Quinazoline compounds, their manufacturing methods and uses

Abstract

The present disclosure provides novel compounds, e.g., compounds having Formula I, Formula II, or Formula III, or pharmaceutically acceptable salts thereof. The present disclosure further provides methods for preparing the compounds, as well as methods for inhibiting KRAS, e.g., in cancer cells. G12D and / or for treating various cancers such as pancreatic, colorectal, lung or endometrial cancer.

Description

[Technical Field]

[0001] Cross-citation of related applications This disclosure claims priority to the international application PCT / CN2020 / 099104 filed on 30 June 2020 and the international application PCT / CN2021 / 075828 filed on 7 February 2021, with all its contents incorporated herein by reference.

[0002] In various embodiments, this disclosure generally relates to novel quinazoline compounds, compositions thereof, methods for producing the same, and methods for using the same, for example, to suppress RAS and / or to treat multiple diseases or conditions such as cancer. [Background technology]

[0003] RAS (KRAS, NRAS, and HRAS) proteins regulate vital cellular pathways that transmit signals received from cell membrane receptors to downstream molecules (e.g., Raf, MEK, ERK, and PI3K), which are crucial for cell proliferation and survival. RAS proteins circulate between an inactive GDP-bound form and an active GTP-bound form. RAS proteins mutate in cancer, with KRAS accounting for approximately 80% of all RAS mutations. KRAS mutations occur in approximately 86% of pancreatic cancers, 41% of colorectal cancers, 36% of lung adenocarcinomas, and 20% of endometrial cancers (F. McCormick, 2017, Clin Cancer Res 21: 1797-1801. Cancer Genome AtlasNetwork, 2017, Cancer Cell 32: 185-203). RAS hotspot mutations occur at codons 12, 13, and 61, and 75% of KRAS mutations occur at codon 12 (glycine) (DK Simanshu, DV Nissley, and F. McCormick, 2017, Cell, 170:17-33). G12D (The mutation of glycine to aspartic acid at codon 12) is common in pancreatic adenocarcinoma, colon adenocarcinoma, and lung adenocarcinoma. However, in small molecules, KRAS G12DTargeting the mutation is challenging because the pocket is shallow.

[0004] There is a significant unmet medical need for the treatment and intervention of cancer patients with RAS mutations. SUMMARY OF THE INVENTION

[0005] In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, and methods for their manufacture and use. Generally, the compounds of the present disclosure are RAS inhibitors, such as mutant KRAS (e.g., G12C, G12D, G12V, or G12A, more particularly G12D) inhibitors. The compounds and compositions of the present disclosure are used to treat various diseases or conditions, such as cancer or cancer metastasis.

[0006] In some embodiments, the present disclosure provides compounds of Formula I, Formula II, or Formula III or their pharmaceutically acceptable salts. TIFF0007860003000001.tif87165 wherein R 1 、R 2 、R 3 、R 13 、R 14 、R 15 、R 16 、R 21 、R 22 、G 1 、A 1 、A 2 、G 2 、G 3 、R 100 、m, n1, n2, and q are defined in the present disclosure.

[0007] Specific embodiments of the present disclosure include one or more compounds of the present disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E2, II-3, I The present disclosure relates to a pharmaceutical composition comprising a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any compound shown in Table A of this disclosure or any pharmaceutically acceptable salt thereof, and any pharmaceutically acceptable excipient. The pharmaceutical compositions relating to this disclosure are prepared for different routes of administration, such as oral administration, parenteral administration, or inhalation.

[0008] Certain embodiments relate to methods for treating diseases or conditions associated with RAS, for example, KRAS G12D. In some embodiments, the method provides a therapeutically effective amount of the compounds of the Disclosure to a patient in need (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E1) The method includes administering a therapeutically effective amount of a pharmaceutical composition relating to this disclosure (2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition relating to this disclosure. Diseases or conditions related to RAS, e.g., KRAS G12D, that are suitable to be treated by this method include those relating to this disclosure.

[0009] In some embodiments, a method for treating cancer is provided. In some embodiments, the method provides a therapeutically effective amount of the compounds of the Disclosure to a subject in need (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E1) 2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of the pharmaceutical composition relating to this disclosure. In various embodiments, the cancer may be pancreatic cancer, endometrial cancer, colorectal cancer or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancer is hematological cancer (e.g., relating to this disclosure). In some embodiments, the cancer may be appendiceal cancer, cholangiocarcinoma, urothelial carcinoma of the bladder, ovarian cancer, gastric cancer, breast cancer, or bile duct cancer.

[0010] In some embodiments, a method for treating cancer metastasis or tumor metastasis is provided. In some embodiments, the method provides a therapeutically effective amount of the compounds of the Disclosure to a subject in need (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E1) 2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of the pharmaceutical composition relating to this disclosure.

[0011] The administration in the methods disclosed herein is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhaled, oral cavity, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral.

[0012] The compounds of this disclosure can be used as monotherapy or in combination therapy. In some embodiments, combination therapy includes treating the subject with a targeted therapy, a chemotherapy agent, a therapeutic antibody, radiation, cell therapy, or immunotherapy.

[0013] It should be understood that the above summary and the following detailed description are illustrative and explanatory only and do not limit the invention as described herein. [Modes for carrying out the invention]

[0014] In various embodiments, this disclosure provides novel compounds, pharmaceutical compositions, methods of production, and methods of use.

[0015] compound Some embodiments of this disclosure are directed to novel compounds. The compounds of this disclosure may generally be inhibitors of KRAS proteins, particularly KRAS G12D mutant proteins, and may be used to treat various diseases or conditions related to this disclosure, such as cancer.

[0016] In some embodiments, the present disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof. TIFF0007860003000002.tif50117 Here, G 1 However, CR 10 or N; G 2 and G 3 However, each time they appear, they become independent, CR 11 R 12 , O or NR 20 And, however, G 2 and G 3 At least one example of this is NR 20 and; n1 and n2 are independent integers of 1, 2, 3, or 4; A 1 and A 2 However, each operates independently, and then combines and CR. 11 R 12 , O or NR 20 And, however, A 1 and A 2 At least one of them is O or NR 20 Not; R 1 However, hydrogen, -(L 1 ) j1 -OR 30 , halogen, -(L 1 ) j1 -NR 21 R 22 , or may be substituted, heterocyclic or heteroaryl rings; R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 100 However, each time they appear, independently, F, Cl, Br, I, CN, -OH, -C(O)NH2, -C(O)NH(C 1~6 Alkyl(alkyl group), -C(O)N(C 1~6 (Alkyl group)(C 1~6 C (alkyl group), may be substituted. 1~4 Alkyl groups (e.g., methyl group, ethyl group, CF3, etc.), cyclopropyl group, cyclobutyl group, may be substituted. 1~4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), cyclopropyloxy group, cyclobutyloxy group, SR A , S(O)R A Or S(O)2R A And; among them, R A However, each time it appears, it can be independently replaced by hydrogen or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, CF3, etc.), cyclopropyl group or cyclobutyl group, and m is 0, 1, 2, or 3; Among them: j1 is either 0 or 1, and if j1 is 1, L 1 However, these may be substituted alkylene groups, substituted carbocyclylene groups, or substituted heterocyclylene groups; R 10 , R 11 or R 12 However, each time it appears, it is independently hydrogen, F, -OH or substituted C. 1~6 It is an alkyl group, or R 11 and R 12 However, they link together with the carbon atoms they connect to form an oxo group, an imino group, or a ring; R 20 However, each time it appears, it may independently be hydrogen, a nitrogen protecting group, or a substituted C 1~6 It is an alkyl group; R 21 and R 22However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1~6 Alkyl alkyl group, optionally substituted carbon ring, or optionally substituted heterocycle; or R 21 and R 22 However, they may be linked and substituted to form heterocyclic or heteroaryl rings; and R 30 However, hydrogen, oxygen protecting groups, and substitutions may be made of C. 1~6 It is an alkyl group, a substituted or substituted carbon ring, a substituted or substituted aryl group, a substituted or substituted heteroaryl group, or a substituted or substituted heterocycle.

[0017] Compounds of formula I (including sub-formulas applicable to any of the disclosures) may exist in the form of a single enantiomer, diastereomer, atropisomer and / or geometric isomer (where applicable) or a mixture of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, where applicable, compounds of formula I (including sub-formulas applicable to any of the disclosures) may exist as a mixture of atropisomers in any proportion (including about 1:1). In some embodiments, where applicable, compounds of formula I (including sub-formulas applicable to any of the disclosures) may exist as a single atropisomer in isolation, such single atropisomer being essentially free from other atropisomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other atropisomers by weight, HPLC area, or both).

[0018] In some embodiments, G in formula I 1 However, it is N.

[0019] In some embodiments, G in formula I 1 However, CR 10 In some embodiments, R 10 However, hydrogen, F, -OH or C 1~6It may be an alkyl group (e.g., methyl group, ethyl group, etc.), and these may be substituted with, for example, F, -OH, methoxy group, etc. Usually, G 1 is CR 10 In the case of 10 R is hydrogen.

[0020] A in formula I 1 and A 2 may independently be a bond, a carbon-based linker, an oxygen or nitrogen-based linker. Usually, A in formula I 1 and A 2 may independently be a bond or CR 11 R 12 In some embodiments, one of A 1 and A 2 is a bond. In some embodiments, A 1 and A 2 are both bonds, so that the two crosslinking points are both directly linked to G 1 In some embodiments, one of A 1 and A 2 is CR 11 R 12 wherein R 11 and R 12 may independently be hydrogen, F, -OH or C 1~6 alkyl group (e.g., methyl group, ethyl group, etc.), and these may be substituted with, for example, F, -OH, methoxy group, etc. In some embodiments, one of A 1 and A 2 is CR 11 R 12 wherein R 11 and R 12 are linked together with the carbon to which they are both linked to form an oxo group or an imino group or a ring (e.g., cyclopropyl group), for example, A 1 may be C=O, C=NH, etc. In some embodiments, A 1 and A 2 are both independently selected from the group consisting of CR 11 R 12 wherein R 11 and R12 A is defined in this disclosure. For example, in some embodiments, A 1 and A 2 However, all of them are CH2. In some embodiments, A 1 and A 2 One of them is CH2, and A 1 and A 2 Another of these is C=O or C=NH. In some embodiments, A 1 and A 2 However, in all cases, C=O.

[0021] In some embodiments, G 2 However, each time it appears, independently, CR 11 R 12 In such embodiments, G 3 At least one example of this is NR 20 In some embodiments, G 2 However, it may be the same thing each time it appears. In some embodiments, G 2 However, they may be different each time they appear, or G 2 Some of them may be the same, while other parts may be different. In some embodiments, G 2 However, each time it appears, independently, CR 11 R 12 It may be so, and among them R 11 and R 12 However, independently, hydrogen, F, -OH or C 1~6 Alkyl groups (e.g., methyl group, ethyl group, etc.) may be used, and they may be substituted with, for example, F, -OA, methoxy group, etc. In some embodiments, G 2 One or two examples of this are CR 11 R 12 It may be so, and among them, R 11 and R 12 However, they link together with the carbon atoms they are linked to to form an oxo group, an imino group, or a ring (e.g., a cyclopropyl group). For example, in some embodiments, G 2 One example of this could be C=O or C=NH.

[0022] In some embodiments, G 2 One or two examples of this are O or NR 20 It is fine. Usually, G 2 One or less of these are parts based on complex atoms, for example, O or NR 20 And G 2 Other examples include, independently, CR 11 R 12 That is the case.

[0023] In some embodiments, G 3 However, each time it appears, independently, CR 11 R 12 In such embodiments, G 2 At least one example of this is NR 20 In some embodiments, G 3 However, it may be the same each time it appears. In some embodiments, G 3 However, they may be different each time they appear, or G 3 Some of them may be the same, while other parts may be different. In some embodiments, G 3 However, each time it appears, independently, CR 11 R 12 It may be so, and among them, R 11 and R 12 However, independently, hydrogen, F, -OH or C 1~6 Alkyl groups (e.g., methyl group, ethyl group, etc.) may be used, and they may be substituted with F, -OH, methoxy group, etc. In some embodiments, G 3 One or two examples of this are CR 11 R 12 It may be so, and among them, R 11 and R 12 However, they link together with the carbon atoms they are linked to to form an oxo group, an imino group, or a ring (e.g., a cyclopropyl group). For example, in some embodiments, G 3 One example of this could be C=O or C=NH.

[0024] In some embodiments, G 3 One or two examples of this are O or NR 20 It is fine. Usually, G 3 One or less of these are parts based on complex atoms, for example, O or NR 20 And G 3 Other examples include, independently, CR 11 R 12 That is the case.

[0025] Typically, formula I is 1, 2, or 3 G 2 Includes (as defined in this disclosure), i.e., n1 is 1, 2, or 3. In some embodiments, formula I is 1, 2, or 3 G 3 This includes (as defined in this disclosure), i.e., n2 is 1, 2, or 3.

[0026] As stated above in this disclosure, all G 2 and G 3 At least one example of this is NR 20 In some embodiments, all G 2 and G 3 One example of this is all G 2 and G 3 One of the G 2 or one G 3 However, NR 20 For example, in some embodiments, all G 2 and G 3 Of these, one G 2 or one G 3 NR 20 And among them R 20 is hydrogen or C 1~4 It is an alkyl group (for example, a methyl group). In some embodiments, R 20 However, each time it appears, it independently produces hydrogen, a nitrogen protecting group (e.g., as relating to this disclosure), or C 1~6The alkyl group may be an alkyl group (e.g., a methyl group, an ethyl group, an isopropyl group, etc.), and may be substituted with, for example, one, two, or three substituents, the substituents independently being F, -OH, a protected hydroxyl group, an oxo group, NH2, a protected ammonia group, NH(C) 1~4 Alkyl alkyl groups) or their protected derivatives, N(C 1~4 (Alkyl group)(C 1~4 (Alkyl alkyl group), C 1~4 Alkyl alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 1~4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 A group selected from the group consisting of a cycloalkoxy group, a phenyl group, a 5 or 6-membered heteroaryl group containing 1, 2 or 3 independently selected ring-forming heteroatoms from the group consisting of O, S and N, and a 3 to 7-membered heterocyclic group containing 1 or 2 independently selected ring-forming heteroatoms from the group consisting of O, S and N, wherein each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, cycloalkoxy group, phenyl group, heteroaryl group, and heterocyclic group contains 1, 2 or 3 independently selected F, -OH, oxo group (if applicable), C 1~4 Alkyl group, cyclopropyl group, fluorine-substituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy groups and fluorine-substituted C 1~4 It may be substituted with substituents selected from the group consisting of alkoxy groups.

[0027] In some embodiments, the compound of formula I may be identified as having formula I-1, I-2, or I-3. TIFF0007860003000003.tif119166 In this file, the variable R 1 , R 3 , R 100 , R 20 , m, G 2 n1 is defined in this disclosure. For example, in some embodiments, n1 is 1, 2 or 3, and each G 2However, CH2 may also be used. In some embodiments, R 20 However, hydrogen may also be used.

[0028] In some specific embodiments, part of formula I TIFF0007860003000004.tif4044 is Selected from the group consisting of TIFF0007860003000005.tif36166.

[0029] For example, in some embodiments, the compound of formula I may be identified as having formula I-1-A, I-2-A, or I-3-A. TIFF0007860003000006.tif84166 Among them, the variable R 1 , R 3 , R 100 and m are defined in this disclosure.

[0030] Various groups are R in formula I. 1 Suitable as. In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A) 1 However, it may be hydrogen. In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A) 1 However, it may be a halogen, for example, F or Cl. Various R suitable for formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 However, this disclosure provides specific examples and explanations.

[0031] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A) 1 However, -(L 1 ) j1 -OR 30It may also be the case that, in some embodiments, j1 is 0, i.e., R 1 However, -OR 30 In some embodiments, R 30 However, C may be substituted. 1~6 It may be an alkyl group, for example, in some embodiments, R 30 However, it may be a methyl group. In some embodiments, j1 is 1, and L 1 However, C may be substituted. 1~4 Alkylene group, substituted KilC 3-6 The group may be a carboccrine group, or a substituted 3-7 membered heterocyclene group. For example, in some embodiments, j1 is 1, and L 1 However, C 1~4 Alkylene groups, such as -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-, may also be used.

[0032] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 However, -OR 30 And among them, R 30 However, -C 1~6 Alkilen-R 101 And among them, R 101 However, NR 23 R 24 A 4- to 10-membered heterocycle, in which the C may be substituted. 1~6 The alkylene group may be substituted with, for example, one or more substituents, and these substituents may independently be F, OH, NR 25 R 26 and C which may be substituted with 1 to 3 fluorines 1~4 Selected from the group consisting of alkyl groups, or two substituents of the alkylene group are linked to form a ring; R 23 and R 24 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1~6Alkyl alkyl group, optionally substituted carbon ring, or optionally substituted heterocycle; or R 23 and R 24 However, they may be linked and substituted to form a heterocyclic or heteroaryl ring; and R 25 and R 26 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1~6 Alkyl alkyl group, optionally substituted carbon ring, or optionally substituted heterocycle; or R 25 and R 26 However, they form a heterocycle or heteroaryl ring which may be linked and substituted. In some embodiments, R 30 -C in 1~6 Alkylene-unit is unsubstituted C 1~4 It is an alkylene group (straight-chain or branched-chain). In some embodiments, R 30 -C in 1~6 The alkylene unit may be substituted with one, two, or three substituents, preferably one or two substituents. 1~4 The alkylene group, and these substituents are independently selected from the group consisting of F, -OH, methyl group, ethyl group, and CF3. In some embodiments, R 30 -C in 1~6 Alkylene - Unit is C 1~4 The alkylene group is such that two substituents (for example, those on the same carbon) are linked to form a cyclic propyl group, a cyclobutyl group, or a 5-6 membered heterocycle such as a pyrrolidine, piperidine, tetrahydrofuran, or tetrahydropyran ring, and the ring may be substituted with substituents such as F, -OH, a methyl group, an ethyl group, and CF3. In some embodiments, R 30 -C in 1~6 Alkylene units are -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, TIFF0007860003000007.tif1681 or Selected from the group consisting of TIFF0007860003000008.tif1560. In some embodiments, R 30 However, -CH2-R 101 -CH2-CH2-R 101-CH2-CH2-CH2-R 101 , TIFF0007860003000009.tif15103 or It is TIFF0007860003000010.tif1969, and within it, R 101 However, this is as defined in this disclosure.

[0033] R 101 However, normally, NR 23 R 24 Alternatively, it is a substituted 4-10 membered heterocycle having 1-3 independently selected ring-forming heteroatoms from the group consisting of O, S, and N.

[0034] In some embodiments, R 101 However, NR 23 R 24 And among them, R 23 and R 24 However, independently, hydrogen or substituted C 1~4 It is an alkyl group, such as a methyl group, an ethyl group, or an isopropyl group. For example, in some embodiments, R 101 However, NH2, NH(C 1~4 Alkyl(alkyl group) or N(C) 1~4 (Alkyl group)(C 1~4 It is an alkyl group. As used in this disclosure, N(C 1~4 (Alkyl group)(C 1~4 Two C in an alkyl group 1~4 The alkyl groups may be the same or different, including, for example, N(CH3)2 and N(CH3)(C2H5). Other similar notations are understood in the same way. In some embodiments, R 101 However, NR 23 R 24 And among them, R 23 and R 24 One of them is hydrogen or a substituted C 3-6 It is a cycloalkyl group, and R 23 and R 24 Another of these is defined in this disclosure, and in some embodiments, R 23 and R24 The other of these is hydrogen, which may be substituted with C. 3-6 C such as a cycloalkyl group or methyl group 1~4 It is an alkyl group. In some embodiments, R 101 However, NR 23 R 24 And among them, R 23 and R 24 One of these is a 4-8 membered heterocycle which may have hydrogen or be substituted, for example, having one or two heteroatoms independently selected from the group consisting of O and N, preferably the ring has one or fewer oxygen atoms, R 23 and R 24 Another of these is defined in this disclosure, and in some embodiments, R 23 and R 24 The other of these is C, such as hydrogen or a methyl group. 1~4 It is an alkyl group.

[0035] In some embodiments, R 101 However, NR 23 R 24 And among them, R 23 and R 24 However, they are linked together with N to form a substituted 4- to 8-membered monocyclic heterocycle having one or two ring-forming heteroatoms (e.g., one ring-forming nitrogen atom, two ring-forming nitrogen atoms, one ring-forming nitrogen atom and one ring-forming sulfur atom, or one ring-forming nitrogen atom and one ring-forming oxygen atom, etc.). For example, in some embodiments, R 101 However, NR 23 R 24 And among them, R 23 and R 24 However, when connected together with N, A ring is formed by selecting from the group consisting of TIFF0007860003000011.tif27159, Each of these may be substituted, for example, with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1 to 3 fluorines. 1~4C may be substituted with an alkoxy group, an oxo group, or 1 to 3 fluorines. 1~4 Alkyl alkyl groups, NH2, NH(C 1~4 Alkyl(C)(alkyl group), N(C) 1~4 (Alkyl group)(C 1~4 The substituents are selected from the group consisting of a 4-6 membered heterocycle having an alkyl group, a cyclopropyl group, a cyclobutyl group, and one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S, and preferably the substituents are independently selected from the group consisting of F, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, -N(CH3)2, -OH, and -OCH3. The substituents may be linked to any possible position on the ring, including a usable ring nitrogen atom. Although not prohibited, substitutions at ring-forming nitrogen are generally preferred not to form a quaternary salt, in other words, usually only one substituent is linked to the ring-forming nitrogen (if substituted).

