2-pyrazolyl group, -CH2O-cyclopropyl group, -CH2O-cyclobutyl group, -(CH2)2O-cyclobutyl group, -CH2O-cyclopentyl group, -(CH2)2O-cyclopentyl group, -CH2O-azetidinyl group, -CH2O-oxetanyl group, -CH2O-tetrahydrofuranyl group, -CH2O-pyrrolidinyl group, -CH2O-spiro[2.3]hexyl group, -CH2O-spiro[3.3] Heptyl group, -CH2SH, -(CH2)2SH, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, oxetanyl group, tetrahydropyranyl group, azetidinyl group, or pyrrolidinyl group, and the above -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -(CH2)2-cyclopentyl group, -(CH2)3-cyclopentyl group, -(CH2)2-cyclohexyl group, -CH2-phenyl group, -CH2-imidazolyl group, -CH2-pyrazo The lyl group, -CH2O-cyclopropyl group, -CH2O-cyclobutyl group, -(CH2)2O-cyclobutyl group, -CH2O-cyclopentyl group, -(CH2)2O-cyclopentyl group, -CH2O-azetidinyl group, -CH2O-oxetanyl group, -CH2O-tetrahydrofuranyl group, -CH2O-pyrrolidinyl group, -CH2O-spiro[2.3]hexyl group, -CH2O-spiro[3.3]heptyl group, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, oxetanyl group, tetrahydropyranyl group, azetidinyl group, or pyrrolidinyl group can each be independently and arbitrarily D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 , -NR 6 R 7 -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , substituted with 1, 2, 3 or 4 substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups, where R 6 , R 7 and R 6a Each of these terms has the definition described in the present invention.

[0121] In some embodiments, T is [ka] And here, R 5 q1 and q1 each have the definitions described in the present invention.

[0122] Several embodiments, each R 5 These are independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -C 1~4 Alkylene S(=O)2N(R) 7b )2, C 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 1~4 Alkoxy group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl groups, -NH(C) 1~4 Alkyl), -N(C 1~4 Alkyl)2, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, 6-10 membered aryl group, 5-10 membered heteroaryl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4Alkylthio group, C 1~4 Alkoxy group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, -NH(C 1~4 Alkyl), -N(C 1~4 Alkyl) 2, 6-10 membered aryl group, 5-10 membered heteroaryl group, C 3~6 Each cycloalkyl group and 3-6 membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. 8 It is replaced by, here, R 6b , R 7c , R 6c and R 8 Each of these terms has the definition described in the present invention.

[0123] In some embodiments, two R atoms bonded to the same carbon atom 5 Together [ka] Forms R 6h , R 7h and R 7k Each of these terms has the definition described in the present invention.

[0124] In some embodiments, two R atoms bonded to the same carbon atom 5 Together with the carbon atoms bonded to them, C 3~6 Forming a cycloalkyl group or a 3-6 membered heterocyclyl group, the above C 3~6 Each cycloalkyl group and 3-6 membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. 8 It is replaced by, here, R 8 This has the definition described in the present invention.

[0125] In some embodiments, two R atoms bonded to two adjacent atoms 5 Together with the two adjacent atoms bonded to them, C 3~6 Forming a cycloalkyl group or a 3-6 membered heterocyclyl group, the above C 3~6Each cycloalkyl group and 3-6 membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. 8 It is replaced by, here, R 8 This has the definition described in the present invention.

[0126] Several embodiments, each R 8 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Hydroxyalkyl group, C 6~10 Aryl group, 6-10 membered heteroaryl group, -C(=O)OC 1~4 Alkyl group, -C(=O)NHC 1~4 Alkyl group, -C(=O)N(C 1~4 Alkyl)2, In some embodiments, R 6h , R 7h and R 7k These are, independently, -H, -D, or C 1~4 It is an alkyl group.

[0127] Several embodiments, each R 5 These are independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c -CH2S(=O)2N(R 7b2. -(CH2)2S(=O)2N(R) 7b)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3 , -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2C F3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, aziridinyl The group is -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3,-O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2 CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -C H2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N( (CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, - SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, cyclopropyl group The cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group may each be independently and optionally have 1, 2, 3, or 4 R groups. 8 It is replaced by, here, R 6b , R 7c , R 6c and R 8 Each of these terms has the definition described in the present invention.

[0128] In some embodiments, two R atoms bonded to the same carbon atom 5These groups, together with the carbon atoms bonded to them, form a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, or morpholinyl group, and the above cyclo The ropropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, thioxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group can each be independently and optionally have 1, 2, 3, or 4 R groups. 8 It is replaced by, here, R 8 This has the definition described in the present invention.

[0129] In some embodiments, two R atoms bonded to two adjacent atoms 5 These groups, together with two adjacent atoms bonded to them, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyranyl, azilidinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl groups. The above cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group may each be independently and optionally have 1, 2, 3, or 4 R groups. 8 It is replaced by, here, R 8 This has the definition described in the present invention.

[0130] Several embodiments, each R 8 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, py These are loryl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2, or -C(=O)N(CH3)CH2CH3.

[0131] In some embodiments, R 6h , R 7h and R 7k These are, independently, -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group.

[0132] In some embodiments, T is [ka] That is the case. In some embodiments, ring B is [ka] It is one of the substructures of [the structure].

[0133] Several embodiments, each R 2These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 2~4 Hydroxyalkynyl group, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 2~4 Hydroxyalkynyl group, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~6 It is substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, where R 6b , R 6c and R 7b Each of these terms has the definition described in the present invention.

[0134] Several embodiments, each R 2 These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C ≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH 2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl The group is a nyl group, a tetrahydrofuranyl group, a piperidinyl group, or a piperazinyl group, and the above are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2) 2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group,The pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group and piperazinyl group are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group and piperazinyl group, where R, 6b , R 6c and R 7b Each of these terms has the definition described in the present invention.

[0135] In some embodiments, [ka] teeth, [ka] That is the case.

[0136] In some embodiments, R 4 It is a 3-6 member heterocyclyl group, [ka] -L-pyrrolidinyl group, -L-piperidinyl group, -L-morpholinyl group, -L-oxetanyl group, -L-oxyranyl group, -L-tetrahydrofuranyl group, -L-octahydroindolidinyl group, -L-cyclopropyl group, -L-cyclopentyl group, -L-octahydropentalenyl group, -L-octahydro-1H-indenyl group, -L-decahydronaphthyl group, -L-pyridyl group, -L-pyrazolyl group, or -L-phenyl group. The above 3-6 member heterocyclyl group, -L-cyclopropyl group, -L-cyclopentyl group, -L-octahydropentalenyl group, -L-octahydro-1H-indenyl group, -L-decahydronaphthyl group, -L-pyridyl group, -L-pyrazolyl group, and -L-phenyl group each independently optionally have 1, 2, 3, or 4 R 9a Replaced by the above [ka] -L-pyrrolidinyl group, -L-piperidinyl group, -L-morpholinyl group, -L-oxetanyl group, -L-oxyranyl group, -L-tetrahydrofuranyl group and -L-octahydroindolidinyl group may each optionally have 1, 2, 3 or 4 R groups. 9b It is replaced by, here, L, R 9a and R 9b Each of these terms has the definition described in the present invention.

[0137] In some embodiments, L is C 1~4 It is an alkylene group.

[0138] In some embodiments, R 9a -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Haloalkyl group, C1~4 Haloalkoxy group, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl alkyl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Haloalkyl group, C 1~4 Haloalkoxy group, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl alkyl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1~4 Alkyl and C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, where R 6d , R 7d , R 6e , R 7e Each of these terms has the definition described in the present invention.

[0139] In some embodiments, R 9b -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Haloalkyl group, C 1~4Haloalkoxy group, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl alkyl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 1~4 Haloalkyl group, C 1~4 Haloalkoxy group, phenyl-C 1~4 Alkyl group, (5-6 member heteroaryl)-C 1~4 Alkyl group, (3-6 member heterocyclyl)-C 1~4 Alkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl alkyl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1~4 Alkyl and C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, where R 6d and R 7d Each of these terms has the definition described in the present invention.

[0140] In some embodiments, two R atoms bonded to the same ring carbon atom 9b Together [ka] Forms R 6j and R 7j Each of these has the definitions described in the present invention. In some embodiments, R 6j and R 7j These are, independently, -H, -D, or C 1~4 It is an alkyl group.

[0141] In some embodiments, R 4 These are piperidinyl group, piperazinyl group, pyrrolidinyl group, imidazolidinyl group, [ka] -CH2-pyrrolidinyl group, -CH2-morpholinyl group, -(CH2)2-morpholinyl group, -CH2-oxetanyl group, -CH2-oxyranyl group, -CH2-tetrahydrofuranyl group, -CH2-octahydroindolidinyl group, -CH2-cyclopropyl group, -CH2-cyclopentyl group, -CH2-octahydropentarenyl group, -CH2-octahydro-1H-indenyl group, -CH2-decahydronaphthyl group, -CH2-pyridyl group, -(CH2)2-pyridyl group, -CH2-pyrazolyl group, -(CH2) The group is either a 2-pyrazolyl group or a -CH2-phenyl group, and each of the above-mentioned piperidinyl group, piperazinyl group, pyrrolidinyl group, imidazolidinyl group, -CH2-cyclopropyl group, -CH2-cyclopentyl group, -CH2-octahydropentarenyl group, -CH2-octahydro-1H-indenyl group, -CH2-decahydronaphthyl group, -CH2-pyridyl group, -(CH2)2-pyridyl group, -CH2-pyrazolyl group, -(CH2)2-pyrazolyl group and -CH2-phenyl group can each be independently and optionally have 1, 2, 3 or 4 R 9a Replaced by the above [ka] -CH2-pyrrolidinyl group, -CH2-morpholinyl group, -(CH2)2-morpholinyl group, -CH2-oxetanyl group, -CH2-oxyranyl group, -CH2-tetrahydrofuranyl group and -CH2-octahydroindolidinyl group may each optionally have 1, 2, 3 or 4 R 9b It is replaced by, here, L, R 9a and R 9b Each of these terms has the definition described in the present invention.

[0142] In some embodiments, R 9a -D, -OH, -F, -Cl, -Br, -I, -CN, -NR6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy group, -CHF2, -CF3, -OCF3, phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group, or azetidinyl group, and the above methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy The xy group, -CHF2, phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group, and azetidinyl group are each independently and optionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl group, ethyl group, n-propyl group, and isopropyl group. In some embodiments, R 9b -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d-CH2OC(=O)NR 6d R 7d , methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy group, -CHF2, -CF3, -OCF3, phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group, or azetidinyl group, and the above methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy The group, -CHF2, phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group and azetidinyl group are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl group, ethyl group, n-propyl group and isopropyl group, where R 6d and R 7d Each of these terms has the definition described in the present invention.

[0143] In some embodiments, two R atoms bonded to the same ring carbon atom 9b Together [ka] It forms.

[0144] In some embodiments, R 6j and R 7j These are, independently, -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group.

[0145] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e These are, independently, -H, -D, or C 1~4 It is an alkyl group, and the above C 1~4 Alkyl groups can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1~4 Alkoxy group, C 6~10 Aryl group, C 3~6 It is substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups.

[0146] In some embodiments, R 6 and R 7 These, together with the same N atoms bonded to them, form a 4-6 member heteroring, and the above 4-6 member heteroring can optionally be -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~4 Alkyl alkyl group, C 1~4 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkoxy group or C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0147] In some embodiments, R 6b and R 7bThese, together with the same N atoms bonded to them, form a 4-6 member heteroring, and the above 4-6 member heteroring can optionally be -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~4 Alkyl alkyl group, C 1~4 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkoxy group or C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0148] In some embodiments, R 6d and R 7d Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the above 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~4 Alkyl alkyl group, C 1~4 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkoxy group or C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0149] In some embodiments, R 6e and R 7e These, together with the same N atoms bonded to them, form a 4-6 member heteroring, and the above 4-6 member heteroring can optionally be -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1~4 Alkyl alkyl group, C 1~4 Alkylamino group, C 3~6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C1~4 Hydroxyalkyl group, C 1~4 Haloalkoxy group or C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0150] In some embodiments, R 6a , R 6c , R 6g and R 7g These are, independently, -H, -D, or C 1~4 It is an alkyl group.

[0151] In some embodiments, R 4 teeth, [ka] That is the case.

[0152] In some embodiments, R 4 teeth, [ka] That is the case.

[0153] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e Each of these is independently -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group, and the above methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and t-butyl group can be arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g, substituted with 1, 2, 3 or 4 substituents selected from methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxyranyl, oxetanyl, azetidinyl and pyrrolidinyl groups, In some embodiments, R 6 and R 7 These groups, together with the same N atom bonded to them, form pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, or imidazolidine, and each of these pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, and imidazolidine groups are independently and optionally substituted with one, two, three, or four substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methylamino group, dimethylamino group, ethylamino group, cyclopropyl group, cyclopentyl group, pyrrolidinyl group, methoxy group, ethoxy group, isopropoxy group, cyanomethyl group, hydroxymethyl group, hydroxyethyl group, trifluoromethoxy group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, or 1,2-dichloroethyl group.

[0154] In some embodiments, R 6b and R 7bThese groups, together with the same N atom bonded to them, form pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, or imidazolidine, and each of these pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, and imidazolidine groups are independently and optionally substituted with one, two, three, or four substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methylamino group, dimethylamino group, ethylamino group, cyclopropyl group, cyclopentyl group, pyrrolidinyl group, methoxy group, ethoxy group, isopropoxy group, cyanomethyl group, hydroxymethyl group, hydroxyethyl group, trifluoromethoxy group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, or 1,2-dichloroethyl group.

[0155] In some embodiments, R 6d and R 7d These groups, together with the same N atom bonded to them, form pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, or imidazolidine, and each of these pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, and imidazolidine groups are independently and optionally substituted with one, two, three, or four substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methylamino group, dimethylamino group, ethylamino group, cyclopropyl group, cyclopentyl group, pyrrolidinyl group, methoxy group, ethoxy group, isopropoxy group, cyanomethyl group, hydroxymethyl group, hydroxyethyl group, trifluoromethoxy group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, or 1,2-dichloroethyl group.

[0156] In some embodiments, R 6e and R 7eThese groups, together with the same N atom bonded to them, form pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, or imidazolidine, and each of these pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, and imidazolidine groups are independently and optionally substituted with one, two, three, or four substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methylamino group, dimethylamino group, ethylamino group, cyclopropyl group, cyclopentyl group, pyrrolidinyl group, methoxy group, ethoxy group, isopropoxy group, cyanomethyl group, hydroxymethyl group, hydroxyethyl group, trifluoromethoxy group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, or 1,2-dichloroethyl group.

[0157] In some embodiments, R 6a , R 6c , R 6g and R 7g These are, independently, -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group.

[0158] In some embodiments, the compounds described in the present invention are compounds represented by formula (I-1), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of compounds represented by formula (I-1). [ka] In the formula, R 1 , R 3 , R 4 Y and T each have the definitions described in the present invention. R 2a , R 2b and R 2c These are, respectively, R as described in the present invention. 2 It has the same definition.

[0159] In some embodiments, R 2a , R 2b and R 2c These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR. 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1~6 Alkyl alkyl group, C 1~6 Alkylthio group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 2~6 Hydroxyalkynyl group, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl group, C 2~6 Haloalkenyl group, C 2~6 Haloalkynyl group, C 1~6 Haloalkoxy group, C 1~6 Haloalkylthio group, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~6 Alkyl alkyl group, C 1~6 Alkylthio group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 2~6 Hydroxyalkynyl group, C 1~6 Alkoxy group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl group, C 2~6 Haloalkenyl group, C 2~6 Haloalkynyl group, C 1~6 Haloalkoxy group, C 1~6 Haloalkylthio group, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 3~6The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~6 Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, R 6b , R 7b and R 6c Each of these has the definitions described in the present invention. In some embodiments, R 2a , R 2b and R 2c These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR. 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 2~4 Hydroxyalkynyl group, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 The above C is a cycloalkyl group or a 3-6 membered heterocyclyl group. 1~4 Alkyl alkyl group, C 1~4 Alkylthio group, C 2~4 Alkenyl group, C 2~4Alkynyl group, C 2~4 Hydroxyalkynyl group, C 1~4 Alkoxy group, C 1~4 Cyanoalkyl group, C 1~4 Hydroxyalkyl group, C 1~4 Haloalkyl group, C 2~4 Haloalkenyl group, C 2~4 Haloalkynyl group, C 1~4 Haloalkoxy group, C 1~4 Haloalkylthio group, C 6~10 Aryl group, 5-12 membered heteroaryl group, C 3~6 The cycloalkyl groups and 3- to 6-membered heterocyclyl groups can each be independently and arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~6 Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3-6 membered heterocyclyl groups, R 6b , R 7b and R 6c Each of these terms has the definition described in the present invention.

[0160] In some embodiments, R 2a , R 2b and R 2c These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, and -CH2C(=O)NR. 6b R 7b -C(=O)R 6c , -C(=O)OR 6c -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C ≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH 2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl The group is a nyl group, a tetrahydrofuranyl group, a piperidinyl group, or a piperazinyl group, and the above are -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2) 2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group,The pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group, and piperazinyl group are each independently and optionally substituted with one, two, three, or four substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group, and piperazinyl group.

[0161] In some embodiments, the compounds described in the present invention are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound having the structure, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0162] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound described in the present invention.

[0163] In some embodiments, the pharmaceutical composition described in the present invention further comprises a pharmaceutically acceptable adjuvant.

[0164] In some embodiments, the auxiliary agents described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be in the form of a liquid, solid, semi-solid, gel, or spray.

[0165] In another aspect, the present invention provides the use of the pharmaceutical compositions described in the present invention in the manufacture of drugs for preventing, treating or alleviating diseases associated with KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations.

[0166] In some embodiments, the disease associated with the KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutation described in the present invention is cancer.

[0167] In some embodiments, the cancers described in the present invention include: Cancers of the heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma, etc.; Cancers of the lungs: bronchial cancers (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondrodic hamartoma, mesothelioma, etc.; Cancers of the gastrointestinal tract: esophageal cancers (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancers (lymphoma, leiomyosarcoma), pancreatic cancers (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, cartilage Cancers of the small intestine (adenocarcinoma, bile ductus, carcinoid tumor, Kaboshi sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyosarcoma), etc.; cancers of the genitourinary system: kidney cancer (adenocarcinoma, nephroblastoma, lymphoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonic carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), etc.; cancers of the liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma , hemangiomas, etc.; biliary tract cancer: gallbladder cancer, ampulla cancer, bile duct cancer, etc.; bone cancer: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell tumor / chordoma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, giant cell tumor, etc.; nervous system cancer: cranial osteomas (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, Gynecological cancers such as sarcomas: uterine cancer (endometrial cancer, granulosynovial cell tumor, stromal cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (fetal rhabdomyosarcoma), fallopian tube cancer, ovarian cancer, breast cancer, etc.), hematological cancers: acute or chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), etc.; skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kabosi sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.And cancers of the adrenal gland: such as neuroblastoma.

[0168] In another aspect, the present invention further provides a method for preventing or treating a disease related to KRAS, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention to a patient.

[0169] In another aspect, the present invention further provides the prevention or treatment of diseases associated with KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations using the compounds or pharmaceutical compositions thereof described in the present invention.

[0170] In another aspect, the present invention relates to a method for producing, separating, and purifying compounds of formula (I) or (I-1).

[0171] Unless otherwise specified, all stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of the present invention fall within the scope of the present invention.

[0172] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" implies that the substance or composition must conform to chemical or toxicological standards and be relevant to the other components of the preparation and to the mammal for which it is intended to be used.

[0173] The salts of the compounds of the present invention include intermediates for producing or purifying the compounds represented by formula (I) or (I-1), or salts of enantiomers isolated from the compounds represented by formula (I) or (I-1), but are not necessarily pharmaceutically acceptable salts.

[0174] Formulation, administration, and use of the compound pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I) or (I-1), a compound listed in the present invention or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the present invention can effectively treat or alleviate KRAS-mediated diseases in patients.

[0175] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by the patient, compounds described in other embodiments of the present invention, their metabolites or other residues.

[0176] As described in the present invention, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which are applicable to the present invention and include any solvent, diluent or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid adhesive or lubricant, etc., suitable for specific target dosage forms. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York, the combined content of this literature shows that different adjuvants can be applied to formulations of pharmaceutically acceptable compositions and known methods of manufacturing them. The use of any common adjuvants is also considered within the scope of the present invention, except to the extent that they are incompatible with the compounds of the present invention, for example, to the extent that they result in any undesirable biological effects or interactions with any other components of a pharmaceutically acceptable composition that occur in a detrimental manner.

[0177] Substances that can serve as pharmaceutically acceptable carriers include ion exchangers, buffers such as ion exchangers, aluminum, aluminum stearate, lecithin, serum albumins such as human serum albumin, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, electrolytes such as water, salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylic acid esters, waxes, polyethylene-polyoxypropylene-block polymers, sugars such as lanolin, lactose, glucose and sucrose, starches such as corn starch and potato starch, sodium carboxymethylcellulose, ethylcellulose and cellulose. This includes, but is not limited to, cellulose and its derivatives such as rose acetate, auxiliary materials such as rubber powder, malt, gelatin, talc, cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, castor oil, olive oil, corn oil and soybean oil, glycol compounds such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, buffers such as agar, magnesium hydroxide and aluminum hydroxide, alginic acid, water free of pyrogenic substances, isotonic salts, Ringer's solution, ethanol, phosphate buffer, and other non-toxic suitable lubricants, colorants, release agents, coating materials, sweeteners, flavors and fragrances, preservatives and antioxidants such as sodium lauryl sulfate and magnesium stearate.

[0178] In manufacturing the pharmaceutical composition according to the present invention, the active ingredient and the excipient are usually mixed and diluted with the excipient, or encapsulated in such a carrier in the form of, for example, a capsule, pouch, paper, or other container. When the excipient is used as a diluent, the excipient may be a solid, semi-solid, or liquid material, and it serves as a carrier, support, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low-melting-point wax, cocoa butter, and the like. Accordingly, the composition may be in the form of tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or liquid medium), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In another embodiment, the composition is formulated as tablets or capsules.

[0179] The compounds or pharmaceutical compositions of the present invention may be administered orally, for example, as tablets, capsules (including sustained-release or timely-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, and all dosage forms used are well known to those skilled in the art of pharmaceuticals. They may be administered alone, but generally, one pharmaceutical carrier is selected and administered together based on the chosen method of administration and standard pharmaceutical practice.

[0180] The compounds or pharmaceutical compositions of the present invention may be administered intranasally by topical use of a suitable intranasal carrier or transdermally by transdermal patch. When administered in the form of a transdermal delivery system, the dose administered over the entire duration of administration is continuous rather than intermittent.

[0181] The compounds or pharmaceutical compositions of the present invention may be administered in the form of liposome delivery systems, for example, in the form of small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. The liposomes may be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

[0182] The compounds or pharmaceutical compositions of the present invention may be coupled with soluble polymers, and the polymers may be used as target drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate amide phenol, polyhydroxyethyl asparagine phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled with biodegradable polymers to complete controllable drug release, such as polylactic acid, polyhydroxyacetic acid, copolymers of polylactic acid and polyhydroxyacetic acid, poly-ε-caprolactone, polyhydroxybutyrate, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate, or crosslinked or amphiphilic block copolymers with hydrogels.

[0183] The administration plan for the compounds or pharmaceutical compositions of the present invention will vary depending on various known factors, such as the pharmacokinetic characteristics of a particular reagent, its mode and route of administration, the subject's race, age, sex, health status, medical condition and weight, the nature and severity of symptoms, the type of parallel treatment, the frequency of treatment, the route of administration, the patient's renal and hepatic function and the desired effect. A physician or veterinarian may determine and prescribe an effective dose of the drug to prevent, counteract, or inhibit the progression of cancer.

[0184] The compounds and compositions described herein may be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention may be administered simultaneously or successively with other therapeutic agents via the same or different routes of administration. The compounds of the present invention may be contained in a single formulation together with other therapeutic agents, or in a single formulation.

[0185] When the compound of the present invention is administered together with other therapeutic agents, the typical daily dose and the amount of each component in a typical dosage form may be reduced compared to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0186] The compounds according to the present invention, or pharmaceutically acceptable salts thereof, or hydrates thereof, or pharmaceutical compositions thereof, can prevent, treat, or mitigate diseases in patients mediated by KRAS wild-type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations, particularly cancer.