[0036] In some embodiments, R 101 However, it may also be a monocyclic 4-8 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of N, O, and S, or a condensed or spiro-dicyclic 6-10 membered heterocycle having one to three independently selected ring-forming heteroatoms from the group consisting of N, O, and S, in which case the monocyclic or dicyclic ring may be substituted. The monocyclic or dicyclic ring may have -C at any possible position. 1~6 Alkylene - Connected to the R portion 30 This may form a two-ring structure. For a two-ring structure, the connection point may be on either of the two rings.

[0037] For example, in some embodiments, R 101 but, The monocyclic formula may be selected from the group consisting of TIFF0007860003000012.tif23156, and each of them may be substituted, for example, with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1 to 3 fluorines. 1~4 C may be substituted with an alkoxy group, an oxo group, or 1 to 3 fluorines.1~4 Alkyl alkyl groups, NH2, NH(C 1~4 Alkyl(C)(alkyl group), N(C) 1~4 (Alkyl group)(C 1~4 The substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4- to 6-membered heterocycle having one or two ring-forming heteroatoms independently selected from the group consisting of O, N, and S, and preferably the substituent is independently selected from the group consisting of F, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, -N(CH3)2, -OH, and -OCH3.

[0038] In some embodiments, R 101 but, The C molecule may be a bicyclic molecule selected from the group consisting of TIFF0007860003000013.tif73153, each of which may be substituted, for example, with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, or 1 to 3 fluorines. 1~4 C may be substituted with an alkoxy group, an oxo group, or 1 to 3 fluorines. 1~4 Alkyl alkyl groups, NH2, NH(C 1~4 Alkyl(C)(alkyl group), N(C) 1~4 (Alkyl group)(C 1~4 The substituents are selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4- to 6-membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S, and preferably the substituents are independently selected from the group consisting of F, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, -N(CH3)2, -OH, and -OCH3. It should be clearly explained here that the linking point of the two spiro-dicyclic structures may be a ring atom derived from a cyclobutyl group or an azetidine or pyrrolidine ring. In some embodiments, the linking point is on a ring atom derived from a cyclobutyl group, for example, on a carbon not adjacent to the spirocenter.

[0039] Any R 101 This refers to any of the -Cs relating to this disclosure. 1~6Alkylene-components suitable for formula I (e.g., subformulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 30 It may form R 1 However, -OR 30 For example, in some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 but, TIFF0007860003000014.tif150166TIFF0007860003000015.tif1447 or Selected from the group consisting of TIFF0007860003000016.tif1851.

[0040] In some embodiments, the compound of formula I may be identified as having formula I-1-A-1, I-1-A-2, or I-1-A-3. TIFF0007860003000017.tif96166 Among them, R 3 , R 100 and m are defined in this disclosure, where q1 is 1 or 2, q2 is 0, 1 or 2, and R 110 However, each time it appears, it is independently either F or a hydroxyl group. In some embodiments, q2 in formula I-1-A-2 or I-1-A-3 is 0. In some embodiments, q2 in formula I-1-A-2 is 1, and R 110 However, it is F or a hydroxyl group. In some embodiments, q2 in formula I-1-A-3 is 1 and R 110 However, F. In some embodiments, q2 in formula I-1-A-2 or I-1-A-3 is 2, and R 110 However, F is the compound. In some embodiments, the compound of formula I may be identified as having formula I-1-A-4 or I-1-A-5. TIFF0007860003000018.tif51166 Among them R 3 , R 100 and m are defined in this disclosure. The name “trans form” in formula I-1-A-4 means that the part linked to the F substitution and quinazoline is in the trans form. To avoid any ambiguity, formula I-1-A-4 includes a single stereoisomer (e.g., an enantiomer) and a mixture of stereoisomers in any proportion (including racemic mixtures). In some embodiments, the compound of formula I-1-A-4 may have the structural formula I-1-A-4-E1 or I-1-A-4-E2. TIFF0007860003000019.tif50166 Among them, R 3 , R 100 and m are defined in this disclosure. In some embodiments, the compounds of formula I-1-A-4-E1 or I-1-A-4-E2 may primarily exist as the described stereoisomers (relative to the two chiral centers of the shown stereochemical diagram), and may have other stereoisomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable, for example, by weight, by HPLC area, or both. For example, as illustrated in this disclosure, the stereoisomers can typically be separated by chiral HPLC.

[0041] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 Also, -OR 30 It may be so, and among them, R 30 However, C may be substituted. 3-6 It is a carbocyclic or a 4- to 10-membered heterocyclic ring. Oxygen can be linked to a carbocyclic or heterocyclic ring at any possible linkage point, but is not usually linked to a heteroatom or a carbon atom adjacent to a heteroatom. In some embodiments, R 30The ring is a monocyclic 4-8 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of N, O, and S, or a condensed or spiro-dicyclic 6-10 membered heterocycle having one to three independently selected ring-forming heteroatoms from the group consisting of N, O, and S, wherein the monocyclic or dicyclic ring may be substituted.

[0042] In some embodiments, R 30 However, it is a 4- to 8-membered monocyclic saturated ring having one ring-forming heteroatom and one ring-forming nitrogen. For example, in some embodiments, R 30 but, A monocyclic saturated ring selected from the group consisting of TIFF0007860003000020.tif1995, each of which may be substituted, for example, with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, or 1 to 3 fluorines. 1~4 C may be substituted with an alkoxy group, an oxo group, or 1 to 3 fluorines. 1~4 Alkyl alkyl groups, NH2, NH(C 1~4 Alkyl(C)(alkyl group), N(C) 1~4 (Alkyl group)(C 1~4 The substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4- to 6-membered heterocycle having one or two ring-forming heteroatoms independently selected from the group consisting of O, N, and S, and preferably the substituent is independently selected from the group consisting of F, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a tetrahydropyranyl group, -N(CH3)2, -OH, and -OCH3.

[0043] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 Also, -OR 30 It may be so, and among them, R 30 However, it is an aryl group or heteroaryl ring that may be substituted.

[0044] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 but, The group consisting of TIFF0007860003000021.tif47117 may also be selected.

[0045] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 Also, -(L 1 ) j1 -NR 21 R 22 It may also be the case that, in some embodiments, j1 is 0, i.e., R 1 NR 21 R 22 In some embodiments, j1 is 1, and L 1 However, C may be substituted. 1~6 Alkylene group, substituted KilC 3-6 The group may be a carboccrine group, or a substituted 3-7 membered heterocyclene group. For example, in some embodiments, j1 is 1, and L 1 However, C 1~4 Alkylene groups, such as -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-, may also be used.

[0046] For example, in some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 However, NR 21 R 22 or -C 1~6 Alkilen-NR 21 R22 It may also be R 21 and R 22 However, hydrogen may be substituted on C independently. 1~6 It is an alkyl group or a substituted heterocycle; or, R 21 and R 22 However, they link together with N to form a heterocycle which may be substituted and have one or two ring-forming heteroatoms. In some embodiments, R 21 and R 22 One of these is a substituted 4- to 8-membered monocyclic saturated heterocycle, for example, having one or two heteroatoms independently selected from the group consisting of O and N, preferably the ring having one or fewer oxygen atoms. In some embodiments, the 4- to 8-membered monocyclic saturated heterocycle may be substituted with one or more (e.g., one or two) substituents, the substituents independently being F, -(CH2) x -OH,-(CH2) x -C 1~4 Alkoxy group (may be substituted with 1 to 3 fluorines), oxo group, C (may be substituted with 1 to 3 fluorines) 1~4 Alkyl group, -(CH2) x -NH2, -(CH2) x -NH(C 1~4 Alkyl(alkyl group), -(CH2) x -N(C 1~4 (Alkyl group)(C 1~4 Alkyl(alkyl group), -(CH2) x -Cyclopropyl group, -(CH2) x -Cyclobutyl group and -(CH2) x-Selected from the group consisting of (a 4- to 6-membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), where x is 0, 1, 2, or 3, and preferably the substituent is independently selected from the group consisting of F, methyl group, ethyl group, isopropyl group, cyclopropyl group, -(CH2)-N(CH3)2, -N(CH3)2, -OH, and -OCH3. In some embodiments, the 4- to 8-membered monocyclic saturated heterocycle has one ring-forming heteroatom that is a ring-forming nitrogen atom (e.g., azetidine, pyrrolidine, piperazine, etc.). Typically, the linkage point is not the ring-forming nitrogen atom or a carbon atom adjacent to the ring-forming nitrogen. In some embodiments, R 21 and R 22 The other of these is hydrogen or a substituted C 1~6 It is an alkyl group, for example, C 1~4 It is an alkyl group, such as a methyl group, an ethyl group, or an isopropyl group.

[0047] In some embodiments, R 21 and R 22 However, when you connect them together with N, A ring is formed by selecting from the group consisting of TIFF0007860003000022.tif25160, each of which may be substituted, for example, by one or more (e.g., 1 or 2) substituents, and the substituents are independently F,-(CH2) x -OH,-(CH2) x -C 1~4 Alkoxy group (may be substituted with 1 to 3 fluorines), oxo group, C (may be substituted with 1 to 3 fluorines) 1~4 Alkyl group, -(CH2) x -NH2, -(CH2) x -NH(C 1~4 Alkyl(alkyl group), -(CH2) x -N(C 1~4 (Alkyl group)(C 1~4 Alkyl(alkyl group), -(CH2) x -Cyclopropyl group, -(CH2) x -Cyclobutyl group and -(CH2) x-Selected from the group consisting of (a 4- to 6-membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), where x is 0, 1, 2, or 3, and preferably the substituent is independently selected from the group consisting of F, methyl group, ethyl group, isopropyl group, cyclopropyl group, -(CH2)-N(CH3)2, -N(CH3)2, -OH, and -OCH3.

[0048] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 but, TIFF0007860003000023.tif41166 is also acceptable.

[0049] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 It may also be a substituted heterocycle or heteroaryl ring. In some embodiments, R 1 However, the heterocycle may be substituted, preferably a monocyclic 4-8 membered heterocycle having 1 or 2 independently selected ring-forming heteroatoms from the group consisting of N, O, and S, or a condensed or spiro-dicyclic 6-10 membered heterocycle having 1-3 independently selected ring-forming heteroatoms from the group consisting of N, O, and S, wherein the monocyclic or dicyclic ring may be substituted. In some embodiments, R 1 However, the ring is a substituted 4- to 8-membered monocyclic saturated heterocycle, for example, having one or two independent heteroatoms selected from the group consisting of O and N, preferably having one or fewer oxygen atoms. In some embodiments, the 4- to 8-membered monocyclic saturated heterocycle may be substituted with one or more (e.g., one or two) substituents, wherein the substituents are independently F, -(CH2) x-OH,-(CH2) x -C 1~4 Alkoxy group (may be substituted with 1 to 3 fluorines), oxo group, C (may be substituted with 1 to 3 fluorines) 1~4 Alkyl group, -(CH2) x -NH2, -(CH2) x -NH(C 1~4 Alkyl(alkyl group), -(CH2) x -N(C 1~4 (Alkyl group)(C 1~4 Alkyl(alkyl group), -(CH2) x -Cyclopropyl group, -(CH2) x -Cyclobutyl group and -(CH2) x -Selected from the group consisting of (a 4- to 6-membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), where x is 0, 1, 2, or 3, and preferably the substituent is independently selected from the group consisting of F, methyl group, ethyl group, isopropyl group, cyclopropyl group, -(CH2)-N(CH3)2, -N(CH3)2, -OH, and -OCH3. In some embodiments, the 4- to 8-membered monocyclic saturated heterocycle has one ring-forming heteroatom which is the ring-forming nitrogen atom (e.g., azetidine, pyrrolidine, piperazine, etc.).

[0050] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 1 However, it may also be a substituted condensation or a spiro-dicyclic 6-10 membered heterocycle having 1-3 independently selected ring-forming heteroatoms from the group consisting of N, O, and S. For example, in some embodiments, R 1 but, Selected from the group consisting of TIFF0007860003000024.tif72163, each of which may be substituted, for example, with one or more (e.g., 1 or 2) substituents, wherein the substituents are independently F, -(CH2) x -OH,-(CH2)x -C 1~4 Alkoxy group (may be substituted with 1 to 3 fluorines), oxo group, C (may be substituted with 1 to 3 fluorines) 1~4 Alkyl group, -(CH2) x -NH2, -(CH2) x -NH(C 1~4 Alkyl(alkyl group), -(CH2) x -N(C 1~4 (Alkyl group)(C 1~4 Alkyl(alkyl group), -(CH2) x -Cyclopropyl group, -(CH2) x -Cyclobutyl group and -(CH2) x -Selected from the group consisting of (a 4- to 6-membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), where x is 0, 1, 2, or 3, and preferably the substituent is independently selected from the group consisting of F, methyl group, ethyl group, isopropyl group, cyclopropyl group, -(CH2)-N(CH3)2, -N(CH3)2, -OH, and -OCH3. For example, in some embodiments, R 1 but, The group consisting of TIFF0007860003000025.tif76144 may also be selected.

[0051] Typically, one or two R's 100 However, in equation I (for example, sub-equations I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5), that is, m is 1 or 2. Various groups, R 100 Suitable for. In some embodiments, R 100 However, each time it appears, it is independently F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH2-cyclopropyl group, -C(O)NHMe, CF3, SCF3, methyl group, ethyl group, isopropyl group, or cyclopropyl group. Two R 100 If present, they are preferably as shown in F-4: TIFF0007860003000026.tif3738 All are R3 The base and ortho positions are formed, and the remaining part of formula I (for example, subformulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5) is not shown by F-4, and among them, R 100A and R 100B Each of the R in this disclosure is independently defined in this disclosure. 100 In some embodiments, R in F-4 100A F is F, and R in the F-4 100B is F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH2-cyclopropyl group, -C(O)NHMe, CF3, SCF3, methyl group, ethyl group, isopropyl group, or cyclopropyl group. In some preferred embodiments, R in F-4 100A F is F, and R in the F-4 100B is Cl or CN. In some preferred embodiments, R in F-4 100A F is F, and R in the F-4 100B F is F. In some preferred embodiments, R in F-4 100A F is F, and R in the F-4 100B is a methoxy group or an ethoxy group. In some embodiments, two R 100 If they exist, one of them is R, as shown in F-5. 3 It is in the ortho position of the base, and the other is R 3 It is at the meta position of the base, The remaining part of expression I (for example, sub-expressions I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5) is not shown in F-5, and among them, R 100A and R 100C Each of the R in this disclosure is independently defined in this disclosure. 100 In some embodiments, R in F-5 100A F is F, and R in F-5100C F, Cl, -CN, -OH, C 1~4 Alkyl or C 1~4 The group is an alkoxy group (e.g., a methoxy group, an ethoxy group, or an isopropyloxy group). In some embodiments, R in F-5 100A F is F, and R in F-5 100C This group is either F, Cl, a methoxy group, an ethoxy group, or an isopropyloxy group.

[0052] R suitable for formula I (for example, sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5) 100 Various selections and combinations are illustrated in the specific embodiments of this disclosure. In some specific embodiments, the compound of formula I may be identified as having formula I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, or I-1-A-12. TIFF0007860003000028.tif188166 Among them, R 1 and R 3 and R 100 R is defined in this disclosure. For example, in some embodiments, R in formula I-1-A-12 100 However, F, Cl, -CN, -OH or C 1~4 These are alkoxy groups (for example, methoxy groups, ethoxy groups, or isopropyloxy groups).

[0053] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3However, it may be a phenyl group or a 5 or 6-membered heteroaryl group, for example, a pyridyl group, and they may be substituted. In some embodiments, R 3 However, the phenyl group is substituted with 1 to 3 substituents, and the substituents may be independently F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 Selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, R 3 However, the pyridyl group is substituted with 1 to 3 substituents, and the substituents may be independently substituted with F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 The substituents are selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2.

[0054] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3 However, these may be naphthyl groups, and they may be substituted with, for example, 1 to 3 substituents, and the substituents may independently be F, Cl, Br, I, -OH, C 1~4Selected from the group consisting of alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group), CF3, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or less substituents are OH, -NH2, protected -OH, or protected -NH2. In some embodiments, R 3 However, the following applies: TIFF0007860003000029.tif4188 Here, 1) G B is OH, G A H is G C and G D C may be independently substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3, preferably G D However, it is an H, F, or methyl group; 2) G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, G A H is G B However, it is H or OH, G D However, H, F, Cl, CN, and C may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3, preferably G D However, it is an H, F, or methyl group; or, 3) G A However, it is Cl, and G B However, it is H, F or a methyl group, G C and G D C may be independently substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3, preferably G C and G D These are independently H, F, or a methyl group.

[0055] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3 However, the naphthyl group may be substituted, for example, a naphthyl group that may be substituted with one or more (usually 1 to 3) substituents, and the substituents may independently be F, Cl, Br, I, -OH, or C 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 The substituent is selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2. In some embodiments, R 3 However, the following applies: TIFF0007860003000030.tif3580 Here, G C and G D C may be independently substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 Alkyl group (e.g., methyl group, ethyl group, or CF3), cyclopropyl group, or C 2~4 An alkynyl group (e.g., an ethynyl group), preferably G D However, it is H, F or a methyl group. In some embodiments, in F-3-A, G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D However, H, F, Cl, CN, and C may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group (e.g., a methyl group, an ethyl group, or CF3). In some embodiments, G is present in F-3-A. CHowever, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D However, it is H or F. In some embodiments, R 3 However, the following applies: TIFF0007860003000031.tif4273 Here, G C and G D C may be independently substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 Alkyl group (e.g., methyl group, ethyl group, or CF3), cyclopropyl group, or C 2~4 An alkynyl group (e.g., an ethynyl group), preferably G D However, it is H, F or a methyl group, and among them G A1 However, each time it appears, it is independently a halogen (e.g., F or Cl), OH, CN, cyclopropyl group, or possibly substituted C 1~4 C may be an alkyl group or substituted. 1~4 It is an alkoxy group, and k is 1, 2, or 3. Note that G in F-3-B A1 However, substitution may occur at any possible position of the naphthylene ring, preferably with 1 or 2 G A1 However, it is located in the ortho position of the OH group. In some embodiments, in F-3-B, G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D However, H, F, Cl, CN, and C may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group (e.g., a methyl group, an ethyl group, or CF3). In some embodiments, G is present in F-3-B. C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D However, it is H or F. In some embodiments, k is 1 and G A1 However, it is located in the ortho position of the OH group, and G A1 However, C may be substituted with F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group. In some embodiments, k is 2 and there are two G A1 However, all of them are located in the ortho position of the OH group, and each G A1However, C may be independently substituted with F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group.

[0056] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3 However, these may be bicyclic heteroaryl groups (e.g., benzothiazolyl, indazolyl, or isoquinolinyl groups), which may be substituted with, for example, 1 to 3 substituents, and the substituents may be independently substituted with F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 The substituent is selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2. For example, in some embodiments, R 3 However, the following applies: TIFF0007860003000032.tif30122 Here, q3 is 0, 1 or 2, and G E However, each time it appears, it may be independently substituted with F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4These are alkynyl groups (e.g., ethynyl groups), cyclopropyl groups, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, q3 is 0, 1, or 2, and G E However, each time it appears, F, Cl, C 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group), C 2~4 Alkenyl group, C 2~4 The group is an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, CH2CH2-CN, CF2H, CF3, or -CN.

[0057] Formula I (e.g. sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I R suitable for -1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3 Various selections of are illustrated in the specific embodiments of this disclosure. In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3 but, The group consisting of TIFF0007860003000033.tif142166 may also be selected.

[0058] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3but, The data may be selected from the group consisting of TIFF0007860003000034.tif52145.

[0059] In some preferred embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) 3 but, The group consisting of TIFF0007860003000035.tif24113 may also be selected.

[0060] In some embodiments, the present disclosure provides compounds of formula II or pharmaceutically acceptable salts thereof. TIFF0007860003000036.tif42101 Here, R 13 and R 14 However, each time they appear, hydrogen or C appears independently. 1~4 It is an alkyl group, q is an integer from 0 to 6, R 15 , R 16 , R 21 and R 22 However, together with the intervening carbon and nitrogen atoms, they form a 6-10 membered condensed biring, which may be substituted. R 2 However, it has a ring or ring-chain structure, for example, having a pKa of about 6 or more. R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 100 However, each time they appear, independently, F, Cl, Br, I, -CN, -OH, -C(O)NH2, -C(O)NH(C 1~6 Alkyl(alkyl group), -C(O)N(C 1~6 (Alkyl group)(C 1~6 C (alkyl group), may be substituted. 1~4Alkyl groups (e.g., methyl group, ethyl group, CF3, etc.), cyclopropyl group, cyclobutyl group, may be substituted. 1~4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), cyclopropyloxy group, cyclobutyloxy group, or SR A , S(O)R A Or S(O)2R A And; among them, R A However, each time it appears, it can be independently replaced by hydrogen or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, CF3, etc.), cyclopropyl group or cyclobutyl group; and m is 0, 1, 2, or 3.