[0187] In some embodiments, the cancerous conditions in patients that can be effectively prevented, treated, or alleviated by the compounds or pharmaceutical compositions of the present invention include: Cancers of the heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma, etc.; Cancers of the lungs: bronchial cancers (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondrodic hamartoma, mesothelioma, etc.; Cancers of the gastrointestinal tract: esophageal cancers (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancers (lymphoma, leiomyosarcoma). Cancers such as: sarcoma, pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaboshi sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyosarcoma), etc.; genitourinary cancers: kidney cancer (adenocarcinoma, nephroblastoma, lymphoma), bladder cancer and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonic carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, Cancers of the liver: fibroadenoma, adenoid tumor, lipoma, etc.; Cancers of the liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, etc.; Cancers of the biliary tract: gallbladder cancer, ampulla cancer, cholangiocarcinoma, etc.; Cancers of the bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell tumor / chordoma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, giant cell tumor, etc.; Cancers of the nervous system: cranial osteomas (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal gland) Cancers include: uterine cancer (endometrial cancer, granulosynovitis, stromal cell tumor, anaplastic germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (fetal rhabdomyosarcoma), fallopian tube cancer, ovarian cancer, breast cancer, etc.), hematological cancers: acute or chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), etc.Skin cancers: including, but not limited to, melanoma, basal cell carcinoma, squamous cell carcinoma, Kabosi sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; and cancers of the adrenal gland: including, but not limited to, neuroblastoma, etc.

[0188] General synthesis process To illustrate the present invention, the present invention further describes the technical solutions of the present invention using the following embodiments. The following embodiments are merely for the purpose of illustrating specific methods of carrying out the present invention so that those skilled in the art can understand the present invention, and do not limit the scope of protection of the present invention. In specific methods of carrying out the present invention, technical solutions or methods that are not specifically described are common technical solutions or methods of the art.

[0189] Unless otherwise specified, the definitions of substituents are as described in the present invention. The following reaction schemes and examples are used to further illustrate the contents of the present invention by example.

[0190] As those skilled in the art will recognize, many other compounds of the present invention may be appropriately produced by the chemical reactions described herein, and any other method for producing the compounds of the present invention is considered to be within the scope of the present invention. For example, the synthesis of those non-exemplary compounds according to the present invention can be successfully completed by those skilled in the art by modification methods, for example, by using other known reagents other than those described herein to appropriately protect interfering groups, or by making some common modifications to the reaction conditions. Furthermore, it is recognized that the reactions disclosed herein or known reaction conditions are also applicable to the production of other compounds of the present invention.

[0191] In the examples described below, unless otherwise specified, all temperatures are set in degrees Celsius, and the room temperature in the examples is between 15°C and 30°C, and in some examples, the room temperature is between 20°C and 30°C. The reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and none were further purified before use. Unless otherwise specified, general reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Jin Huayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Marine Chemical Plant.

[0192] Anhydrous tetrahydrofuran, dioxane, toluene, and ethyl ether are obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after being pre-dried with anhydrous sodium sulfate.

[0193] The following reactions are generally carried out under positive pressure of nitrogen or argon gas, or by filling a dry tube with an anhydrous solvent (unless otherwise specified), sealing the reaction flask with a suitable rubber stopper, and injecting the substrate with a syringe. All glass containers are dry.

[0194] A silica gel column will be used as the chromatography column. The silica gel (300-400 mesh) will be purchased from Qingdao Marine Chemical Plant.

[0195] Using a Bruke R 400MHz or 600MHz nuclear magnetic resonance spectrometer, 1 Record the 1H NMR spectrum. 1¹H NMR spectra are prepared using CDC13, DMSO-d6, CD3OD, or acetone-d6 as the solvent (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference. When multiple lines appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), bR.s (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0196] The measurement conditions for low-resolution mass spectral (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (chromatography column type: Zorbax SB-C18, 2.1 × 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL / min). Mobile phase: The ratio of 5% to 95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid) was detected by electrospray ionization (ESI) at 210 nm / 254 nm under UV light.

[0197] For pure compounds, detection was performed using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (chromatography column type: NOVASEP 50 / 80mm DAC) under UV light at 210nm / 254nm.

[0198] The following abbreviations are used throughout this invention. BoC2O Di-t-butyl dicarbonate TMPMgCl-LiCl 2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex TBAF Tetrabutylammonium Fluoride Conc.H2SO4 concentrated sulfuric acid Xphos Pd G3 Methanesulfonate (2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) DMAP N,N-dimethylaminopyridine TFA, CF3COOH Trifluoroacetic acid THF (Tetrahydrofuran) DMSO-d6 Deuterated Dimethyl Sulfoxide Pd(PPH3)2Cl2 Dichlorobis(triphenylphosphine)palladium MeOH, CH3OH methanol TMSOTf Trimethylsilyl Trifluoromethanesulfonate PE (Petroleum Ether) CuI (Cuprous Iodide) EA ethyl acetate TEA (Triethylamine) DIPEA N,N-diisopropylethylamine NH3 / MeOH Ammonia in methanol solution POCl3 phosphoryl chloride K3PO4·7H2O Potassium phosphate heptahydrate DCM Dichloromethane ACN Acetonitrile rt room temperature CsF (Cesium Fluoride) M, mol / L (moles / liter) DMF (N,N-dimethylformamide) H time THF / H2O: A mixed solution of tetrahydrofuran and water. °C (Celsius) equiv. MTBE methyl t-butyl ether TMS (trimethylsilyl) DABCO Triethylenediamine Xphos Pd G4 Methanesulfonate (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) HCl / Dioxane, HCl / 1,4-dioxane: Hydrogen chloride solution of 1,4-dioxane. K3PO4·7H2O Potassium phosphate heptahydrate MOM Methoxymethyl Et2Zn Diethylzinc equiv. TIPS Triisopropylsilyl

[0199] The compounds, pharmaceutical compositions, and their uses according to the present invention will be further described below with reference to examples.

[0200] Synthesis Scheme 1 [ka]

[0201] Compound (IA) can be synthesized by referring to the method of synthesis scheme 1. In the formula, X, q1, R 1 , R 2 , R 3 and R 5 n1 is a natural number from 1 to 6, Hal is a halogen, preferably Cl or Br, and R a is C 1~4 It is an alkyl group, preferably a methyl group or an ethyl group, R b C 1~6 Alkyl alkyl group, C 1~6 Cyanoalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy C 1~6 Alkyl, (C 3~12 Cycloalkyl)-C 1~6 Alkyl group, (3-12 member heterocyclyl)-C 1~6 Alkyl, (C 6~10 Ariel)-C1~6 Alkyl group, (5-12 member heteroaryl)-C 1~6 Alkyl, (C 3~12 Cycloalkyl)-OC 1~6 Alkyl alkyl groups, (3-12 member heterocyclyl)-OC 1~6 Alkyl alkyl group or C 1~6 The mercaptoalkyl group is a natural number from 1 to 6, preferably 1 or 2, and the 3 to 12-membered heterocyclyl group has the definition described in the present invention and may optionally be substituted with substituents described in the present invention. Compound (IA-1) is reacted with di-t-butyl dicarbonate under appropriate conditions (e.g., in dichloromethane solvent under the action of DMAP and imidazole) to obtain compound (IA-2), compound (IA-2) is reacted with TMPMgCl-LiCl and then with 1,2-dibromotetrachloroethane to obtain compound (IA-3), compound (IA-3) is deaminonated under acidic conditions to obtain compound (IA-4), compound (IA-4) is coupled with compound (IA-15) under appropriate conditions (e.g., under the action of Pd(PPH3)2Cl2 and CuI) to obtain compound (IA-5), and compound (IA-5) is coupled with 2,2,2-trichloroacetyl Compound (IA-6) was obtained by reacting it with a luisocyanate, compound (IA-6) was obtained by reacting it with a methanol solution of ammonia to obtain compound (IA-7), compound (IA-7) was obtained by reacting it with phosphoryl chloride under the action of DIPEA to obtain compound (IA-8), compound (IA-8) was obtained by reacting it with compound (IA-9) under appropriate conditions (e.g., in the presence of DIPEA) to obtain compound (IA-10), compound (IA-10) was obtained by reacting it with compound (IA-11) under appropriate conditions (e.g., under heating and under the action of DIPEA) to obtain compound (IA-12), compound (IA-12) was obtained by reacting it with compound (IA-13) under appropriate catalytic conditions (e.g., XPhos Pd G3) to obtain compound (IA-14), and compound (IA-14) was obtained by reacting it under acidic conditions (e.g., TMSOTf or concentrated sulfuric acid) to obtain compound (IA).

[0202] Synthesis Scheme 2 [ka]

[0203] Compound (IB) can be synthesized by referring to the method of synthesis scheme 2. In the formula, X, q1, n, R 1 , R 2 , R 3 and R 5 Compound (IB-1) is reacted with phosphoryl chloride under the action of DIPEA to obtain compound (IB-2), compound (IB-2) is reacted with compound (IA-9) under appropriate conditions (e.g., in the presence of DIPEA) to obtain compound (IB-3), compound (IB-3) is reacted with compound (IA-11) under appropriate conditions (e.g., under heating and under the action of DIPEA) to obtain compound (IB-4), and compound (IB-4) is reacted with compound (IB-5) under appropriate catalytic conditions (e.g., XPhos Pd G3) to obtain compound (IB). Examples

[0204] Synthesis of intermediate compound M1 [ka]

[0205] Step 1: Synthesis of compound M1-2 Compound M1-1 (10g, 45.74 mmol), DMAP (1.12g, 9.15 mmol), and DCM (200 mL) were added to a 1000 mL necked flask and stirred at room temperature (30°C). Di-t-butyl dicarbonate (21.96g, 100.63 mmol) was added dropwise to the reaction mixture, and after the addition was complete, the mixture was stirred at 30°C for 18 hours. The reaction was stopped, imidazole (3.11g, 45.74 mmol) was added to the reaction mixture, and after stirring for half an hour, saturated ammonium chloride solution was added for washing (100 mL x 3), and the mixture was separated. The organic phase was washed with saturated sodium chloride solution (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 17.4 g of yellow solid product M1-2 in yield (90.82%), which was used directly in the next step. 1 H NMR (599MHz, CDCl3): δ8.79 (s, 1H), 4.37 (q, J = 7.1Hz, 2H), 1.41 (s, 18H), 1.38 (t, J = 7.1Hz, 3H).

[0206] Step 2: Synthesis of compounds M1-3 Compound M1-2 (10 g, 23.88 mmol) and anhydrous THF (100 mL) were added to a 500 mL three-necked flask, stirred, and cooled to -40°C. TMPMgCl-LiCl (35.82 mL, 35.82 mmol, 1 M THF solution) was added dropwise at -40°C. The mixture was continued stirring at -40°C for 4 hours, and then dibromotetrachloroethane (9.33 g, 28.66 mmol) in THF (30 mL) solution was added dropwise. The mixture was continued stirring at -40°C for 4 hours. The reaction was stopped, saturated ammonium chloride solution (100 mL) was added to quench the mixture, and then the mixture was extracted with EA (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / DCM (v / v=100 / 1~1 / 1) eluate to obtain 8.5 g of yellow solid M1-3 in yield 71.5%. 1 H NMR (599MHz, CDCl3): δ4.40 (q, J = 7.2Hz, 2H), 1.42 (s, 18H), 1.37 (t, J = 7.2Hz, 3H).

[0207] Step 3: Synthesis of compound M1 Compound M1-3 (5g, 10.05 mmol), DCM (50 mL), and TFA (14.97 mL, 200.1 mmol) were added to a 250 mL three-necked flask, and the mixture was stirred at 30°C for 5 hours. The reaction was stopped, saturated sodium carbonate aqueous solution was added to adjust the pH to neutral, and the mixture was further extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 2.9 g of a light brown solid M1 in 97% yield. 1 H NMR(599MHz, CDCl3): δ6.07(s,2H),4.41(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H), LC-MS(ESI,pos.ion)m / z:297.1[M+H] + .

[0208] Synthesis of intermediate compound M2 [ka]

[0209] Step 1: Synthesis of compound M2-1 Add compound M1 (1.0 g, 3.36 mmol), Pd(PPH3)2Cl2 (0.472 g, 0.67 mmol), and CuI (0.128 g, 0.67 mmol) to a 50 mL two-necked flask, purge three times with nitrogen gas, add 1-(trimethylsilyl)propyne (0.566 g, 5.04 mmol), TEA (2.33 mL, 16.8 mmol), and anhydrous THF (10 mL), and purge three times with nitrogen gas. The mixture was purged three times with a primary gas, and TBAF (5.04 mL, 5.04 mmol, 1.0 M THF solution) was added dropwise while stirring. After the addition was complete, the mixture was stirred at room temperature (25°C) for 6 hours to stop the reaction. The mixture was filtered through diatomaceous earth, and the filtrate was spin-dried. The filtrate was then purified by column chromatography using PE / DCM (v / v=100 / 1~2 / 1) eluate to obtain 0.523 g of yellow solid M2-1 in 60.6% yield. LC-MS (ESI, pos. ion) m / z: 257.3 [M+H] + .

[0210] Step 2: Synthesis of compound M2-2 Compound M2-1 (0.52 g, 2.03 mmol) and anhydrous THF (6 mL) were added to a 50 mL neck flask and stirred under the protection of nitrogen gas to dissolve. Then, 2,2,2-trichloroacetyl isocyanate (0.497 g, 2.64 mmol) was added, and the mixture was stirred at room temperature (25°C) for 1 hour to stop the reaction. After spin-drying, the mixture was used directly in the next step, and the yield was calculated assuming 100%. LC-MS (ESI, pos. ion) m / z: 445.9 [M+H] + .

[0211] Step 3: Synthesis of compound M2 To the compound M2-2 (0.885 g, 1.99 mmol) obtained in the previous step, methanol (6 mL) was added and stirred to dissolve. Then, a methanol solution of ammonia (2.84 mL, 19.99 mmol, 7 M) was added, and the mixture was stirred at room temperature for 2 hours to stop the reaction. The crude product was concentrated and slurryed with MTBE (10 mL) for 0.5 hours. The mixture was filtered to obtain 0.48 g of white solid M2. The yield for both steps 2 and 3 was 95%. LC-MS (ESI, pos. ion) m / z: 254.1 [M+H] + .

[0212] Synthesis of intermediate compound M3 [ka]

[0213] Step 1: Synthesis of compound M3-1 Compound M1 (705.1 mg, 2.37 mmol), (buta-1-in-1-yl)trimethylsilane (448.89 mg, 3.56 mmol), Pd(PPH3)2Cl2 (332.70 mg, 0.47 mmol), CuI (90.27 mg, 0.47 mmol), TEA (1.64 mL, 11.85 mmol), and anhydrous THF (10 mL) were added to a 50 mL neck flask. The flask was purged three times with nitrogen gas, and a THF solution of tetrabutylammonium fluoride (2.84 mL, 2.84 mmol, 1 M) was added dropwise at 25°C. After the addition was complete, the mixture was stirred at room temperature (30°C) for 6 hours. The reaction was stopped, the solution was filtered through diatomaceous earth, the filtrate was dried over anhydrous sodium sulfate, and then spin-dried. Purification by column chromatography using PE / DCM (v / v=100 / 1-2 / 1) eluate yielded 354 mg of yellow solid M3-1 in 55.2% yield. LC-MS (ESI, pos. ion) m / z: 271.3 [M+H] + , 1 H NMR (400MHz, CDCl3): δ6.25(s,2H),4.46-4.34(m,2H),2.46(q,J=7.5Hz,2H),1.46-1.37(m,3H),1.25(m,3H).

[0214] Step 2: Synthesis of compound M3-2 Compound M3-1 (350 mg, 1.29 mmol) and anhydrous THF (6 mL) were added to a 50 mL neck flask, stirred to dissolve, and then 2,2,2-trichloroacetyl isocyanate (365 mg, 1.94 mmol) was added. The mixture was stirred at room temperature (30°C) for 1 hour to stop the reaction, and after spin-drying, it was used directly in the next step. The yield was calculated at 100%. LC-MS (ESI, pos. ion) m / z: 460.0 [M+H] + .

[0215] Step 3: Synthesis of compound M3 Methanol (6 mL) was added to compound M3-2 obtained in the previous step, and the mixture was stirred to dissolve it. Then, a methanol solution of ammonia (1.84 mL, 12.9 mmol, 7 M) was added, and the mixture was stirred at room temperature (30°C) for 2 hours to stop the reaction. The crude product was concentrated and slurryed with MTBE (10 mL) for 0.5 hours. The mixture was filtered and dried to obtain 320 mg of white solid M3. The yield for both steps 2 and 3 was 92.5%. LC-MS (ESI, pos. ion) m / z: 268.1 [M+H] + .

[0216] Synthesis of intermediate compound M6 [ka]

[0217] Step 1: Synthesis of compound M6-1 In a 500 mL two-necked flask, M1 (9 g, 30.25 mmol), Pd(PPH3)2Cl2 (2.17 g, 3.03 mmol), and CuI (0.58 g, 3.03 mmol) were added, and the mixture was purged three times with nitrogen gas. Then, 2,2,2-trichloroacetyl isocyanate (7.32 g, 39.33 mmol), TEA (12.58 mL, 90.75 mmol), and anhydrous THF (180 mL) were added, and the mixture was purged three times with nitrogen gas. The mixture was stirred at room temperature for 2 hours to stop the reaction, filtered, and the filtrate was spin-dried. The filtrate was then purified by column chromatography using PE / EA (v / v=80 / 1-30 / 1) eluate to obtain 10.45 g of yellow solid M6-1 in yield 86.6%. 1 H NMR (400MHz, CDCl3): δ6.14 (s, 2H), 4.44 (q, J = 7.1Hz, 2H), 1.40 (t, J = 7.1Hz, 3H), 1.18-1.07 (m, 21H).

[0218] Step 2: Synthesis of compound M6-2 In a 500 mL necked flask, M6-1 (10.34 g, 25.92 mmol) and anhydrous THF (200 mL) were added and stirred to dissolve. Then, 2,2,2-trichloroacetyl isocyanate (6.17 g, 31.10 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours to stop the reaction. After spin-drying, the mixture was used directly in the next step, and the yield was calculated at 100%.

[0219] Step 3: Synthesis of compound M6 Methanol (200 mL) was added to M6-2 (15.22 g, 25.92 mmol) obtained in the previous step, and the mixture was stirred to dissolve it. Then, a methanol solution of ammonia (18.51 mL, 129.55 mmol, 7 M) was added, and the mixture was stirred at room temperature for 1.5 hours to stop the reaction. The crude product was concentrated and slurryed in PE / EA (100 mL / 10 mL) for 0.5 hours. The mixture was filtered to obtain 8.72 g of white solid M6. The yield for both steps 2 and 3 was 85%. LC-MS (ESI, pos. ion) m / z: 396.4 [M+H] + .

[0220] Example 1: Synthesis of Compound 1 [ka]

[0221] Step 1: Synthesis of Compound 1-1 Compound M2 (1.00 g, 3.94 mmol) and anhydrous toluene (10 mL) were added to a 100 mL necked flask. Then phosphoryl chloride (1.08 mL, 11.82 mmol) and DIPEA (3.26 mL, 19.7 mmol) were added, and the mixture was heated to 70°C and stirred for 1 hour. The reaction was stopped, the mixture was cooled, concentrated, and then used directly in the next step. The yield was calculated at 100%.

[0222] Step 2: Synthesis of Compounds 1-2 To compound 1-1 obtained in the previous step, anhydrous dichloromethane (15 mL) was added, the mixture was purged three times with nitrogen gas, stirred to dissolve, cooled to -40°C and stirred for 5 minutes, DIPEA (3.27 mL, 19.8 mmol) was added, followed by homomorpholine hydrochloride (0.49 g, 3.56 mmol). After stirring at -40°C for 0.5 hours, the reaction was stopped, saturated ammonium chloride solution (30 mL) was added to quench, the mixture was returned to room temperature, and DCM (30 mL x 2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=3 / 2) eluate to obtain 360 mg of yellow solid compound 1-2. The yield of the two steps, Step 1 and Step 2, was 25.6%. LC-MS (ESI, pos. ion) m / z: 355.1 [M+H] + .

[0223] Step 3: Synthesis of compounds 1-3 Compounds 1-2 (355 mg, 1.0 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (240 mg, 1.5 mmol), DIPEA (0.33 mL, 2 mmol), and anhydrous 1,4-dioxane (8 mL) were added to a 50 mL neck flask. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 22 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (30 mL), washed with saturated ammonium chloride solution (30 mL), separated, separated again, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 281 mg of yellow solid compound 1-3 in yield 58.83%. LC-MS(ESI,pos.ion)m / z:478.2[M+H] + .

[0224] Step 4: Synthesis of compounds 1-4 Compounds 1-3 (200 mg, 0.42 mmol, 1 equiv.), M4 (0.17 g, 0.34 mmol, An Naeji Chemical), Xphos Pd G3 (36 mg, 0.042 mmol), K3PO4·7H2O (140 mg, 0.42 mmol), and THF / H2O (v / v=5 mL / 0.8 mL) were added to a 25 mL neck flask. The mixture was purged with nitrogen gas three times, stirred at room temperature for 2.5 hours, and the reaction was detected by TLC. A large amount of starting material 1-3 remained, along with M4 (0.8 equiv.) and Xphos Pd G3 (0.1 equiv.) and K3PO4·7H2O (1.5 equiv.) were added, and the mixture was stirred for 1.5 hours. Since the reaction was still incomplete, the process of adding these materials was repeated until the starting materials 1-3 were nearly completely reacted. A saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted with DCM (30 mL x 3). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 244 mg of red solid compounds 1-4 in 70.4% yield. LC-MS (ESI, pos. ion) m / z: 829.0 [M+H] + .

[0225] Step 5: Synthesis of compounds 1-5 Compounds 1-4 (235 mg, 0.28 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.04 mL, 0.74 mmol, 98% purity) was added dropwise, and the mixture was stirred for 45 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 3), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 184 mg of red solid compound 1-5 in yield 82.7%. LC-MS (ESI, pos. ion) m / z: 784.4 [M+H] + .

[0226] Step 6: Synthesis of Compound 1 Compound 1-5 (184 mg, 0.23 mmol), cesium fluoride (520 mg, 3.45 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and water (20 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 100 mg of red solid compound 1-5 in yield 67.9%. LC-MS (ESI, pos. ion) m / z: 628.3 [M+H] + HRMS(ESI):628.2530[M+H] + , 1 H NMR(400MHz,CD3OD):δ7.84(dd,J=9.0,5.7Hz,1H),7.38-7.27(m,2H),7.23(s, 1H),5.30(d,J=54.0Hz,1H),4.35-4.17(m,4H),4.16-4.01(m,2H),3.99-3.84( m,2H),3.79(t,J=5.3Hz,2H),3.41-3.36(m,1H),3.29-3.18(m,2H),3.09-2.94 (m,1H),2.39-2.19(m,2H),2.16(s,3H),2.15-2.08(m,2H),2.08-1.81(m,5H). 19 FNMR (376MHz, CD3OD): δ-111.52 (1F), -140.76 (1F), -173.59 (1F).

[0227] Example 2: Synthesis of Compound 2 [ka]

[0228] Step 1: Synthesis of Compound 2-1 Compounds 1-3 (80 mg, 0.17 mmol, 1 equiv.), M5 (0.061 g, 0.17 mmol, Bi De Pharmaceutical), Xphos Pd G3 (22 mg, 0.026 mmol), K3PO4·7H2O (86 mg, 0.26 mmol), and THF / H2O (v / v=3 mL / 0.5 mL) were added to a 25 mL neck flask. The mixture was purged with nitrogen gas three times and stirred at room temperature for 15 hours. Some of the starting materials 1-3 remained, so M5 (1 equiv.), Xphos Pd G3 (0.1 equiv.), and K3PO4·7H2O (1.5 equiv.) were added and stirred for another 1.5 hours. The mixture still did not react completely, so the process of adding materials was repeated until the starting materials 1-3 were almost completely reacted. The reaction was stopped, the reaction mixture was diluted with DCM (20 mL), washed with saturated ammonium chloride solution (30 mL), extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 85 mg of yellow solid compound 2-1 in 75.1% yield. LC-MS (ESI, pos. ion) m / z: 676.3 [M+H] + .