[0061] Compounds of formula II (including any possible sub-formulas relating to this disclosure) may exist in the form of a single enantiomer, diastereomer, atropisomer and / or geometric isomer (where applicable) or a mixture of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, where applicable, compounds of formula II (including any possible sub-formulas relating to this disclosure) may exist as a mixture of atropisomers in any proportion (including about 1:1). In some embodiments, where applicable, compounds of formula II (including any possible sub-formulas relating to this disclosure) may exist as a single atropisomer in isolation and may not contain any other atropisomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other atropisomers by weight, HPLC area, or both).

[0062] Typically, in Equation II, q is 1 to 3. In some embodiments, q is 1. In some embodiments, q is 2. R in Equation II 13 and R 14 However, it is usually a hydrogen or methyl group. For example, in some embodiments, R 13 and R 14 However, each time it appears, it is independently either a hydrogen atom or a methyl group.

[0063] In some embodiments, R 15 , R 16 , R 21 and R 22 However, together with the intervening carbon and nitrogen atoms, they form a 6-10 membered condensed biring, which may be substituted, Selected from the group consisting of TIFF0007860003000037.tif69154, each of which may be substituted, for example, with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, or 1 to 3 fluorines. 1~4 C may be substituted with an alkoxy group, an oxo group, or 1 to 3 fluorines. 1~4 Alkyl alkyl groups, NH2, NH(C 1~4 Alkyl(C)(alkyl group), N(C) 1~4 (Alkyl group)(C 1~4 The substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4- to 6-membered heterocycle having one or two ring-forming heteroatoms independently selected from the group consisting of O, N, and S, and preferably the substituent is independently selected from the group consisting of F, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, -N(CH3)2, -OH, and -OCH3.

[0064] In some embodiments, R 15 , R 16 , R 21 and R 22 However, together with the carbon and nitrogen atoms that were mediated TIFF0007860003000038.tif2178 is formed, which may be replaced by one or two rings. In some embodiments, TIFF0007860003000039.tif1968 may be substituted with one or more (e.g., one or two) substituents, and the substituents may be independently substituted with F, -OH, and 1 to 3 fluorines. 1~4 C may be substituted with an alkoxy group, an oxo group, or 1 to 3 fluorines. 1~4 Alkyl alkyl groups, NH2, NH(C 1~4 Alkyl(C)(alkyl group), N(C)1~4 (Alkyl group)(C 1~4 A substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4- to 6-membered heterocycle having one or two ring-forming heteroatoms independently selected from the group consisting of O, N, and S, preferably the substituent is independently F, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, -N(CH 3)2 The group is selected from the group consisting of -OH and -OCH3. In some embodiments, only one pyrrolidine ring is substituted, for example, by a single fluorine atom.

[0065] In some specific embodiments, the compound of formula II may be identified as having formula II-1, formula II-2, or formula II-3. TIFF0007860003000040.tif76166 Among them R 2 , R 3 , R 100 and m are defined in this disclosure. In formula II-2, “trans form” means that the part that links the F substitution and the quinazoline is in the trans form. To avoid any doubt, formula II-2 includes a single stereoisomer (enantiomer, etc.) and a mixture of stereoisomers in any proportion (a racemic mixture). In some embodiments, the compound of formula II-2 may have a structural formula of II-2-E1 or II-2-E2. TIFF0007860003000041.tif39166 Among them, R 2 , R 3 , R 100 and m are defined in this disclosure. In some embodiments, the compounds of formula II-2-E1 or II-2-E2 may be present primarily as the enantiomers described (relative to the two chiral centers of the stereochemical diagram shown), and have other enantiomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable, for example, by weight, by HPLC area, or both. For example, as illustrated in this disclosure, the enantiomers can typically be separated by chiral HPLC.

[0066] Various groups are R in Equation II.2 Suitable as such, some of which are exemplified by the specific compounds of this disclosure. In some embodiments, R 2 However, -(L 2 ) j2 -R 102 It can be shown as follows, where j2 is between 0 and 3, usually 0 or 1, and if j2 is not 0, for example if j2 is 1, L 2 However, each time it appears, it is independently CH2, O, NH or NCH3, and R 102 However, the heterocyclic or heteroaryl ring may be substituted, for example, those heterocyclic or heteroaryl rings having one or two ring-forming nitrogen atoms. For clarity, when the heterocyclic or heteroaryl ring is described as having one or two ring-forming nitrogen atoms, the heterocyclic or heteroaryl ring may also contain other ring-forming heteroatoms such as a ring-forming oxygen atom or a ring-forming sulfur atom. However, in some embodiments, the heterocyclic or heteroaryl ring has only ring-forming nitrogen atoms as ring-forming heteroatoms. In some embodiments, j2 is 0. In some embodiments, j2 is 1.

[0067] In some embodiments, j2 is 0 and R 102 R is a substituted 4- to 10-membered heterocycle having one or two ring-forming nitrogen atoms. For example, in some embodiments, R 102 but, A ring structure selected from the group consisting of TIFF0007860003000042.tif30141, each of which may be substituted, Among them, G 4 ga-(L 3 ) j3 -NH2, -(L 3 ) j3 -NH(C 1~4 If it is an alkyl group, and j3 is 0 or 1, then L 3 However, C 1~4 Alkylene group (e.g., methylene group, ethylene group, propylene group, isopropylene group, etc.), or G 4However, it is linked with one substituent on the ring to form a 4- to 6-membered heterocycle having one or two ring-forming nitrogen atoms. In some embodiments, each of the ring structures described above may be substituted with one to three (usually one or two) substituents, the substituents independently of C 1~4 Alkyl groups (e.g., methyl group, ethyl group, etc.), fluorine-substituted C 1~4 Alkyl group (e.g., CF3), hydroxylated C 1~4 C alkyl groups, alkoxy-substituted C 1~4 Alkyl alkyl groups, cyano-substituted C 1~4 The substituents are selected from the group consisting of alkyl groups and CONH2, or two substituents are bonded together to form an oxo group, an imino group, or a ring structure. The substitution can be carried out at any possible position of the ring, including the ring-forming nitrogen atom.

[0068] In some preferred embodiments, in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, or II-3), R 2 but, Selected from the group consisting of TIFF0007860003000043.tif158162. In some preferred embodiments, in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, or II-3), R 2 but, The filename is TIFF0007860003000044.tif3023.

[0069] In some embodiments, j2 is 1, L 2 is CH2 or NH, and R 102 is a substituted 4- to 10-membered heterocycle having one or two ring-forming nitrogen atoms. For example, in some embodiments, j2 is 1, and L 2 is CH2 or NH, and R 102 It is a 4- to 8-membered heterocycle which may be substituted, for example, a monocyclic saturated 4- to 8-membered ring which may be substituted. For example, in some embodiments, j2 is 1 and L 2 is CH2 or NH, and R 102 but, Selected from the group consisting of TIFF0007860003000045.tif3185, Each of these may be substituted, for example, with 1 to 3 (usually 1 or 2) substituents, and the substituents independently are C 1~4 Alkyl groups (e.g., methyl group, ethyl group, etc.), fluorine-substituted C 1~4 Alkyl group (e.g., CF3), hydroxylated C 1~4 C alkyl groups, alkoxy-substituted C 1~4 Alkyl alkyl groups, cyano-substituted C 1~4 The substituents are selected from the group consisting of alkyl groups and CONH2, or two substituents are bonded together to form an oxo group, an imino group, or a cyclic structure. The substitution can be carried out at any possible position of the ring, including the ring-forming nitrogen atom.

[0070] In some embodiments, in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, or II-3), R 2 but, Selected from the group consisting of TIFF0007860003000046.tif28103.

[0071] In some embodiments, in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, or II-3), R 2 Also, C 3-7 The carbon ring, phenyl group, or 5- or 6-membered heteroaryl ring may be a carbon ring, and at least one of each of these has a nitrogen-containing substituent, for example, a basic nitrogen-containing substituent, e.g., NH2, NH(C) 1~4 Alkyl(alkyl group) or N(C) 1~4 (Alkyl group)(C 1~4 It has an alkyl group. For example, in some embodiments, R 2 but, Selected from the group consisting of TIFF0007860003000047.tif28106.

[0072] Typically, one or two R's 100However, it exists in equation II (for example, sub-equations II-1, II-2, II-2-E1, II-2-E2, or II-3), that is, m is 1 or 2. Various groups exist in R 100 Suitable for. In some embodiments, R 100 However, each time it appears, it is independently F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH2-cyclopropyl group, -C(O)NHMe, CF3, methyl group, ethyl group, isopropyl group, or cyclopropyl group. Two R 100 If present, they are preferably F-4: As shown in TIFF0007860003000048.tif4033, all are R 3 It is in the ortho position of the base, and the rest of equation II (e.g., sub-equations II-1, II-2, II-2-E1, II-2-E2, or II-3) is not shown by F-4, and among them, R 100A and R 100B However, each is independent of the R as defined in this disclosure. 100 In some embodiments, R in F-4 100A F is F, and R in the F-4 100B is F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH2-cyclopropyl group, -C(O)NHMe, CF3, SCF3, methyl group, ethyl group, isopropyl group, or cyclopropyl group. In some preferred embodiments, R in F-4 100A F is F, and R in the F-4 100B is Cl or CN. In some preferred embodiments, R in F-4 100A F is F, and R in the F-4 100B F is F. In some preferred embodiments, R in F-4 100A F is F, and R in the F-4 100B is a methoxy group or an ethoxy group. In some embodiments, two R 100 If they exist, one of them is R, as shown in F-5. 3 It is in the ortho position of the base, and the other is R 3 It is at the meta position of the base, The remainder of formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, or II-3) in TIFF0007860003000049.tif4330 is not shown in F-5, and within that R 100A and R 100C Each of the R in this disclosure is independently defined in this disclosure. 100 In some embodiments, R in F-5 100A F is F, and R in F-5 100C F, Cl, -CN, -OH, C 1~4 Alkyl or C 1~4 The group is an alkoxy group (e.g., a methoxy group, an ethoxy group, or an isopropyloxy group). In some embodiments, R in F-5 100A F is F, and R in F-5 100C This group is either F, Cl, a methoxy group, an ethoxy group, or an isopropyloxy group.

[0073] R suitable for Equation II (e.g., sub-equations II-1, II-2, II-2-E1, II-2-E2, or II-3) 100 Various selections and combinations are illustrated in the specific embodiments of this disclosure. In some specific embodiments, the compound of formula II may be identified as having formula II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, or II-2-C. TIFF0007860003000050.tif122163 Among them, R 2 and R 3 As defined in this disclosure. In some embodiments, compounds of formula II may be identified as having formula II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2. TIFF0007860003000051.tif119161 Among them, R 2 and R 3As defined herein. In some embodiments, compounds of formula II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2 may primarily exist as the described stereoisomers (relative to the two chiral centers of the shown stereochemical diagram), and may have other stereoisomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable, for example, by weight, HPLC area, or both. For example, as illustrated herein, stereoisomers can typically be separated by chiral HPLC.

[0074] In some embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2) 3 However, it may be a phenyl group or a 5 or 6-membered heteroaryl group, such as a pyridyl group, and they may be substituted. In some embodiments, R 3 However, the phenyl group is substituted with 1 to 3 substituents, and the substituents may be independently F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 Selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, R 3 However, the pyridyl group is substituted with 1 to 3 substituents, and the substituents may be independently substituted with F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4Alkenyl group, substitution in Kidney C 2~4 The substituents are selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2.

[0075] In some embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2) 3 However, these may be naphthyl groups, and they may be substituted with, for example, 1 to 3 substituents, and the substituents may independently be F, Cl, Br, I, -OH, C 1~4 Selected from the group consisting of alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, tert-butyl), CF3, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2. In some embodiments, R 3 However, the following applies: TIFF0007860003000052.tif3564 Here, 1) G B is OH, G A H is G C and G D However, independently, H, F, Cl, CN, and C may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3, preferably G D However, it is an H, F, or methyl group; 2) G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, G A H is G B However, it is H or OH, G DHowever, H, F, Cl, CN, and C may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3, preferably G D However, it is an H, F, or methyl group; or, 3) G A Cl is G B However, it is H, F or a methyl group, G C and G D These can be independently H, F, Cl, CN, or C which may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3, preferably G C and G D These are independently H, F, or a methyl group.

[0076] In some embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2) 3 However, it may be a substituted naphthyl group, for example, a naphthyl group that may be substituted with one or more (usually 1 to 3) substituents, and the substituents may independently be F, Cl, Br, I, -OH, or C 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 The substituent is selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2. In some embodiments, R 3 However, the following applies: TIFF0007860003000053.tif3667 Here, GC and G D C may be independently substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 Alkyl group (e.g., methyl group, ethyl group, or CF3), cyclopropyl group, or C 2~4 An alkynyl group (e.g., an ethynyl group), preferably G D However, it is H, F or a methyl group. In some embodiments, in F-3-A, G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D C may be substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3. In some embodiments, G is present in F-3-A. C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D is H or F. In some embodiments, R 3 The following applies: TIFF0007860003000054.tif3969 Here, G C and G D C may be independently substituted with H, F, Cl, CN, or 1 to 3 fluorines. 1~4 Alkyl group (e.g., methyl group, ethyl group, or CF3), cyclopropyl group, or C 2~4 An alkynyl group (e.g., an ethynyl group), preferably G D is H, F or methyl group, and among them G A1 However, each time it appears, it is independently a halogen (e.g., F or Cl), OH, CN, cyclopropyl group, or possibly substituted C 1~4 C may be an alkyl group or substituted. 1~4 It is an alkoxy group and k is 1, 2, or 3. Note that G in F-3-B A1 However, substitution may occur at any possible position of the naphthylene ring, preferably with 1 or 2 G A1 However, it is located in the ortho position of the OH group. In some embodiments, in F-3-B, G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G DHowever, H, F, Cl, CN, and C may be substituted with 1 to 3 fluorines. 1~4 It is an alkyl group, for example, a methyl group, an ethyl group, or CF3. In some embodiments, G in F-3-B. C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, and G D However, it is H or F. In some embodiments, k is 1 and G A1 However, it is located in the ortho position of the OH group, and G A1 However, C may be substituted with F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group. In some embodiments, k is 2 and there are two G A1 However, all of them are located in the ortho position of the OH group, and each G A1 However, C may be independently substituted with F, Cl, CN, or 1 to 3 fluorines. 1~4 It is an alkyl group.

[0077] In some embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2) 3 However, these may be bicyclic heteroaryl groups (e.g., benzothiazolyl, indazolyl, or isoquinolinyl groups), which may be substituted with, for example, 1 to 3 substituents, and the substituents may be independently substituted with F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4The substituent is selected from the group consisting of an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or fewer substituents are OH, -NH2, protected -OH, or protected -NH2. For example, in some embodiments, R 3 but, The filename is TIFF0007860003000055.tif33119. Among them, q3 is 0, 1 or 2, and G E However, each time it appears, it may be independently substituted with F, Cl, Br, I, -OH, or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2CH2-CN, CF2H, or CF3), may be substituted C 2~4 Alkenyl group, substitution in Kidney C 2~4 These are alkynyl groups (e.g., ethynyl groups), cyclopropyl groups, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, q3 is 0, 1, or 2, and G E However, each time it appears, F, Cl, C 1~4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group), C 2~4 Alkenyl group, C 2~4 The group is an alkynyl group (e.g., an ethynyl group), a cyclopropyl group, CH2CH2-CN, CF2H, CF3, or -CN.

[0078] Formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2- R suitable for B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2) 3Various selections and combinations of are illustrated in the specific embodiments of this disclosure. In some embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2) 3 but, It can be selected from the group consisting of TIFF0007860003000056.tif140166.

[0079] In some embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2) 3 but, It can be selected from the group consisting of TIFF0007860003000057.tif52147.

[0080] In some preferred embodiments, R in formula II (e.g., sub-formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2) 3 but, It can be selected from the group consisting of TIFF0007860003000058.tif25109.

[0081] In some embodiments, the disclosure further provides compounds of formula III or pharmaceutically acceptable salts thereof. TIFF0007860003000059.tif3574 Here, R 1However, hydrogen, -(L 1 ) j1 -OR 30 , halogen, -(L 1 ) j1 -NR 21 R 22 , or may be substituted, heterocyclic or heteroaryl rings; R 2 However, it has a ring or ring-chain structure, for example, having a pKa of about 6 or more. R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 100 However, each time they appear, independently, F, Cl, Br, I, CN, -OH, -C(O)NH2, -C(O)NH(C 1~6 Alkyl(alkyl group), -C(O)N(C 1~6 (Alkyl group)(C 1~6 C (alkyl group), may be substituted. 1~4 Alkyl groups (e.g., methyl group, ethyl group, CF3, etc.), cyclopropyl group, cyclobutyl group, may be substituted. 1~4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), cyclopropyloxy group, cyclobutyloxy group, or SR A , S(O)R A Or S(O)2R A And; among them, R A However, each time it appears, it can be independently replaced by hydrogen or C. 1~4 Alkyl groups (e.g., methyl group, ethyl group, CF3, etc.), cyclopropyl group or cyclobutyl group; and m is 0, 1, 2, or 3; Among them: j1 is either 0 or 1, and if j1 is 1, L 1 However, these may be substituted alkylene groups, substituted carbocyclylene groups, or substituted heterocyclylene groups; R 21 and R 22 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1~6Alkyl alkyl group, optionally substituted carbon ring, or optionally substituted heterocycle; or R 21 and R 22 However, they may be linked and substituted to form heterocyclic or heteroaryl rings; and R 30 However, hydrogen, oxygen protecting groups, and substitutions may be made of C. 1~6 It is an alkyl group, a substituted or substituted carbon ring, a substituted or substituted aryl group, a substituted or substituted heteroaryl group, or a substituted or substituted heterocycle.

[0082] Compounds of formula III (including any possible sub-formulas relating to this disclosure) may exist in the form of a single enantiomer, diastereomer, atropisomer and / or geometric isomer (where applicable) or a mixture of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, where applicable, compounds of formula III (including any possible sub-formulas relating to this disclosure) may exist as a mixture of atropisomers in any proportion (including about 1:1). In some embodiments, where applicable, compounds of formula III (including any possible sub-formulas relating to this disclosure) may exist as a single atropisomer in isolation and may not contain any other atropisomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other atropisomers by weight, HPLC area, or both).

[0083] Compound R of formula III 1 , R 2 and R 3 The base includes any of the bases described herein relating to any combination of Formula I (e.g., its subformulas) and / or Formula II (e.g., its subformulas). The appropriate R of Formula III 100 The definitions of and m further include any of the definitions described herein relating to any combination of Formula I (or its sub-formulas) and / or Formula II (or its sub-formulas). For example, in some embodiments, one or two R 100However, it exists in Equation III, that is, m is 1 or 2. In some embodiments, R 100 However, each time it appears, it is independently F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH2-cyclopropyl group, -C(O)NHMe, CF3, methyl group, ethyl group, isopropyl group, or cyclopropyl group. In some embodiments, two R 100 There exist, and all of them are R 3 It is in the ortho position of the base. In some embodiments, R 100 One of them is F, and R 100 The other of these is Cl or CN. In some embodiments, the compound of formula III may have formulas III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9. TIFF0007860003000060.tif114157 Among them R 1 , R 2 and R 3 This is as defined in this disclosure.

[0084] For example, in some embodiments, R in Equation III (e.g., sub-equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9) 1 but, It can be selected from the group consisting of TIFF0007860003000061.tif149166, or R 1 However, hydrogen, methoxy group, TIFF0007860003000062.tif1863 or TIFF0007860003000063.tif1543 is also acceptable.

[0085] In some embodiments, R in Equation III (e.g., sub-equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9) 1 but, It can be selected from the group consisting of TIFF0007860003000064.tif48127.

[0086] In some embodiments, R in Equation III (e.g., sub-equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9) 1 but, It can be selected from the group consisting of TIFF0007860003000065.tif87126.

[0087] In some embodiments, R in Equation III (e.g., sub-equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9) 1 but, It can be selected from the group consisting of TIFF0007860003000066.tif74131.

[0088] In some embodiments, R in Equation III (e.g., sub-equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9) 2 but, It can be selected from the group consisting of TIFF0007860003000067.tif162166.

[0089] In some embodiments, R in Equation III (e.g., sub-equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9) 3 but, It can be selected from the group consisting of TIFF0007860003000068.tif188166.

[0090] R of Equation III (for example, Sub-Equations III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9) 1 , R 2 and R 3Other appropriate definitions of include any definition of the respective variables relating to any combination of Formula I (or its sub-formulas) and / or Formula II (or its sub-formulas) relating to this disclosure.