[0229] Step 2: Synthesis of Compound 2 Compound 2-1 (85 mg, 0.13 mmol) and acetonitrile (3 mL) were added to a 25 mL neck flask, cooled to 0°C, and stirred for 5 minutes. TMSOTf (0.047 mL, 0.26 mmol) was added, and the mixture was stirred for 15 minutes to stop the reaction. Saturated sodium bicarbonate (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified using a thin-layer silica gel plate with DCM / MeOH (v / v=12 / 1) developing solution to obtain 30 mg of yellow solid compound 2 in yield 25.2%. LC-MS (ESI, pos. ion) m / z: 632.2 [M+H] + HRMS(ESI):632.2852[M+H] + , 1H NMR(400MHz,CD3OD):δ7.68(dd,J=9.0,5.8Hz,1H),7.34-7.29(m,1H),7.29-7.19(m ,1H),7.08(s,1H),5.46(d,J=52.6Hz,1H),4.63-4.42(m,3H),4.33-4.05(m,4H),4. 01-3.86(m,2H),3.83-3.75(m,2H),3.69-3.54(m,3H),2.61-2.35(m,3H),2.33-2.2 5(m,2H),2.25-2.19(m,2H),2.18(s,3H),2.13-1.99(m,3H),0.83(t,J=7.4Hz,3H). 19 FNMR (376MHz, CD3OD): δ-120.90(1F),-140.63(1F),-173.92(1F).

[0230] Example 3: Synthesis of Compound 3 [ka]

[0231] Step 1: Synthesis of compound 3-1 Compound M3 (1.3 g, 4.86 mmol) and anhydrous toluene (11 mL) were added to a 100 mL necked flask. Then phosphoryl chloride (1.33 mL, 14.58 mmol) and DIPEA (4.02 mL, 24.3 mmol) were added, and the mixture was heated to 70°C and stirred for 1 hour. The reaction was stopped, the mixture was cooled, concentrated, and then used directly in the next step. The yield was calculated at 100%.

[0232] Step 2: Synthesis of Compound 3-2 To compound 3-1 obtained in the previous step, anhydrous dichloromethane (10 mL) was added, the mixture was purged three times with nitrogen gas, stirred to dissolve, cooled to -40°C and stirred for 5 minutes, DIPEA (4.02 mL, 24.3 mmol) was added, followed by homomorpholine hydrochloride (0.67 g, 4.86 mmol). After stirring at -40°C for 1.5 hours, the reaction was stopped, saturated ammonium chloride solution (30 mL) was added to quench, the mixture was returned to room temperature, and DCM (30 mL x 2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=65 / 35) eluate to obtain 588 mg of yellow solid compound 3-2. The yield for both steps 1 and 2 was 32.8%. LC-MS (ESI, pos. ion) m / z: 369.1 [M+H] + .

[0233] Step 3: Synthesis of Compound 3-3 In a 50 mL neck flask, compound 3-2 (584 mg, 1.58 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (380 mg, 2.37 mmol), DIPEA (0.52 mL, 3.16 mmol), and anhydrous 1,4-dioxane (8 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 20 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (30 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 380 mg of yellow solid compound 3-3 in yield 48.8%. LC-MS(ESI,pos.ion)m / z:492.3[M+H] + .

[0234] Step 4: Synthesis of Compounds 3-4 Compound 3-3 (200 mg, 0.41 mmol, 1 equiv.), M4 (0.21 g, 0.61 mmol, An Naeji Chemical), Xphos Pd G3 (35 mg, 0.041 mmol), K3PO4·7H2O (210 mg, 0.61 mmol), and THF / H2O (v / v=5 mL / 1.2 mL) were added to a 50 mL neck flask. The mixture was purged with nitrogen gas three times, stirred at room temperature for 1.5 hours, and the reaction was detected by TLC. A large amount of starting material 3-3 remained, along with M4 (1 equiv.) and Xphos Pd G3 (0.1 equiv.) and K3PO4·7H2O (1.5 equiv.) were added, and the mixture was stirred for 1.5 hours. The reaction was still incomplete, so the process of adding these materials was repeated until the starting material 3-3 was almost completely reacted. The reaction was then stopped, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with DCM (20 mL x 3). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 432 mg of red oily compound 3-4. The yield was calculated at 100%. LC-MS (ESI, pos. ion) m / z: 843.0 [M+H] + .

[0235] Step 5: Synthesis of Compounds 3-5 Compound 3-4 (342 mg, 0.41 mmol) and acetonitrile (6 mL) were added to a 50 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.033 mL, 0.61 mmol, 98% purity) was added dropwise, and the mixture was stirred for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed with DCM (20 mL x 2), the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 160 mg of yellow solid 3-5 in 49.4% yield. LC-MS (ESI, pos. ion) m / z: 799.1 [M+H] + .

[0236] Step 6: Synthesis of Compound 3 Compounds 3-5 (160 mg, 0.20 mmol), cesium fluoride (460 mg, 3.0 mmol), and DMF (0.8 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 22 hours to stop the reaction, water (20 mL) was added to precipitate the solid, and the mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=25 / 1) eluate to obtain 103 mg of yellow solid compound 3 in yield of 80.06%. LC-MS (ESI, pos. ion) m / z: 642.9 [M+H] + HRMS(ESI):642.2685[M+H] + , 1 H NMR(400MHz,CD3OD):δ7.92-7.77(m,1H),7.41-7.27(m,2H),7.24(s,1H), 5.31(d,J=53.8Hz,1H),4.42-4.17(m,4H),4.15-4.01(m,2H),4.00-3.84( m,2H),3.82-3.69(m,2H),3.42-3.36(m,1H),3.28-3.15(m,2H),3.09-2.9 7(m,1H),2.55(q,J=7.4Hz,2H),2.43-1.69(m,9H),1.26(t,J=7.2Hz,3H). 19 FNMR (376MHz, CD3OD): δ-111.53 (1F), -140.75 (1F), -173.58 (1F).

[0237] Example 4: Synthesis of Compound 4 [ka]

[0238] Step 1: Synthesis of Compound 4-1 Compound 3-3 (80 mg, 0.16 mmol, 1 equiv.), M5 (0.058 g, 0.16 mmol, Bi De Pharmaceutical), Xphos Pd G3 (20 mg, 0.024 mmol), K3PO4·7H2O (110 mg, 0.32 mmol), and THF / H2O (v / v=3 mL / 0.5 mL) were added to a 25 mL neck flask. The mixture was purged with nitrogen gas three times, stirred at room temperature for 3.5 hours, and detected by TLC. Some of the starting material 3-3 remained, so M5 (1 equiv.), Xphos Pd G3 (0.15 equiv.), and K3PO4·7H2O (1.5 equiv.) were added, and the mixture was stirred for another 1.5 hours until the starting material 3-3 had reacted almost completely. The reaction was stopped, the reaction mixture was diluted with DCM (20 mL), washed with saturated ammonium chloride solution (30 mL), extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 96 mg of yellow solid compound 4-1 in yield 85.6%. LC-MS (ESI, pos. ion) m / z: 690.2 [M+H] + .

[0239] Step 2: Synthesis of Compound 4 Compound 4-1 (96 mg, 0.14 mmol) and acetonitrile (4 mL) were added to a 25 mL neck flask. The mixture was cooled to -15°C and stirred for 5 minutes. TMSOTf (0.051 mL, 0.28 mmol) was added, and the mixture was stirred for 30 minutes to stop the reaction. Saturated sodium bicarbonate (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified twice by preparative thin-layer chromatography using DCM / MeOH (v / v=15 / 1) developing solution to obtain 34 mg of yellow solid compound 4 in yield 37.8%. LC-MS (ESI, pos. ion) m / z: 646.6 [M+H] + HRMS(ESI):646.3031[M+H] + , 1H NMR(400MHz,CD3OD):δ7.67(dd,J=9.0,5.9Hz,1H),7.33-7.29(m,1H),7.28-7.20(m,1H),7.08( s,1H),5.41(d,J=53.5Hz,1H),4.53-4.34(m,2H),4.30-4.05(m,4H),4.02-3.83(m,2H),3.83-3 .72(m,2H),3.68-3.40(m,3H),3.25-3.13(m,1H),2.56(q,J=7.5Hz,2H),2.50-2.32(m,3H),2.3 2-2.20(m,2H),2.19-2.09(m,3H),2.07-1.95(m,2H),1.28-1.24(m,3H),0.84(t,J=7.3Hz,3H). 19 FNMR (376MHz, CD3OD): δ-120.91 (1F), -140.55 (1F), -173.84 (1F).

[0240] Example 5: Synthesis of Compound 5 [ka]

[0241] Step 1: Synthesis of compound 5-1 In a 100 mL two-necked flask, NaH (3.74 g, 93.6 mmol, content: 60%) and anhydrous DMF (30 mL) were added, and the mixture was purged three times with nitrogen gas. After cooling to 0°C and stirring, cyclobutanol (4.5 g, 62.4 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. Then, 3-bromo-1-trimethylsilyl-1-propyne (10.73 g, 56.16 mmol) was added, and the mixture was stirred at 0°C for 0.5 hours. The temperature was then raised to 30°C and the mixture was stirred for 12 hours. The reaction was stopped, the mixture was cooled, and saturated ammonium chloride solution (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, the organic phase was washed with water (50 mL x 5), dried over anhydrous sodium sulfate, and concentrated to obtain 7.6 g of viscous liquid, which was used directly in the next step.

[0242] Step 2: Synthesis of Compound 5-2 In a 50 mL necked flask, M1 (4.05 g, 9.53 mmol), compound 5-1 (7.6 g) obtained in the previous step, Pd(PPH3)2Cl2 (1.338 g, 1.91 mmol), CuI (363 mg, 1.91 mmol), TEA (13.21 mL, 95.3 mmol), and anhydrous THF (30 mL) were added. The mixture was purged three times with nitrogen gas and stirred at 35°C for 1.5 hours. The reaction was stopped, filtered through diatomaceous earth, diluted with DCM (100 mL), washed with saturated ammonium chloride solution (20 mL x 3), washed again with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using PE / EA (v / v=100 / 1-5 / 1) eluate to obtain 2.0 g of yellow oily substance 5-2 in 9.9% yield. LC-MS(ESI,pos.ion)m / z:327.0[M+H] + .

[0243] Step 3: Synthesis of Compound 5-3 5-2 (2.0 g, 6.12 mmol) and anhydrous THF (20 mL) were added to a 100 mL necked flask, stirred to dissolve, and then 2,2,2-trichloroacetyl isocyanate (1.38 g, 7.34 mmol) was added. The mixture was stirred at room temperature for 1 hour to stop the reaction, and after spin-drying, a brown solid was obtained, which was used directly in the next step, and the yield was calculated at 100%.

[0244] Step 4: Synthesis of Compounds 5-4 To compound 5-3 obtained in the previous step, methanol (20 mL) was added and stirred to dissolve. Then, a methanol solution of ammonia (8.21 mL, 57.5 mmol, 7 M) was added, and the mixture was stirred at room temperature for 4 hours to stop the reaction. The mixture was then filtered by suction to obtain a solid. The solid was washed with PE (20 mL) to obtain 1.84 g of white solid 5-4 in 98.92% yield. LC-MS (ESI, pos. ion) m / z: 324.1 [M+H] + .

[0245] Step 5: Synthesis of Compound 5-5 Compound 5-4 (0.9 g, 2.78 mmol) and anhydrous toluene (20 mL) were added to a 100 mL necked flask. Further additions of phosphoryl chloride (1.55 mL, 16.68 mmol) and DIPEA (2.30 mL, 13.90 mmol) were added, and the mixture was heated to 70°C under the protection of nitrogen gas and stirred for 1 hour. The reaction was then stopped, the mixture was cooled, concentrated, and used directly in the next step. The yield was calculated at 100%.

[0246] Step 6: Synthesis of Compounds 5-6 To compound 5-5 obtained in the previous step, anhydrous dichloromethane (10 mL) was added, the mixture was purged three times with nitrogen gas, stirred to dissolve, cooled to -40°C and stirred for 5 minutes, DIPEA (2.30 mL, 13.9 mmol) was added, followed by homomorpholine hydrochloride (0.383 g, 2.78 mmol). After stirring at -40°C for 0.5 hours, the reaction was stopped, diluted with 100 mL of DCM (100 mL), the organic phase was washed with saturated ammonium chloride solution (100 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=100 / 1~9 / 1) eluate to obtain 700 mg of yellow solid compound 5-6. The yield of the two steps was 59.2%. LC-MS (ESI, pos. ion) m / z: 425.1 [M+H] + .

[0247] Step 7: Synthesis of compounds 5-7 In a 50 mL neck flask, 5-6 (700 mg, 1.65 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (657 mg, 4.13 mmol), DIPEA (1.37 mL, 8.25 mmol), and anhydrous 1,4-dioxane (10 mL) were added. The mixture was purged three times with nitrogen gas, heated to 90 °C, and stirred for 12 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with DCM (50 mL), washed with saturated ammonium chloride solution (20 mL x 3), separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using PE / EA (v / v=100 / 1~1 / 1) eluate to obtain 645 mg of the yellow solid compound 5-7 in 71.5% yield. LC-MS(ESI,pos.ion)m / z:548.3[M+H] + .

[0248] Step 8: Synthesis of compounds 5-8 Compounds 5-7 (350 mg, 0.64 mmol), M4 (656 mg, 1.28 mmol), Xphos Pd G3 (135.4 mg, 0.16 mmol), K3PO4·7H2O (191 mg, 0.90 mmol), and THF / H2O (v / v=6 mL / 0.5 mL) were added to a 50 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at 30°C for 6 hours to stop the reaction, and saturated ammonium chloride solution (30 mL) was added. Extraction was performed using DCM (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=100 / 1-19 / 1) eluate to obtain 323 mg of brown compound 5-8 in yield 56.3%. LC-MS (ESI, pos. ion) m / z: 899.3 [M+H] + .

[0249] Step 9: Synthesis of compounds 5-9 Compound 5-8 (323 mg, 0.36 mmol) and acetonitrile (10 mL) were added to a 50 mL necked flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.096 mL, 1.8 mmol, 98% purity) was added dropwise, and the mixture was stirred for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 300 mg of brown solid 5-9 in 97.7% yield. LC-MS (ESI, pos. ion) m / z: 855.2 [M+H] + .

[0250] Step 10: Synthesis of Compound 5 In a 25 mL neck flask, 5-9 (264 mg, 0.35 mmol), cesium fluoride (532 mg, 3.5 mmol), and anhydrous DMF (2 mL) were added. The mixture was purged three times with nitrogen gas, stirred at room temperature for 4 hours to stop the reaction, and water (8 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using a silica gel preparative plate with DCM / MeOH (v / v=12 / 1) developing solution to obtain 105 mg of brown solid compound 5 in 42.8% yield. LC-MS (ESI, pos. ion) m / z: 698.3 [M+H] + HRMS(ESI):698.2950[M+H] + , 1 H NMR(400MHz,CD3OD):δ7.84(dd,J=9.1,5.7Hz,1H),7.37-7.27(m,2H),7.27 -7.23(m,1H),5.34(d,J=53.5Hz,1H),4.43-4.30(m,4H),4.29-4.04(m,5H), 3.97-3.85(m,2H),3.82-3.74(m,2H),3.50-3.33(m,3H),3.15-3.05(m,1H), 2.46-2.13(m,6H),2.13-1.99(m,4H),2.00-1.83(m,3H),1.77-1.45(m,2H). 19 FNMR (376MHz, CD3OD): δ-111.40--111.50(1F),-139.53(1F),-173.27--174.07(1F).

[0251] Example 6: Synthesis of Compound 6 [ka]

[0252] Step 1: Synthesis of Compound 6-1 Compounds 5-7 (300 mg, 0.55 mmol), M5 (0.297 g, 0.83 mmol), Xphos Pd G3 (116.4 mg, 0.14 mmol), K3PO4·7H2O (191 mg, 0.90 mmol), and THF / H2O (v / v=6 mL / 0.5 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at 30°C for 6 hours to stop the reaction, diluted with DCM (20 mL), washed with saturated ammonium chloride solution (30 mL), extracted with DCM (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=100 / 1~19 / 1) eluate to obtain 245 mg of brown solid compound 6-1 in 60.0% yield. LC-MS(ESI,pos.ion)m / z:747.0[M+H] + .

[0253] Step 2: Synthesis of Compound 6 Add 6-1 (245 mg, 0.33 mmol) and acetonitrile (5 mL) to a 25 mL neck flask, cool to 0°C and stir for 5 minutes, add concentrated sulfuric acid (0.088 mL, 1.56 mmol, 98% purity), stir at 0°C for 30 minutes to stop the reaction, add saturated sodium bicarbonate aqueous solution (20 mL) to quench, extract with DCM (20 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by thin-layer chromatography on a silica gel preparative plate using DCM / MeOH (v / v=14 / 1) developing solution to obtain 110 mg of yellow solid compound 6 in yield 47.7%. LC-MS (ESI, pos. ion) m / z: 702.3 [M+H] + HRMS(ESI):702.3264[M+H] + , 1H NMR(400MHz,CD3OD):δ7.66(dd,J=9.0,5.9Hz,1H),7.32-7.28(m,1H),7.27-7.20(m,1H),7.11- 7.07(m,1H),5.31(d,J=54.0Hz,1H),4.40-4.25(m,4H),4.25-4.04(m,5H),3.96-3.83(m,2H),3. 81-3.73(m,2H),3.40-3.32(m,1H),3.30-3.18(m,2H),3.09-2.99(m,1H),2.46-2.29(m,2H),2. 29-2.16(m,4H),2.16-2.05(m,3H),2.04-1.85(m,5H),1.77-1.47(m,2H),0.83(t,J=7.3Hz,3H). 19 FNMR (376MHz, CD3OD): δ-120.65--120.90(1F),-139.04(1F),-173.22--173.83(1F).

[0254] Example 7: Synthesis of Compound 7 [ka]

[0255] Step 1: Synthesis of Compound 7-1 Compound M6 (2.0 g, 5.1 mmol) and anhydrous toluene (40 mL) were added to a 250 mL necked flask. Then phosphoryl chloride (1.9 mL, 2.04 mmol) and DIPEA (3.4 mL, 20.4 mmol) were added, and the mixture was heated to 100 °C and stirred for 1 hour. The reaction was stopped, the mixture was cooled, concentrated, and then used directly in the next step. The yield was calculated at 100%.

[0256] Step 2: Synthesis of Compound 7-2 To compound 7-1 obtained in the previous step, anhydrous dichloromethane (30 mL) was added, the mixture was purged three times with nitrogen gas, stirred to dissolve, and DIPEA (5.3 g, 40.8 mmol) was added, followed by the slow addition of homomorpholine hydrochloride (0.88 g, 6.4 mmol). After stirring at room temperature for 1 hour, the reaction was stopped, saturated ammonium chloride solution (50 mL) was added for quenching, and DCM (50 mL x 2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=10 / 1) eluate to obtain 1.73 g of yellow solid compound 7-2. The yield of the two steps, Step 1 and Step 2, was 68.8%. LC-MS (ESI, pos. ion) m / z: 497.3 [M+H] + .

[0257] Step 3: Synthesis of Compound 7-3 In a 100 mL necked flask, compound 7-2 (1 g, 2.01 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (480 mg, 3.01 mmol), DIPEA (0.66 mL, 4.02 mmol), and anhydrous 1,4-dioxane (25 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 20 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (30 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 860 mg of yellow solid compound 7-3 in yield 68.9%. LC-MS(ESI,pos.ion)m / z:620.5[M+H] + .

[0258] Step 4: Synthesis of Compound 7-4 Compound 7-3 (200 mg, 0.32 mmol, 1 equiv.), M4 (0.33 g, 0.64 mmol, Jiangsu Aikang Bio), Xphos Pd G4 (83 mg, 0.096 mmol), K3PO4·7H2O (430 mg, 1.28 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 50 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 18 hours to stop the reaction, diluted with ethyl acetate (15 mL), washed with saturated sodium chloride (20 mL), extracted with EA (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 282 mg of yellow solid compound 7-4 in 90.1% yield.

[0259] Step 5: Synthesis of Compound 7-5 Compound 7-4 (220 mg, 0.23 mmol) and acetonitrile (3 mL) were added to a 50 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.069 g, 0.69 mmol, 98% concentration) was added dropwise, and the mixture was stirred for 60 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 155 mg of yellow solid 7-5 in yield 73.8%. LC-MS (ESI, pos. ion) m / z: 463.8 [M + 2H] 2+ .

[0260] Step 6: Synthesis of Compound 7 Compound 7-5 (150 mg, 0.16 mmol), cesium fluoride (489 mg, 3.2 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas and stirred at room temperature for 3.5 hours to quench the reaction. 20 mL of water was added to precipitate the solid, which was then filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=25 / 1) eluate to obtain 64 mg of yellow solid compound 7 in 64.3% yield. LC-MS (ESI, pos. ion) m / z: 614.3 [M+H] + HRMS(ESI):614.2385[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.88(dd,J=9.1,5.7Hz,1H),7.41-7.25(m,3H),5.45-5.25(m,1H),4.66-4.46(m,1H),4.41-4.21(m,4H),4.2 0-4.05(m,2H),4.01-3.89(m,2H),3.86-3.77(m,2H),3.44-3.35(m,2H),3.32-3.25(m,2H),3.14-3.03(m,1H),2.34-1.94(m,8H). 19 FNMR (376MHz, CD3OD) δ -114.48 (1F), -138.98 (1F), -173.66 (1F).

[0261] Example 8: Synthesis of Compound 8 [ka]

[0262] Step 1: Synthesis of Compound 8-1 Compound 7-3 (200 mg, 0.32 mmol, 1 equiv.), M5 (0.35 g, 0.96 mmol), Xphos Pd G4 (110 mg, 0.13 mmol), K3PO4·7H2O (433 mg, 1.28 mmol), and THF / H2O (v / v=6 mL / 2 mL) were added to a 50 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 18 hours to stop the reaction, diluted with ethyl acetate (15 mL), washed with saturated sodium chloride (20 mL), extracted with EA (20 mL), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 204 mg of yellow solid compound 8-1 in 77.3% yield. LC-MS (ESI, pos. ion) m / z: 818.7 [M+H] + .

[0263] Step 2: Synthesis of Compound 8-2 Compound 8-1 (204 mg, 0.25 mmol) and acetonitrile (5 mL) were added to a 50 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.075 g, 0.75 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 120 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the mixture was extracted with DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 165 mg of yellow solid 8-2 in yield 85.4%. LC-MS (ESI, pos. ion) m / z: 774.7 [M+H] + .

[0264] Step 3: Synthesis of Compound 8 Compound 8-2 (165 mg, 0.21 mmol), cesium fluoride (260 mg, 1.68 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 4 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The solid was filtered to obtain the crude product, and the crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 85 mg of yellow solid compound 8 in 64.5% yield. LC-MS (ESI, pos. ion) m / z: 618.4 [M+H] + HRMS(ESI):618.2726[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.69(dd,J=9.0,5.8Hz,1H),7.35-7.31(m,1H),7.26-7.22(m,1H ),7.13-7.09(m,1H),5.34(d,J=53.5Hz,1H),4.64-4.42(m,1H),4.41-4.28(m,3H),4. 27-4.05(m,4H),4.00-3.86(m,2H),3.84-3.75(m,2H),3.43-3.34(m,1H),3.30-3.21( m,1H),3.12-3.02(m,1H),2.47-2.24(m,4H),2.17-1.88(m,6H),0.86(t,J=7.4Hz,3H). 19 FNMR(376MHz,CD3OD)δ-120.83(1F),-138.55(1F),-173.68(1F).

[0265] Example 9: Synthesis of Compound 9 [ka]

[0266] Step 1: Synthesis of Compound 9-1 In a 50 mL necked flask, combine compound 7-3 (250 mg, 0.40 mmol, 1 equiv.), 2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.42 g, 1.20 mmol, iKang Bio), and Xphos Pd G4 (137 mg, 0.16 mmol), K3PO4·7H2O (541 mg, 1.6 mmol), and THF / H2O (v / v=6 mL / 2 mL) were added, the mixture was purged three times with nitrogen gas, stirred at room temperature for 24 hours to stop the reaction, diluted with DCM (15 mL), washed with saturated ammonium chloride (20 mL), extracted with DCM (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 200 mg of yellow solid compound 9-1 in yield 61.5%. LC-MS (ESI, pos. ion) m / z: 806.4 [M+H] + .

[0267] Step 2: Synthesis of Compound 9-2 Compound 9-1 (200 mg, 0.25 mmol) and acetonitrile (5 mL) were added to a 50 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.041 mL, 0.75 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 90 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the solution was extracted with DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 120 mg of yellow solid 9-2 in yield 63.5%. LC-MS (ESI, pos. ion) m / z: 762.7 [M+H] + .

[0268] Step 3: Synthesis of Compound 9 Compound 9-2 (120 mg, 0.16 mmol), cesium fluoride (190 mg, 1.28 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 5 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 62 mg of yellow solid compound 9 in 65.0% yield. LC-MS (ESI, pos. ion) m / z: 606.4 [M+H] + HRMS(ESI):606.2089[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.75(dd,J=11.0,6.4Hz,1H),7.40-7.32(m,3H),7.24-7.21(m,1H),5.45-5.25(m,1H),4.43-4.23(m,5H),4.22 -4.00(m,3H),3.98-3.84(m,2H),3.83-3.75(m,2H),3.48-3.37(m,1H),3.31-3.28(m,1H),3.07(d,J=5.6Hz,1H),2.34-1.87(m,8H). 19 FNMR(376MHz,CD3OD)δ-139.16(1F),-173.66(1F).

[0269] Example 10: Synthesis of Compound 10 [ka]

[0270] Step 1: Synthesis of compound 10-1 Add NaH (0.070 g, 1.76 mmol, 60% mass fraction) to a 100 mL two-necked flask, purge with nitrogen gas, add THF (7 mL), stir at 0°C for 5 minutes, and slowly add (2,6-dimethylethylenetetrahydro-1H-pyrroline-7a(5H)-yl)methanol (0.073 g, 0.44 mmol, iKang Bio) dissolved in THF (3 mL), while allowing the reaction to proceed while maintaining 0°C. 7-2 (220 mg, 0.44 mmol) dissolved in THF (5 mL) was slowly added dropwise, stirring was stopped, saturated ammonium chloride solution (30 mL) was added to quench the reaction, liquid-liquid was separated, the aqueous phase was extracted with EA (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 160 mg of the yellow solid compound 10-1 in yield 57.7%. LC-MS (ESI, pos. ion) m / z: 626.5 [M+H] + .

[0271] Step 2: Synthesis of compound 10-2 Compound 10-1 (160 mg, 0.33 mmol, 1 equiv.), M4 (0.59 g, 1.16 mmol), Xphos Pd G4 (113 mg, 0.13 mmol), K3PO4·7H2O (447 mg, 1.32 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 50 mL two-necked flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 18 hours to stop the reaction, diluted with EA (15 mL), washed with saturated ammonium chloride (20 mL), extracted with EA (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 258 mg of yellow solid compound 10-2 in yield 93.4%. LC-MS(ESI,pos.ion)m / z:976.8[M+H] + .

[0272] Step 3: Synthesis of compound 10-3 In a 50 mL neck flask, compound 10-2 (303 mg, 0.31 mmol) and acetonitrile (5 mL) were added. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.051 mL, 0.93 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 120 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the mixture was extracted with DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 243 mg of yellow solid 10-3 in yield 84%. LC-MS (ESI, pos. ion) m / z: 932.8 [M+H] + .

[0273] Step 4: Synthesis of compound 10 Compound 10-3 (243 mg, 0.26 mmol), cesium fluoride (320 mg, 2.08 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 12 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 113 mg of yellow solid compound 10 in 70.0% yield. LC-MS (ESI, pos. ion) m / z: 620.5 [M+H] + HRMS(ESI):620.2456[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.91-7.79(m,1H),7.39-7.18(m,3H),5.10-4.93(m,4H),4.41-4.19(m,4H),4.19-4.03(m,2H) ,4.00-3.85(m,2H),3.86-3.71(m,4H),3.44-3.22(m,4H),2.86-2.70(m,2H),2.68-2.50(m,2H),2.23-1.91(m,2H). 19 FNMR(376MHz,CD3OD)δ-111.43(1F),-138.73(1F).

[0274] Example 11: Synthesis of Compound 11 [ka]

[0275] Step 1: Synthesis of compound 11-1 Add NaH (0.18 g, 4.52 mmol, 60% mass fraction) to a 100 mL two-necked flask, purge with nitrogen gas, add THF (7 mL), stir at 0°C for 5 minutes, and slowly add (hexahydro-1H-pyrrolizidine-7α-yl)methanol (0.16 g, 1.13 mmol, Shaoyuan Technology) dissolved in THF (3 mL), reacting for 25 minutes while maintaining 0°C. 400 mg (1.13 mmol) of compound 1-2, dissolved in 5 mL of THF, was slowly added dropwise. The reaction was allowed to proceed at 0°C for 12 hours. After stopping the stirring, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the solution was separated. The aqueous phase was extracted using two 20 mL bottles of DCM, and the organic phase was combined. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 160 mg of yellow solid compound 11-1 in 30.9% yield. LC-MS (ESI, pos. ion) m / z: 460.4 [M+H] + .

[0276] Step 2: Synthesis of compound 11-2 Compound 11-1 (180 mg, 0.39 mmol, 1 equiv.), M4 (0.50 g, 0.98 mmol), Xphos Pd G4 (100 mg, 0.12 mmol), K3PO4·7H2O (528 mg, 1.56 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 50 mL two-necked flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 12 hours to stop the reaction, and saturated ammonium chloride solution (20 mL) was added. Extraction was performed with DCM (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 160 mg of yellow solid compound 11-2 in 50.5% yield. LC-MS(ESI,pos.ion)m / z:810.4[M+H] + .

[0277] Step 3: Synthesis of compound 11-3 Compound 11-2 (153 mg, 0.19 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.057 g, 0.57 mmol, 98% purity) was added dropwise, and the mixture was stirred at 0°C for 120 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 3), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 88 mg of yellow solid compound 11-3 in 60.8% yield. LC-MS (ESI, pos. ion) m / z: 766.7 [M+H] + .

[0278] Step 4: Synthesis of Compound 11 Compound 11-3 (83 mg, 0.11 mmol), cesium fluoride (100 mg, 0.66 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to quench the reaction, and water (20 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 20 mg of red solid compound 1-5 in 30.3% yield. LC-MS (ESI, pos. ion) m / z: 610.3 [M+H] + HRMS(ESI):610.2602[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.89(dd,J=9.2,5.7Hz,1H),7.40-7.30(m,2H),7.28-7.23(m,1H),4.74-4.54(m,4H),4.37-4.22(m,2H),4 .22-4.10(m,2H),4.01-3.90(m,2H),3.88-3.77(m,2H),3.78-3.67(m,2H),3.40(s,1H),2.41-2.30(m,2H),2.26-2.03(m,11H). 19 FNMR(376MHz,CD3OD)δ-111.47(1F),-141.27(1F).

[0279] Example 12: Synthesis of Compound 12 [ka]

[0280] Step 1: Synthesis of compound 12-1 Compound 1-2 (300 mg, 0.84 mmol), N-methyl-L-prolinol (190 mg, 1.68 mmol, Saeun Chemical), DIPEA (0.49 mL, 2.94 mmol), and anhydrous 1,4-dioxane (10 mL) were added to a 100 mL neck flask. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 36 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with DCM (20 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 210 mg of yellow solid compound 12-1 in yield 57.3%. LC-MS(ESI,pos.ion)m / z:434.2[M+H] + .

[0281] Step 2: Synthesis of compound 12-2 Compound 12-1 (199.6 mg, 0.46 mmol, 1 equiv.), M4 (0.59 g, 1.15 mmol), Xphos Pd G4 (120 mg, 0.14 mmol), K3PO4·7H2O (620 mg, 1.84 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 50 mL two-necked flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 12 hours to stop the reaction, and saturated ammonium chloride solution (20 mL) was added. Extraction was performed with DCM (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 190 mg of yellow solid compound 12-2 in yield 52.7%. LC-MS(ESI,pos.ion)m / z:784.4[M+H] + .

[0282] Step 3: Synthesis of Compound 12-3 Compound 12-2 (188 mg, 0.24 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.072 g, 0.72 mmol, 98% purity) was added dropwise, and the mixture was stirred at 0°C for 60 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 92 mg of yellow solid compound 12-3 in yield 51.8%. LC-MS (ESI, pos. ion) m / z: 740.2 [M+H] + .

[0283] Step 4: Synthesis of Compound 12 Compound 12-3 (90 mg, 0.12 mmol), cesium fluoride (109 mg, 0.72 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and water (20 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 46 mg of pale yellow solid compound 12 in 64.8% yield. LC-MS (ESI, pos. ion) m / z: 584.1 [M+H] + HRMS(ESI):584.2482[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.93-7.84(m,1H),7.44-7.30(m,2H),7.27-7.22(m,1H),4.71-4.66(m,1H),4.41-4.08(m, 4H),4.00-3.68(m,6H),3.46-3.37(m,1H),3.28-3.20(m,2H),3.10(s,3H),2.48-2.32(m,2H),2.26-2.02(m,7H). 19 FNMR(376MHz,CD3OD)δ-111.46(1F),-141.16(1F).

[0284] Example 13 Synthesis of Compound 13 [ka]

[0285] Step 1: Synthesis of compound 13 For the synthesis of compound 13, the synthesis of compound 12 was followed, and N-methyl-D-prolinol (purchased from Shaoyuan Technology) was used instead of N-methyl-L-prolinol to obtain the pale yellow solid compound 13. LC-MS (ESI, pos. ion) m / z: 584.3 [M+H] + HRMS(ESI):584.2417[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.88(dd,J=9.1,5.7Hz,1H),7.39-7.30(m,2H),7.27-7.22(m,1H),4.67-4.51(m,3H),4.34-4.20(m,2H),4.20-4.05(m,2H) ),4.01-3.89(m,2H),3.88-3.78(m,2H),3.41(s,1H),3.21-3.10(m,1H) ,2.71(s,3H),2.70-2.62(m,1H),2.28-2.04(m,6H),2.02-1.81(m,3H). 19 FNMR(376MHz,CD3OD)δ-111.56(1F),-140.92(1F).

[0286] Example 14: Synthesis of Compound 14 [ka]

[0287] Step 1: Synthesis of compound 14-1 Add NaH (0.13 g, 3.36 mmol, 60% mass fraction) to a 100 mL two-necked flask, purge with nitrogen gas, add THF (7 mL), stir at 0°C for 5 minutes, and slowly add (2,6-dimethylethylenetetrahydro-1H-pyrroline-7a(5H)-yl)methanol (0.17 g, 1.01 mmol) dissolved in THF (3 mL), reacting for 20 minutes while maintaining 0°C. 1-2 (220 mg, 0.44 mmol) dissolved in THF (5 mL) was slowly added dropwise, and the reaction was allowed to proceed at 0°C for 12 hours. After stopping stirring, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the solution was separated. The aqueous phase was extracted using DCM (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 230 mg of yellow solid compound 14-1 in 56% yield. LC-MS (ESI, pos. ion) m / z: 484.2 [M+H] + .

[0288] Step 2: Synthesis of compound 14-2 Compound 14-1 (184 mg, 0.38 mmol, 1 equiv.), M4 (0.49 g, 0.95 mmol), Xphos Pd G4 (98 mg, 0.11 mmol), K3PO4·7H2O (510 mg, 1.52 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 50 mL two-necked flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 18 hours to stop the reaction, diluted with EA (15 mL), washed with saturated ammonium chloride (20 mL), extracted with EA (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 258 mg of yellow solid compound 14-2 in 54% yield. LC-MS(ESI,pos.ion)m / z:834.4[M+H] + .

[0289] Step 3: Synthesis of compound 14-3 Compound 14-2 (219 mg, 0.33 mmol) and acetonitrile (5 mL) were added to a 50 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (75.06 mg, 0.75 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 120 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the mixture was extracted with DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 56 mg of yellow solid 14-3 in 29% yield. LC-MS (ESI, pos. ion) m / z: 790.1 [M+H] + .

[0290] Step 4: Synthesis of Compound 14 Compound 14-3 (50 mg, 0.063 mmol), cesium fluoride (57.4 mg, 0.38 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 7 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 30 mg of yellow solid compound 14 in 75% yield. LC-MS (ESI, pos. ion) m / z: 634.1 [M+H] + HRMS(ESI):634.2624[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.87(dd,J=9.1,5.7Hz,1H),7.40-7.28(m,2H),7.27-7. 21(m,1H),5.11-5.01(m,4H),4.43-4.36(m,2H),4.32-4.18(m,2H),4.16-4.0 4(m,2H),3.99-3.89(m,2H),3.89-3.85(m,1H),3.85-3.78(m,3H),3.46-3.38 (m,3H),2.89-2.77(m,2H),2.69-2.57(m,2H),2.18(s,3H),2.16-2.03(m,2H). 19 FNMR(376MHz,CD3OD)δ-111.58(1F),-140.74(1F).

[0291] Example 15 Synthesis of Compound 15 [ka]

[0292] Step 1: Synthesis of compound 15-1 Add NaH (0.11 g, 2.7 mmol, 60% mass fraction) to a 100 mL two-necked flask, purge with nitrogen gas, add THF (5 mL), stir at 0°C for 5 minutes, and slowly add (2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (0.19 g, 1.08 mmol, Shanghai Tebo Chemical) dissolved in THF (1.5 mL), reacting for 60 minutes while maintaining 0°C. 1-2 (320 mg, 0.90 mmol) dissolved in THF (2 mL) was slowly added dropwise, and the reaction was allowed to proceed at 0°C for 1 hour. After stopping the stirring, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the solution was separated. The aqueous phase was extracted using DCM (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=100 / 1) eluate to obtain 203 mg of yellow solid compound 15-1 in 45% yield. LC-MS (ESI, pos. ion) m / z: 496.1 [M+H] + .

[0293] Step 2: Synthesis of compound 15-2 Add compound 15-1 (198 mg, 0.40 mmol, 1 equiv.), M4 (0.41 g, 0.80 mmol), Xphos Pd G3 (68 mg, 0.080 mmol), K3PO4·7H2O (340 mg, 1.0 mmol), and THF / H2O (v / v=4 mL / 2 mL) to a 50 mL two-necked flask, purge three times with nitrogen gas, and stir at room temperature for 2 hours. G3 (0.2 equiv.) was added, and the mixture was stirred at room temperature for 3 hours to quench the reaction. The mixture was then diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), extracted with DCM (20 mL x 2), combined with the organic phase, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=100 / 1) eluate to obtain 215 mg of the yellow solid compound 15-2 in 64% yield. LC-MS (ESI, pos. ion) m / z: 846.2 [M+H] + .

[0294] Step 3: Synthesis of compound 15-3 Compound 15-2 (215 mg, 0.25 mmol) and acetonitrile (5 mL) were added to a 50 mL neck flask, cooled to 0°C, and stirred for 5 minutes. Concentrated sulfuric acid (0.14 mL, 2.5 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the solution was extracted with DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=10 / 1) eluate to obtain 135 mg of yellow solid 15-3 in 66% yield. LC-MS (ESI, pos. ion) m / z: 802.2 [M+H] + .

[0295] Step 4: Synthesis of Compound 15 Compound 15-3 (135 mg, 0.17 mmol), cesium fluoride (210 mg, 1.36 mmol), and DMF (0.5 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 13 hours to stop the reaction, and 10 mL of water was added to precipitate the solid. The solid was filtered to obtain the crude product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=9 / 1) eluate to obtain 60 mg of yellow solid compound 15 in 55% yield. LC-MS (ESI, pos. ion) m / z: 646.1 [M+H] + HRMS(ESI):646.2478[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.86(dd,J=9.1,5.7Hz,1H),7.38-7.28(m,2H),7.26-7.20(m,1H),4.63(s,1H),4.35-4.18(m,4H),4.16-4.04(m,2H),3.99- 3.85(m,2H),3.84-3.77(m,2H),3.53-3.36(m,2H),3.24-3.07(m,2H),2. 68-2.50(m,1H),2.41-2.25(m,1H),2.21-1.96(m,7H),1.96-1.84(m,2H). 19 FNMR(376MHz,CD3OD)δ-99.21(ddd,J=283.9,234.1,33.4Hz,2F),-111.60(s,1F),-140.76(d,J=4.4Hz,1F).

[0296] Example 16: Synthesis of Compound 16 [ka]

[0297] Step 1: Synthesis of compound 16-1 In a 100 mL two-necked flask, LiAlH4 (0.46 g, 12.12 mmol) was added, and the mixture was purged three times with nitrogen gas. Under conditions of 0°C, THF (12.5 mL) was added and stirred for 5 minutes. N-BOC-trans-4-fluoro-L-proline methyl ester (1.00 g, 4.04 mmol, Shanghai Bi De Pharmaceutical), dissolved in 2 mL of THF, was slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and stirred for 16.5 hours to allow the reaction to proceed. The mixture was then transferred to 0°C and stirred for 5 minutes. Sodium sulfate decahydrate was slowly added to quench the reaction, filtered through diatomaceous earth, concentrated, and dried by suction to obtain 445 mg of a pale yellow oily substance 16-1 in yield 82.6%. LC-MS (ESI, pos. ion) m / z: 134.1 [M+H] + .

[0298] Step 2: Synthesis of compound 16-2 Compounds 16-1 (130 mg, 1.01 mmol), 16-2 (300 mg, 0.84 mmol), 1,4-dioxane (6 mL), DIPEA (0.28 mL, 1.68 mmol), and DMAP (0.010 g, 0.084 mmol) were added to a 50 mL necked flask. The flask was purged with nitrogen gas, the temperature was raised to 80°C, and the mixture was stirred for 16 hours. After stopping the stirring, the reaction mixture was concentrated, diluted with 25 mL of EA, and sequentially washed with saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 56 mg of yellow solid compound 16-2 in 15% yield. LC-MS (ESI, pos. ion) m / z: 452.0 [M+H] + .

[0299] Step 3: Synthesis of compound 16-3 Add compound 16-2 (56 mg, 0.12 mmol, 1 equiv.), M4 (0.12 g, 0.24 mmol), Xphos Pd G4 (21 mg, 0.024 mmol), K3PO4·7H2O (120 mg, 0.36 mmol) and THF / H2O (v / v=2.1 mL / 0.72 mL) to a 25 mL two-necked flask, purge three times with nitrogen gas, stir at room temperature for 2 hours, and then Xphos Pd G4 (0.2 equiv.) was added, and the mixture was stirred at room temperature for 2 hours to quench the reaction. The mixture was then diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), extracted with DCM (20 mL x 2), combined with the organic phase, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=100 / 1) eluate to obtain 54 mg of the yellow solid compound 16-3 in 54% yield. LC-MS (ESI, pos. ion) m / z: 401.8 [M+2H] 2+ .

[0300] Step 4: Synthesis of compound 16-4 Compound 16-3 (54 mg, 0.067 mmol) and acetonitrile (2 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.018 mL, 0.34 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (15 mL) was added to quench the reaction, and the mixture was extracted using DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 51 mg of the yellow solid crude product 16-4, which was used directly in the next step, and the yield was calculated at 100%. LC-MS (ESI, pos. ion) m / z: 379.8 [M + 2H] 2+ .

[0301] Step 5: Synthesis of Compound 16 Compound 16-4 (51 mg, 0.067 mmol), cesium fluoride (81 mg, 0.54 mmol), and DMF (0.4 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 18 hours to stop the reaction, and 10 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=92 / 8) eluate to obtain 20 mg of yellow solid compound 16 in 49% yield. LC-MS (ESI, pos. ion) m / z: 602.2 [M+H] + HRMS(ESI):602.2358[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.86(dd,J=9.1,5.7Hz,1H),7.40-7.27(m,2H),7.26-7.19(m,1H),5.22(d,J=55.2Hz,1H),4.63-4.47(m,2H),4.34-4.03(m, 4H),3.99-3.86(m,2H),3.85-3.74(m,2H),3.68-3.49(m,1H),3.41(s,1H) ),2.91-2.71(m,1H),2.64(s,3H),2.44-2.26(m,1H),2.22-1.96(m,7H). 19 FNMR (376MHz, CD3OD) δ -111.56 (1F), -140.88 (1F), -171.92 (1F).

[0302] Example 17 Synthesis of Compound 17 [ka]

[0303] Step 1: Synthesis of compound 17-1 Add NaH (0.14 g, 3.39 mmol, 60% mass fraction) to a 100 mL two-necked flask, purge with nitrogen gas, add THF (3 mL), stir at 0°C for 5 min, and slowly add (2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methanol (0.20 g, 1.24 mmol, Beijing Leyan Technology) dissolved in THF (1.5 mL), reacting for 60 minutes while maintaining 0°C. 400 mg (1.13 mmol) of compound 1-2, dissolved in anhydrous THF (5 mL), was slowly added dropwise. The reaction was allowed to proceed at 0°C for 2.5 hours. After stopping the stirring, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was separated. The aqueous phase was extracted using DCM (30 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 164 mg of black oily compound 17-1 in 30% yield. LC-MS (ESI, pos. ion) m / z: 477.9 [M+H] + .

[0304] Step 2: Synthesis of compound 17-2 Add compound 17-1 (164 mg, 0.34 mmol, 1 equiv.), M4 (0.35 g, 0.68 mmol), Xphos Pd G3 (58 mg, 0.068 mmol), K3PO4·7H2O (290 mg, 0.85 mmol) and THF / H2O (v / v=3.5 mL / 1.7 mL) to a 50 mL two-necked flask, purge three times with nitrogen gas, stir at room temperature for 1 hour, and then Xphos Pd G3 (0.2 equiv.) was added, and the mixture was stirred at room temperature for 2 hours to quench the reaction. The mixture was then diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), extracted with DCM (20 mL x 2), combined with the organic phase, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=98.3 / 1.7) eluate to obtain 102 mg of red oily compound 17-2 in 36% yield. LC-MS (ESI, pos. ion) m / z: 828.5 [M+H] + .

[0305] Step 3: Synthesis of compound 17-3 Compound 17-2 (102 mg, 0.12 mmol) and acetonitrile (2.5 mL) were added to a 50 mL neck flask, cooled to 0°C, and stirred for 5 minutes. Concentrated sulfuric acid (0.039 mL, 0.72 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 60 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=10 / 1) eluate to obtain 45 mg of yellow solid 17-3 in 47% yield. LC-MS (ESI, pos. ion) m / z: 783.8 [M+H] + .

[0306] Step 4: Synthesis of Compound 17 Compound 17-3 (45 mg, 0.057 mmol), cesium fluoride (69 mg, 0.46 mmol), and DMF (0.4 mL) were added to a 25 mL necked flask. The mixture was purged three times with nitrogen gas and stirred at room temperature for 10.5 hours to quench the reaction. 8 mL of water was added to precipitate the solid, which was then filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=9 / 1) eluate to obtain 21 mg of yellow solid compound 17 in 58% yield. LC-MS (ESI, pos. ion) m / z: 627.8 [M+H] + HRMS(ESI):628.2607[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.86(dd,J=9.1,5.7Hz,1H),7.38-7.28(m,2H),7.26-7.20(m,1H),5.37(d,J=52.9Hz,1H),4.52-4.35(m,2H),4.32-4.04 (m,4H),3.99-3.86(m,2H),3.85-3.76(m,2H),3.60-3.46(m,1H),3.44- 3.35(m,1H),3.07-2.82(m,2H),2.60-2.44(m,1H),2.23-1.94(m,11H). 19 FNMR(376MHz,CD3OD)δ-111.59(1F),-140.86(1F),-176.23(1F).

[0307] Example 18: Synthesis of Compound 18 [ka]

[0308] Step 1: Synthesis of compound 18-1 In a 100 mL neck flask, compound 1-2 (400 mg, 1.13 mmol), (2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methanol (180 mg, 1.13 mmol), DIPEA (0.37 mL, 2.26 mmol), and anhydrous 1,4-dioxane (6 mL) were added. The mixture was purged three times with nitrogen gas, heated to 90 °C, and stirred for 15 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (20 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 72 mg of yellow solid compound 18-1 in yield of 13.4%. LC-MS(ESI,pos.ion)m / z:477.9[M+H] + .

[0309] Step 2: Synthesis of compound 18-2 Add compound 18-1 (72 mg, 0.15 mmol, 1 equiv.), M4 (0.15 g, 0.30 mmol), Xphos Pd G3 (25 mg, 0.030 mmol), K3PO4·7H2O (150 mg, 0.45 mmol) and THF / H2O (v / v=2.5 mL / 0.9 mL) to a 50 mL two-necked flask, purge with nitrogen gas three times, stir at room temperature for 1 hour, and then Xphos Pd G3 (0.2 equiv.) was added, and the mixture was stirred at room temperature for 1 hour to quench the reaction. The mixture was then diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), extracted with DCM (20 mL x 2), combined with the organic phase, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 63 mg of red oily compound 18-2 in 50.5% yield. LC-MS (ESI, pos. ion) m / z: 828.1 [M+H] + .