[0091] In some embodiments, the disclosure further provides compounds selected from the group consisting of the compounds shown in Table A below, or pharmaceutically acceptable salts thereof. TIFF0007860003000069.tif247166TIFF0007860003000070.tif227166TIFF0007860003000071.t if226166TIFF0007860003000072.tif223166TIFF0007860003000073.tif219166TIFF00078600030 00074.tif229166TIFF0007860003000075.tif221166TIFF0007860003000076.tif228166TIFF000 7860003000077.tif220166TIFF0007860003000078.tif230166TIFF0007860003000079.tif146166

[0092] In some of the specific compounds in Table A above and in the specific compounds in the Examples section below, the structure is denoted as “trans.” Unless otherwise specified, such a designation should be understood as meaning that the specific compound with the name “trans” is racemic with respect to a pair of chiral centers in the pyrrolizidine ring and can be divided into two enantiomers. For clarity, the divided / enriched single enantiomer is also a compound of this disclosure.

[0093] In some embodiments, to the extent applicable, the types of compounds in this disclosure exclude any compounds specifically manufactured and disclosed prior to this disclosure.

[0094] Synthesis method According to this disclosure, those skilled in the art can easily synthesize the compounds of this disclosure. Exemplary synthesis is shown in the Examples section.

[0095] The following method for synthesizing formula I is descriptive, and those skilled in the art can synthesize compounds of formula II or III in the same manner by using appropriate synthetic starting materials or intermediates. In some embodiments, as shown in the scheme of this disclosure, this disclosure further provides synthetic methods and synthetic intermediates for producing compounds of formula I, II, or III.

[0096] As shown in Scheme 1, the compounds of formula I can usually be synthesized by three coupling reactions. In some embodiments, compound S-1 is R 3 It can be coupled with supply unit S-2, and among them, M 1 However, hydrogen, metals (for example, Zn 2+ ), or boric acid or ester, tributyltin, etc., may be used, and the coupling reaction is usually carried out under the catalysis of a transition metal, for example, the palladium-catalyzed coupling reaction exemplified in this disclosure. Lg 3 However, the detaching group relating to this disclosure is typically a halide or sulfonate detaching group suitable for metal-catalyzed coupling reactions. By adjusting the reaction conditions, R 3 Replacement Lg 3 It is possible to introduce [a specific compound]. Subsequently, compound S-3 can be converted to S-5 by a secondary coupling reaction. 1 Due to its properties, such coupling can be performed with or without a transition metal catalyst. In some embodiments, M 2 However, it may also be hydrogen, and G in S-4 1 -M 2 The NH group is NH, and the crosslinking ring is Lg 1 By substituting, compound S-5 can be produced, Lg 1However, the detaching group may be the detaching group relating to this disclosure, or for example, a halogen (e.g., Cl), and is typically carried out under basic conditions in an aprotonate solvent such as dimethyl sulfoxide. Subsequently, compound S-5 can be converted to formula I by reacting with S-6. R in S-6 1 -M 3 These typically contain an -OH or -NH functional group, for example, M 3 However, hydrogen may also be used, and in this way they react with S-5 to form a leaving group Lg 2 Lg can be replaced 2 However, it may be a halogen or other detaching group relating to this disclosure, for example, a sulfone. Example 1 shows exemplary reaction conditions for converting the S-1 compound to the compound of formula I. The variable R in the formula of Scheme 1 1 , R 3 , G 1 , A 1 , A 2 , G 2 , G 3 , R 100 m, n1, and n2 are defined as described above in relation to Equation I. JPEG0007860003000080.jpg122159

[0097] The coupling sequence shown in Scheme 1 is not necessarily required, and those skilled in the art can produce compounds of formula I by a slightly different coupling sequence by referring to this disclosure, for example, by introducing the crosslinking ring first and Lg 1 Replace with R 1 We introduce the base, and finally R 3 A base can be introduced.

[0098] Suitable coupling partners, for example, S-1, S-4, or S-6, can be manufactured by methods known in the art or by methods relating to this disclosure, see, for example, the Examples section. Also, see, for example, U.S. Patent Application No. 2019 / 0127336.

[0099] As will be apparent to those skilled in the art, some functional groups may require common protecting groups to avoid undesirable reactions. Appropriate protecting groups for each functional group, and the appropriate conditions for protecting and deprotecting specific functional groups, are known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis" (4th edition, PGMWuts, TW Greene, John Wiley, 2007) and the references cited therein. Reagents for the reactions according to the present invention can usually be prepared from known compounds or by known procedures or obvious modifications thereof. For example, some reagents are commercially available, including those from Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other compounds can be prepared by following the procedures described in the references, or obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (Wiley, 7th edition), and Larock's Comprehensive Organic Transformations (Wiley VCH, 1999), and any available updated versions of these documents.

[0100] Pharmaceutical composition A particular embodiment relates to a pharmaceutical composition comprising one or more compounds of the present disclosure.

[0101] The pharmaceutical composition may optionally contain pharmacokinetically acceptable excipients. In some embodiments, the pharmaceutical composition may contain the compounds of the Disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E2, The compounds include II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), compounds of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any of the compounds shown in Table A of this disclosure or their pharmaceutically acceptable salts), and pharmaceutically acceptable excipients. Pharmacologically acceptable excipients are well known in the art. Suitable non-limiting excipients include, for example, encapsulants or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, leavening agents, fillers, flavorings, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. Furthermore, prior art for each excipient used to prepare pharmaceutical compositions and their manufacture is disclosed in Remington's The Science and Practice of Pharmacy, 21 st See Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005, which is incorporated herein by reference).

[0102] A pharmaceutical composition may contain any one or more compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition may contain, for example, a therapeutically effective amount of a compound of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), a compound of formula II (e.g., formulas II-1, II-2, II-2-E1) The compounds include II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), compounds of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any of the compounds shown in Table A of this disclosure or pharmaceutically acceptable salts thereof. In any embodiment of this disclosure, the pharmaceutical composition may, for example, contain a therapeutically effective amount of a compound selected from the group consisting of any of the compounds shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof.

[0103] The pharmaceutical composition may also be prepared to be administered by any known route of administration, which includes, but is not limited to, oral administration, parenteral administration, inhalation administration, etc.

[0104] In some embodiments, pharmaceutical compositions can be prepared for oral administration. Each oral formulation contains a predetermined amount of the active compound and can be expressed in individual units such as capsules, pills, cachets, lozenges, or tablets; or as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. Excipients for preparing oral administration compositions are well known in the art. Suitable non-limiting excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropanol, physiological saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, and peanut oil. Contains oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium laurate sulfate, sodium sorbitol, soybean oil, stearic acid, stearin fumaric acid, sucrose, surfactant, talc, tragacanth, tetrahydrofuryl alcohol, triglycerides, water and mixtures thereof.

[0105] In some embodiments, the pharmaceutical composition is prepared in dosage forms for parenteral administration (e.g., intravenous injection or drip infusion, subcutaneous injection or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions or emulsions. Excipients for the manufacture of parenteral formulations are well known in the art. Non-limiting suitable excipients include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, glucose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water and mixtures thereof.

[0106] In some embodiments, pharmaceutical compositions are prepared into inhalation formulations. The inhalable formulations are prepared, for example, as nasal sprays, dry powders, or aerosols that can be administered by a metered-dose atomizing inhaler. Excipients for the manufacture of inhalation formulations are well known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders and mixtures thereof. The sprays may further contain propellants such as chlorofluorocarbons and unsubstituted volatile volatile hydrogen compounds such as butane and propane.

[0107] Pharmaceutical compositions may contain varying amounts of the compounds of this disclosure depending on various factors such as the intended use, efficacy, and selectivity of the compounds. In some embodiments, the pharmaceutical composition may contain a therapeutically effective amount of the compounds of this disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)), compounds of formula II (e.g., formulas II-1, II-2, II-2-E) The compounds include (1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), compounds of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any of the compounds shown in Table A of this disclosure, or pharmaceutically acceptable salts thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of this disclosure and a pharmaceutically acceptable excipient. As used in this disclosure, the therapeutically effective dose of a compound in this disclosure means an effective dose for treating the disease or condition relating to this disclosure, and which depends on the patient being treated, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound (e.g., inhibition of KRAS G12C), its clearance rate, and whether it is used in combination with other drugs.

[0108] For veterinary use, the compounds of this disclosure can be administered as appropriately acceptable formulations in accordance with normal veterinary practice. Veterinarians can easily determine the most appropriate administration plan and route for a particular animal.

[0109] In some embodiments, the compounds of the Disclosure may be used alone or in combination with other therapeutic or interventional agents conventionally used for the treatment of such diseases to package all the components necessary for the treatment of KRAS-related diseases into a kit. Specifically, in some embodiments, the present invention provides a kit for therapeutic intervention of a disease comprising a group of packaged drugs, which includes the compounds disclosed herein, buffers and other components for preparing the drugs into a usable form, and / or a device for delivering such drugs, and / or any drug for combination therapy with the compounds of the Disclosure, and / or disease treatment instructions in the drug package. These instructions may be fixed in any tangible medium such as printed paper, or in a computer-readable magnetic or optical medium, or in instructions referencing a remote computer data source (e.g., a World Wide Web page accessible via the Internet).

[0110] Treatment method The compounds disclosed herein are KRAS G12D It can be used as a therapeutic active substance to treat and / or prevent RAS-related diseases or conditions such as those described above.

[0111] In some embodiments, the present disclosure is a method for suppressing cellular signaling via the RAS, comprising: a cell (e.g., a cancer cell); and an effective amount of one or more compounds of the present disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)); and compounds of formula II (e.g., formula II The present invention provides a method comprising contacting a compound of formula III (e.g., formula III-1, III-2, III-3, II-4, III-5, III-6, III-7, III-8, or III-9), any of the compounds shown in Table A of this disclosure or any pharmaceutically acceptable salt thereof, with a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9). The suppression of signal transduction via the RAS can be evaluated and demonstrated by various methods known in the art. Non-limiting examples include (a) decreased GTPase activity of RAS; (b) decreased GTP binding affinity or increased GDP binding affinity; (c) K of GTP off Improvement or GDP off (d) a decrease in the levels of downstream signaling molecules of the RAS pathway, such as pMEK, pERK, or pAKT; and / or (e) a decrease in the binding of the RAS complex to downstream signaling molecules (including, but not limited to, Raf). Kits and commercially available assay methods are used to measure one or more of the above.

[0112] In some embodiments, this disclosure relates to KRAS in cells (e.g., cancer cells). G12D , HRAS G12D and / or NRAS G12DA method for inhibiting a cell, comprising: and an effective amount of one or more of the compounds of the present disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) and compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2 The present invention provides a method comprising contacting a compound of formula III (e.g., formula III-1, III-2, III-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof) with a compound of formula III.

[0113] In some embodiments, this disclosure relates to KRAS mutant proteins in cells (e.g., cancer cells), for example, KRAS in cells. G12DA method for inhibiting a cell, comprising: and an effective amount of one or more of the compounds of the present disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) and compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2 The present invention provides a method comprising contacting a compound of formula III (e.g., formula III-1, III-2, III-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof) with a compound of formula III.

[0114] In some embodiments, the present disclosure is a method for inhibiting the proliferation of a group of cells (e.g., a group of cancer cells), comprising the group of cells and an effective amount of one or more compounds of the present disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), compounds of formula II (e.g., formula II-1) The present invention provides a method comprising contacting a compound of formula III (e.g., formula III-1, III-2, III-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), any compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, inhibition of proliferation is measured as a decrease in the cellular vitality of the cell population.

[0115] In some embodiments, the present disclosure is a method for treating cancer in a test subject, wherein the test subject is given one or more therapeutically effective amounts of the compounds of the present disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, The present invention provides a method comprising administering a therapeutically effective amount of a compound of formula III (e.g., formula III-1, III-2, III-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition relating to this disclosure. In some embodiments, the cancer is pancreatic cancer, lung cancer, colorectal cancer, endometrial cancer, appendiceal cancer, bile duct cancer, bladder urothelial carcinoma, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, or hematological malignancy. In some embodiments, the examinee is KRAS G12D , HRAS G12D and / or NRAS G12D It has mutations.

[0116] In some embodiments, the present disclosure is a method for treating cancer metastases or tumor metastases in a test subject, wherein the test subject is given one or more therapeutically effective amounts of the compounds of the present disclosure (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)), compounds of formula II (e.g., formulas II-1, II-2, II- The present invention provides a method comprising administering a therapeutically effective amount of a pharmaceutical composition relating to this disclosure (2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount thereof.

[0117] In some embodiments, the test subject needs to have a disease or condition (e.g., cancer associated with the G12D mutation in KRAS, HRAS and / or NRAS, e.g., KRAS G12DThe present invention provides a method for treating cancers related to [the subject]. In some embodiments, the method provides a therapeutically effective amount of the compounds of the present disclosure to a test subject (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E2, I The process involves administering a therapeutically effective amount of a pharmaceutical composition relating to this disclosure (I-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition relating to this disclosure.

[0118] In some embodiments, a method for treating cancer, wherein an effective amount of any compound disclosed (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12)) and compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2- The present invention provides a method comprising administering a pharmaceutical composition of a compound of formula III (e.g., formula III-1, III-2, III-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any compound shown in Table A of this disclosure or any pharmaceutically acceptable salt thereof, or a compound of a compound of the present disclosure. In some embodiments, the cancer comprises a G12D mutation in KRAS, HRAS, and / or NRAS, e.g., a KRAS-G12D mutation. It is known in the art that a tumor or cancer may contain a G12D mutation in KRAS, HRAS, and / or NRAS by PCR kits or DNA sequencing. In various embodiments, the cancer may be pancreatic cancer, colorectal cancer, lung cancer, or endometrial cancer. In some embodiments, the cancer may be appendiceal cancer, cholangiocarcinoma, urothelial carcinoma of the bladder, ovarian cancer, gastric cancer, breast cancer, or bile duct cancer. In some embodiments, the cancer may be a hematological malignancy (e.g., acute myeloid leukemia).

[0119] In some embodiments, the present disclosure provides a method for treating a disease or condition mediated by a Ras mutant protein (e.g., K-Ras, H-Ras, and / or N-Ras) in a test subject who needs it, a) confirming whether the test subject has a Ras mutation; and b) if the test subject is confirmed to have a Ras mutation, administering to the test subject a therapeutically effective amount of at least one compound of the present disclosure (e.g., a compound of formula I (e.g., I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10) The present invention provides a method comprising administering a compound of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E2, II-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2, or II-2-C-E2), a compound of formula III (e.g., formulas III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any compound shown in Table A of this disclosure or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition relating to this disclosure. In some embodiments, the disease or condition is a cancer, such as lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, colorectal cancer, endometrial cancer, appendiceal cancer, bile duct cancer, bladder urothelial carcinoma, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, or a hematological malignancy such as acute osteomyelitis. In some embodiments, the disease or condition is a polypoid disorder associated with MYH.

[0120] In some embodiments, the present disclosure is a method for treating a disease or condition (e.g., cancer as described herein) in a test subject who needs to treat a disease or condition (e.g., cancer as described herein), wherein the test subject has a G12D mutation in KRAS, HRAS and / or NRAS, e.g., KRAS G12D To confirm whether the person has the mutation, and for the examinee to have KRAS, HRAS and / or NRAS G12DIf a mutation is confirmed, for example, the KRAS G12D mutation, the examinee will be required to take at least one of the compounds of this disclosure in an effective therapeutic dose (e.g., compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12) or compounds of formula II (e.g., formulas II-1, II-2, II-2-E1, II-2-E2, II-3) The present invention provides a method comprising administering a pharmaceutical composition comprising (II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II-2-B-E2 or II-2-C-E2), a compound of formula III (e.g., formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9), any of the compounds shown in Table A of this disclosure or any pharmaceutically acceptable salt thereof), or at least one compound of this disclosure.

[0121] G12D mutations in KRAS, HRAS, and / or NRAS have already been found in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain embodiments relate to methods for treating hematological malignancies in examinees who need such treatment, typically comprising administering the compounds of the Disclosure (e.g., as pharmaceutical compositions) to the examinee. Such malignancies include, but are not limited to, leukemias and lymphomas, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute mononuclear leukemia (AMoL), and / or other leukemias. In some embodiments, hematological malignancies also include lymphomas such as Hodgkin lymphoma or non-Hodgkin lymphoma, plasma cell malignancies such as multiple myeloma, epithelial cell lymphoma, and Fahrenheit macroglobulinemia.

[0122] The compounds of this disclosure can be used as monotherapy or in combination therapy. In some embodiments, combination therapy involves treating the subject with a chemotherapy agent, therapeutic antibody, radiation, cell therapy, or immunotherapy. In some embodiments, the compounds of this disclosure may be further used in combination with additional pharmacoactive compounds to treat the subject who requires them (e.g., KRAS according to this specification). G12D The compounds can be administered simultaneously to test subjects with mutation-related cancers, or in any order. In some embodiments, additional pharmacoactive compounds may be targeted agents (e.g., MEK inhibitors), chemotherapeutic agents (e.g., cisplatin or docetaxel), therapeutic antibodies (e.g., anti-PD-1 antibodies), etc. Any known therapeutic agent can be used in combination with the compounds of this disclosure. In some embodiments, the compounds of the present invention can be used in combination with radiotherapy, hormone therapy, cell therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0123] The compounds of this disclosure can be used in combination with various chemotherapeutic agents currently known in the art. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules, such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), venetoclax, and Adriamycin and a series of chemotherapeutic agents. Non-limiting examples of chemotherapy agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and pigosulfan; aziridines such as benzodopa, carboquan, meturedopa and uredopa; and etiletamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine. Ethylenes and methylamelamines; chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, dichloromethyl mechloretamine hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trophosphamide, uracil mustard, and other nitrogen mustards; carmustine, chlorozotosine, fotemustine, lomustine, nimustine, ranimustine, and other nitrosureas;Aclacinomycins, actinomycin, autoramycin, azaserin, bleomycin, kakutinomycin C, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olivomycins, peplomycin, potfiromycin, puromycin, keramycin, ro Antibiotics such as dorbicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepithiostan, and testotractone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; frolinic acid Folic acid supplements such as acid; acegraton; aldofamide glycosides; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolsin; diaziquan; elfomithine; eriptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; ronidamin; mitoglucon; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet;This includes pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex; razoxane; schizophyllan; spirogermanium; tenuazonic acid; triadiquan; 2,2′,2′′′-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobromane; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes such as paclitaxel and docetaxel; retinoic acid; esperamicin; capecitabine; and any pharmacokinetically acceptable salts, acids, or derivatives of the above.

[0124] Appropriate chemotherapeutic cell modulators include antihormone agents that act to modulate or inhibit hormonal effects on tumors, such as tamoxifen (Nolvadex™), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, and LY. 117018, including anti-estrogen agents such as onapristone and toremifene (Fareston); and anti-androgenic drugs such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0125] If necessary, the compounds or pharmaceutical compositions of this disclosure may be used in combination with commonly prescribed anticancer drugs, such as Herceptin®, Avastin®, Elbitax®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, Avisin, Avagovomab, Acridine Carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, and 3-Aminopyridine-2-carboxaldehyde Thiosemicarbazone. thiosemicarbazone), amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drug, antitumor herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, afatinib 2992 (BIBW 2992), biricoda, brostarlicin, bryostatin, butionine sulfoximine, CBV (chemotherapy), calculin, cell cycle nonspecific antitumor drug, dichloroacetic acid, discorder molide, erusamitrusine, enocitabine, epothirone, eribulin, everolimus, exatecan, exislind, ferginol, forodesine, phosfestrol, ICE chemotherapy regimen, IT-101, imexone, imiquimod, India Locarbazole, Ilofluben, Lanikidar, Larotaxel, Lenalidomide, Lucanton, Lulutotecan, Maphosphamide, Mitozolomide, Nafoxidin, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitors, Rebeccamycin, Reciquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford VV) It can be used in combination with Swinesonin, talaporfin, tariquidar, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uracil mustard, vadimezan, vinflunin, ZD6126, or zosuquidar.

[0126] The compounds of this disclosure can further be used in combination with additional pharmaceutically active compounds that disrupt or inhibit the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway. In other such combinations, the additional pharmaceutically active compounds are PD-1 and PD-L1 antagonists. The compounds or pharmaceutical compositions of this disclosure can further be used in combination with a certain amount of one or more substances selected from the group consisting of EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40 agents, GITR agonists, CAR-T cells and BiTEs.

[0127] Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (Disclosure No. WO 2006 / 121168) A1) discloses exemplary anti-PD-1 or anti-PD-L-1 antibodies and methods of use thereof, each explicitly addressed herein by reference, including pembrolizumab (Keytruda®), nivolumab (Opdivo®), Yervoy® (pirimumab), or tremelimumab (anti-CTLA-4), galiximab (anti-B7.1), M7824 (bifunctional anti-PD-L1 / TGF-βTrap fusion protein), AMP224 (anti-B7DC), BMS-936559 (anti-B7-H1), MPDL3280A (anti-B7-H1), MEDI-570 (anti-ICOS), and AMG. This includes 404, AMG557 (anti-B7H2), MGA271 (anti-B7H3), IMP321 (anti-LAG-3), BMS-663513 (anti-CD137), PF-05082566 (anti-CD137), CDX-1127 (anti-CD27), anti-OX40 (Providence Health Services), huMAbOX40L (anti-OX40L), Ataccept (anti-TACI), CP-870893 (anti-CD40), Lucatumumab (anti-CD40), Dacetuzumab (anti-CD40), Muromonab-CD3 (anti-CD3), and Ipilumumab (anti-CTLA-4). The immunotherapy further includes genetically modified T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs). Additional reagents of non-limiting usefulness further include anti-EGFR antibodies and small molecule EGFR inhibitors, such as cetuximab (Erbitux), panitumumab (Vectibix), zaltumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, and osimertinib.Additional reagents of non-limiting usefulness further include CDK inhibitors, e.g., CDK4 / 6 inhibitors, e.g., palbociclib, abemaciclib, ribociclib, dinaciclib, etc. Additional reagents of non-limiting usefulness further include MEK inhibitors, e.g., trametinib and binimetinib. Additional reagents of non-limiting usefulness further include SHP2 inhibitors, e.g., TNO155, RMC-4630 and RLY-1971.