[0310] Step 3: Synthesis of Compound 18-3 Compound 18-2 (63 mg, 0.076 mmol) and acetonitrile (3 mL) were added to a 50 mL necked flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.021 mL, 0.38 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 60 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the solution was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=10 / 1) eluate to obtain 40 mg of yellow solid 17-3 in 67% yield. LC-MS (ESI, pos. ion) m / z: 783.8 [M+H] + .

[0311] Step 4: Synthesis of Compound 18 Compound 18-3 (40 mg, 0.051 mmol), cesium fluoride (62 mg, 0.41 mmol), and DMF (0.4 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 4 hours to stop the reaction, and 8 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=10 / 1) eluate to obtain 20 mg of yellow solid compound 18 in yield 62.4%. LC-MS (ESI, pos. ion) m / z: 627.9 [M+H] + HRMS(ESI):628.2582[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.86(dd,J=9.1,5.7Hz,1H),7.37-7.28(m,2H),7.26- 7.19(m,1H),5.38(d,J=52.3Hz,1H),4.55-4.39(m,2H),4.34-4.18(m,2H),4 .16-4.06(m,2H),3.98-3.87(m,2H),3.85-3.75(m,2H),3.62-3.46(m,1H),3 .43-3.34(m,1H),3.19-3.04(m,1H),3.03-2.84(m,2H),2.21-1.99(m,11H). 19 FNMR (376MHz, CD3OD) δ -111.58 (1F), -140.90 (1F), -176.34 (1F).

[0312] Example 19: Synthesis of Compound 19 [ka]

[0313] Step 1: Synthesis of compound 19-1 In a 50 mL two-necked flask, 1-2 (400 mg, 1.13 mmol), DMF (2 mL), THF (3.5 mL), cesium carbonate (1.1 g, 3.39 mmol), and (1-(morpholinomethyl)cyclopropyl)methanol (0.23 g, 1.36 mmol, Beijing Feilongrui Trading Co.) were added and stirred at room temperature for 3 hours. Then DABCO (0.013 g, 0.11 mmol) was added and stirred at room temperature for 3.5 hours. The reaction was stopped, saturated ammonium chloride solution (20 mL) was added to quench the reaction, liquid-liquid was separated, the aqueous phase was extracted with EA (30 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=98 / 2) eluate to obtain 375 mg of black oily compound 19-1 in 68% yield. LC-MS(ESI,pos.ion)m / z:490.3[M+H] + .

[0314] Step 2: Synthesis of compound 19-2 Add compound 19-1 (375 mg, 0.77 mmol, 1 equiv.), M4 (0.59 g, 1.16 mmol), Xphos Pd G3 (130 mg, 0.15 mmol), K3PO4·7H2O (780 mg, 2.31 mmol) and THF / H2O (v / v=8 mL / 4 mL) to a 100 mL two-necked flask, purge three times with nitrogen gas, stir at room temperature for 1 hour, and then Xphos Pd G3 (0.2 equiv.) was added, and the mixture was stirred at room temperature for 1 hour to quench the reaction. EA (20 mL) was added for dilution, and the mixture was washed with saturated ammonium chloride (20 mL). Extraction was performed with EA (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=100 / 1) eluate to obtain 295 mg of black solid compound 19-2 in 46% yield. LC-MS (ESI, pos. ion) m / z: 840.4 [M+H] + .

[0315] Step 3: Synthesis of Compound 19-3 Compound 19-2 (295 mg, 0.35 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask, cooled to 0°C, and stirred for 5 minutes. Concentrated sulfuric acid (0.095 mL, 1.75 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the solution was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 162 mg of yellow solid 19-3 in 58% yield. LC-MS (ESI, pos. ion) m / z: 796.3 [M+H] + .

[0316] Step 4: Synthesis of Compound 19 Compound 19-3 (162 mg, 0.20 mmol), cesium fluoride (240 mg, 1.6 mmol), and DMF (0.8 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and 10 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=10 / 1) eluate to obtain 94 mg of yellow solid compound 19 in 72% yield. LC-MS (ESI, pos. ion) m / z: 640.3 [M+H] + HRMS(ESI):640.2742[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.85(dd,J=9.0,5.8Hz,1H),7.37-7.27(m,2H),7.26-7.20(m,1H),4.43(s,2H),4.32-4.17(m,2H),4.16-4.02(m,2H) ),4.00-3.86(m,2H),3.84-3.76(m,2H),3.70-3.57(m,4H),3.39(s,1H),2.61-2.35(m,6H),2.19-2.01(m,5H),0.71(s,2H),0.51(s,2H). 19 FNMR(376MHz,CD3OD)δ-111.55(1F),-140.81(1F).

[0317] Example 20: Synthesis of Compound 20 [ka]

[0318] Step 1: Synthesis of compound 20-1 Add N-BOC-trans-4-fluoro-L-proline methyl ester (5.00 g, 20.2 mmol, Shanghai Bi De Pharmaceutical) to a 250 mL three-necked flask, cool to -45°C and stir for 10 minutes, then add LiHMDS (30.33 mL, 30.33 mmol, 1 M). Slowly add THF solution dropwise, stir at -45°C for 60 min, slowly add 3-chloro-2-(chloromethyl)propan-1-ene (3.03 g, 24.26 mmol, dissolved in 15 mL of anhydrous THF) dropwise, and after addition is complete, slowly raise the temperature to room temperature (approximately 1 hour), stop stirring, slowly add saturated ammonium chloride solution (20 mL) to quench the reaction, separate the liquid and liquid phases, extract the aqueous phase with EA (50 mL x 2), combine with the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=20 / 1~5 / 1) eluate to obtain 6.06 g of yellow oily compound 20-1 in 89% yield. LC-MS (ESI, pos. ion) m / z: 236.0 [M-Boc+H] + .

[0319] Step 2: Synthesis of compound 20-2 Add 20-1 (6.06 g, 18.05 mmol) and DCM (100 mL) to a 250 mL neck flask, cool to 0°C, and stir for 5 minutes. Add hydrogen chloride dioxane solution (22.56 mL, 90.25 mmol, 4 M) dropwise, and stir at room temperature for 14.5 hours after the addition is complete. Stop stirring, concentrate the reaction mixture, and dry it by vacuum. Use this mixture in the next step, and calculate the yield at 100%. LC-MS (ESI, pos. ion) m / z: 236.0 [M+H] + .

[0320] Step 3: Synthesis of compound 20-3 In a 250 mL neck flask, 20-2 (4.25 g, 18.03 mmol), acetonitrile (50 mL), sodium bicarbonate (7.57 g, 90.15 mmol), and potassium iodide (0.30 g, 1.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After stopping the stirring, the reaction mixture was filtered, washed with acetonitrile (50 mL), concentrated, and purified by column chromatography using PE / EA (v / v=4 / 1~3 / 2) eluate to obtain 3.00 g of yellow oily compound 20-3 in 83.5% yield. LC-MS (ESI, pos. ion) m / z: 200.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ5.29-5.12(m,1H),4.95(d,J=13.7Hz,2H),3.87(d,J=14.8Hz,1H),3.75(s,3H),3.59- 3.40(m,1H),3.27-3.16(m,1H),2.98-2.86(m,2H),2.85-2.73(m,1H),2.57-2.48(m,1H),2.21-1.93(m,1H).

[0321] Step 4: Synthesis of compound 20-4 Add 20-3 (400 mg, 2.01 mmol) to a 100 mL neck flask, purge three times with nitrogen gas, add anhydrous DCM (12 mL), cool to -20°C and stir for 10 minutes, slowly add diethylzinc reagent (10.05 mL, 10.05 mmol, 1 M n-hexane solution) dropwise and stir for 30 minutes. Slowly add methylene iodide (1.62 mL, 20.10 mmol) dropwise, transfer to 0°C and stir for 3 hours to react. Quench with saturated ammonium chloride (20 mL). Extract the aqueous phase with EA (20 mL x 2), combine with the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=7 / 3) eluate to obtain 223 mg of yellow oily compound 20-4 in 52% yield. LC-MS(ESI,pos.ion)m / z:214.4[M+H] + , 1H NMR(400MHz,CDCl3)δ5.37-5.16(m,1H),3.77(s,3H),3.68-3.52(m,1H),3.19(d,J=10.6Hz,1H),3.10-2.92(m ,1H),2.91-2.76(m,1H),2.63(d,J=10.6Hz,1H),2.25-2.02(m,2H),1.89(d,J=12.9Hz,1H),0.66-0.42(m,4H).

[0322] Step 5: Synthesis of compound 20-5 In a 100 mL two-necked flask, LiAlH4 (0.79 g, 2.08 mmol) was added, and the mixture was purged three times with nitrogen gas. Under conditions of -10°C, THF (2 mL) was added and stirred for 5 minutes. 221 mg (1.04 mmol) dissolved in 3 mL of THF was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and the mixture was stirred for 3.5 hours to allow the reaction to proceed. Sodium sulfate decahydrate was slowly added to quench the reaction, and the mixture was filtered through diatomaceous earth. After concentration, it was dried by suction to obtain 162 mg of a yellow oily substance, 20.5, in 84% yield. LC-MS (ESI, pos. ion) m / z: 186.2 [M+H] + .

[0323] Step 6: Synthesis of compound 20-6 Compounds 1-2 (300 mg, 0.84 mmol), 20-5 (160 mg, 0.84 mmol), DIPEA (0.42 mL, 2.52 mmol), and anhydrous 1,4-dioxane (5 mL) were added to a 100 mL neck flask. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 11 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (20 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 65 mg of yellow solid compound 20-6 in yield 15.3%. LC-MS (ESI, pos. ion) m / z: 504.2 [M+H] + .

[0324] Step 7: Synthesis of compound 20-7 Add compound 20-6 (65 mg, 0.13 mmol, 1 equiv.), M4 (0.17 g, 0.33 mmol), Xphos Pd G3 (22 mg, 0.026 mmol), K3PO4·7H2O (130 mg, 0.39 mmol) and THF / H2O (v / v=2.5 mL / 0.8 mL) to a 25 mL neck flask, purge three times with nitrogen gas, stir at room temperature for 1 hour, and then Xphos Pd G3 (0.2 equiv.) was added, and the mixture was stirred at room temperature for 1 hour to stop the reaction. EA (20 mL) was added for dilution, and the mixture was washed with saturated ammonium chloride (20 mL). Extraction was performed with EA (20 mL x 2), the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by thin-layer chromatography using DCM / MeOH (v / v=12 / 1) eluate to obtain 65 mg of the red oily compound 18-2 in 59% yield. LC-MS (ESI, pos. ion) m / z: 854.3 [M+H] + .

[0325] Step 8: Synthesis of compound 20-8 Compound 20-7 (65 mg, 0.076 mmol) and acetonitrile (3 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.021 mL, 0.38 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 60 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (15 mL) was added to quench the reaction, and the mixture was extracted using DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and dried by vacuum. The resulting solution was then used in the next step, and the yield was calculated at 100%. LC-MS (ESI, pos. ion) m / z: 810.4 [M+H] + .

[0326] Step 9: Synthesis of Compound 20 Compound 20-8 (61.6 mg, 0.076 mmol), cesium fluoride (69 mg, 0.46 mmol), and DMF (0.4 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 3.5 hours to stop the reaction, and 10 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=1 1 / 1) eluate to obtain 34 mg of yellow solid compound 20 in yield 68.4%. LC-MS (ESI, pos. ion) m / z: 654.3 [M+H] + HRMS(ESI):654.2749[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.86(dd,J=9.1,5.7Hz,1H),7.38-7.28(m,2H),7.26-7.21 (m,1H),5.42(d,J=51.9Hz,1H),4.55-4.44(m,2H),4.35-4.20(m,2H),4.18-4.03 (m,2H),4.00-3.86(m,2H),3.84-3.75(m,2H),3.67-3.45(m,1H),3.44-3.37(m, 1H),3.25-3.06(m,2H),2.80-2.70(m,1H),2.27-2.01(m,9H),0.71-0.54(m,4H). 19 FNMR (376MHz, CD3OD) δ -111.59 (1F), -140.82 (1F), -175.79 (1F).

[0327] Example 21: Synthesis of Compound 21 [ka]

[0328] Step 1: Synthesis of compound 21-1 Compound 11-1 (150 mg, 0.33 mmol, 1 equiv.), M5 (0.30 g, 0.83 mmol), Xphos Pd G4 (85 mg, 0.099 mmol), K3PO4·7H2O (450 mg, 1.32 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 50 mL two-necked flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), extracted with EA (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 42 mg of yellow solid compound 21-1 in 20% yield. LC-MS(ESI,pos.ion)m / z:658.2[M+H] + .

[0329] Step 2: Synthesis of Compound 21 Compound 21-1 (40 mg, 0.061 mmol) and acetonitrile (5 mL) were added to a 50 mL neck flask, cooled to 0°C, and stirred for 5 minutes. Concentrated sulfuric acid (18.3 mg, 0.18 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 1.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the solution was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 20 mg of yellow solid 21 in 53% yield. LC-MS (ESI, pos. ion) m / z: 614.1 [M+H] + HRMS(ESI):614.2985[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.70(dd,J=8.8,5.8Hz,1H),7.37-7.22(m,2H),7.13-7.06(m,1H),4.70-4.60(m,6H),4.33-4.07(m, 4H),4.01-3.88(m,2H),3.87-3.79(m,2H),3.75-3.66(m,2H),2.44-2.29(m,4H),2.26-2.09(m,9H),0.85(t,J=7.4Hz,3H).19 FNMR(376MHz,CD3OD)δ-120.86(1F),-140.73(1F).

[0330] Example 22: Synthesis of Compound 22 [ka]

[0331] Step 1: Synthesis of Compound 22-1 Compounds 1-5 (700 mg, 0.89 mmol), pyridine (0.28 g, 3.56 mmol), and DCM (15 mL) were added to a 50 mL neck flask. After purging with nitrogen gas three times, the mixture was cooled to 0°C and stirred for 5 minutes. TF2O (1.00 g, 3.56 mmol) was slowly added dropwise, and after completion of the addition, the mixture was heated to 30°C and stirred for 2.5 hours. The reaction was stopped, saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 140 mg of brown solid 22-1 in 17% yield. LC-MS (ESI, pos. ion) m / z: 916.0 [M+H] + .

[0332] Step 2: Synthesis of compound 22-2 Compound 22-1 (140 mg, 0.15 mmol, 1 equiv.), benzophenone imine (140 mg, 0.75 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), XantPhos (52 mg, 0.090 mmol), cesium carbonate (150 mg, 0.45 mmol), and toluene (3 mL) were added to a 25 mL two-necked flask. The mixture was purged three times with nitrogen gas and stirred at 120 °C for 15 hours. Pd2(dba)3 (0.3 equiv.) and XantPhos (0.6 equiv.) were added, and the mixture was stirred at 120°C for 6 hours to quench the reaction. The mixture was then diluted with EA (20 mL), washed with saturated ammonium chloride (20 mL), extracted with EA (20 mL x 2), combined with the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 70 mg of the yellow solid compound 22-2 in 48% yield. LC-MS (ESI, pos. ion) m / z: 947.3 [M+H] + .

[0333] Step 3: Synthesis of Compound 22-3 Compound 22-2 (90 mg, 0.095 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (28.52 mg, 0.29 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 70 mg of yellow solid 22-3 in 94% yield. LC-MS (ESI, pos. ion) m / z: 392.2 [M + 2H] 2+ .

[0334] Step 4: Synthesis of Compound 22 Compound 22-3 (70 mg, 0.089 mmol), cesium fluoride (110 mg, 0.71 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The solid was filtered to obtain the crude product, and the crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 23 mg of yellow solid compound 22 in 41% yield. LC-MS (ESI, pos. ion) m / z: 627.3 [M+H] + HRMS(ESI):627.2686[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.77(dd,J=8.9,5.7Hz,1H),7.30-7.15(m,3H),5.51(d,J=53.4Hz,1H),4.60-4.50(m,2H),4.36-4.21(m,2H),4 .22-4.07(m,2H),4.01-3.89(m,2H),3.89-3.79(m,2H),3.77-3.61(m,3H),3.43-3.34(m,2H),2.67-2.41(m,2H),2.39-2.02(m,9H). 19 FNMR(376MHz,CD3OD)δ-113.29(1F),-141.12(1F),-173.96(1F).

[0335] Example 23: Synthesis of Compound 23 [ka]

[0336] Step 1: Synthesis of compound 23-1 In a 25 mL two-necked flask, combine compounds 1-3 (300 mg, 0.63 mmol, 1 equiv.), 2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.549 g, 1.57 mmol, iKang Bio), and Xphos Pd G4 (162 mg, 0.19 mmol), K3PO4·7H2O (852 mg, 2.52 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added, the mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 220 mg of yellow solid compound 23-1 in 53% yield. LC-MS (ESI, pos. ion) m / z: 664.3 [M+H] + .

[0337] Step 2: Synthesis of Compound 23 Compound 23-1 (219 mg, 0.33 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (99 mg, 0.99 mmol, 98% purity) was added dropwise, and the mixture was stirred for 1.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 95 mg of yellow solid compound 23 in 46% yield. LC-MS (ESI, pos. ion) m / z: 620.5 [M+H] + HRMS(ESI):620.2251[M+H] + , 1H NMR(400MHz,CD3OD)δ7.80-7.71(m,1H),7.41-7.30(m,3H),7.25-7.16(m,1H),5.46-5.25(m,1H),4.42-4.29(m,2H),4.28-4. 06(m,4H),3.99-3.83(m,2H),3.84-3.74(m,2H),3.49-3.34(m,3H),3.15-3.04(m,1H),2.49-2.25(m,2H),2.22-1.91(m,9H). 19 FNMR (376MHz, CD3OD) δ -140.99 (1F), -173.66 (1F).

[0338] Example 24: Synthesis of Compound 24 [ka]

[0339] Step 1: Synthesis of compound 24-1 In a 25 mL two-necked flask, combine compounds 1-3 (350 mg, 0.73 mmol, 1 equiv.), 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.606 g, 1.82 mmol, Shanghai Zaiqi Bio), and Xphos Pd G4 (188 mg, 0.22 mmol), K3PO4·7H2O (988 mg, 2.92 mmol), and THF / H2O (v / v=6 mL / 2 mL) were added, the mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 400 mg of yellow solid compound 24-1 in 84% yield. LC-MS (ESI, pos. ion) m / z: 648.1 [M+H] + .

[0340] Step 2: Synthesis of Compound 24 Compound 24-1 (400 mg, 0.62 mmol) and acetonitrile (10 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (186 mg, 1.86 mmol, 98% purity) was added dropwise, and the mixture was stirred for 1.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 210 mg of yellow solid compound 24 in 50% yield. LC-MS (ESI, pos. ion) m / z: 604.1 [M+H] + HRMS(ESI):604.2563[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.65-7.53(m,1H),7.45-7.29(m,2H),7.22-7.14(m,1H),6.99-6.85(m,1H),5.44-5.21(m,1H),4.68-4.59(m,1H) ,4.38-4.06(m,6H),3.98-3.83(m,2H),3.84-3.74(m,2H),3.29-3.20(m,2H),3.10-2.97(m,1H),2.42-2.22(m,2H),2.22-1.85(m,9H). 19 FNMR (376MHz, CD3OD) δ -115.94 (1F), -141.97 (1F), -173.62 (1F).

[0341] Example 25: Synthesis of Compound 25 [ka]

[0342] Step 1: Synthesis of compound 25-1 In a 100 mL two-necked flask, compound NaBH4 (0.71 g, 18.76 mmol) and anhydrous THF (30 mL) were added, the mixture was purged three times with nitrogen gas, stirred to dissolve, cooled to 0°C, N-Boc-3-oxoazepane (2.0 g, 9.38 mmol, Shaoyuan Technology) was added, and the mixture was stirred at 0°C for 1.5 hours to stop the reaction. Saturated ammonium chloride solution (20 mL) was added to quench the mixture, and the mixture was returned to room temperature. Extraction was performed by adding EA (20 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain 2.0 g of colorless, transparent oily compound 25-1 in 99% yield. 1 H NMR(400MHz,CDCl3)δ3.90-3.78(m,1H),3.72-3.54(m,1H),3.55-3.38(m,2H),3.38-3. 27(m,1H),3.10-2.97(m,1H),1.85-1.73(m,1H),1.73-1.52(m,3H),1.50-1.21(m,11H).

[0343] Step 2: Synthesis of compound 25-2 Compound 25-1 (2 g, 9.29 mmol) and anhydrous DCM (50 mL) were added to a 250 mL two-necked flask, the mixture was purged three times with nitrogen gas, stirred to dissolve, cooled to 0°C, DAST (4.91 mL, 37.16 mmol) was added dropwise, stirred at 0°C for 4 hours, the reaction was stopped, saturated sodium bicarbonate solution (200 mL) was added to quench, the mixture was returned to room temperature, DCM (50 mL) was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=9 / 1) eluate to obtain 0.8 g of yellow liquid compound 25-2 in 40% yield. 1 H NMR (400MHz, CDCl3) δ4.97-4.62(m,1H),4.09-3.71(m,1H),3.68-3.54(m,1H),3.38-3.00(m,2H),1.97-1.59(m,6H),1.45(s,9H).

[0344] Step 3: Synthesis of compound 25-3 Compound 25-2 (0.8 g, 3.68 mmol) and DCM (15 mL) were added to a 50 mL necked flask, stirred to dissolve, and 4 M hydrochloric acid / 1,4-dioxane solution (8 mL, 32 mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours to stop the reaction, and the solution was concentrated to obtain 0.5 g of white solid 25-3 in 88% yield.

[0345] Step 4: Synthesis of compound 25-4 Add compound 25-3 (0.24 g, 1.58 mmol) to a 50 mL necked flask, dissolve with DCM (4 mL), add DIPEA (2.09 mL, 12.64 mmol), and stir for 15 minutes. Add compound 1-1 (0.46 g, 1.58 mmol) to another 50 mL necked flask, dissolve with anhydrous DCM (4 mL), purge three times with nitrogen gas, and stir to dissolve. Add the previously prepared 25-3 solution dropwise, stir at room temperature for 12 hours to stop the reaction, quench with saturated ammonium chloride solution (30 mL), return to room temperature, extract with DCM (30 mL x 2), separate the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=3 / 1) eluate to obtain 360 mg of yellow solid compound 25-4 in 61% yield. LC-MS(ESI,pos.ion)m / z:371.1[M+H] + .

[0346] Step 5: Synthesis of compound 25-5 In a 100 mL neck flask, compound 25-4 (360 mg, 0.97 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (280 mg, 1.75 mmol), DIPEA (0.48 mL, 2.91 mmol), and anhydrous 1,4-dioxane (15 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 20 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 215 mg of yellow solid compound 25-5 in 45% yield. LC-MS(ESI,pos.ion)m / z:494.3[M+H] + .

[0347] Step 6: Synthesis of Compound 25-6 Compound 25-5 (195 mg, 0.39 mmol, 1 equiv.), M4 (0.60 g, 1.17 mmol), Xphos Pd G4 (134 mg, 0.16 mmol), K3PO4·7H2O (528 mg, 1.56 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and saturated ammonium chloride solution (20 mL) was added. Extraction was performed with EA (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 282 mg of yellow solid compound 25-6 in 84% yield. LC-MS (ESI, pos. ion) m / z: 844.7 [M+H] + .

[0348] Step 7: Synthesis of compound 25-7 Compound 25-6 (282 mg, 0.33 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (100 mg, 1.00 mmol, 98% purity) was added dropwise, and the mixture was stirred for 1.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 152 mg of yellow solid compound 25-7 in 46% yield. LC-MS (ESI, pos. ion) m / z: 800.7 [M+H] + .

[0349] Step 8: Synthesis of Compound 25 Compound 25-7 (152 mg, 0.19 mmol), cesium fluoride (230 mg, 1.52 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and water (20 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 85 mg of yellow solid compound 25 in 69% yield. LC-MS (ESI, pos. ion) m / z: 644.3 [M+H] + HRMS(ESI):644.2678[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.86(dd,J=8.9,5.9Hz,1H),7.37-7.29(m,2H),7.27-7.15(m,1H),5.33(d,J=54.1Hz,1H),5.03(d,J=45.9Hz,1H),4.71-4. 56(m,1H),4.40-4.25(m,3H),4.22-3.94(m,2H),3.84-3.67(m,1H),3.3 0-3.18(m,3H),3.09-2.96(m,1H),2.42-2.10(m,7H),2.08-1.67(m,8H). 19 FNMR (376MHz, CD3OD) δ -111.60 (1F), -140.84 (1F), -173.57 (1F), -176.83 (1F).