[0128] The administration of the present disclosure is not limited to a specific route of administration. For example, in some embodiments, the method of administration may be oral, nasal, transdermal, pulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral administration. In some embodiments, the method of administration is oral administration.

[0129] The dosage regimen, including the administration plan, may vary and be adjusted depending on the patient being treated, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether it is used in combination with other drugs.

[0130] definition Furthermore, it should be understood that all components and their combinations maintain an appropriate compound value.

[0131] It should be understood that specific embodiments of the variable parts relating to this disclosure may be the same as or different from other specific embodiments having the same reference numerals.

[0132] The appropriate atoms or groups used in the variables of this disclosure are selected independently. The definitions of the variables may be combined. For example, in formula I, R in formula I... 1 , R 3 , G 1 , A 1 , A 2 , G 2 , G 3 , R100 、 either the definition of one of m, n1, and n2, R in formula I 1 、 R 3 、 G 1 、 A 1 、 A 2 、 G 2 、 G 3 、 R 100 、 may also be combined with the definition of any one of the others of m, n1, and n2. Such combinations are also invented and are within the scope of the present invention.

[0133] The definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, inside cover of Handbook of Chemistry and Physics, 75th Edition), and specific functional groups are generally defined as described herein. Also, the general principles of organic chemistry, and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March′s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary lists of substituents described herein.

[0134] The compounds of this disclosure may contain one or more chiral centers and / or axial chirality, and thus may exist in various isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds of this disclosure may be in the form of individual enantiomers, diastereomers, atropisomers, or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); and Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure further includes the compounds relating to the disclosure as individual isomers that do not contain other isomers in any particular sense, or as mixtures of various isomers, including racemic mixtures. In embodiments of the present disclosure, unless otherwise specified, when stereochemistry is specifically described, it should be understood that, with respect to a particular chiral center or axial chirality, the compound exists primarily as the described stereoisomer and has other stereoisomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable, for example, by weight, by HPLC area, or both. According to the present disclosure, those skilled in the art can determine the presence and / or amount of stereoisomers by methods including determination by chiral HPLC.

[0135] The compounds of the present disclosure can have atropisomers. In any embodiment according to the present disclosure, when applicable, the compounds of the present disclosure can exist as a mixture of atropisomers in any ratio. In some embodiments, when applicable, the compound can exist as an isolated single atropisomer and substantially does not contain other atropisomers (e.g., contains less than 20%, less than 10%, less than 5%, less than 1% by weight, in HPLC area, or both, or has an undetectable amount). The Examples section shows some exemplary isolated atropisomers of the compounds of the present disclosure. As will be understood by those skilled in the art, when rotation around a single bond (e.g., the single bond of a biaryl group) is restricted, the compound exists as a mixture of atropisomers, and each single atropisomer can be isolated.

[0136] When describing a range of values, it is intended to encompass each value and subrange within the range. For example, "C" 1~6 " means C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 are intended to be encompassed.

[0137] As used in this disclosure, the terms “a compound of the present disclosure” or “a compound of the present invention” mean the compounds of formula I (e.g., formulas I-1, I-2, I-3, I-1-A, I-2-A, I-3-A, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-4-E1, I-1-A-4-E2, I-1-A-5, I-1-A-6, I-1-A- 7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), compounds of formula II (e.g. formula II-1, II-2, II-2-E1, II-2-E2, I I-3, II-1-A, II-1-B, II-1-C, II-2-A, II-2-B, II-2-C, II-2-A-E1, II-2-B-E1, II-2-C-E1, II-2-A-E2, II This means compounds of formula III (e.g., formulas III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9), any of the compounds shown in Table A of this disclosure, any of the title compounds of the Examples section or those compounds identified in Table 1, their isotopically labeled compounds (e.g., deuterium analogs in which one of the hydrogen atoms is substituted with a deuterium atom, and the abundance of the deuterium atom is higher than its natural abundance), their possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), geometric isomers, atropisomers, tautomers, conformosomers, and / or pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). Hydrates and solvates of the compounds of this disclosure are recognized as compositions of this disclosure, in which the compounds are coupled with water or a solvent, respectively.

[0138] The compounds of this disclosure may exist in isotopically labeled or isotopically rich forms, containing one or more atoms having atomic weights or mass numbers different from those most abundant in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include 2 H, 3 H, 13 C, 14C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 This includes, but is not limited to, I. Compounds containing these and / or other isotopes of atoms are within the scope of the present invention.

[0139] As used in this disclosure, the terms “administer” the compound, “administer” the compound, or other variations thereof mean providing the compound or a prodrug of the compound to an individual in need of treatment.

[0140] As used in this disclosure, the term “alkyl group” means a linear or branched aliphatic saturated hydrocarbon when used alone or as part of another group. In some embodiments, an alkyl group consists of 1 to 12 carbon atoms (i.e., C 1~12 It may include an alkyl group or a specified number of carbon atoms (i.e., a C1 alkyl group, e.g., a methyl group; a C2 alkyl group, e.g., an ethyl group; a C3 alkyl group, e.g., a propyl group or an isopropyl group, etc.). In one embodiment, the alkyl group is a linear C 1~10 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~10 It is an alkyl group. In another embodiment, the alkyl group is a linear C 1~6 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~6 It is an alkyl group. In another embodiment, the alkyl group is a linear C 1~4 It is an alkyl group. In one embodiment, the alkyl group is selected from the group consisting of methyl group, ethyl group, propyl group (n-propyl group), isopropyl group, butyl group (n-butyl group), sec-butyl group, tert-butyl group and isobutyl group. 1~4It is an alkyl group. As used in this disclosure, the term “alkylene group” means a divalent group derived from an alkyl group, when used alone or as part of another group. For example, non-limiting linear alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0141] As used in this disclosure, the term “heteroalkyl group” means an alkyl group defined as having one or more carbon atoms substituted with a complex atom (e.g., O or N). Those skilled in the art will understand that an O atom substitutes a CH2 unit and an N atom substitutes a CH unit. Heteroalkyl groups can be specified by their number of carbon atoms. For example, C 1~4 A heteroalkyl group refers to a heteroalkyl group containing one to four carbon atoms. Examples of heteroalkyl groups include, but are not limited to, -O-CH2CH2-OCH3, HO-CH2CH2-O-CH2-, -CH2CH2-N(H)-CH3, -N-(CH3)2, -CH(CH3)(OCH3), etc. If optionally substituted, the heteroatoms or carbon atoms of the heteroalkyl group may be substituted with acceptable substituents. As used in this disclosure, the term “heteroalkylene group” means a divalent group derived from a heteroalkyl group, when used alone or as part of another group.

[0142] As used in this disclosure, the term “alkenyl group” means a linear or branched fatty hydrocarbon containing one or more, for example, one, two, or three carbon-carbon double bonds, when used alone or as part of another group. In one embodiment, the alkenyl group is C 2~6 It is an alkenyl group. In another embodiment, the alkenyl group is C 2~4 These are alkenyl groups. Non-exclusive exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl groups.

[0143] As used in this disclosure, the term “alkynyl group” means a linear or branched fatty hydrocarbon containing one or more, for example, one to three carbon-carbon triple bonds, when used alone or as part of another group. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2~6 In another embodiment, the alkynyl group is C 2~4 These are alkynyl groups. Non-exclusive exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0144] As used in this disclosure, the term “alkoxy group” means a group of the formula OR when used alone or as part of another group. a1 It means the base of, and among them, R a1 However, it is an alkyl group.

[0145] As used in this disclosure, the term “haloalkyl group” means an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms, when used alone or as part of another group. In preferred embodiments, a haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C 1~4 It is a haloalkyl group.

[0146] A "carbocyclic group" or "carbocyclic ring" is a non-aromatic ring system that, when used alone or as part of another group, consists of 3 to 10 ring-forming carbon atoms ("C"). 3-10The term "carbocyclic group" refers to a non-aromatic cyclic hydrocarbon group having zero heteroatoms. A carbocyclic group may be monocyclic ("monocyclic carbocyclic group"), or bicyclic, including condensation, bridging, or spirocyclic systems ("bicyclic carbocyclic group"), and may be saturated or partially unsaturated. A "carbocyclic group" also includes a cyclic system in which the carbocyclic group defined above is condensed with one or more aryl or heteroaryl groups, the linkage being on the carbocyclic ring, and in this case, the number of carbon atoms still represents the number of carbon atoms in the carbocyclic system. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, dekalinyl, adamantyl, cyclopentenyl, and cyclohexenyl groups.

[0147] In some embodiments, "carbon ring group" refers to a monocyclic saturated carbon ring group having 3 to 10 ring-forming carbon atoms ("C 3~10 A cycloalkyl group is a cycloalkyl group. In some embodiments, the cycloalkyl group consists of 3 to 8 ring-forming carbon atoms ("C"). 3~8 The cycloalkyl group has 3 to 6 ring-forming carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 6 ring-forming carbon atoms ("C"). 3~6 The cycloalkyl group has 5 to 6 ring-forming carbon atoms ("C"). In some embodiments, the cycloalkyl group has 5 to 6 ring-forming carbon atoms ("C"). 5~6 The cycloalkyl group has 5 to 10 ring-forming carbon atoms ("C"). In some embodiments, the cycloalkyl group has 5 to 10 ring-forming carbon atoms ("C"). 5~10 It has a cycloalkyl group.

[0148] "Heterocyclic group" or "heterocyclic" means a 3- to 10-membered non-aromatic ring group ("3- to 10-membered heterocyclic group") having a ring-forming carbon atom and 1 to 4 ring-forming heteroatoms (wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) when used alone or as part of another group. Where the compound value is acceptable, in a heterocyclic group containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom. A heterocyclic group may be monocyclic ("monocyclic heterocyclic group"), condensed, bridged, or spirocyclic, for example, a bicyclic ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A heterocyclic or bicyclic system may contain one or more heteroatoms in one or two rings. A "heterocyclic group" also includes a ring system formed by the fusion of a heterocyclic group as defined above with one or more carbocyclic groups, where the linking point is located on a carbocyclic group or a heterocyclic group, and a ring system formed by the fusion of a heterocyclic group as defined above with one or more aryl or heteroaryl groups, where the linking point is located on a heterocyclic group, and in this case, the number of ring members still represents the number of ring members in the heterocyclic system.

[0149] A three-membered heterocyclic group containing an exemplary single heteroatom includes, but is not limited to, an azilidinyl group, an oxyranyl group, and a thyranyl group. A four-membered heterocyclic group containing an exemplary single heteroatom includes, but is not limited to, an azetidinyl group, an oxetanyl group, and a thietanyl group. A five-membered heterocyclic group containing an exemplary single heteroatom includes, but is not limited to, a tetrahydrofuryl group, a dihydrofuryl group, a tetrahydrothienyl group, a dihydrothienyl group, a pyrrolidinyl group, a dihydropyrrolyl group, and pyrrole-2,5-dione. A five-membered heterocyclic group containing exemplary two heteroatoms includes, but is not limited to, a dioxolane, an oxathiolane, a dithiolanyl group, and an oxazolidine-2-one. A five-membered heterocyclic group containing exemplary three heteroatoms includes, but is not limited to, a triazolinyl group, an oxadiazolinyl group, and a thiadiazolinyl group. A six-membered heterocyclic group containing one exemplary heteroatom includes, but is not limited to, a piperidinyl group, a tetrahydropyranyl group, a dihydropyridinyl group, and a tetrahydrothianyl group. A six-membered heterocyclic group containing two exemplary heteroatoms includes, but is not limited to, a piperazinyl group, a morpholinyl group, a 1,4-dithianyl group, and a dioxanyl group. A six-membered heterocyclic group containing two exemplary heteroatoms includes, but is not limited to, a triazinyl group. A seven-membered heterocyclic group containing one exemplary heteroatom includes, but is not limited to, an azepanyl group, an oxepanyl group, and a thiepanyl group. An eight-membered heterocyclic group containing one exemplary heteroatom includes, but is not limited to, an azokanyl group, an oxecanyl group, and a thiokanyl group. The five-membered heterocyclic group (hereinafter also referred to as a 5,6-bicyclic heterocycle) that condenses with an exemplary C6 aryl ring includes, but is not limited to, an indolyl group, an isoindolyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a benzoxazolinonyl group, and the like. The six-membered heterocyclic group (hereinafter also referred to as a 6,6-bicyclic heterocycle) that condenses with an exemplary aryl ring includes, but is not limited to, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, and the like.

[0150] An "aryl group" is an aromatic ring group ("C") used alone or as part of another group. 6~14 An aryl group is a monocyclic or polycyclic (e.g., dicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a ring array) provided by an aryl group, comprising 6 to 14 carbon atoms and 0 heteroatoms. In some embodiments, the aryl group has 6 ring-forming carbon atoms ("C6 aryl group"; e.g., a phenyl group). In some embodiments, the aryl group has 10 ring-forming carbon atoms ("C6 aryl group"). 10 The aryl group has an aryl group (for example, a naphthyl group, e.g., a 1-naphthyl group and a 2-naphthyl group). In some embodiments, the aryl group has 14 ring-forming carbon atoms ("C"). 14 Having an "aryl group" (e.g., an anthuryl group). The "aryl group" further includes ring systems formed by the fusion of the aryl ring defined above with one or more carbocyclic or heterocyclic groups, where the radical or linkage point is on the aryl ring, and in this case, the number of carbon atoms still represents the number of carbon atoms in the aromatic ring system.

[0151] An "aralkyl group" is an alkyl group that, when used alone or as part of another group, is substituted with one or more aryl groups, preferably with one aryl group. Examples of aralkyl groups include benzyl and phenethyl groups. When it is stated that the aralkyl group may be substituted, the alkyl group portion or the aryl group portion of the aralkyl group may be substituted.

[0152] A "heteroaryl group" is a group having a 5-10 member monocyclic or dicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared in a ring array) of a ring-forming carbon atom and 1-4 ring-forming heteroatoms (where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur) when used alone or as part of another group ("5-10 member heteroaryl group"). Where the compound value is acceptable, in a heteroaryl group of one or more nitrogen atoms, the linking point may be a carbon or a nitrogen atom. A heteroaryl dicyclic system contains one or more heteroatoms in one or two rings. A "heteroaryl group" is formed by the condensation of the heteroaryl ring defined above with one or more carbocyclic or heterocyclic groups, including ring systems where the linking point is in the heteroaryl ring, and in this case, the number of ring members still represents the number of ring members in the heteroaryl ring system. A "heteroaryl group" also includes a ring system formed by the condensation of a heteroaryl ring as defined above with one or more aryl groups, where the linking point is located in an aryl group or a heteroaryl ring, and in this case, the number of ring members represents the number of ring members in the fused (aryl group / heteroaryl group) ring system. Among these, a dicycloheteroaryl group in which one ring does not contain a heteroatom (e.g., an indolyl group, a quinolinyl group, a cabazolyl group, etc.) may have its linking point in either ring, i.e., in a ring with a heteroatom (e.g., a 2-indolyl group) or in a ring without a heteroatom (e.g., a 5-indolyl group).

[0153] A 5-membered heteroaryl group containing one exemplary heteroatom includes, but is not limited to, a pyrrolyl group, a furyl group, and a thienyl group. A 5-membered heteroaryl group containing two exemplary heteroatoms includes, but is not limited to, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, and an isothiazolyl group. A 5-membered heteroaryl group containing three exemplary heteroatoms includes, but is not limited to, a triazolyl group, an oxadiazolyl group, and a thiadiazolyl group. A 5-membered heteroaryl group containing four exemplary heteroatoms includes, but is not limited to, a tetrazolyl group. A 6-membered heteroaryl group containing one exemplary heteroatom includes, but is not limited to, a pyridinyl group. A 6-membered heteroaryl group containing two exemplary heteroatoms includes, but is not limited to, a piperazinyl group, a pyrimidinyl group, and a pyrazinyl group. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, a triazinyl group and a tetradinyl group, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, an azepinyl group, an oxepinyl group and a thiepinyl group. Exemplary 5,6-dicycloheteraryl groups include, but are not limited to, an indolyl group, an isoindolyl group, an indazolyl group, a benzotriazolyl group, a benzothienyl group, an isobenzothienyl group, a benzofuryl group, a benzoisofuryl group, a benzimidazolyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzoxadiazolyl group, a benzothiazolyl group, a benzoisothiazolyl group, a benzothiadiazolyl group, an indolidinyl group and a prinyl group. Exemplary 6,6-dicycloheteroaryl groups include, but are not limited to, naphthilidinyl, pteridinyl, quinolinyl, isoquinolinyl, synnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl groups.

[0154] A "heteroaralkyl group" is an alkyl group that, when used alone or as part of another group, is substituted with one or more heteroaryl groups, preferably with one heteroaryl group. When it is stated that the heteroaralkyl group may be substituted, the alkyl group portion or the heteroaryl group portion of the heteroaralkyl group may be substituted.

[0155] As is generally understood by those skilled in the art, alkylene groups, alkenylene groups, alkynylene groups, carbocyclylene groups, heterocyclylene groups, arylene groups, and heteroarylene groups are the corresponding divalent groups of alkyl groups, alkenyl groups, alkynyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups, respectively.

[0156] The terms “substitutable” groups, such as optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, mean either unsubstituted or substituted groups. Typically, the term “substitutable” precedes the term “optional” but is a substituent in which at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is substituted with an acceptable substituent, such that the substitution thereon produces a stable compound, for example, a compound that is not subject to spontaneous transformation (e.g., rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, an “optional” group has substituents at one or more substituted positions on the group, and if multiple positions on any given structure are substituted, the substituents may be the same or different at each position. The substituents may, as they may be, carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents.

[0157] Unless otherwise expressly stated, combinations of substituents and / or variables are permitted only if such combinations result in a chemically acceptable and stable compound. A “stable” compound is one that can be manufactured and isolated, and whose structure and properties remain unchanged or essentially unchanged for a period sufficient to enable the use of the compound for the purposes described herein (e.g., therapeutic administration to a test subject).

[0158] In some embodiments, the "may be substituted" alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic groups in this disclosure may be unsubstituted, or may be substituted with 1, 2, 3, or 4 substituents, the substituents independently of F, Cl, -OH, protected hydroxyl group, oxo group (if applicable), NH2, protected ammonia group, NH(C) 1~4 Alkyl alkyl groups) or their protected derivatives, N(C 1~4 (Alkyl group)(C 1~4 (Alkyl alkyl group), C 1~4 Alkyl alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 3~6 A group selected from the group consisting of a cycloalkoxy group, a phenyl group, a 5 or 6-membered heteroaryl group containing 1, 2 or 3 independently selected ring-forming heteroatoms from the group consisting of O, S and N, and a 3 to 7-membered heterocyclic group containing 1 or 2 independently selected ring-forming heteroatoms from the group consisting of O, S and N, wherein each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, cycloalkoxy group, phenyl group, heteroaryl group, and heterocyclic group may be substituted with 1, 2 or 3 substituents, and the substituents may independently be F, -OH, oxo group (if applicable), C 1~4 Alkyl alkyl groups, fluorine-substituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy groups and fluorine-substituted C 1~4It is selected from the group consisting of alkoxy groups. In some embodiments, the "optionally substituted" aryl group or heteroaryl group in the present disclosure may be unsubstituted or may be substituted with 1, 2, 3 or 4 substituents, and the substituents are independently F, Cl, -OH, -CN, NH2, protected ammonia group, NH(C 1~4 alkyl group) or a protected derivative thereof, N(C 1~4 alkyl group)(C 1~4 alkyl group), -S(=O)(C 1~4 alkyl group), -SO2(C 1~4 alkyl group), C 1~4 alkyl group, C 2~4 alkenyl group, C 2~4 alkynyl group, C 1~4 alkoxy group, C 3~6 cycloalkyl group, C 3~6 cycloalkoxy group, phenyl group, 5- or 6-membered heteroaryl group containing 1, 2 or 3 ring-forming heteroatoms independently selected from the group consisting of O, S and N, 3- to 7-membered heterocyclic group containing 1 or 2 ring-forming heteroatoms independently selected from the group consisting of O, S and N, and among them, each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, cycloalkoxy group, phenyl group, heteroaryl group and heterocyclic group may be substituted with 1, 2 or 3 substituents, and the substituents are independently F, -OH, oxo group (when applicable), C 1~4 alkyl group, fluorine-substituted C 1~4 alkyl group, C 1~4 alkoxy group and fluorine-substituted C 1~4 alkoxy group, and are selected from the group consisting of.

[0159] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SRaa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)Raa ,-P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbon ring group, 3-14 membered heterocyclic group, C 6~14 This includes, but is not limited to, aryl groups and 5-14 membered heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently contains 0, 1, 2, 3, 4, or 5 R dd Substituted with the base; among them, X- However, it is a counterion; or, two gem hydrogens on a carbon atom form the group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb or =NOR cc Replaced by;R aa Each of these examples is independent of C 1~10 Alkyl alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbon ring group, 3-14 membered heterocyclic group, C 6~14 Selected from the group consisting of aryl groups and 5-14 membered heteroaryl groups, or two R aa The groups are linked together to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, in which each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R bb Each of these examples is independent of hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)(R aa)2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbon ring group, 3-14 membered heterocyclic group, C 6~14 Selected from the group consisting of aryl groups and 5-14 membered heteroaryl groups, or two R bb The groups are linked together to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, in which each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; among them X - However, it is a counterion; R cc Each of these examples is independent of hydrogen, C 1~10 Alkyl alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbon ring group, 3-14 membered heterocyclic group, C 6~14 Selected from the group consisting of aryl groups and 5-14 membered heteroaryl groups, or two R cc The groups are linked together to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, in which each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R dd Each of these examples is independent of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee-SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2,-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)(OR) ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. C 1~6 Arukaraki, C 1~6 Haruka Raki, C 2-6 アルケニbase, C 2-6 アルキニbased, C 3~10 Carbon ring group, 3~10 member complex ring group, C6~10 Selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by the base, or two gem R dd The substituents may be linked to form =O or =S; among them X - is a counterion; R ee Each of these examples is independent of C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 carbocyclic group, C 6~10 Selected from the group consisting of aryl groups, 3-10 membered heterocyclic groups, and 3-10 membered heteroaryl groups, each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with the base; R ff Each of these examples is independent of hydrogen, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 Carbon ring group, 3-10 membered heterocyclic group, C 6~10 Selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, or two R ff The groups are linked together to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, in which each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base; and R gg Each of these examples is independent of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OC. 1-6 Alkyl, -ON(C 1-6Alkyl(2,-N(C) 1-6 Alkyl(2,-N(C) 1-6 (Alkyl)3 + X - , -NH(C 1-6 Alkyl(2) + X - -NH2(C 1-6 (Alkyl group) + X - , -NH3 + X - , -N(OC 1-6 (Alkyl group)(C 1-6 Alkyl(alkyl group), -N(OH)(C 1-6 Alkyl(-), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl(alkyl group), -C(=O)(C 1-6 Alkyl()), -CO2H, -CO2(C 1-6 Alkyl(alkyl group), -OC(=O)(C 1-6 Alkyl(alkyl group), -OCO2(C 1-6 Alkyl(alkyl group), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl(alkyl)2,-OC(=O)NH(C 1-6 Alkyl(alkyl group), -NHC(=O)(C 1-6 Alkyl(C)(-N(C)) 1-6 Alkyl(C)(=O)(C) 1-6 Alkyl(alkyl group), -NHCO2(C 1-6 Alkyl(alkyl group), -NHC(=O)N(C 1-6 Alkyl(2),-NHC(=O)NH(C) 1-6 Alkyl(alkyl group), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl(alkyl group),-OC(=NH)(C 1-6 Alkyl(alkyl group), -OC(=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl(2),-C(=NH)NH(C 1-6 Alkyl(alkyl group), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl(alkyl)2,-OC(NH)NH(C 1-6 alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl(2), -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl(alkyl group), -SO2N(C 1-6 Alkyl(alkyl)2,-SO2NH(C 1-6 Alkyl(alkyl group), -SO2NH2,-SO2C 1-6 Alkyl alkyl groups, -SO2OC 1-6 Alkyl alkyl group, -OSO2C 1-6 Alkyl alkyl groups, -SOC 1-6 Alkyl group, -Si(C 1-6 Alkyl(3), -OSi(C 1-6 Alkyl(3-C(=S)N(C) 1-6 Alkyl(2), C(=S)NH(C 1-6 Alkyl(C), C(=S)NH2, -C(=O)S(C 1-6 Alkyl(alkyl group), -C(=S)SC 1-6 Alkyl group, -SC(=S)SC 1-6 Alkyl alkyl group, -P(=O)(OC 1-6 Alkyl(2), -P(=O)(C 1-6 Alkyl(2), -OP(=O)(C 1-6 Alkyl(2), -OP(=O)(OC 1-6 Alkyl(2), C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 carbocyclic group, C 6~10 It is an aryl group, a 3-10 membered heterocyclic group, or a 5-10 membered heteroaryl group; or two gem R gg The substituents may be linked to form =O or =S; among them X - This is a counterion.

[0160] A "counterion" or "anion counterion" is a negatively charged group that is associated with a positively charged group to maintain neutrality. Anion counterions may be monovalent (i.e., containing one formal negative charge). Anion counterions may be polyvalent (i.e., containing one or more formal negative charges), for example, divalent or trivalent. An example counterion is a halogen ion (e.g., F- Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - HSO4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, ethane-1-sulfonic acid-2-sulfonate ion, etc.), carbolate ions (e.g., acetate ion, propionate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, gluconate ion, etc.), BF4 - PF4 - PF6 - AsF6 - SbF6 - , B[3,5-(CF3)2C6H3]4] - , BPh4 - Al(OC(CF3)3)4 - and carborane anions (e.g., CB) 11 H 12 - or (HCB 11 Me5Br6) - ) contains. An example of a polyvalent counterion is CO3 2- HPO4 2- , PO4 3- B4O7 2- SO4 2- , S2O3 2-The ions may also be carboxylate anions (for example, tartrate ions, citrate ions, fumarate ions, maleate ions, malate ions, malonate ions, glucose ions, succinate ions, glutarate ions, adipate ions, pimephosphate ions, suberate ions, azelaate ions, sebacate ions, salicylate ions, phthalate ions, aspartate ions, glutamate ions, etc.) and carborane ions.

[0161] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0162] An "acyl group" is -C(=O)R aa -CHO, -CO2R aa -C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa -C(=S)N(R bb )2, -C(=O)SR aa , or -C(=S)SR aa It means a portion selected from a group consisting of R aa and R bb However, this is as defined in this disclosure.

[0163] Where the compound value is acceptable, the nitrogen atom may be substituted or unsubstituted and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )Raa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbon ring group, 3-14 membered heterocyclic group, C 6~14 This includes, but is not limited to, aryl groups and 5- to 14-membered heteroaryl groups, or two R groups linked to a nitrogen atom. cc The groups are linked to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, in which each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently have 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the group, and among them, R aa , R bb , R cc and R dd However, it is defined as described above.

[0164] In some embodiments, the substituent on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and are incorporated by reference in Protectivegroups in Organic Synthesis, TWGreene and PGMWuts, 3 rdExamples of nitrogen protecting groups include those that form carbamic acid esters, such as carboxybenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, Troc, 9-fluorenylmethoxycarbonyl (Fmoc) group, etc.; those that form amides, such as acetyl group, benzoyl group, etc.; those that form benzylamines, such as benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, etc.; those that form sulfamides, such as toluenesulfonyl group, p-nitrobenzenesulfonyl group, etc.; and others, such as p-methoxyphenyl group, etc.

[0165] Exemplary oxygen atom substituents are -R aa -C(=O)SR aa -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2 includes, but is not limited to, X - , R aa , R bb and R ccHowever, this is as defined in this disclosure. In some embodiments, the oxygen atom substituent on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are incorporated by reference in Protectivegroups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This includes, but is not limited to, those described in detail in edition, John Wiley & Sons, 1999. Exemplary oxygen-protecting groups include alkyl ethers or substituted alkyl ethers, e.g., methyl group, allyl group, benzyl group, substituted benzyl group (e.g., 4-methoxybenzyl group), methoxymethyl group (MOM), benzyloxymethyl group (BOM), 2-methoxyethoxymethyl group (MEM), etc.; silyl ethers, e.g., trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), tert-butyldimethylsilyl group (TBDMS), etc.; acetals or ketals, e.g., tetrahydropyranyl group (THP); esters, e.g., formate esters, acetate esters, chloroacetate esters, dichloroacetate esters, trichloroacetate esters, trifluoroacetate esters, methoxyacetate esters, etc.; carbonates, sulfonates, e.g., methanesulfonates (methanesulfonic acid esters), benzylsulfonates and toluenesulfonates (Ts), etc.

[0166] The term "leaving group" has its usual meaning in the field of synthetic organic chemistry, and refers, for example, to an atom or group that can be substituted with a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Suitable examples of leaving groups include, but are not limited to, halogens (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyl groups, aryloxycarbonyl groups, alkylsulfonyloxy groups, arylsulfonyloxy groups, alkylcarbonyl groups (e.g., acetoxy group), arylcarbonyl groups, aryloxy groups, methoxy groups, N,O-dimethylhydroxyamino groups, 9-phenylpyrixyl (pixyl), and haloform ester groups.

[0167] The term "pharmacologically acceptable salt" refers to a salt that, within the bounds of reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. Pharmacologically acceptable salts are well known in the art.

[0168] The term “tautomer” or “tautomerism” refers to two or more compounds that are convertible to each other by the formal transfer of at least one hydrogen atom and at least one change in valence (e.g., single bond to double bond, triple bond to single bond, or vice versa). The exact ratio of tautomers varies depending on several factors, such as temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by an acid or a base. Exemplary tautomerizations include ketone-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(different enamine) tautomerizations.

[0169] As used in this disclosure, the term “test subject” (or “patient” as used in this disclosure) means an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experimentation.

[0170] As used in this Disclosure, the term “treatment” means eliminating, reducing, or improving a disease or condition and / or symptoms associated therewith. Treatment of a disease or condition does not necessarily have to eliminate the disease, condition or symptoms associated therewith, though not excluded. As used in this Disclosure, the terms “treatment,” etc., may include “preventive treatment,” which means reducing the likelihood of a disease or condition recurrence or a previously controlled disease or condition recurrence in a test subject who is at risk of a disease or condition recurrence or a disease or condition recurrence, or who has a tendency to recur a disease or condition recurrence or a disease or condition recurrence, but who has not experienced a recurrence or recurrence of the disease or condition. The term “treatment” and its synonyms mean administering a therapeutically effective amount of the compound relating to this Disclosure to a test subject who requires such treatment.

[0171] As used in this disclosure, the singular forms "a," "an," and "the" include plurals unless explicitly stated otherwise or the context clearly indicates otherwise.

[0172] The term "and / or" as used in phrases such as "A and / or B" in this disclosure is intended to include A and B; A or B; A (alone); B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); C (alone).

[0173] Titles and subtitles are used solely for convenience or formal compliance purposes and are not intended to limit the thematic technology, nor are they related to the interpretation of the description of the thematic technology. In various embodiments, features described under one title or one subtitle of this disclosure may be combined with features described under other titles or subtitles. Furthermore, not all features under a single title or a single subtitle may be used together in the embodiments.

[0174] Examples Various starting materials, intermediates, and compounds of the preferred examples can be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, as needed. Characterization of these compounds can be performed using conventional methods such as melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of the synthesis steps of the products described herein are described in more detail below. JPEG0007860003000081.jpg94166

[0175] Step 1: At 95°C under a nitrogen atmosphere, a mixture of 4-bromonaphthylene-2-ol (3.0 g, 13.4 mmol), bis(pinacolato)diborone (4.1 g, 16.1 mmol), Pd(dppf)Cl2 (0.98 g, 1.35 mmol), and KOAc (3.9 g, 40.3 mmol) in 1,4-dioxane (30 mL) was stirred for 2 hours. The mixture was cooled and then diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 2-1.

[0176] Step 2: A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (4.68 g, 20 mmol) and nCS (2.68 g, 20 mmol) in DMF (50 mL) was stirred at 70°C for 16 hours. The mixture was then inverted into ice water (200 mL) and stirred for 30 minutes. The precipitate was filtered and collected, then dried to obtain 2-2.

[0177] Step 3: A mixture of 2-2 (5g, 18.6 mmol) and urea (9g, 149 mmol) was heated to 200°C and stirred for 2 hours. The mixture was cooled to room temperature and 200 mL of water was added. The mixture was heated to 100°C and stirred for 3 hours. The precipitate was filtered and collected, then dried to obtain 2-3.

[0178] Step 4: The mixture of 2-3 (5 g, 17 mmol) and N,N-diisopropylethylamine (5 mL) in phosphorus trichloride (50 mL) was stirred under reflux for 16 hours. The mixture was concentrated. The residue was tilted into water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 2-4.

[0179] Step 5: To a solution of (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (970 mg, 4.6 mmol) in DMSO (50 mL), N,N-diisopropylethylamine (1.2 g, 9.2 mmol) and 2-4 (1.5 g, 4.6 mmol) were added. The mixture was reacted at room temperature with stirring for 2 hours. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 2-5.

[0180] Step 6: The mixture of 2-5 (600 mg, 1.18 mmol), (2S)-1-methylpyrrolidine-2-yl]methanol (409 mg, 3.55 mmol), triethylenediamine (133 mg, 1.18 mmol), and Cs2CO3 (1.16 g, 3.5 mmol) in DMF (4 mL) and THF (4 mL) was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate and washed with water. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol = 10 / 1) to obtain 2-6.

[0181] Step 7: A mixture of 2-6 (140 mg, 0.24 mmol), 2-1 (84 mg, 0.31 mmol), Na2CO3 (63 mg, 0.60 mmol), and Pd(PPh3)4 (28 mg, 0.024 mmol) in 1,4-dioxane / water (1.5 mL / 0.3 mL) was stirred at 95°C for 4 hours under a nitrogen atmosphere. The mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol / ammonia = 100 / 10 / 0.5) to obtain 2-7.

[0182] Step 8: Trifluoroacetic acid (1 mL) was added to a solution of 2-7 (100 mg, 0.15 mmol) of dichloromethane (4 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated and purified by preparative HPLC (aqueous solution of acetonitrile containing 0.1% formic acid: 5% to 25%) to obtain 2, which was 0.6 equivalents of formate. LCMS (ESI, m / z): [M+H] + =548.5; HNMR(300MHz,DMSO-d6,ppm): δ 8.30-8.20(m,0.6H),7.94(s,1H),7.81(d,J=8.4Hz,1H),7.49-7.39(m,1H),7 .29(d,J=2.4Hz,1H),7.22(d,J=4.2Hz,2H),7.07(d,J=2.4Hz,1H),4.39-4.35 (m,3H),4.20-4.13(m,1H),3.60-3.40(m,4H),2.99-2.91(m,1H),2.62-2.58( m,1H),2.36(s,3H),2.25-2.15(m,1H),2.05-1.87(m,1H),1.74-1.56(m,7H). FNMR(282MHz,DMSO-d6,ppm): δ -122.46(1F). JPEG0007860003000082.jpg118166

[0183] Step 1: A mixture of 1-bromo-8-chloronaphthylene (5.0 g, 20.7 mmol), bis(pinacolato)diborone (5.8 g, 22.8 mmol), Pd(dppf)Cl2 (1.5 g, 2.1 mmol), and KOAc (6.1 g, 62.1 mmol) in DMF (120 mL) was stirred at 80°C for 3 hours under a nitrogen atmosphere. The mixture was cooled and then diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 28-1.

[0184] Step 2: At -78°C under an argon atmosphere, n-butyllithium (136.0 mL, 340.2 mmol, 2.5 M hexane solution) was added dropwise to a solution of diisopropylamine (37.1 g, 366.4 mmol) in THF. The mixture was stirred at -78°C for 20 minutes, after which 1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylic acid (60.0 g, 261.7 mmol) was added to THF. The resulting mixture was stirred at -78°C for 1 hour, after which 1-chloro-3-iodopropane (107.0 g, 523.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight, after which it was quenched with saturated NH4Cl (aqueous solution). The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 28-2.

[0185] Step 3: At 0°C, TMSCl (122.6 g, 1128.2 mmol) was added to a methanol (1.4 L) solution of 28-2 (69.0 g, 225.6 mmol). The mixture was stirred overnight at room temperature. The mixture was based to pH 8 with saturated NaHCO3 solution. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (dichloromethane / methanol = 10 / 1) to obtain 28-3.

[0186] Step 4: At 0°C under a nitrogen atmosphere, LiAlH4 (6.7g, 177.3 mmol) was added in several portions to a solution of 28-3 (20.0g, 118.2 mmol) in THF (200 mL). The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched at 0°C with Na2SO4·10H2O (20g), followed by 15% NaOH (5 mL). The mixture was filtered and washed with THF. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 28-4.

[0187] Compound 28 was prepared according to the synthesis process of Compound 2 in Example 1, and it was a formate salt. LCMS(ESI,m / z): [M+H] + =566.2; HNMR(400MHz,DMSO-d6,ppm): δ 8.28(s,1H),8.21(d,J=8.2Hz,1H),8.11(d,J=8.1Hz,1H),7.88(s,1H),7.74(t,J=7.7Hz,1H),7.66(d,J=7.3Hz, 1H),7.61-7.45(m,2H),4.14(s,2H),3.95-3.45(m,4H),3.17-2.93(m,6H),2.75-2.65(m,2H),2.05-1.65(m,8H). FNMR(282MHz,DMSO-d6,ppm): δ -122.25(1F). JPEG0007860003000083.jpg85166

[0188] Step 1: A mixture of 5-bromo-1-nitronaphthylene (25 g, 100 mmol), benzophenone imine (24 g, 130 mmol), Pd2(dba)3 (4.6 g, 5 mmol), XantPhos (2.9 g, 5 mmol), and Cs2CO3 (49 g, 150 mmol) in DMF (250 mL) was stirred at 100 °C for 5 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was inverted into water. The mixture was filtered again, and the filtrate cake was dried to obtain 11-1.

[0189] Step 2: 11-1 (31.3 g, 89 mmol) in a 200 mL solution of dioxane was mixed with 100 mL of 4 N HCl. The mixture was stirred at room temperature for 1 hour. The mixture was then filtered and dried to obtain 11-2.

[0190] Step 3: Over 30 minutes, a suspension of 11-2 (78.8 g, 350 mmol) in concentrated HCl (175 mL) and water at 0°C was mixed with a solution of sodium nitrite (25.4 g, 367.5 mmol) in water (51 mL). Over 1 hour at room temperature, the reaction mixture was mixed with a vigorously stirred solution of CuCl (41.6 g, 420 mmol) in concentrated HCl (131 mL) and water (175 mL). The mixture was diluted with water and filtered. The filtered cake was dissolved in dichloromethane and washed with water, saturated NaHCO3 solution, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 11-3.

[0191] Step 4: The mixture of 11-3 (67.6 g, 327 mmol) and 5% Pd / C (13.5 g) in ethyl acetate (2.37 L) was stirred overnight at room temperature under an H2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated and polished with heptane to obtain 11-4.

[0192] Step 5: At room temperature, a solution of bromine (97.9 g, 613.1 mmol) in acetic acid (470 mL) was added to a solution of 11-4 (49.5 g, 278.7 mmol) in acetic acid (200 mL). The mixture was stirred at 70°C for 4 hours. The reaction was allowed to cool the mixture to room temperature and then filtered. The filtered cake was washed with acetic acid (120 mL), and then suspended in 20% NaOH (600 mL). The mixture was stirred at room temperature for 20 minutes and then filtered. The solid was dissolved in dichloromethane, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain 11-5.

[0193] Step 6: At 5°C, sodium nitrite (13.0 g, 188.1 mmol) was added in several portions to a solution of 11-5 (45.1 g, 134.3 mmol) in acetic acid (870 mL) and propionic acid (145 mL). The mixture was stirred at 5°C for 1 hour. The mixture was then filtered, and the filtrate was inverted into water. The resulting mixture was filtered. The filtrate cake was dissolved in dichloromethane, washed with brine, dried over Na2SO4, filtered, and concentrated to obtain 11-6.

[0194] Step 7: At 5°C, sodium borohydride (8.17 g, 216.15 mmol) was added in several portions to a suspension of 11-6 (30.6 g, 108.1 mmol) in ethanol (310 mL). The mixture was stirred at 5°C for 1 hour, quenched with water (300 mL), and adjusted to approximately pH 5 with 1N HCl. The mixture was concentrated to remove the organic solvent. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 11-7.

[0195] Step 8: A mixture of 11-7 (6 g, 23.3 mmol), bis(pinacolato)diborone (11.84 g, 46.6 mmol), potassium acetate (6.85 g, 69.9 mmol), and Pd(dppf)Cl2 (1.7 g, 2.33 mmol) in 1,4-dioxane (100 mL) was stirred at 95°C for 7 hours under an N2 atmosphere. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 11-8.

[0196] Step 9: At 0°C, boron trichloride (88.8 mL, 88.8 mmol, 1 M in dichloromethane) was added to a solution of 11-8 (13.5 g, 44.4 mmol) in dichloromethane (300 mL). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (200 mL) at 0°C and then filtered. The filtered cake was dissolved in ethyl acetate (200 mL). The filtrate was extracted with ethyl acetate. The ethyl acetate layer was combined, dried over sodium sulfate, and concentrated to obtain 11-9, which was used as is without purification.