[0350] Example 26: Synthesis of Compound 26 [ka]

[0351] Step 1: Synthesis of compound 26-1 Compound 3-1 (1.14 g, 3.74 mmol) was added to a 100 mL necked flask, purged three times with nitrogen gas, dissolved with DCM (15 mL), added DIPEA (1.45 g, 11.22 mmol), the temperature was lowered to -30°C, 25-3 (0.445 g, 2.90 mmol) was added, and the reaction was allowed to proceed at -30°C for 30 minutes to stop the reaction. Saturated ammonium chloride solution (20 mL) was added to quench the reaction, the mixture was returned to room temperature, and DCM (20 mL x 2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=9 / 1) eluate to obtain 326 mg of yellow solid compound 26-1 in 23% yield. LC-MS (ESI, pos. ion) m / z: 385.5 [M+H] + .

[0352] Step 2: Synthesis of compound 26-2 In a 100 mL neck flask, compound 26-1 (326 mg, 0.85 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (270 mg, 1.7 mmol), DIPEA (0.33 g, 2.55 mmol), and anhydrous 1,4-dioxane (5 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 12 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=19 / 1) eluate to obtain 340 mg of yellow oily compound 26-2 in 79% yield. LC-MS(ESI,pos.ion)m / z:508.2[M+H] + .

[0353] Step 3: Synthesis of compound 26-3 Compound 26-2 (340 mg, 0.67 mmol, 1 equiv.), M4 (0.69 g, 1.34 mmol), Xphos Pd G3 (110 mg, 0.13 mmol), K3PO4·7H2O (680 mg, 2.01 mmol), and THF / H2O (v / v=5 mL / 1 mL) were added to a 100 mL two-necked flask. The mixture was purged three times with nitrogen gas, stirred at 30 °C for 15 hours to quench the reaction, and saturated ammonium chloride solution (10 mL) was added. Extraction was performed with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=49 / 1) eluate to obtain 460 mg of reddish-brown solid compound 26-3 in 80% yield. LC-MS (ESI, pos. ion) m / z: 858.4 [M+H] + .

[0354] Step 4: Synthesis of compound 26-4 Compound 26-3 (460 mg, 0.54 mmol) and acetonitrile (6 mL) were added to a 25 mL neck flask, cooled to 0°C, and TMSOTf (0.29 mL, 1.62 mmol) was added dropwise. The mixture was stirred at 0°C for 0.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the mixture, and the solution was extracted with EA (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=49 / 1) eluate to obtain 377 mg of yellow solid compound 26-4 in 86% yield. LC-MS (ESI, pos. ion) m / z: 814.4 [M+H] + .

[0355] Step 5: Synthesis of Compound 26 Compound 26-4 (377 mg, 0.46 mmol), cesium fluoride (350 mg, 2.3 mmol), and DMF (2 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 5 hours to stop the reaction, and water (100 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by thin-layer chromatography using DCM / MeOH (v / v=8 / 1) eluate to obtain 200 mg of yellow solid compound 26 in 66% yield. LC-MS (ESI, pos. ion) m / z: 658.3 [M+H] + HRMS(ESI):658.2796[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.88(dd,J=9.1,5.8Hz,1H),7.41-7.26(m,3H),5.37(d,J=54.2Hz,1H),5.04(d,J=45.5Hz,1H),4.80-4.49(m,2H),4.49-4.26 (m,3H),4.19-3.95(m,1H),3.88-3.66(m,1H),3.47-3.35(m,2H),3.27-3 .05(m,2H),2.58(q,J=7.4Hz,2H),2.47-1.68(m,12H),1.14-1.06(m,3H). 19 FNMR (376MHz, CD3OD) δ -111.66 (1F), -140.97 (1F), -173.68 (1F), -176.96 (1F).

[0356] Example 27: Synthesis of Compound 27 [ka]

[0357] Step 1: Synthesis of compound 27-1 Add compound 3,3-difluoroazepane hydrochloride (0.43g, 2.51 mmol, purchased from iKang Bio) to a 50 mL necked flask, add DCM (10 mL) and dissolve, add DIPEA (3.32 mL, 20.08 mmol) and stir for 15 minutes. Add 1-1 (0.73g, 2.5 mmol) to another 50 mL necked flask, add anhydrous DCM (10 mL) and dissolve, purge with nitrogen gas three times, stir and dissolve, and further... The previously prepared 3,3-difluoroazepane solution was added dropwise, stirred at -20°C for 12 hours to quench the reaction, 20 mL of saturated ammonium chloride solution was added to quench the mixture, and the mixture was returned to room temperature. DCM (20 mL x 2) was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=50 / 1-10 / 1) eluate to obtain 179 mg of the yellow solid compound 25-4 in 19% yield. LC-MS (ESI, pos. ion) m / z: 389.2 [M+H] + .

[0358] Step 2: Synthesis of compound 27-2 In a 100 mL neck flask, compound 25-4 (348 mg, 0.89 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (260 mg, 1.60 mmol), DIPEA (0.44 mL, 2.67 mmol), and anhydrous 1,4-dioxane (20 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 17 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 260 mg of yellow solid compound 27-2 in 57% yield. LC-MS(ESI,pos.ion)m / z:512.3[M+H] + .

[0359] Step 3: Synthesis of compound 27-3 Compound 27-2 (260 mg, 0.51 mmol, 1 equiv.), M4 (523 mg, 1.02 mmol), Xphos Pd G4 (129 mg, 0.15 mmol), K3PO4·7H2O (518 mg, 1.53 mmol), and THF / H2O (v / v=5.1 mL / 1.7 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and saturated ammonium chloride solution (20 mL) was added. Extraction was performed with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 215 mg of yellow solid compound 27-3 in 49% yield. LC-MS (ESI, pos. ion) m / z: 862.4 [M+H] + .

[0360] Step 4: Synthesis of compound 27-4 Compound 27-3 (215 mg, 0.25 mmol) and acetonitrile (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (75 mg, 0.75 mmol, 98% purity) was added dropwise, and the mixture was stirred for 1.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed using DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 200 mg of yellow solid compound 25-7 in 98% yield. LC-MS (ESI, pos. ion) m / z: 818.4 [M+H] + .

[0361] Step 5: Synthesis of Compound 27 Compound 27-4 (200 mg, 0.24 mmol), cesium fluoride (290 mg, 1.92 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to quench the reaction, and water (20 mL) was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 130 mg of yellow solid compound 27 in 80% yield. LC-MS (ESI, pos. ion) m / z: 662.3 [M+H] + HRMS(ESI):662.2572[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.88(dd,J=9.1,5.8Hz,1H),7.40-7.20(m,3H),5.44-5.21(m,1H),4.75-4.53(m,2H),4.43-4.20(m,4H),3.9 9-3.81(m,1H),3.28-3.20(m,2H),3.20-3.13(m,1H),3.10-2.97(m,1H),2.41-2.07(m,9H),2.07-1.87(m,4H),1.85-1.65(m,2H). 19 FNMR (376MHz, CD3OD) δ -93.93 (2F), -111.44 (1F), -140.06 (1F), -173.60 (1F).

[0362] Example 28: Synthesis of Compound 28 [ka]

[0363] Step 1: Synthesis of compound 28-1 In a 100 mL neck flask, 7-1 (1.09 g, 2.52 mmol) and anhydrous dichloromethane (10 mL) were added, the mixture was purged three times with nitrogen gas, cooled to -40°C, and stirred to dissolve. DIPEA (2.08 mL, 12.6 mmol) was added, followed by the slow addition of homopiperidine (0.28 mL, 2.52 mmol). After stirring at -40°C for 0.5 hours, the reaction was stopped, saturated ammonium chloride solution (30 mL) was added to quench, and DCM (15 mL x 2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using PE / EA (v / v=25 / 1) eluate to obtain 695 mg of the yellow solid compound 28-1 in 56% yield. LC-MS (ESI, pos. ion) m / z: 495.2 [M+H] + .

[0364] Step 2: Synthesis of compound 28-2 In a 100 mL neck flask, compound 28-1 (200 mg, 0.40 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (76 mg, 0.48 mmol), DIPEA (0.13 mL, 0.80 mmol), and anhydrous 1,4-dioxane (4 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 15 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 53 mg of yellow solid compound 28-2 in 21% yield. LC-MS(ESI,pos.ion)m / z:618.5[M+H] + .

[0365] Step 3: Synthesis of compound 28-3 Compound 28-2 (53 mg, 0.086 mmol, 1 equiv.), M4 (88 mg, 0.17 mmol), Xphos Pd G4 (15 mg, 0.017 mmol), K3PO4·7H2O (73 mg, 0.21 mmol), and THF / H2O (v / v=2 mL / 0.4 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, diluted with DCM (15 mL), washed with saturated sodium chloride (20 mL), extracted with DCM (15 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography using DCM / MeOH (v / v=40 / 1) eluate to obtain 47 mg of yellow solid compound 28-4 in 57% yield. LC-MS(ESI,pos.ion)m / z:968.4[M+H] + .

[0366] Step 4: Synthesis of compound 28-4 Compound 28-3 (47 mg, 0.23 mmol) and DCM (2 mL) were added to a 25 mL neck flask, cooled to 0°C and stirred for 5 minutes, HCl / 1,4-dioxane (0.12 mL, 0.48 mmol, 4 M) was added dropwise, the mixture was transferred to room temperature and stirred for 30 minutes to stop the reaction, and the mixture was concentrated to obtain 44.8 mg of yellow solid 28-4. The yield was calculated at 100%, and LC-MS showed no signal.

[0367] Step 5: Synthesis of Compound 28 Compound 28-4 (44.8 mg, 0.048 mmol), cesium fluoride (110 mg, 0.72 mmol), and DMF (0.3 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 16 hours to stop the reaction, and 10 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=10 / 1) eluate to obtain 20 mg of red solid compound 28 in 67% yield. LC-MS (ESI, pos. ion) m / z: 612.3 [M+H] + HRMS(ESI):612.2565[M+H] + , 1H NMR(400MHz,CD3OD)δ7.87(dd,J=9.1,5.7Hz,1H),7.39-7.29(m,2H),7.28-7.22(m,1H),5.40(d,J=52.5Hz,1H),4.63-4.55(m,3H),4.49-4.34 (m,2H),4.20-3.97(m,4H),3.67-3.51(m,1H),3.51-3.36(m,3H),3.24 -3.10(m,1H),2.52-2.30(m,2H),2.28-2.05(m,4H),2.05-1.82(m,6H). 19 FNMR (376MHz, CD3OD) δ -114.46 (1F), -138.48 (1F), -173.78 (1F).

[0368] Example 29: Synthesis of Compound 29 [ka]

[0369] Step 1: Synthesis of compound 29-1 Add 1-1 (1.15 g, 3.96 mmol) and anhydrous dichloromethane (20 mL) to a 100 mL necked flask, purge three times with nitrogen gas, and stir to dissolve. Add homopiperidine (0.39 g, 3.96 mmol) dropwise, then add DIPEA (3.93 mL, 23.76 mmol) dropwise. Stir at room temperature for 1.5 hours, then stop the reaction. Quench with saturated ammonium chloride solution (30 mL), extract with DCM (30 mL x 2), separate the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=10 / 1) eluate to obtain 390 mg of yellow solid compound 29-1 in 28% yield. LC-MS (ESI, pos. ion) m / z: 353.1 [M+H] + .

[0370] Step 2: Synthesis of compound 29-2 In a 100 mL neck flask, compound 29-1 (380 mg, 1.08 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (260 mg, 1.62 mmol), DIPEA (0.36 mL, 2.16 mmol), and anhydrous 1,4-dioxane (20 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 20 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 215 mg of yellow solid compound 29-2 in 42% yield. LC-MS(ESI,pos.ion)m / z:476.4[M+H] + .

[0371] Step 3: Synthesis of Compound 29-3 Compound 29-2 (200 mg, 0.42 mmol, 1 equiv.), M4 (430 mg, 0.84 mmol), Xphos Pd G4 (108 mg, 0.13 mmol), K3PO4·7H2O (568 mg, 1.68 mmol), and THF / H2O (v / v=6 mL / 2 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, diluted with EA (15 mL), washed with saturated sodium chloride (20 mL), extracted with EA (20 mL x 2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 306 mg of yellow solid compound 29-3 in 88% yield. LC-MS(ESI,pos.ion)m / z:826.4[M+H] + .

[0372] Step 4: Synthesis of compound 29-4 Compound 29-3 (306 mg, 0.37 mmol) and ACN (5 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.060 mL, 1.11 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 2 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the reaction, and the mixture was extracted with DCM (15 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 160 mg of yellow solid 29-4 in 55% yield. LC-MS (ESI, pos. ion) m / z: 782.7 [M+H] + .

[0373] Step 5: Synthesis of Compound 29 Compound 29-4 (150 mg, 0.19 mmol), cesium fluoride (230 mg, 1.52 mmol), and DMF (1 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 3 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=20 / 1) eluate to obtain 68 mg of yellow solid compound 29 in 57% yield. LC-MS (ESI, pos. ion) m / z: 626.3 [M+H] + HRMS(ESI):626.2739[M+H] + , 1 H NMR(400MHz,CD3OD)δ8.00-7.73(m,1H),7.42-7.15(m,3H),5.47-5.17(m,1H),4.43-4.21(m,2H) ,4.22-3.82(m,5H),3.57-3.13(m,5H),3.13-2.75(m,1H),2.48-2.07(m,7H),2.08-1.76(m,8H). 19 FNMR (376MHz, CD3OD) δ -114.48 (1F), -140.98 (1F), -173.52 (1F).

[0374] Example 30: Synthesis of Compound 30 [ka]

[0375] Step 1: Synthesis of compound 30-1 Add 3-1 (1.48 g, 4.86 mmol) and anhydrous dichloromethane (10 mL) to a 100 mL necked flask, purge three times with nitrogen gas, cool to -40°C, and stir to dissolve. Add homopiperidine hydrochloride (0.66 g, 4.86 mmol), then add DIPEA (4.02 mL, 24.3 mmol) dropwise. Stir at -40°C for 2 hours, then stop the reaction. Quench with saturated ammonium chloride solution (50 mL), extract with DCM (30 mL x 2), separate the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=92 / 8) eluate to obtain 484 mg of yellow solid compound 30-1 in 27% yield. LC-MS (ESI, pos. ion) m / z: 367.5 [M+H] + .

[0376] Step 2: Synthesis of compound 30-2 In a 100 mL neck flask, compound 30-1 (480 mg, 1.31 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (310 mg, 1.97 mmol), DIPEA (0.43 mL, 2.62 mmol), and anhydrous 1,4-dioxane (10 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 33 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (30 mL), washed with saturated ammonium chloride solution (50 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=50 / 1) eluate to obtain 341 mg of yellow solid compound 30-2 in 53% yield. LC-MS(ESI,pos.ion)m / z:490.2[M+H] + .

[0377] Step 3: Synthesis of compound 30-3 Compound 30-2 (170 mg, 0.35 mmol, 1 equiv.), M4 (360 mg, 0.70 mmol), K3PO4·7H2O (360 mg, 0.10 mmol), and THF / H2O (v / v=5 mL / 1 mL) were added to a 25 mL neck flask, the mixture was purged three times with nitrogen gas, and Xphos Pd G3 (88 mg, 0.105 mmol) was added in batches. The mixture was stirred at room temperature for 15 hours to stop the reaction, diluted with DCM (20 mL), washed with saturated sodium chloride (20 mL), extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=98 / 2) eluate to obtain 256 mg of red oily compound 30-3 in 88% yield. LC-MS(ESI,pos.ion)m / z:840.5[M+H] + .

[0378] Step 4: Synthesis of compound 30-4 Compound 30-3 (256 mg, 0.30 mmol) and ACN (7 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. TMSOTf (0.076 mL, 0.42 mmol) was added dropwise, and the mixture was stirred at 0°C for 0.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed with DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 146 mg of yellow solid 30-4 in 60% yield. LC-MS (ESI, pos. ion) m / z: 796.4 [M+H] + .

[0379] Step 5: Synthesis of compound 30 Compound 30-4 (146 mg, 0.18 mmol), cesium fluoride (410 mg, 2.70 mmol), and DMF (0.7 mL) were added to a 25 mL neck flask. The flask was purged three times with nitrogen gas, stirred at room temperature for 15 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The solid was filtered to obtain the crude product, and the crude product was purified by column chromatography using DCM / MeOH (v / v=40 / 1) eluate to obtain 103 mg of yellow solid compound 30 in 87% yield. LC-MS (ESI, pos. ion) m / z: 640.3 [M+H] + HRMS(ESI):640.2902[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.84(dd,J=8.9,5.8Hz,1H),7.37-7.27(m,2H),7.26-7 .16(m,1H),5.30(d,J=53.9Hz,1H),4.40-4.19(m,2H),4.16-3.90(m,4H),3. 39-3.31(m,1H),3.30-3.16(m,3H),3.10-2.94(m,1H),2.53(q,J=7.4Hz,2H) ,2.42-2.07(m,3H),2.06-1.79(m,7H),1.68-1.51(m,4H),0.93-0.79(m,3H). 19 FNMR (376MHz, CD3OD) δ -114.48 (1F), -141.02 (1F), -173.52 (1F).

[0380] Example 31: Synthesis of Compound 31 [ka]

[0381] Step 1: Synthesis of compound 31-1

[0382] Compound 30-2 (80 mg, 0.16 mmol, 1 equiv.), M5 (116 mg, 0.32 mmol), K3PO4·7H2O (165 mg, 0.48 mmol), and THF / H2O (v / v=3 mL / 0.6 mL) were added to a 25 mL neck flask, the mixture was purged three times with nitrogen gas, Xphos Pd G3 (40 mg, 0.48 mmol) was added in batches, the mixture was stirred at room temperature for 15 hours to stop the reaction, diluted with DCM (20 mL), washed with saturated sodium chloride (20 mL), extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=20 / 2) eluate to obtain 123 mg of red oily compound 31-1, and the yield was calculated at 100%. LC-MS(ESI,pos.ion)m / z:689.0[M+H] + .

[0383] Step 4: Synthesis of Compound 31 Compound 31-1 (112 mg, 0.16 mmol) and ACN (4 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. TMSOTf (0.043 mL, 0.24 mmol) was added dropwise, and the mixture was stirred at 0°C for 0.5 hours to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed with DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated, and purified by column chromatography using DCM / MeOH (v / v=40 / 1) eluate to obtain 58 mg of yellow solid 31 in 55% yield. LC-MS (ESI, pos. ion) m / z: 644.4 [M+H] + HRMS(ESI):644.3216[M+H] + , 1H NMR(400MHz,CD3OD)δ7.75-7.58(m,1H),7.33-7.17(m,2H),7.10(s,1H),5.33(d,J =53.8Hz,1H),4.43-4.22(m,2H),4.21-3.91(m,4H),3.44-3.33(m,1H),3.29-3.21( m,2H),3.16-2.97(m,1H),2.54(q,J=7.3Hz,2H),2.46-2.34(m,2H),2.33-2.11(m,4 H),2.10-1.76(m,8H),1.48-1.29(m,2H),1.27-1.22(m,3H),0.83(t,J=7.3Hz,3H). 19 FNMR(376MHz,CD3OD)δ-120.89(1F),-140.68(1F),-173.64(1F).

[0384] Example 32: Synthesis of Compound 32 [ka]

[0385] Step 1: Synthesis of compound 32-1 Add 3-1 (1.37 g, 4.50 mmol) and anhydrous dichloromethane (5 mL) to a 100 mL neck flask, purge three times with nitrogen gas, cool to -40°C, and stir to dissolve. Add 3-oxoazepane hydrochloride (0.34 g, 2.25 mmol), then add DIPEA (2.97 mL, 18 mmol) dropwise. Stir at -40°C for 0.5 hours, then stop the reaction. Quench with saturated ammonium chloride solution (30 mL), extract with DCM (20 mL x 2), separate the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=3 / 1) eluate to obtain 179 mg of yellow solid compound 30-1 in 10% yield. LC-MS (ESI, pos. ion) m / z: 381.1 [M+H] + .

[0386] Step 2: Synthesis of compound 32-2 In a 100 mL neck flask, compound 32-1 (362 mg, 0.95 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (180 mg, 1.14 mmol), DIPEA (0.31 mL, 1.9 mmol), and anhydrous 1,4-dioxane (6 mL) were added. The mixture was purged three times with nitrogen gas, heated to 95 °C, and stirred for 14.5 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (20 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 288 mg of yellow solid compound 32-2 in 60% yield. LC-MS(ESI,pos.ion)m / z:504.3[M+H] + .

[0387] Step 3: Synthesis of compound 32-3 Compound 32-2 (200 mg, 0.40 mmol, 1 equiv.), M4 (420 mg, 0.80 mmol), K3PO4·7H2O (405 mg, 1.2 mmol), and THF / H2O (v / v=5 mL / 1.6 mL) were added to a 25 mL neck flask, the mixture was purged three times with nitrogen gas, and Xphos Pd G3 (102 mg, 0.12 mmol) was added in batches. The mixture was stirred at room temperature for 15 hours to stop the reaction, diluted with DCM (20 mL), washed with saturated sodium chloride (20 mL), extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=40 / 1) eluate to obtain 339 mg of red oily compound 32-3. The yield was calculated at 100%. LC-MS(ESI,pos.ion)m / z:854.4[M+H] + .

[0388] Step 4: Synthesis of compound 32-4 Compound 32-3 (339 mg, 0.40 mmol) and ACN (8 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. Concentrated sulfuric acid (0.033 mL, 0.60 mmol, 98% mass fraction) was added dropwise, and the mixture was stirred at 0°C for 15 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture, and the solution was extracted with DCM (20 mL x 2). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=40 / 1) eluate to obtain 146 mg of yellow solid 32-4 in 45% yield. LC-MS (ESI, pos. ion) m / z: 810.4 [M+H] + .

[0389] Step 5: Synthesis of Compound 32 Compound 32-4 (146 mg, 0.18 mmol), cesium fluoride (410 mg, 2.70 mmol), and DMF (0.7 mL) were added to a 25 mL neck flask. The mixture was purged three times with nitrogen gas, stirred at room temperature for 12.5 hours to stop the reaction, and 20 mL of water was added to precipitate the solid. The mixture was filtered to obtain the crude solid product. The crude product was purified by column chromatography using DCM / MeOH (v / v=30 / 1) eluate to obtain 42 mg of yellow solid compound 32 in 36% yield. LC-MS (ESI, pos. ion) m / z: 654.3 [M+H] + HRMS(ESI):654.2704[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.87(dd,J=9.1,5.7Hz,1H),7.40-7.28(m,2H),7.24( s,1H),5.44(d,J=51.7Hz,1H),4.62-4.38(m,4H),3.71-3.47(m,3H),3.36- 3.33(m,1H),3.28-3.20(m,1H),2.89-2.73(m,3H),2.72-2.60(m,1H),2.59 -2.24(m,3H),2.23-1.88(m,7H),1.73-1.56(m,2H),0.88(t,J=7.3Hz,3H). 19 FNMR(376MHz,CD3OD)δ-112.01(1F),-145.55(1F),-173.86(1F).

[0390] Example 33: Synthesis of Compound 33 [ka]

[0391] Step 1: Synthesis of compound 33-1 Compound 32-2 (80 mg, 0.16 mmol, 1 equiv.), M5 (116 mg, 0.32 mmol), K3PO4·7H2O (165 mg, 0.48 mmol), and THF / H2O (v / v=3 mL / 0.6 mL) were added to a 25 mL neck flask, the mixture was purged three times with nitrogen gas, Xphos Pd G3 (40 mg, 0.048 mmol) was added in batches, the mixture was stirred at room temperature for 15 hours to stop the reaction, diluted with DCM (20 mL), washed with saturated sodium chloride (20 mL), extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=97 / 3) eluate to obtain 70 mg of red oily compound 33-1 in 63% yield. LC-MS(ESI,pos.ion)m / z:703.1[M+H] + .