[0197] Compounds 11-11 were prepared according to the synthesis process of compound 2 in Example 1.

[0198] Step 10: Under a nitrogen atmosphere and microwave conditions, at 105°C, the mixture of 11-11 (90 mg, 0.15 mmol), 11-9 (68 mg, 0.3 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol), and Na2CO3 (48 mg, 0.45 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was stirred for 1 hour. The mixture was cooled, tilted in water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse chromatography (aqueous solution of acetonitrile containing 0.1% formic acid: 5% to 95%) to obtain 11-12.

[0199] Compound 11 was prepared according to the synthesis process of Compound 2 in Example 1, yielding 0.55 equivalents of formate. LCMS(ESI,m / z): [M+H] +=596.1; HNMR (400MHz, methanol-d4, ppm): δ 8.51 (brs, 0.55 H),7.94(d,J=1.4Hz,1H),7.75(dd,J=8.0,1.4Hz,1H),7.37-7.30(m,3H),6.98(d,J=2.6Hz,1H),4.75(dd,J=12.4,3.2Hz,2H),4.69-4.58(m,2 H),3.99-3.80(m,2H),3.56-3.48(m,4H),3.93-2.98(m,1H),2.89(s,3 H),2.30(dd,J=15.0,7.8Hz,1H),2.15-1.95(m,8H),1.71-1.64(m,1H). JPEG0007860003000084.jpg84166

[0200] Step 1: Under a nitrogen atmosphere at 30°C, the mixture of 2-5 (400 mg, 0.79 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (264 mg, 1.2 mmol), Xantphos Pd G2 (60 mg, 0.079 mmol), and Na2CO3 (251 mg, 2.4 mmol) in water (2.0 mL) and 1,4-dioxane (20.0 mL) was stirred overnight. The mixture was tilted over water. The resulting solution was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse flash chromatography (aqueous solution of acetonitrile containing 0.1% formic acid: 5% to 95%) to obtain 60-1.

[0201] Step 2: Under a nitrogen atmosphere at 90°C, the mixture of 60-1 (150 mg, 0.26 mmol), 2-1 (121 mg, 0.47 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), and Na2CO3 (84 mg, 0.79 mmol) in water (2 mL) and 1,4-dioxane (10 mL) was stirred for 3 hours. The mixture was cooled to room temperature and then tilted in water. The resulting solution was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse flash chromatography (aqueous solution of acetonitrile containing 0.1% formic acid: 5% to 95%) to obtain 60-2.

[0202] Step 3: Pd(OH)2 (20 mg) was added to a solution of 60-2 (80 mg, 0.12 mmol) in propa-2-ol (5 mL). The resulting solution was stirred at room temperature under a hydrogen atmosphere for 8 hours. The mixture was filtered, and the filtered cake was washed with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse flash chromatography (aqueous solution of acetonitrile containing 0.1% formic acid: 5% to 95%) to obtain 60-3.

[0203] Step 4: At 0°C, a solution of 1,4-dioxane (3 mL) in 4M HCl was added to a solution of 60-3 (40 mg, 0.063 mmol) in 1,4-dioxane (3 mL). The mixture was stirred at room temperature for 6 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to obtain 60 (aqueous solution of acetonitrile containing 0.1% formic acid: 5% to 35%). LCMS (ESI, m / z): [M+H] +=532.1; HNMR(400MHz, methanol-d4, ppm): δ 8.02(d,J=1.4Hz,1H),7.77(d,J=8.4Hz,1H),7.42(dd,J=8.4,2.8Hz,1H),7.28(d ,J=2.4Hz,1H),7.19(d,J=4.8Hz,2H),7.03(d,J=2.4Hz,1H),4.75(d,J=13.6Hz,2H ),4.26-4.21(m,2H),3.90(d,J=14.2Hz,2H),3.66(d,J=12.8Hz,2H),3.20(t,J=1 1.8Hz,3H),2.89(s,3H),2.38-2.35(m,2H),2.29-2.22(m,2H),2.18-2.12(m,4H). JPEG0007860003000085.jpg102166

[0204] Step 1: Trifluoroacetic acid (80 mL) was slowly added to a solution of 5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-ethyl (100 g, 388.7 mmol) in dichloromethane (160 mL) at room temperature. The mixture was stirred at room temperature for 16 hours and then concentrated. The residue was diluted with saturated NaHCO3 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain 81-1.

[0205] Step 2: Under a nitrogen atmosphere at -40°C, LiHMDS (655 mL, 1.0 M tetrahydrofuran solution, 655 mmol) was added to a solution of 81-1 (49 g, 311.8 mmol) and 3-chloro-2-(chloromethyl group)propa-1-ene (100 g, 800 mmol) in tetrahydrofuran (200 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 81-2.

[0206] Step 3: Under a nitrogen atmosphere at 0°C, a solution of tetrahydrofuran (100 mL) containing 81-2 (13.6 g, 55.35 mmol) was added dropwise to a solution of tetrahydrofuran (1 L) containing sodium hydride (2.72 g, 68.1 mmol). The mixture was then heated to reflux and stirred for 9 hours. The mixture was cooled to 0°C and quenched with water (500 mL). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 81-3.

[0207] Step 4: 2,6-dimethylpyridine (9.25 g, 86.3 mmol), water (370 mL), and sodium periodate (36.9 g, 172.6 mmol) were sequentially added to a solution of 81-3 (9.0 g, 43.15 mmol) in acetonitrile (245 mL) and dichloromethane (245 mL). Then, a solution of ruthenium(III) chloride (313 mg, 1.51 mmol) in water (40 mL) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 81-4.

[0208] Step 5: Diethylaminosulfur trifluoride (20.13 g, 125 mmol) was added to a solution of 81-4 (10.55 g, 50 mmol) in dichloromethane (150 mL) at an N2 atmosphere and 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with ethanol. The mixture was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 81-5.

[0209] Step 6: Under a nitrogen atmosphere at 0°C, a solution of tetrahydrofuran (60 mL) containing 81-5 (6.3 g, 27 mmol) was added to a solution of tetrahydrofuran (40 mL) containing LiAlH4 (3.08 g, 81 mmol). The mixture was stirred under reflux for 1 hour. The mixture was then cooled to 0°C, quenched with sodium sulfate decahydrate, and filtered. The filtrate was concentrated to obtain 81-6.

[0210] Compound 81 was prepared according to the synthesis process of Compound 2 in Example 1, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] + =610.3; HNMR (400MHz, methanol-d4, ppm): δ 8.02(s,1H),7.76-7.35(m,1H),7.43-7.48(m,1H),7.37-7.25(m,1H),7.21-7.15(m,2H),7.02-7.00(m,1H),4.78-4.67(m,4H),4.24-4.15(m,3H),3.92-3.80(m,4H),3.46-3.39(m,1H),3.02-2.75(m,2H),2.46-2.13(m,8H). FNMR (376MHz, methanol-d4, ppm): δ -98.31(1F),-100.55(1F),-123.38(1F). JPEG0007860003000086.jpg124166

[0211] Step 1: A mixture of 2-1 (2.7 g, 10 mmol), N,N-diisopropylethylamine (2.6 g, 20 mmol), and chloro(methoxy)methane (1.21 g, 15 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 9 / 1) to obtain 73-1.

[0212] Step 2: At room temperature, N-iodosucciimide (6.75 g, 30 mmol) was added to a solution of 2-amino-4-bromo-3-fluorobenzoic acid (4.66 g, 20 mmol) in dimethylformamide (20 mL). The mixture was stirred at 80°C for 2 hours, then cooled and inverted into water. The mixture was then filtered and washed with water. The filtered cake was polished with acetonitrile and filtered to obtain 73-2.

[0213] Step 3: A solution of 73-2 (3.59 g, 10 mmol) in sulfuryl chloride (60 mL) was stirred at 50°C for 3 hours. The solution was concentrated, and the residue was dissolved in acetone (15 mL), which was then added dropwise to a solution of ammonium thiocyanate (836 mg, 11 mmol) in acetone (40 mL). The mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filter cake was washed with water, and then dissolved in 10% NaOH. The mixture was filtered again, and the pH was adjusted to approximately 2 with 1 M HCl filtrate. The mixture was filtered again, and the filter cake was polished with methanol to obtain 73-3.

[0214] Step 4: To a methanol (60 mL) solution of 73-3 (2.3 g, 5.75 mmol), a solution of NaOH (460 mg, 11.5 mmol) in water (46 mL) and a solution of iodomethane (1.62 g, 11.5 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was then turned into water and adjusted to approximately pH 6 with 1 M HCl. The mixture was then filtered, and the filter cake was polished with methanol to obtain 73-4.

[0215] Step 5: At room temperature, N,N-diisopropylethylamine (1 mL) was added to a solution of 73-4 (1 g, 2.4 mmol) in phosphoryl chloride (8 mL). The mixture was stirred at 100 °C for 2 hours, cooled, concentrated, diluted with ethyl acetate, and washed sequentially with water and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. At room temperature, the residue was dissolved in dimethyl sulfoxide (15 mL), and then 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (636 mg, 3 mmol) and N,N-diisopropylethylamine (645 mg, 5 mmol) were added. The mixture was stirred for 1 hour, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 4) to obtain 73-5.

[0216] Step 6: The mixture of 73-5 (1.22 g, 2 mmol) and copper(I) cyanide (360 mg, 4 mmol) in N,N-dimethylformamide (10 mL) was stirred for 6 hours at 100°C under an N2 atmosphere. The mixture was cooled, diluted with ethyl acetate, and washed sequentially with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 4) to obtain 73-6.

[0217] Step 7: Under an N2 atmosphere and microwave conditions, at 95°C, the mixture of 73-6 (250 mg, 0.5 mmol), 73-1 (188 mg, 0.6 mmol), sodium carbonate (212 mg, 2 mmol), and tetra(triphenylphosphin)palladium (58 mg, 0.05 mmol) in 1,4-dioxane / water (4 / 1,3 mL) was stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 4) to obtain 73-7.

[0218] Steps 8 and 9: A mixture of 73-7 (215 mg, 0.35 mmol) and 3-chloroperbenzoic acid (71 mg, 0.35 mmol) in dichloromethane (10 mL) was stirred at 0°C for 0.5 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), and washed sequentially with water (50 mL) and brine (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain 73-8. Under N₂ conditions at 0°C, a toluene (2 mL) solution of 73-8 was added to a pre-stirred toluene (5 mL) solution of 28-4 (148 mg, 1.05 mmol) and sodium tert-butoxide (58 mg, 0.6 mmol). The reaction was stirred for 0.5 hours and then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol / ammonia = 10 / 1 / 0.05) to obtain 73-9.

[0219] Step 10: Trifluoroacetic acid (0.5 mL) was added to a solution of 73-9 (43 mg, 0.06 mmol) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 10% to 95%) to obtain 73, which was 3 equivalents of the TFA salt. LCMS (ESI, m / z): [M+H] +=565.3; HNMR (400MHz, methanol-d4, ppm): δ 8.38-8.36 (m,1H), 7.79-7.76 (m,1H), 7.46-7.41 (m,1H), 7.32-7.20 (m,3H), 7.14-7.12 (m,1H), 4.82-4.77 (m,2H), 4.67 (s,2H), 4.25-4.21 (m,2H), 3.99-3.93 (m,2H), 3.72-3.64 (m,2H), 3.29-3.24 (m,2H), 2.35-2.05 (m,12H). FNMR (376MHz, methanol-d4, ppm): δ -124.53 (1F). JPEG0007860003000087.jpg92166

[0220] Step 1: Under an N2 atmosphere at room temperature, the mixture of 11-2 (19 g, 101 mmol), triethylamine (20.4 g, 202 mmol), and selectflour (93 g, 263 mmol) in ethanol / 1-methyl-2-pyrrolidinone (150 mL / 150 mL) was stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 71-1.

[0221] Step 2: Under an N2 atmosphere at 0°C, tert-butyl nitrite (16.2 g, 57.5 mmol) was added to a mixture of 71-1 (21 g, 105 mmol) and copper chloride (15.5 g, 115.5 mmol) in acetonitrile (200 mL). The mixture was then stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to obtain 71-2.

[0222] Step 3: The mixture of 71-2 (18.6 g, 83 mmol) and 5% Pd / C (2.0 g) ethyl acetate (200 mL) was stirred for 24 hours under a hydrogen atmosphere at room temperature. The mixture was then filtered and concentrated to obtain the residue, which was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) and preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 25% to 95%) to obtain 71-3.

[0223] Step 4: Bromine (11.9 g, 74.5 mmol) was added to a mixture of 71-3 (6.6 g, 33.8 mmol) in acetic acid (300 mL) at room temperature. The mixture was stirred at 70°C for 6 hours. The mixture was then filtered, and the filtrate was concentrated to obtain 71-4.

[0224] Step 5: At 0°C, sodium nitrite (2.15 g, 31 mmol) was added to a solution of 71-4 (9.1 g, 25.9 mmol) in acetic acid / propionic acid (100 mL / 25 mL). The mixture was stirred at 0°C for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 71-5.

[0225] Step 6: Triethylsilane (6.42 g, 55.3 mmol) was added to the mixture of 71-5 (8.3 g, 27.7 mmol) in isopropanol (200 mL). The mixture was stirred overnight at 100°C under an N2 atmosphere. The mixture was then concentrated, and the residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 71-6.

[0226] Step 7: 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bis(1,3,2-dioxaborolane) (2.4 g, 9.5 mmol), potassium acetate (2.15 g, 21.9 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (534 mg, 0.73 mmol) were added to the mixture of 71-6 (2.0 g, 7.3 mmol) in dioxane (30 mL). The mixture was stirred at 95°C for 4 hours under an N2 atmosphere. The mixture was filtered, the filtrate was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 71-7.

[0227] Step 8: Boron chloride (1.0 M in dichloromethane, 6.2 mL, 6.2 mmol) was added to a solution of 71-7 (1 g, 3.1 mmol) in dichloromethane (5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ice water and extracted with dichloromethane. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 71-8.

[0228] Compounds 71-9 were prepared according to the synthesis process of compound 2 in Example 1.

[0229] Compound 71 was prepared according to the synthesis process of Compound 2 in Example 1, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] +=626.3; HNMR (400MHz, methanol-d4, ppm): δ 7.93-7.92 (m, 1H), 7.80 (dd, J=9.2, 5.6Hz, 1H), 7.40-7.35 (m, 2H), 7.01-7.00 (d, J=2.4Hz, 1H), 4.77-4.74 (m, 2H), 4.64-4.62 (m, 3H), 4.25-4.22 (m, 2H), 3.93-3.90 (m, 1H), 3.83-3.79 (m, 1H), 3.70-3.62 (m, 2H), 3.26-3.24 (m, 1H), 2.33-2.06 (m, 12H). FNMR (376MHz, methanol-d4, ppm): δ -116.5 (1F), -123.7 (1F). JPEG0007860003000088.jpg88166

[0230] Step 1: TEA (3.6 g, 35.6 mmol, 4.96 mL) and tert-butyl dicarbonate (5.69 g, 26.1 mmol) were added to a solution of 1H-pyrrolo[2,3-c]pyridine (2.8 g, 23.7 mmol) in DCM (30 mL). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 42-1.

[0231] Step 2: At 4 atm H2 and room temperature, the mixture of 42-1 (1.51 g, 6.92 mmol) and PtO2 (314 mg, 1.38 mmol) in AcOH (10 mL) was stirred for 15 hours. The mixture was filtered, and the filtrate was concentrated to obtain 42-2, which was used directly in the next step without purification.

[0232] Step 3: At 0°C, TEA (1.05 g, 10.34 mmol, 1.44 mL) and benzyl chloroformate (1.29 g, 7.58 mmol) were added to a solution of 42-2 (1.56 g, 6.89 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 42-3.

[0233] Step 4: At 0°C, TFA (801 mg, 7.0 mmol) was added to a 5 mL solution of 42-3 (507 mg, 1.41 mmol) of dichloromethane. The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated to obtain 42-4.

[0234] Step 5: At room temperature, HCHO (324 mg, 3.53 mmol, 37 wt%) and the catalyst acetic acid were added to a solution of 42-4 (366 mg, 1.41 mmol) in CH3OH (5 mL). The resulting solution was stirred at room temperature for 15 minutes, after which NaBH3CN (265 mg, 4.22 mmol) was added. The resulting solution was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 42-5.

[0235] Step 6: Pd / C (30 mg) was added to a CH3OH (5 mL) solution of 42-5 (302 mg, 1.1 mmol). The resulting solution was stirred with H2 at room temperature for 15 hours. The mixture was filtered and concentrated to obtain 42-6, which was used directly in the next step without purification.

[0236] Step 7: The mixture of 42-6 (133 mg, 0.95 mmol), 2-5 (150 mg, 0.3 mmol), and DIEA (230 mg, 1.78 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 42-7.

[0237] Compound 42 was prepared according to the synthesis process of Compound 2 in Example 1, yielding 1.5 equivalents of formate. LCMS(ESI,m / z): [M+H] + =573.2; HNMR(400MHz, methanol-d4, ppm): δ 8.44(s,1.5H),7.80-7.73(m,2H),7.41(t,J=1.2Hz,1H),7.39-7.17(m,3H),7.00(s,1H) ),5.18-5.06(m,2H),4.67-4.57(m,1H),4.52-4.47(m,2H),4.07-4.00(m,2H),3.71-3.5 2(m,4H),3.27-3.23(m,1H),3.04-3.01(m,1H),2.98(s,3H),2.68-2.52(m,1H),2.28-2 .22(m,1H),2.08-1.99(m,4H),1.98-1.96(m,1H),1.70-1.57(m,1H),1.54-1.50(m,1H). JPEG0007860003000089.jpg53166

[0238] Step 1: A mixture of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl (2 g, 8.15 mmol), imidazole (1.67 g, 24.46 mmol), DMAP (49.81 mg, 0.4 mmol), and TBDPSCl (2.69 g, 9.79 mmol) in dichloromethane (40 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 80-1.

[0239] Step 2: The mixture of 80-1 (2 g, 4.14 mmol) and LiAlH4 (1 M in THF, 16 mL, 16 mmol) in dry THF (40 mL) was stirred at 70°C for 3 hours. The reaction was cooled to 0°C and then quenched by adding potassium bisulfate (2 M, 5 mL). The resulting slurry was filtered and washed with THF. The filtrate was concentrated. The residue was purified by reverse HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 80-2.

[0240] 80-4 was synthesized following a similar procedure to that in Example 1.

[0241] Step 3: At 0°C, TBAF (1 M in THF, 2 mL) was added to a solution of 80-4 (100 mg, 0.11 mmol) in THF (5 mL). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by reverse HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 80-5.

[0242] Compound 80 was prepared according to the synthesis process of Compound 2 in Example 1. LCMS(ESI,m / z): [M+H] +=564.1; HNMR(400MHz,DMSO-d6,ppm): δ 10.00(s,1H),7.94(s,1H),7.80(d,J=8.4Hz,1H),7.46-7.42(m,1H),7.27(d,J=2.4Hz ,1H),7.21(d,J=4.2Hz,2H),7.05(d,J=2.4Hz,1H),4.76(d,J=4.4Hz,1H),4.36-4.31( m,3H),4.19-4.14(m,2H),3.55-3.50(m,4H),3.18(dd,J=9.4,6.0Hz,1H),2.85-2.78( m, 1H), 2.34 (s, 3H), 2.12 (dd, J=9.4, 6.2Hz, 1H), 1.87-1.74 (m, 2H), 1.65-1.63 (m, 4H). JPEG0007860003000090.jpg113166

[0243] Step 1: Under a nitrogen atmosphere, 5-bromo-1-nitronaphthylene (70 g, 278 mmol), ethylboronic acid (41.15 g, 556 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.1 g, 13.9 mmol) were added to a mixture of potassium phosphate (176 g, 714 mmol) in toluene / water (896 mL / 112 mL). The mixture was stirred at 100 °C for 16 hours. The mixture was filtered, and the filtrate was washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 95 / 5) to obtain 77-1.

[0244] Compound 77-6 was prepared according to the synthesis process of compound 71-7 in Example 7.

[0245] Step 2: At 0°C and under a nitrogen atmosphere, sodium borohydride (475 mg, 12.55 mmol) was added in several portions to a solution of 81-4 (10.6 g, 50.2 mmol) in methanol (100 mL), and the mixture was stirred at 0°C for 5 minutes. The mixture was concentrated and purified by silica gel column chromatography (from petroleum ether to ethyl acetate) to obtain 77-7.

[0246] Step 3: At -78°C, diethylaminosulfur trifluoride (4.1 g, 2.35 mmol) was added to a solution of 77-7 (4.8 g, 22.6 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then quenched with methanol, diluted with water, and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 77-8.

[0247] Step 4: At 0°C and under a nitrogen atmosphere, a solution of lithium aluminum hydride (1.25 g, 33 mmol) in tetrahydrofuran (33 mL) was added to a solution of 77-8 (2.36 g, 11 mmol) in tetrahydrofuran (10 mL). The mixture was stirred under reflux for 2 hours and then cooled to 0°C. Water (1.3 mL), 15% aqueous NaOH solution (1.3 mL), and water (3.9 mL) were added. The mixture was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain 77-9.