[0392] Step 2: Synthesis of compound 33 Compound 33-1 (66 mg, 0.094 mmol) and ACN (3 mL) were added to a 25 mL neck flask. The mixture was cooled to 0°C and stirred for 5 minutes. TMSOTf (0.026 mL, 0.14 mmol) was added dropwise, and the mixture was stirred at 0°C for 30 minutes to stop the reaction. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the mixture. Extraction was performed with DCM (20 mL x 2), and after combining the organic phases, the mixture was dried over anhydrous sodium sulfate. The mixture was concentrated and purified by thin-layer chromatography using DCM / MeOH (v / v=15 / 1) eluate to obtain 17 mg of yellow solid 33 in 27% yield. LC-MS (ESI, pos. ion) m / z: 658.3 [M+H] + HRMS(ESI):658.3020[M+H] + , 1H NMR(400MHz,CD3OD)δ7.68(dd,J=8.9,5.9Hz,1H),7.34-7.28(m,1H),7.28-7.19( m,1H),7.14-7.07(m,1H),5.39(d,J=53.2Hz,1H),4.57-4.37(m,3H),4.35-4.25(m ,2H),4.23-4.09(m,1H),3.76-3.35(m,4H),3.25-3.08(m,1H),2.91-2.64(m,1H) ,2.56(q,J=7.5Hz,2H),2.51-1.88(m,12H),1.29-1.25(m,3H),0.87-0.79(m,3H). 19 FNMR (376MHz, CD3OD) δ -112.79 (1F), -139.74 (1F), -173.65 (1F).

[0393] Example 34: Synthesis of Compound 34 [ka]

[0394] For the synthesis of compound 34, the synthesis of compound 32 was followed, and compound 1-1 (see step 1 of Example 1 for structure and synthesis) was used instead of compound 3-1 to obtain the yellow solid compound 34. LC-MS (ESI, pos. ion) m / z: 640.3 [M+H] + , 1 H NMR(400MHz,CD3OD)δ7.85(dd,J=9.1,5.7Hz,1H),7.37-7.26(m,2H),7.24-7.16(m,1H),5.56-5.24(m,1H),4.69-4.33(m,5H),3.69-3.6 0(m,1H),3.60-3.41(m,3H),3.33(s,1H),3.24-3.14(m,1H),2.89-2.74(m,3H),2.74-2.61(m,1H),2.56-2.22(m,4H),2.16-1.91(m,7H). 19 FNMR (376MHz, CD3OD) δ -111.98 (1F), -145.58 (1F), -173.83 (1F).

[0395] Example 35: Synthesis of Compound 35 [ka]

[0396] For the synthesis of compound 35, refer to the synthesis of compound 32, using compound 1-1 instead of 3-1 (see step 1 of Example 1 for structure and synthesis), (hexahydro-1H-pyrrolidine-7a-yl)methanol instead of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol, and M5 instead of M4 to obtain the yellow solid compound 35. LC-MS (ESI, pos.ion) m / z: 626.1 [M+H] + HRMS(ESI):626.2943[M+H] + , 1 H NMR(400MHz,CD3OD)δ7.69(dd,J=9.0,5.7Hz,1H),7.36-7.17(m,2H),7.14-7.07(m,1H),4.66-4.38(m,7H),4.31-4.15(m,1H),3.74-3.59(m, 2H),3.29-3.22(m,2H),2.54-2.40(m,2H),2.31-2.15(m,9H),2.12-2. 04(m,2H),2.00-1.87(m,2H),1.86-1.76(m,2H),0.83(t,J=7.3Hz,3H). 19 FNMR (376MHz, CD3OD): δ-120.77 (1F), -139.84 (1F).

[0397] Example 36: Synthesis of Compound 36 [ka]

[0398] Step 1: Synthesis of compound 36-1 Add 3-1 (1.14 g, 3.74 mmol) and anhydrous dichloromethane (20 mL) to a 100 mL neck flask, purge three times with nitrogen gas, cool to -40°C, and stir to dissolve. Add 1,4-oxazepine-6-one hydrochloride (0.55 g, 3.61 mmol), then add DIPEA (2.99 mL, 18.05 mmol) dropwise. Stir at -40°C for 0.5 hours, then stop the reaction. Quench with saturated ammonium chloride solution (50 mL), extract with DCM (30 mL x 2), separate the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography using PE / EA (v / v=100 / 1~4 / 1) eluate to obtain 267 mg of yellow solid compound 36-1 in 19% yield. LC-MS (ESI, pos. ion) m / z: 383.3 [M+H] + .

[0399] Step 2: Synthesis of compound 36-2 In a 100 mL neck flask, compound 36-1 (540 mg, 1.41 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (561 mg, 3.52 mmol), DIPEA (1.17 mL, 7.05 mmol), and anhydrous 1,4-dioxane (10 mL) were added. The mixture was purged three times with nitrogen gas, heated to 90 °C, and stirred for 12 hours to stop the reaction. After cooling to room temperature, the reaction mixture was concentrated, diluted with EA (20 mL), washed with saturated ammonium chloride solution (20 mL), separated, extracted with EA (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH (v / v=100 / 1~30 / 1) eluate to obtain 450 mg of yellow solid compound 36-2 in 63% yield. LC-MS(ESI,pos.ion)m / z:506.1[M+H] + .

[0400] Step 3: Synthesis of compound 36-3 Compound 36-2 (250 mg, 0.49 mmol, 1 equiv.), M4 (502 mg, 0.98 mmol), K3PO4·7H2O (830 mg, 2.45 mmol), and THF / H2O (v / v=6 mL / 0.5 mL) were added to a 25 mL neck flask, and the mixture was purged three times with nitrogen gas. Xphos Pd G3 (104 mg, 0.12 mmol) was added in batches, and the mixture was stirred at 30°C for 6 hours to stop the reaction. The mixture was diluted with DCM (50 mL), washed with saturated sodium chloride (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chrom...

Claims

1. A compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound represented by formula (I). 【Chemistry 1】 (In the formula, R １ is -H, -D, -CN, -NH ２ , -C(=O)H, -C(=O)OH, -C(=O)OR ６ａ , -C(=O)NR ６ R ７ , -NR ６ C(=O)R ７ , -NR ６ａ C(=O)NR ６ R ７ , -C(=O)R ６ａ , -C(=O)OR ６ａ , -NR ６ , -NR ２ S(=O) ７ , -S(=O) ２ NR ６ R ７ , -NR ６ａ S(=O) ２ NR ６ R ７ , -NR ６ R ７ , -C １～６ alkyl -NR ６ C(=O)R ７ , -C １～６ alkyl -NR ６ R ７ , -C １～６ alkyl -C(=O)OR ６ , -C １～６ alkyl -C(=O)NR ６ R ７ , C １～６ alkyl group, C １～６ cyanoalkyl group, C １～６ hydroxyalkyl group, C １～６ haloalkyl group, C １～６ alkoxy C １～６ alkyl group, (C ３～１２ cycloalkyl)-C １～６ alkyl group, (3 - 12 membered heterocyclyl)-C １～６ alkyl group, (C ６～１０ aryl)-C １～６ alkyl group, (5 - 12 membered heteroaryl)-C １～６ alkyl group, (C ３～１２ cycloalkyl)-O -C １～６ alkyl group, (3 - 12 membered heterocyclyl)-O -C １～６ alkyl group, C １～６ Mercaptoalkyl group, C ６～１２ Aryl group, 5-12 membered heteroaryl group, C ３～１２ The C is a cycloalkyl group or a 3- to 12-membered heterocyclyl group. １～６ Alkoxy C １～６ Alkyl alkyl group, (C ３～１２ Cycloalkyl)-C １～６ Alkyl group, (3-12 member heterocyclyl)-C １～６ Alkyl alkyl group, (C ６～１０ Aryl) - C １～６ Alkyl group, (5-12 member heteroaryl)-C １～６ Alkyl alkyl group, (C ３～１２ Cycloalkyl)-O-C １～６ Alkyl alkyl groups, (3-12 member heterocyclyl)-O-C １～６ alkyl group, C ６～１２ Aryl group, 5-12 membered heteroaryl group, C ３～１２ The cycloalkyl group and the 3- to 12-membered heterocyclyl group can each be independently and optionally D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR ６ , -NR ６ R ７ , -C(=O)NR ６ R ７ , -NR ６ C(=O)R ７ and C １～６ Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, T is, 【Chemistry 2】 And, X is a bond, -O-, -S-, -NH-, -CH ２ -ien-CH ２ -NH-, -CH ２ -NH-CH ２ -, - (CH ２ ) ３ -, - (CH ２ ) ２ -, -NH-CH ２ -, -O-CH ２ -ien-CH ２ -O-, -CH ２ -S- or -S-CH ２ - and Each R ５ is independently H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R ６ｃ , -C(=O)OR ６ｃ , -C(=O)NR ６ｂ R ７ｂ , -NR ６ｂ C(=O)R ７ｂ , -NR ６ｂ , -NR ２ S(=O) ７ｂ , -S(=O) ２ N(R ７ｂ ) ２ , -NR ６ｂ C(=O)N(R ７ｂ ) ２ , -NR ６ｂ S(=O) ２ N(R ７ｂ ) ２ , -OS(=O) ２ N(R ７ｂ ) ２ , -S(=O) ２ R ６ｃ , -C １～４ alkylene - S(=O) ２ N(R ７ｂ ) ２ , C １～６ alkyl group, C １～６ alkylthio group, C １～６ alkoxy group, C ２～６ alkenyl group, C ２～６ alkynyl group, C １～６ cyanoalkyl group, C １～６ hydroxyalkyl group, C １～６ haloalkyl group, -NH(C １～６ alkyl), -N(C １～６ alkyl) ２ , C ２～６ haloalkenyl group, C ２～６ haloalkynyl group, C １～６ haloalkoxy group, C １～６ haloalkylthio group, C ６～１０ aryl group, 5 - to 10 - membered heteroaryl group, C ３～６ cycloalkyl group or 3 - to 6 - membered heterocyclyl group, wherein the C １～６ alkyl group, C １～６ Alkylthio group, C １～６ Alkoxy group, C ２～６ Alkenyl group, C ２～６ Alkynyl group, -NH(C) １～６ Alkyl), -N(C １～６ Alkyl) ２ , C ６～１０ Aryl group, 5-10 membered heteroaryl group, C ３～６ Each cycloalkyl group and 3- to 6-membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Alternatively, two R atoms bonded to the same carbon atom ５ Together 【Transformation 3】 Forming, Alternatively, two R atoms bonded to the same carbon atom ５ Together with the carbon atoms bonded to them, C ３～６ A cycloalkyl group or a 3-6 membered heterocyclyl group is formed, and the C ３～６ Each cycloalkyl group and 3- to 6-membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Alternatively, two R atoms bonded to two adjacent atoms ５ It becomes C together with the two adjacent atoms bonded to them. ３～６ A cycloalkyl group or a 3-6 membered heterocyclyl group is formed, and the C ３～６ Each cycloalkyl group and 3- to 6-membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Each R ８ These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , -C(=O)OH, -C(=O)NH ２ , oxo, C １～６ alkyl group, C １～６ Alkoxy group, C １～６ Hydroxyalkyl group, C ６～１０ Aryl group, 6-10 membered heteroaryl group, -C(=O)OC １～６ Alkyl alkyl group, -C(=O)NHC １～６ Alkyl alkyl group, -C(=O)N(C １～６ Alkyl) ２ And, As a condition, T is 【Chemistry 4】 Instead, Ring B is C ６～１２ It is an aryl group or a 5- to 12-membered heteroaryl group. Each R ２ These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH ２ C(=O)NR ６ｂ R ７ｂ , -C(=O)R ６ｃ , -C (=O) OR ６ｃ , -C(=O)NR ６ｂ R ７ｂ , -NR ６ｂ C(=O)R ７ｂ , -NR ６ｂ R ７ｂ , C １～６ alkyl group, C １～６ Alkylthio group, C ２～６ Alkenyl group, C ２～６ Alkynyl group, C ２～６ Hydroxyalkynyl group, C １～６ Alkoxy group, C １～６ Cyanoalkyl group, C １～６ Hydroxyalkyl group, C １～６ Haloalkyl group, C ２～６ Haloalkenyl group, C ２～６ Haloalkynyl group, C １～６ Haloalkoxy group, C １～６ Haloalkylthio group, C ６～１２ Aryl group, 5-12 membered heteroaryl group, C ３～６ The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. １～６ alkyl group, C １～６ Alkylthio group, C ２～６ Alkenyl group, C ２～６ Alkynyl group, C ２～６ Hydroxyalkynyl group, C １～６ Alkoxy group, C １～６ Cyanoalkyl group, C １～６ Hydroxyalkyl group, C １～６ Haloalkyl group, C ２～６ Haloalkenyl group, C ２～６ Haloalkynyl group, C １～６ Haloalkoxy group, C １～６ Haloalkylthio group, C ６～１２ Aryl group, 5-12 membered heteroaryl group, C ３～６ The cycloalkyl group and the 3- to 6-membered heterocyclyl group can each be independently and optionally -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , -C(=O)H, -C(=O)OH, C １～６ alkyl group, C １～６ Alkoxy group, C ３～６ Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups, R ３ -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, or C １～４ It is a haloalkyl group, Y is a bond, O or S, R ４ These are 3-10 member heterocyclyl groups, -L- (3-12 member heterocyclyl), and -L- (C ３～１２ Cycloalkyl), -L- (5-12 member heteroaryl), or -L- (C ６～１０ (aryl), and the 3-10 membered heterocyclyl group, -L-(C ３～１２ Cycloalkyl), -L- (5-12 member heteroaryl), and -L- (C ６～１０ Each of the R's (aryls) can be any one, two, three, or four R's, independently of each other. ９ａ Substituted with, the -L- (3-12 member heterocyclil) is optionally 1, 2, 3 or 4 R ９ｂ Replaced by, R ９ａ and R ９ｂ These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR ６ｄ R ７ｄ , -C(=O)NR ６ｄ R ７ｄ ien-CH ２ NR ６ｄ R ７ｄ ien-CH ２ OC(=O)NR ６ｄ R ７ｄ , C １～６ alkyl group, C １～６ Alkoxy group, C １～６ Haloalkyl group, C １～６ Haloalkoxy group, (C ６～１０ Aryl) - C １～６ Alkyl group, (5-12 member heteroaryl)-C １～６ Alkyl alkyl groups, (3-6 member heterocyclyl)-C １～６ Alkyl alkyl group, (C ３～６ Cycloalkyl)-C １～６ alkyl group, C ３～６ The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. １～６ alkyl group, C １～６ Alkoxy group, C １～６ Haloalkyl group, C １～６ Haloalkoxy group, (C ６～１０ Aryl) - C １～６ Alkyl group, (5-12 member heteroaryl)-C １～６ Alkyl alkyl groups, (3-6 member heterocyclyl)-C １～６ Alkyl alkyl group, (C ３～６ Cycloalkyl)-C １～６ alkyl group, C ３～６ The cycloalkyl group and the 3- to 6-membered heterocyclyl group can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR ６ｅ R ７ｅ , -C(=O)C １～６ Alkyl and C １～６ Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, Alternatively, two R atoms bonded to the same ring carbon atom ９ｂ Together 【Transformation 5】 Forming, L is C １～６ It is an alkylene group, R ６ , R ７ , R ６ｂ , R ７ｂ , R ６ｄ , R ７ｄ , R ６ｅ and R ７ｅ These are, independently, -H, -D, or C １～６ It is an alkyl group, and the C １～６ Alkyl groups can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR ６ｇ R ７ｇ , C １～６ Alkoxy group, C ６～１２ Aryl group, C ３～６ Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups, Or, R ６ and R ７ , or R ６ｂ and R ７ｂ , or R ６ｄ and R ７ｄ , or R ６ｅ and R ７ｅ Each of these, together with the N atom bonded to them, forms a 4-6 member heteroring, and the 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , C １～６ alkyl group, C １～６ Alkylamino group, C ３～６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １～６ Alkoxy group, C １～６ Cyanoalkyl group, C １～６ Hydroxyalkyl group, C １～６ Haloalkoxy group and C １～６ Substituted with one, two, three, or four substituents selected from haloalkyl groups, R ６ａ , R ６ｃ , R ６ｇ , R ７ｇ , R ６ｈ , R ７ｈ , R ７ｋ , R ６ｊ and R ７ｊ These are, independently, -H, -D, or C １～６ It is an alkyl group, n is 0, 1, 2, 3, 4, 5, 6, or 7. q1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. R １ -H, -D, -CN, -NH ２ , -C(=O)H, -C(=O)OH, -C(=O)OR ６ａ , -C(=O)NR ６ R ７ , -NR ６ C(=O)R ７ , -NR ６ａ C(=O)NR ６ R ７ , -C(=O)R ６ａ , -C (=O) OR ６ａ , -NR ６ S (=O) ２ R ７ , -S (=O) ２ NR ６ R ７ , -NR ６ａ S (=O) ２ NR ６ R ７ , -NR ６ R ７ , -C １～４ Alkyl-NR ６ C(=O)R ７ , -C １～４ Alkyl-NR ６ R ７ , -C １～４ Alkyl-C(=O)OR ６ , -C １～４ Alkyl-C(=O)NR ６ R ７ , C １～６ alkyl group, C １～４ Cyanoalkyl group, C １～４ Hydroxyalkyl group, C １～４ Haloalkyl group, C １～４ Alkoxy C １～４ Alkyl alkyl group, (C ３～６ Cycloalkyl)-C １～４ Alkyl alkyl group, (C ７～１２ Cycloalkyl)-C １～４ Alkyl alkyl groups, (3-6 member heterocyclyl)-C １～４ Alkyl group, (7-12 member heterocyclyl)-C １～４ Alkyl, phenyl-C １～４ Alkyl group, (5-6 member heteroaryl)-C １～４ Alkyl alkyl group, (C ３～６ Cycloalkyl)-O-C １～４ Alkyl alkyl group, (C ７～１２ Cycloalkyl)-O-C １～４ Alkyl alkyl groups, (3-6 member heterocyclyl)-O-C １～６ Alkyl alkyl groups, (3-7 member heterocyclyl)-O-C １～６ Alkyl group, (7-12 member heterocyclyl)-O-C １～４ alkyl group, C １～４ Mercaptoalkyl group, C ６～１０ Aryl group, 5-12 membered heteroaryl group, C ３～６ The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. １～４ Alkoxy C １～４ Alkyl alkyl group, (C ３～６ Cycloalkyl)-C １～４ Alkyl alkyl group, (C ７～１２ Cycloalkyl)-C １～４ Alkyl alkyl groups, (3-6 member heterocyclyl)-C １～４ Alkyl group, (7-12 member heterocyclyl)-C １～４ Alkyl, phenyl-C １～４ Alkyl group, (5-6 member heteroaryl)-C １～４ Alkyl alkyl group, (C ３～６ Cycloalkyl)-O-C １～４ Alkyl alkyl group, (C ７～１２ Cycloalkyl)-O-C １～４ Alkyl alkyl groups, (3-6 member heterocyclyl)-O-C １～６ Alkyl alkyl groups, (3-7 member heterocyclyl)-O-C １～６ Alkyl group, (7-12 member heterocyclyl)-O-C １～４ alkyl group, C ６～１０ Aryl group, 5-12 membered heteroaryl group, C ３～６ Each cycloalkyl group or 3- to 6-membered heterocyclyl group can be independently and optionally D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR ６ , -NR ６ R ７ , -C(=O)NR ６ R ７ , -NR ６ C(=O)R ７ and C １～４ The compound according to claim 1, substituted with one, two, three, or four substituents selected from alkyl groups.

3. R １ は、-H、-D、-CN、-NH ２ 、-C(=O)H、-C(=O)OH、-C(=O)OR ６ａ 、-C(=O)NR ６ R ７ 、-NR ６ C(=O)R ７ 、-NR ６ａ C(=O)NR ６ R ７ 、-C(=O)R ６ａ 、-C(=O)OR ６ａ 、-NR ６ S(=O) ２ R ７ 、-S(=O) ２ NR ６ R ７ 、-NR ６ａ S(=O) ２ NR ６ R ７ 、-NR ６ R ７ 、-CH ２ NR ６ C(=O)R ７ 、-CH ２ NR ６ R ７ 、-(CH ２ ) ２ NR ６ R ７ 、-CH ２ C(=O)OR ６ 、-(CH ２ ) ２ C(=O)OR ６ 、-(CH ２ ) ３ C(=O)OR ６ 、-CH ２ C(=O)NR ６ R ７ 、-(CH ２ ) ２ C(=O)NR ６ R ７ 、-(CH ２ ) ３ C(=O)NR ６ R ７ 、-CH ３ 、-CH ２ CH ３ 、-(CH ２ ) ２ CH ３ 、-(CH ２ ) ２ CH(CH ３ ) ２ 、-(CH ２ ) ３ CH ３ 、-C(CH ３ ) ３ 、-CH(CH ３ ) ２ 、-CH ２ CH(CH ３ ) ２ 、-CH ２ CN, - (CH ２ ) ２ CN, - (CH ２ ) ３ CN, -CH(CH) ３ )CN,!-C(CH) ３ ) ２ CN, -CH ２ OH, -(CH) ２ ) ２ OH, -(CH) ２ ) ３ OH、-CH(OH)CH ３ 、-(CH ２ ) ２ CHF ２ 、-(CH ２ ) ２ CF(CF ３ ) ２ -CF ３ 、-CHF ２ 、-CH ２ F, -(CH) ２ ) ２ F, -(CH) ２ ) ２ Cl, -CH ２ CF ３ 、-CH ２ OCH ３ 、-(CH ２ ) ２ OCH ３ 、-(CH ２ ) ２ OCH ２ CH ３ 、-CH ２ OCH ２ CH ３ 、-CH ２ OC(CH) ３ ) ３ ien-CH ２ -Cyclopropyl group, -CH ２ -Cyclobutyl group, -CH ２ -Cyclopentyl group, -CH ２ -Cyclohexyl group, -(CH ２ ) ２ -Cyclopentyl group, -(CH ２ ) ３ -Cyclopentyl group, -(CH ２ ) ２ -Cyclohexyl group, -CH ２ -phenyl group, -CH ２ -Imidazolyl group, -CH ２ -Pyrazolyl group, -CH ２ O-cyclopropyl group, -CH ２ O-cyclobutyl group, -(CH ２ ) ２ O-cyclobutyl group, -CH ２ O-cyclopentyl group, -(CH ２ ) ２ O-cyclopentyl group, -CH ２ O-azetidinyl group, -CH ２ O-oxetanyl group, -CH ２ O-tetrahydrofuranyl group, -CH ２ O-pyrrolidinyl group, -CH ２ O-spiro[2,3]hexyl group, -CH ２ O-spiro[3,3]heptyl group, -CH ２ SH, -(CH ２ ) ２ SH, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, oxetanyl group, tetrahydropyranyl group, azetidinyl group, or pyrrolidinyl group, and the -CH ２ OCH ３ ,-(CH ２ ) ２ OCH ３ ,-(CH ２ ) ２ OCH ２ CH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ OC(CH ３ ) ３ ien-CH ２ -Cyclopropyl group, -CH ２ -Cyclobutyl group, -CH ２ -Cyclopentyl group, -CH ２ -Cyclohexyl group, -(CH ２ ) ２ -Cyclopentyl group, -(CH ２ ) ３ -Cyclopentyl group, -(CH ２ ) ２ -Cyclohexyl group, -CH ２ -phenyl group, -CH ２ -Imidazolyl group, -CH ２ -Pyrazolyl group, -CH ２ O-cyclopropyl group, -CH ２ O-cyclobutyl group, -(CH ２ ) ２ O-cyclobutyl group, -CH ２ O-cyclopentyl group, -(CH ２ ) ２ O-cyclopentyl group, -CH ２ O-azetidinyl group, -CH ２ O-oxetanyl group, -CH ２ O-tetrahydrofuranyl group, -CH ２ O-pyrrolidinyl group, -CH ２ O-spiro[2,3]hexyl group, -CH ２ O-spiro[3,3]heptyl group, phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, oxetanyl group, tetrahydropyranyl group, azetidinyl group, or pyrrolidinyl group can each be independently and arbitrarily D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR ６ , -NR ６ R ７ , -C(=O)NR ６ R ７ , -NR ６ C(=O)R ７ The compound according to claim 1 or 2, which is substituted with one, two, three or four substituents selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a t-butyl group.

4. T is, 【Transformation 6】 And, Each R ５ These are independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R ６ｃ , -C (=O) OR ６ｃ , -C(=O)NR ６ｂ R ７ｂ , -NR ６ｂ C(=O)R ７ｂ , -NR ６ｂ S (=O) ２ R ７ｂ , -S (=O) ２ N(R) ７ｂ ) ２ , -NR ６ｂ C(=O)N(R) ７ｂ ) ２ , -NR ６ｂ S (=O) ２ N(R) ７ｂ ) ２ , -OS (=O) ２ N(R) ７ｂ ) ２ , -S (=O) ２ R ６ｃ , -C １～４ Alkylene S (= O) ２ N(R) ７ｂ ) ２ , C １～４ alkyl group, C １～４ Alkylthio group, C １～４ Alkoxy group, C ２～４ Alkenyl group, C ２～４ Alkynyl group, C １～４ Cyanoalkyl group, C １～４ Hydroxyalkyl group, C １～４ Haloalkyl group, -NH(C) １～４ Alkyl), -N(C １～４ Alkyl) ２ , C ２～４ Haloalkenyl group, C ２～４ Haloalkynyl group, C １～４ Haloalkoxy group, C １～４ Haloalkylthio group, 6-10 membered aryl group, 5-10 membered heteroaryl group, C ３～６ The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. １～４ alkyl group, C １～４ Alkylthio group, C １～４ Alkoxy group, C ２～４ Alkenyl group, C ２～４ Alkynyl group, -NH(C) １～４ Alkyl), -N(C １～４ Alkyl) ２ , aryl group with 6 to 10 members, heteroaryl group with 5 to 10 members, C ３～６ Each cycloalkyl group and 3- to 6-membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Alternatively, two R atoms bonded to the same carbon atom ５ Together 【Transformation 7】 Forming, Alternatively, two R atoms bonded to the same carbon atom ５ Together with the carbon atoms bonded to them, C ３～６ A cycloalkyl group or a 3-6 membered heterocyclyl group is formed, and the C ３～６ Each cycloalkyl group and 3- to 6-membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Alternatively, two R atoms bonded to two adjacent atoms ５ It becomes C together with the two adjacent atoms bonded to them. ３～６ A cycloalkyl group or a 3-6 membered heterocyclyl group is formed, and the C ３～６ Each cycloalkyl group and 3- to 6-membered heterocyclyl group can independently optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Each R ８ These are independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , -C(=O)OH, -C(=O)NH ２ , oxo, C １～４ alkyl group, C １～４ Alkoxy group, C １～４ Hydroxyalkyl group, C ６～１０ Aryl group, 6-10 membered heteroaryl group, -C(=O)OC １～４ Alkyl alkyl group, -C(=O)NHC １～４ Alkyl alkyl group, -C(=O)N(C １～４ Alkyl) ２ And, R ６ｈ , R ７ｈ and R ７ｋ These are, independently, -H, -D, or C １～４ A compound according to any one of claims 1 to 3, wherein the compound is an alkyl group.

5. T is, 【Transformation 8】 And, Each R ５ These are independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R ６ｃ , -C (=O) OR ６ｃ , -C(=O)NR ６ｂ R ７ｂ , -NR ６ｂ C(=O)R ７ｂ , -NR ６ｂ S (=O) ２ R ７ｂ , -S (=O) ２ N(R) ７ｂ ) ２ , -NR ６ｂ C(=O)N(R) ７ｂ ) ２ , -NR ６ｂ S (=O) ２ N(R) ７ｂ ) ２ , -OS (=O) ２ N(R) ７ｂ ) ２ , -S (=O) ２ R ６ｃ ien-CH ２ S (=O) ２ N(R) ７ｂ ) ２ ,-(CH ２ ) ２ S (=O) ２ N(R) ７ｂ ) ２ ien-CH ３ ien-CH ２ CH ３ ,-(CH ２ ) ２ CH ３ ,-(CH ２ ) ３ CH ３ , -C(CH ３ ) ３ , -CH(CH ３ ) ２ , -SCH ３ , -SCH ２ CH ３ , -S(CH ２ ) ２ CH ３ , -SCH ２ CH (CH ３ ) ２ 、-SCH(CH) ３ ) ２ 、-OCH ３ 、-OCH ２ CH ３ 、-O(CH ２ ) ２ CH ３ 、-OCH ２ CH(CH ３ ) ２ 、-OCH(CH ３ ) ２ 、-CH=CH ２ 、-CH=CHCH ３ 、-CH ２ CH=CH ２ 、-C≡CH、-C≡CCH ３ 、-CH ２ C≡CH, -CH ２ CN, - (CH ２ ) ２ CN, - (CH ２ ) ３ CN, -CH ２ OH, -(CH) ２ ) ２ OH, -(CH) ２ ) ３ OH、-CH(OH)CH ３ -CF ３ 、-CHF ２ 、-CH ２ F, -(CH) ２ ) ２ F, -(CH) ２ ) ２ Cl, -CH ２ CF ３ 、-NHCH ３ 、-NH(CH) ２ CH ３ )、-NH((CH ２ ) ２ CH ３ )、-NH((CH ２ ) ３ CH ３ )、-NH(CH(CH ３ ) ２ )、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、-N((CH ２ ) ２ CH ３ ) ２ , -CHFCH=CH ２ , -CH=CHF, -CH=CHCl, -CH=CHCH ２ F, -C ≡ CCH ２ F, -OCF ３ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCH ２ CHF ２ , -SCF ３ , -SCH ２ F, -SCHF ２ , -SCH ２ CF ３ , -SCH ２ CHF ２ , phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, or morpholinyl group, and the above-CH ３ ien-CH ２ CH ３ ,-(CH ２ ) ２ CH ３ ,-(CH ２ ) ３ CH ３ , -C(CH ３ ) ３ , -CH(CH ３ ) ２ , -SCH ３ , -SCH ２ CH ３ , -S(CH ２ ) ２ CH ３ , -SCH ２ CH(CH ３ ) ２ 、-SCH(CH) ３ ) ２ 、-OCH ３ 、-OCH ２ CH ３ 、-O(CH ２ ) ２ CH ３ 、-OCH ２ CH(CH ３ ) ２ 、-OCH(CH ３ ) ２ 、-CH=CH ２ 、-CH=CHCH ３ 、-CH ２ CH=CH ２ 、-C≡CH、-C≡CCH ３ 、-CH ２ C≡CH, -CH ２ CN, - (CH ２ ) ２ CN, - (CH ２ ) ３ CN, -CH ２ OH, -(CH) ２ ) ２ OH, -(CH) ２ ) ３ OH、-CH(OH)CH ３ 、-CHF ２ 、-CH ２ F, -(CH) ２ ) ２ F, -(CH) ２ ) ２ Cl, -CH ２ CF ３ 、-NHCH ３ 、-NH(CH) ２ CH ３ )、-NH((CH ２ ) ２ CH ３ )、-NH((CH ２ ) ３ CH ３ )、-NH(CH(CH ３ ) ２ )、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、-N((CH ２ ) ２ CH ３ ) ２ , -CHFCH=CH ２ , -CH=CHF, -CH=CHCl, -CH=CHCH ２ F, -C ≡ CCH ２ F, -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCH ２ CHF ２ , -SCH ２ F, -SCHF ２ , -SCH ２ CF ３ , -SCH ２ CHF ２ ,phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group and morpholinyl group each independently optionally have 1, 2, 3 or 4 R ８ Replaced by, Alternatively, two R atoms bonded to the same carbon atom ５ Together 【Chemistry 9】 Forming, Alternatively, two R atoms bonded to the same carbon atom ５ These groups, together with the carbon atoms bonded to them, form a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, or morpholinyl group, and the cyclo The ropropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, thioxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group can each be independently and optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Alternatively, two R atoms bonded to two adjacent atoms ５ These groups, together with two adjacent atoms bonded to them, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyranyl, azilidinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl groups. The cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group may each be independently and optionally have 1, 2, 3, or 4 R groups. ８ Replaced by, Each R ８ is independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , -C(=O)OH, -C(=O)NH ２ , oxo, -CH ３ , -CH ２ CH ３ , -(CH ２ ) ２ CH ３ , -(CH ２ ) ３ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH(CH ３ ) ２ , -C(CH ３ ) ３ , -OCH ３ , -OCH ２ CH ３ , -O(CH ２ ) ２ CH ３ , -CH ２ OH, -(CH ２ ) ２ OH, -(CH ２ ) ３ OH, -CH(OH)CH ３ , phenyl group, furyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrrolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, thienyl group, thiazolyl group, triazolyl group, tetrazolyl group, benzopyridyl group, benzimidazolyl group, benzopyrrolyl group, benzopyrazolyl group, -C(=O)OCH ３ , -C(=O)OCH ２ CH ３ , -C(=O)O(CH ２ ) ２ CH ３ , -C(=O)OCH(CH ３ ) ２ , -C(=O)NHCH ３ , -C(=O)NHCH ２ CH ３ , -C(=O)N(CH ３ ) ２ or -C(=O)N(CH ３ )CH ２ CH ３ And, R ６ｈ , R ７ｈ and R ７ｋ The compound according to any one of claims 1 to 4, wherein each of them is independently -H, -D, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a t-butyl group.

6. Ring B is, 【Chemistry 10】 It is one of the substructures of Each R ２ is independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH ２ C(=O)NR ６ｂ R ７ｂ , -C(=O)R ６ｃ , -C(=O)OR ６ｃ , -C(=O)NR ６ｂ R ７ｂ , -NR ６ｂ C(=O)R ７ｂ , -NR ６ｂ R ７ｂ , C １～４ alkyl group, C １～４ alkylthio group, C ２～４ alkenyl group, C ２～４ alkynyl group, C ２～４ hydroxyalkynyl group, C １～４ alkoxy group, C １～４ cyanoalkyl group, C １～４ hydroxyalkyl group, C １～４ haloalkyl group, C ２～４ haloalkenyl group, C ２～４ haloalkynyl group, C １～４ haloalkoxy group, C １～４ haloalkylthio group, C ６～１０ aryl group, 5- to 12-membered heteroaryl group, C ３～６ cycloalkyl group or 3- to 6-membered heterocyclyl group, wherein the C １～４ alkyl group, C １～４ alkylthio group, C ２～４ alkenyl group, C ２～４ alkynyl group, C ２～４ hydroxyalkynyl group, C １～４ alkoxy group, C １～４ cyanoalkyl group, C １～４ hydroxyalkyl group, C １～４ haloalkyl group, C ２～４ haloalkenyl group, C ２～４ haloalkynyl group, C １～４ haloalkoxy group, C １～４ haloalkylthio group, C ６～１０ aryl group, 5- to 12-membered heteroaryl group, C ３～６ The cycloalkyl group and the 3- to 6-membered heterocyclyl group can each be independently and optionally -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , -C(=O)H, -C(=O)OH, C １～４ alkyl group, C １～４ Alkoxy group, C ３～６ The compound according to any one of claims 1 to 5, substituted with one, two, three, or four substituents selected from a cycloalkyl group and a 3- to 6-membered heterocyclyl group.

7. Each R ２ is independently selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH ２ C(=O)NR ６ｂ R ７ｂ -C(=O)R ６ｃ -C(=O)OR ６ｃ -C(=O)NR ６ｂ R ７ｂ -NR ６ｂ C(=O)R ７ｂ -NR ６ｂ R ７ｂ -CH ３ -CH ２ CH ３ -(CH ２ ) ２ CH ３ -(CH ２ ) ３ CH ３ -C(CH ３ ) ３ -CH(CH ３ ) ２ -SCH ３ -SCH ２ CH ３ -CH=CH ２ -CH=CHCH ３ -CH ２ CH=CH ２ -C≡CH, -C≡CCH ３ -CH ２ C≡CH, -C≡CCH ２ OH, -C≡C(CH ２ ) ２ OH, -OCH ３ -OCH ２ CH ３ -O(CH ２ ) ２ CH ３ -CH ２ CN, -(CH ２ ) ２ CN, -(CH ２ ) ３ CN, -CH ２ OH, -(CH ２ ) ２ OH, -(CH ２ ) ３ OH, -CH(OH)CH ３ -(CH ２ ) ２ F, -CH ２ CHF ２ , -CF ３ ien-CH ２ CF ３ ,-CHF ２ ien-CH ２ F, -(CH ２ ) ２ Cl, -CH=CHF, -CH=CHCl, -CH=CHCH ２ F, -C ≡ CCH ２ F, -C ≡ C (CH ２ ) ２ F, -C≡CF, -OCF ３ , -OCHF ２ , -OCH ２ CHF ２ , -OCH ２ CF ３ , -OCHClCHCl ２ , -OCH ２ CH ２ F, -SCF ３ , -SCH ２ CF ３ , -SCH ２ CHF ２ , a phenyl group, a naphthyl group, a pyridyl group, a pyrimidinyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyrrolidinyl group, an oxazolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, or a piperazinyl group, and the -CH ３ ien-CH ２ CH ３ ,-(CH ２ ) ２ CH ３ ,-(CH ２ ) ３ CH ３ , -C(CH ３ ) ３ , -CH(CH ３ ) ２ , -SCH ３ , -SCH ２ CH ３ ien-CH=CH ２ ien-CH=CHCH ３ ien-CH ２ CH=CH ２ -C≡CH, -C≡CCH ３ 、-CH ２ C≡CH、-C≡CCH ２ OH、-C≡C(CH ２ ) ２ OH、-OCH ３ 、-OCH ２ CH ３ 、-O(CH ２ ) ２ CH ３ 、-CH ２ CN、-(CH ２ ) ２ CN、-(CH ２ ) ３ CN、-CH ２ OH、-(CH ２ ) ２ OH、-(CH ２ ) ３ OH、-CH(OH)CH ３ 、-(CH ２ ) ２ F-CH ２ CHF ２ 、-CH ２ CF ３ 、-CHF ２ 、-CH ２ F、-(CH ２ ) ２ ---CH=CHF、-CH=CHC-、-CH=CHCH ２ F-C≡CCH ２ F-C≡C(CH ２ ) ２ F-OCHF ２ 、-OCH ２ CHF ２ 、-OCH ２ CF ３ 、-OCHC-CHC- ２ 、-OCH ２ CH ２ F-SSCH ２ CF ３ 、-SCH ２ CHF ２ The phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group, and piperazinyl group can each be independently and optionally -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ The compound according to any one of claims 1 to 6, substituted with one, two, three or four substituents selected from -C(=O)H, -C(=O)OH, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, piperidinyl group and piperazinyl group.

8. R ４ These are 3-6 member heterocyclyl groups, 【Chemistry 11】 -L-pyrrolidinyl group, -L-piperidinyl group, -L-morpholinyl group, -L-oxetanyl group, -L-oxyranyl group, -L-tetrahydrofuranyl group, -L-octahydroindolidinyl group, -L-cyclopropyl group, -L-cyclopentyl group, -L-octahydropentalenyl group, -L-octahydro-1H-indenyl group, -L-decahydronaphthyl group, -L-pyridyl group, -L-pyrazolyl group, or -L-phenyl group. The 3-6 member heterocyclyl group, -L-cyclopropyl group, -L-cyclopentyl group, -L-octahydropentalenyl group, -L-octahydro-1H-indenyl group, -L-decahydronaphthyl group, -L-pyridyl group, -L-pyrazolyl group, and -L-phenyl group each independently optionally have 1, 2, 3, or 4 R ９ａ Replaced by the above 【Chemistry 12】 -L-pyrrolidinyl group, -L-piperidinyl group, -L-morpholinyl group, -L-oxetanyl group, -L-oxyranyl group, -L-tetrahydrofuranyl group and -L-octahydroindolidinyl group may each optionally have 1, 2, 3 or 4 R ９ｂ Replaced by, R ９ａ and R ９ｂ These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR ６ｄ R ７ｄ , -C(=O)NR ６ｄ R ７ｄ ien-CH ２ NR ６ｄ R ７ｄ ien-CH ２ OC(=O)NR ６ｄ R ７ｄ , C １～４ alkyl group, C １～４ Alkoxy group, C １～４ Haloalkyl group, C １～４ Haloalkoxy group, phenyl-C １～４ Alkyl group, (5-6 member heteroaryl)-C １～４ Alkyl alkyl groups, (3-6 member heterocyclyl)-C １～４ Alkyl alkyl group, (C ３～６ Cycloalkyl)-C １～４ alkyl group, C ３～６ The C is a cycloalkyl group or a 3-6 membered heterocyclyl group. １～４ alkyl group, C １～４ Alkoxy group, C １～４ Haloalkyl group, C １～４ Haloalkoxy group, phenyl-C １～４ Alkyl group, (5-6 member heteroaryl)-C １～４ Alkyl alkyl groups, (3-6 member heterocyclyl)-C １～４ Alkyl alkyl group, (C ３～６ Cycloalkyl)-C １～４ alkyl group, C ３～６ The cycloalkyl group and the 3- to 6-membered heterocyclyl group can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NR ６ｅ R ７ｅ , -C(=O)C １～４ Alkyl and C １～４ Substituted with one, two, three, or four substituents selected from alkyl groups, or Two R atoms bonded to the same ring carbon atom ９ｂ Together 【Chemistry 13】 Forming, L is C １～４ It is an alkylene group, R ６ｊ and R ７ｊ These are, independently, -H, -D, or C １～４ A compound according to any one of claims 1 to 7, wherein the compound is an alkyl group.

9. R ４ These are piperidinyl group, piperazinyl group, pyrrolidinyl group, imidazolidinyl group, 【Chemistry 14】 ien-CH ２ -Pyrrolidinyl group, -CH ２ -morpholinyl group, -(CH ２ ) ２ -morpholinyl group, -CH ２ -Oxetanyl group, -CH ２ -Oxyranyl group, -CH ２ -Tetrahydrofuranyl group, -CH ２ - Octahydroindolyl group, - CH ２ -Cyclopropyl group, -CH ２ -Cyclopentyl group, -CH ２ - Octahydropentalenyl group, - CH ２ -Octahydro-1H-indenyl group, -CH ２ - Decahydronaphthyl group, -CH ２ -Pyridyl group, -(CH ２ ) ２ - Pyridyl group, - CH ２ -Pyrazolyl group, -(CH ２ ) ２ -Pyrazolyl group or -CH ２ - A phenyl group, and the aforementioned piperidinyl group, piperazinyl group, pyrrolidinyl group, imidazolidinyl group, - CH ２ -Cyclopropyl group, -CH ２ -Cyclopentyl group, -CH ２ - Octahydropentalenyl group, - CH ２ -Octahydro-1H-indenyl group, -CH ２ - Decahydronaphthyl group, -CH ２ -Pyridyl group, -(CH ２ ) ２ -pyridyl group, -CH ２ -Pyrazolyl group, -(CH ２ ) ２ -Pyrazolyl group and -CH ２ - Each phenyl group can independently have 1, 2, 3, or 4 R groups. ９ａ Replaced by the above 【Chemistry 15】 ien-CH ２ -Pyrrolidinyl group, -CH ２ -morpholinyl group, -(CH ２ ) ２ -morpholinyl group, -CH ２ -Oxetanyl group, -CH ２ -Oxyranyl group, -CH ２ -Tetrahydrofuranyl group and -CH ２ - The octahydroindolinyl group can optionally have 1, 2, 3, or 4 R groups. ９ｂ Replaced by, R ９ａ and R ９ｂ These are, independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NR ６ｄ R ７ｄ , -C(=O)NR ６ｄ R ７ｄ ien-CH ２ NR ６ｄ R ７ｄ ien-CH ２ OC(=O)NR ６ｄ R ７ｄ Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy group, -CHF ２ , -CF ３ , -OCF ３ , phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperadinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperadinyl group, or azetidinyl group, and the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group, isopropoxy group, -CHF ２ ,phenylmethyl group, pyridylmethyl group, pyrazolylmethyl group, morpholinomethyl group, pyrrolidinylmethyl group, piperazinylmethyl group, azetidinylmethyl group, piperidinylmethyl group, tetrahydropyranylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentyl group, cyclohexyl group, morpholinyl group, piperidinyl group, pyrrolidinyl group, piperazinyl group and azetidinyl group can each be independently and optionally -D, -F, -Cl, -Br, -I, -OH, -CN, -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , - NHCH ２ CH ３ -C(=O)CH ３ -C(=O)CH ２ CH ３ , substituted with 1, 2, 3 or 4 substituents selected from methyl, ethyl, n-propyl and isopropyl groups, Or, Two R atoms bonded to the same ring carbon atom ９ｂ Together 【Chemistry 16】 It is possible to form, R ６ｊ and R ７ｊ The compound according to any one of claims 1 to 8, wherein each of them is independently -H, -D, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a t-butyl group.

10. R ６ , R ７ , R ６ｂ , R ７ｂ , R ６ｄ , R ７ｄ , R ６ｅ and R ７ｅ These are, independently, -H, -D, or C １～４ It is an alkyl group, and the C １～４ Alkyl groups can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR ６ｇ R ７ｇ , C １～４ Alkoxy group, C ６～１０ Aryl group, C ３～６ Substituted with 1, 2, 3, or 4 substituents selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups, Or, R ６ and R ７ , or R ６ｂ and R ７ｂ , or R ６ｄ and R ７ｄ , or R ６ｅ and R ７ｅ Each of these, together with the same N atom bonded to them, forms a 4-6 member heteroring, and the 4-6 member heteroring can be any of the following: -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , C １～４ alkyl group, C １～４ Alkylamino group, C ３～６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １～４ Alkoxy group, C １～４ Cyanoalkyl group, C １～４ Hydroxyalkyl group, C １～４ Haloalkoxy group and C １～４ Substituted with one, two, three, or four substituents selected from haloalkyl groups, R ６ａ , R ６ｃ , R ６ｇ and R ７ｇ These are, independently, -H, -D, or C １～４ A compound according to any one of claims 1 to 9, wherein the compound is an alkyl group.

11. R ６ , R ７ , R ６ｂ , R ７ｂ , R ６ｄ , R ７ｄ , R ６ｅ and R ７ｅ Each of these is independently -H, -D, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group, and the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and t-butyl group are each arbitrarily -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR ６ｇ R ７ｇ , substituted with one, two, three, or four substituents selected from methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxyranyl, oxetanyl, azetidinyl, and pyrrolidinyl groups, Or, R ６ and R ７ , or R ６ｂ and R ７ｂ , or R ６ｄ and R ７ｄ , or R ６ｅ and R ７ｅ Each of these groups, together with the same N atom bonded to them, forms a pyrrolidine, piperazine, piperidine, morpholinyl group, oxazolidine, or imidazolidine, and each of these pyrrolidines, piperazines, piperidines, morpholinyl groups, oxazolidines, and imidazolidines can independently and arbitrarily be -D, -OH, -F, -Cl, -Br, -I, -CN, -NH ２ , substituted with 1, 2, 3 or 4 substituents selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, methylamino group, dimethylamino group, ethylamino group, cyclopropyl group, cyclopentyl group, pyrrolidinyl group, methoxy group, ethoxy group, isopropoxy group, cyanomethyl group, hydroxymethyl group, hydroxyethyl group, trifluoromethoxy group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group or 1,2-dichloroethyl group, R ６ａ , R ６ｃ , R ６ｇ and R ７ｇ The compound according to any one of claims 1 to 10, wherein each of them is independently -H, -D, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a t-butyl group.

12. A compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound represented by formula (I-1), 【Chemistry 17】 In the formula, R １ , R ３ , R ４ Y and T each have the definitions described in any one of claims 1 to 11. R ２ａ , R ２ｂ and R ２ｃ Each of these is R in any one of claims 1 to 11. ２ A compound according to any one of claims 1 to 11, having the same definition as the compound according to any one of claims 1 to 11. 【Request Item 13】 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 【Chemistry 18-5】 【Chemistry 18-6】 【Chemistry 18-7】 【Chemistry 18-8】 【Chemistry 18-9】 【Chemistry 18-10】 【Chemistry 18-11】 A compound having the structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 12.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, and optionally further comprising a pharmaceutically acceptable adjuvant.

15. Use of the compounds according to claims 1 to 13 or the pharmaceutical composition according to claim 14 in the manufacture of a drug for preventing, treating or mitigating diseases associated with KRAS wild type or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations.

16. The use according to claim 15, wherein the disease associated with the KRAS wild type or the KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutation is cancer.

17. The aforementioned cancers include: heart cancers: sarcoma, myxoma, rhabdomyoma, fibroma, lipoma, or teratoma; lung cancers: bronchial cancer, non-small cell lung cancer, small cell lung cancer, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrodic hamartoma, or mesothelioma; gastrointestinal cancers: esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, or colorectal cancer; genitourinary cancers: kidney cancer, bladder cancer, and urethral cancer, prostate cancer, or testicular cancer; liver cancers: hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular carcinoma Tumors or hemangiomas; biliary tract cancers: gallbladder cancer, ampulla cancer, or bile duct cancer; bone cancers: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor / chordoma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, or giant cell tumor; nervous system cancers: cranial osteoma or brain cancer; gynecological cancers: uterine cancer, vulvar cancer, vaginal cancer, fallopian tube cancer, ovarian cancer, or breast cancer; blood The use according to claim 16, wherein cancer: acute or chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's disease or non-Hodgkin's lymphoma; skin cancer: melanoma, basal cell carcinoma, squamous cell carcinoma, Kabosi sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid or psoriasis; or cancer of the adrenal gland: neuroblastoma.

Images