[0248] Compound 77-10 was prepared according to the synthesis process of compound 2-6 in Example 1, and was a racemic mixture of trans isomers.

[0249] Compound 77 was prepared according to the synthesis process of Compound 2 in Example 1, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] +=620.4; HNMR (400MHz, methanol-d4, ppm): δ 8.00-7.96 (m, 1H), 7.61 (d, J=8.0Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.26 (d, J=2.4Hz, 1H), 7.13-7.11 (m, 1H), 6.80 (d, J=2.4Hz, 1H), 5.61-5.48 (m, 1H), 4.80-4.60 (m, 5H), 4.26-4.21 (m, 2H), 4.05-3.80 (m, 4H), 3.47-3.44 (m, 1H), 2.80-2.03 (m, 12H), 0.92-0.87 (m, 3H). FNMR (376MHz, methanol-d4, ppm): δ -122.65 (1F), -174.3 (1F). JPEG0007860003000091.jpg92166

[0250] Compound 77-10 (2.3 g) was purified by chiral preparative HPLC (column: CHIRALPAK® IA, hexane solution of 30% IPA), yielding 77-10-P1 (900 mg, yield: 38%) and 77-10-P2 (820 mg, yield: 34%), respectively. 77-10-P1: Chiral HPLC analysis: >99% ee; Retention time: 4.873 minutes; Column: CHIRALPAK® IA, hexane solution of 30% IPA; Flow rate: 1 mL / min. 77-10-P2: Chiral HPLC analysis: >99% ee; Retention time: 6.710 minutes; Column: CHIRALPAK® IA, hexane solution of 30% IPA; Flow rate: 1 mL / min.

[0251] Compound 105-0 was prepared from 77-10-P1 according to the synthesis process of Compound 2 in Example 1.

[0252] Compound 105-0 (430 mg) was purified by SFC (column: chiral-OM, MeOH (0.1% DEA) / CO2 = 45 / 55) to obtain 105-1 (110 mg) and 106-1 (225 mg), respectively. 105-1: SFC analysis: >99% ee; Retention time: 4.92 minutes; Column: Chiral-OM, MeOH (0.1% DEA) in CO2, 5% to 40%; Pressure: 100 Bar; Flow rate: 1.5 mL / min. 106-1: SFC analysis: >99% ee; Retention time: 5.24 minutes; Column: Chiral-OM, MeOH (0.1% DEA) in CO2, 5% to 40%; Pressure: 100 Bar; Flow rate: 1.5 mL / min.

[0253] Compound 105 was prepared from 105-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] + =592.3; HNMR(400MHz, methanol-d4, ppm): δ 8.02-8.00(m,1H),7.74(d,J=8.4Hz,1H),7.43-7.38(m,1H),7.26(d,J=2.4Hz,1H),7.21-7.15(m,2H),7.01(d,J=2.4Hz,1H),5.62-5.47 (m,1H),4.76-4.67(m,4H),4.23(s,2H),4.03-3.80(m,5H),3.47-3.40(m,1H),2.74-2.51(m,2H),2.44-2.28(m,3H),2.19-2.10(m,5H). FNMR (376 MHz, methanol-d4, ppm): δ -123.44 (1F), -174.28 (1F).

[0254] Compound 106 was prepared from 106-1 according to the synthesis process of compound 2 in Example 1, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] +=592.3; HNMR(400MHz, methanol-d4, ppm): δ 8.01-8.00(m,1H),7.74(d,J=8.0Hz,1H),7.43-7.38(m,1H),7.26(d,J=2.4Hz,1H),7.21-7.16(m,2H),7.02(d,J=2.4Hz,1H),5.62-5.47 (m,1H),4.80-4.66(m,4H),4.23(s,2H),4.03-3.79(m,5H),3.47-3.38(m,1H),2.74-2.52(m,2H),2.44-2.28(m,3H),2.19-2.08(m,5H). FNMR (376 MHz, methanol-d4, ppm): δ -123.43 (1F), -174.27 (1F). JPEG0007860003000092.jpg69166

[0255] Compound 107-0 was prepared from 77-10-P2 according to the synthesis process of Compound 2 in Example 1.

[0256] Compound 107-0 (269 mg) was purified by SFC (column: chiral-OZ, EtOH (0.1% DEA) / CO2 = 60 / 40) to obtain 107-1 (101 mg) and 108-1 (140 mg), respectively. 107-1: SFC analysis: >99% ee; Retention time: 4.46 minutes; Column: CHIRALCEL® OZ, in CO2 with 40% methanol (0.1% DEA); Pressure: 100 Bar; Flow rate: 3.0 mL / min. 108-1: SFC analysis: >99% ee; Retention time: 6.46 minutes; Column: CHIRALCEL® OZ, in CO2 with 40% methanol (0.1% DEA); Pressure: 100 Bar; Flow rate: 3.0 mL / min.

[0257] Compound 107 was prepared from 107-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] +=592.3; HNMR(400MHz, methanol-d4, ppm): δ 8.02-8.00(m,1H),7.74(d,J=8.4Hz,1H),7.43-7.38(m,1H),7.26(d,J=2.4Hz,1H),7.20-7.15(m,2H),7.01(d,J=2.4Hz,1H),5.62-5.47 (m,1H),4.79-4.65(m,4H),4.23(s,2H),4.04-3.80(m,5H),3.47-3.40(m,1H),2.74-2.51(m,2H),2.44-2.28(m,3H),2.19-2.09(m,5H). FNMR (376 MHz, methanol-d4, ppm): δ -123.46 (1F), -174.30 (1F).

[0258] Compound 108 was prepared from 108-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] + =592.3; HNMR(400MHz, methanol-d4, ppm): δ 8.01-8.00(m,1H),7.74(d,J=8.4Hz,1H),7.42-7.38(m,1H),7.26(d,J=2.4Hz,1H),7.21-7.16(m,2H),7.01(d,J=2.4Hz,1H),5.62-5.47 (m,1H),4.78-4.67(m,4H),4.23(s,2H),4.05-3.81(m,5H),3.47-3.39(m,1H),2.74-2.50(m,2H),2.44-2.28(m,3H),2.19-2.08(m,5H). FNMR (376 MHz, methanol-d4, ppm): δ -123.42 (1F), -174.26 (1F). JPEG0007860003000093.jpg66166

[0259] Compound 101-0 was prepared from 77-10-P1 according to the synthesis process of Compound 2 in Example 1.

[0260] Compound 101-0 (382 mg) was purified by SFC (column: chiral-OZ, MeOH (0.1% DEA) / CO2 = 60 / 40) to obtain compounds 101-1 (187 mg) and 102-1 (170 mg), respectively. 101-1: SFC analysis: >99% ee; Retention time: 4.82 minutes; Column: CHIRALCEL® OZ-H, in CO2 with 40% MeOH (0.1% DEA); Pressure: 100 Bar; Flow rate: 3.0 mL / min. 102-1: SFC analysis: >99% ee; Retention time: 6.22 minutes; Column: CHIRALCEL® OZ-H, in CO2 with 40% MeOH (0.1% DEA); Pressure: 100 Bar; Flow rate: 3.0 mL / min.

[0261] Compound 101 was prepared from 101-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS (ESI, m / z): [M+H]+=626.2; 1H NMR (400 MHz, methanol-d4, ppm): δ 7.93-7.90 (m, 1H), 7.75-7.72 (m, 1H), 7.37-7.28 (m, 3H), 6.95 (d, J=2.4 Hz, 1H), 5.62-5.47 (m, 1H), 4.87-4.60 (m, 4H), 4.27-4.18 (m, 2H), 4.04-3.79 (m, 5H), 3.49-3.40 (m, 1H), 2.75-2.10 (m, 10H). FNMR (376 MHz, methanol-d4, ppm): δ -123.79 (1F), -174.28 (1F).

[0262] Compound 102 was prepared from 102-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS (ESI, m / z): [M+H]+=626.3; 1H NMR (400MHz, methanol-d4, ppm): δ 7.92-7.90 (m, 1H), 7.73 (dd, J=8.0, 1.2Hz, 1H), 7.36-7.28 (m, 3H), 6.96 (d, J=2.4Hz, 1H), 5.62-5.46 (m, 1H), 4.87-4.60 (m, 4H), 4.27-4.17 (m, 2H), 4.04-3.80 (m, 5H), 3.47-3.39 (m, 1H) ), 2.75-2.05 (m, 10H). FNMR (376 MHz, methanol-d4, ppm): δ -123.74 (1F), -174.17 (1F). JPEG0007860003000094.jpg67166

[0263] Compound 103-0 was prepared from 77-10-P2 according to the synthesis process of Compound 2 in Example 1.

[0264] Compound 103-0 was purified by SFC (column: chiral MIC, EtOH (0.1% DEA) / CO2 = 55 / 45) to obtain 103-1 and 104-1, respectively. 103-1: SFC analysis: >99% ee; Retention time: 1.04 minutes; Column: Chiral MIC, EtOH (0.1% DEA) in CO2, 5% to 40%; Pressure: 100 Bar; Flow rate: 1.5 mL / min. 104-1: SFC analysis: >99% ee; Retention time: 1.62 minutes; Column: Chiral MIC, EtOH (0.1% DEA) in CO2, 5% to 40%; Pressure: 100 Bar; Flow rate: 1.5 mL / min.

[0265] Compound 103 was prepared from 103-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] +=626.3; HNMR(400MHz,methanol-d4,ppm): δ 7.92-7.90(m,1H),7.74(dd,J=8.0,1.6Hz,1H),7.37-7.28(m,3H),6.95(d,J=2.8Hz,1H),5.62-5.47(m ,1H),4.87-4.60(m,4H),4.26-4.19(m,2H),4.04-3.76(m,5H),3.45-3.40(m,1H),2.75-2.08(m,10H). FNMR (376MHz, methanol-d4, ppm): δ -123.79(1F), -174.24(1F).

[0266] Compound 104 was prepared from 104-1 according to the synthesis process of compound 2 in Example 1, and was 3 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] + =626.3; HNMR(400MHz,methanol-d4,ppm): δ 7.93-7.90(m,1H),7.74(dd,J=8.4,1.6Hz,1H),7.36-7.29(m,3H),6.95(d,J=2.4Hz,1H),5.62-5.47(m ,1H),4.87-4.60(m,4H),4.27-4.20(m,2H),4.04-3.78(m,5H),3.47-3.40(m,1H),2.75-2.07(m,10H). FNMR (376MHz, methanol-d4, ppm): δ -123.80(1F), -174.29(1F). JPEG0007860003000095.jpg70166

[0267] Compound 45-1 was prepared according to the synthesis process of Compound 2 in Example 1.

[0268] Compound 45-2 was prepared according to the synthesis process of compound 42 in Example 8.

[0269] Compound 45-4 was prepared according to the synthesis process of compound 2 in Example 1.

[0270] Step 1: At room temperature, HCHO (37 wt% in water, 325 mg, 3.53 mmol) and the catalyst acetic acid were added to a solution of 45-4 (174 mg, 0.25 mmol) in CH3OH (3 mL). The solution was stirred at room temperature for 15 minutes, and then NaBH3CN (48 mg, 0.75 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 45-5.

[0271] Step 2: Under a hydrogen atmosphere and at room temperature, the mixture of 45-5 (20 mg, 0.028 mmol) and 10% Pd / C (15 mg) in CH3OH (5 mL) was stirred for 2 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% NH3·H2O: 5% to 95%) to obtain 45. LCMS (ESI, m / z): [M+H] + =573.2; HNMR(400MHz, methanol-d4, ppm): δ 7.74(d,J=1.2Hz,2H),7.41(t,J=1.2Hz,1H),7.38-7.26(m,3H),7.01(s,1H),4.27-4.25(m,2H),3.85- 3.82(m,4H),3.60-3.56(m,2H),3.51~3.49(m,2H),3.25-3.21(m,4H),2.45(s,3H),1.89-1.79(m,8H). JPEG0007860003000096.jpg37166

[0272] Step 1: At -78°C, under an N2 atmosphere, n-butyllithium (0.34 mL, 0.84 mmol) was added dropwise to a solution of 71-9 (426 mg, 0.7 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at -78°C for 1 hour. Chlorotributyltin (455 mg, 1.4 mmol) in a solution of tetrahydrofuran (5 mL) was added dropwise to the above mixture. The mixture was heated to 0°C and stirred for 1 hour. The mixture was quenched with saturated ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (from dichloromethane to methanol / dichloromethane = 1 / 10) to obtain 116-1.

[0273] Step 2: Under an N2 atmosphere at 105°C, the mixture of 116-1 (246 mg, 0.3 mmol), 1-bromoisoquinoline-3-amine (67 mg, 0.3 mmol), CuI (29 mg, 0.15 mmol), lithium chloride (32 mg, 0.75 mmol), and tetra(triphenylphosphin)palladium (173 mg, 0.15 mmol) in dimethylformamide (5 mL) was stirred for 3 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (from dichloromethane to methanol / dichloromethane / ammonia = 1 / 10 / 0.005) to obtain 116-2.

[0274] Step 3: The solution of 116-2 (35 mg, 0.05 mmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (1.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 116, which was 3 equivalents of the TFA salt. LCMS (ESI, m / z): [M+H] +=574.3; HNMR (400MHz, methanol-d4, ppm): δ 8.02-8.01 (m,1H), 7.70-7.67 (m,1H), 7.58-7.53 (m,1H), 7.32-7.29 (m,1H), 7.20-7.15 (m,1H), 7.06 (s,1H), 4.78-4.62 (m,4H), 4.24 (s,2H), 3.95-3.88 (m,2H), 3.71-3.64 (m,2H), 3.29-3.23 (m,2H), 2.35-2.05 (m,12H). FNMR (376MHz, methanol-d4, ppm): δ -124.78 (1F). JPEG0007860003000097.jpg95166

[0275] Step 1: At room temperature, Br2 (150 g, 851 mmol) was added dropwise to a mixture of 11-2 (80 g, 425 mmol) in acetic acid (2.5 L). The mixture was stirred at 70°C for 2 hours, cooled, and filtered. The filtered cake was suspended in 20% NaOH. The mixture was stirred at room temperature for 20 minutes and then filtered. The solid was prepared into a slurry with ethanol, filtered, and the filtered cake was dried to obtain 30-1.

[0276] Step 2: At 5°C, sodium nitrite (13g, 188mmol) was added in several portions to a mixture of 30-1 (54g, 157mmol) in acetic acid (600mL) and propionic acid (150mL). The mixture was stirred at 5°C for 0.5 hours. The mixture was then inverted into water and filtered. The filtered cake (30-2) was used without purification.

[0277] Step 3: At 5°C, sodium borohydride (5.5g, 146 mmol) was added to a mixture of 30-2 (20g, crude, approximately 73 mmol) in ethanol (250 mL). The mixture was stirred at 5°C for 0.5 hours, then quenched with water (20 mL). The mixture was adjusted to pH=5 with 1N hydrochloric acid. The organic solvent was removed by vacuum. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 30-3.

[0278] Step 4: At 0°C, pivaloyl chloride (5.76 g, 48 mmol) was added dropwise to a solution of 30-3 (10.7 g, 40 mmol) and triethylamine (6.06 g, 60 mmol) in dichloromethane (100 mL). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 30-4, which was used without purification.

[0279] Step 5: Under an N2 atmosphere at 80°C, the mixture of 30-4 (8.1 g, 23 mmol), iron powder (6.5 g, 115 mmol), and ammonium chloride (12.2 g, 230 mmol) in ethanol (40 mL) and water (10 mL) was stirred for 10 minutes. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 30-5.

[0280] Step 6: A mixture of 30-5 (5.06 g, 15.76 mmol) and p-toluenesulfonic acid (8.13 g, 47.29 mmol) in acetonitrile (126 mL) was stirred at room temperature for 30 minutes. A solution of sodium nitrite (2.17 g, 31.52 mmol) and potassium iodide (5.23 g, 31.52 mmol) in water (19 mL) was added to the mixture over 30 minutes at 0°C. The resulting mixture was heated to 30°C and stirred for 2 hours. The mixture was diluted with dichloromethane and washed sequentially with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to obtain 30-6.

[0281] Step 7: Under an N2 atmosphere at 80°C, the mixture of 30-6 (3.4 g, 7.87 mmol) and copper(I) cyanide (744 mg, 8.26 mmol) in N,N-dimethylformamide (34 mL) was stirred for 0.5 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was polished with n-hexane to obtain 30-7, which was used without purification.

[0282] Step 8: Under an N2 atmosphere at 95°C, the mixture of 30-7 (1.16 g, 3.5 mmol), bis(pinacolato)diborone (1.33 g, 5.25 mmol), potassium acetate (1.05 g, 10.5 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (205 mg, 0.28 mmol) in 1,4-dioxane (20 mL) was stirred for 6 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to obtain 30-8.

[0283] Step 9: Under an N2 atmosphere at 80°C, the mixture of 77-10 (50 mg, 0.08 mmol), 30-8 (90 mg, 0.24 mmol), sodium carbonate (25 mg, 0.24 mmol), 2-dicyclohexylphosphine-2′,6′-diisopropyloxybiphenyl (3.6 mg, 0.008 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2′,6′-diisopropyloxybiphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (4.3 mg, 0.008 mmol) in 1,4-dioxane / water (5 / 1,4.8 mL) was stirred for 1 hour. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 20% to 95%) to obtain 30-9.

[0284] Step 10: 30-9 (10 mg, 0.013 mmol) was dissolved in ethanol (0.5 mL) and water (0.25 mL) and concentrated hydrochloric acid (0.25 mL) were added. The mixture was stirred at 70°C for 5 hours under an N2 atmosphere. The mixture was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 30, which was 3 equivalents of the TFA salt. LCMS (ESI, m / z): [M+H] + =617.3; HNMR(400MHz, methanol-d4, ppm): δ 8.14-8.11(m,1H),7.97(s,1H),7.76(d,J=7.2Hz,1H),7.54(t,J=8.0Hz,1H),7.42(d,J=2.4Hz,1H),7.16(d,J=2.8Hz,1H),5.61-5.48(m, 1H),4.80-4.60(m,4H),4.26-4.20(m,2H),4.00-3.86(m,5H),3.49-3 .42(m,1H),2.75-2.55(m,2H),2.46-2.26(m,3H),2.20-1.97(m,5H). JPEG0007860003000098.jpg68166

[0285] Step 1: At 0°C, borane-tetrahydrofuran complex (1 M in THF, 19.03 mL, 19.03 mmol) was added to a solution of 1-tert-butyloxycarbonyl-3-hydroxypyrrolidine-2-carboxylic acid (2 g, 8.65 mmol) in THF (20 mL). The resulting solution was stirred at 65°C for 2 hours. The mixture was cooled, quenched with methanol, and concentrated. The residue was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to obtain 25-1, which was used directly in the next step without purification.

[0286] Step 2: At 0°C, TEA (3.31 g, 32 mmol) and methanesulfonyl chloride (2.67 g, 23.3 mmol) were added to a solution of 25-1 (1.69 g, 7.8 mmol) in dichloromethane (20 mL). The resulting solution was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 25-2.

[0287] Step 3: At room temperature, benzylamine (2.06 g, 19.2 mmol) was added to a solution of 25-2 (2.39 g, 6.4 mmol) in toluene (50 mL). The resulting solution was stirred at 110 °C for 15 hours. The solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain 25-3.

[0288] Step 4: The solution of 25-3 (1.1 g, 3.8 mmol) and 10% Pd / C (0.5 g) in THF (15 mL) was stirred for 8 hours at 4 atm H2, 50°C. The mixture was filtered, and the filtrate was concentrated to obtain 25-4, which was used directly in the next step without purification.

[0289] Compounds 25-6 were prepared according to the synthesis process of compound 2 in Example 1.

[0290] Compounds 25-7 were prepared according to the synthesis process of compound 11 in Example 3.

[0291] Compound 25 was prepared according to the synthesis process of Compound 2 in Example 1, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] + =568.1; HNMR(400MHz, methanol-d4, ppm): δ 7.83(s,1H),7.73(d,J=1.2Hz,1H),7.35-7.29(m,3H),6.96(s,1H),5.49-5.47(m,1H),4.49-4.32(m,4H),3.37-3.36 (m,2H),3.30-3.26(m,2H),2.98-2.96(m,1H),2.51(s,3H),2.49-2.46(m,2H),2.20-2.16(m,1H),1.87-1.70(m,4H). JPEG0007860003000099.jpg176166

[0292] Step 1: Under a nitrogen atmosphere at -70°C, lithium bis(trimethylsilyl)amide (1.2 L, 1.2 mol, 1.0 M in tetrahydrofuran) was added dropwise to a solution of (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl group) ester 2-methyl group (247 g, 1 mol) in tetrahydrofuran (2 L). The mixture was stirred at -70°C for 1 hour. Then, a solution of ((chloromethoxy)methyl)benzene (172 g, 1.1 mol) in tetrahydrofuran (300 mL) was added dropwise at -70°C. The mixture was stirred at -30°C for 5 hours, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-1, which was used directly in the next step without purification.

[0293] Step 2: At room temperature, lithium hydroxide monohydrate (114 g, 3 mol) was added to a solution of 119-1 (367 g, 1 mol) in tetrahydrofuran (2 L) and water (600 mL). The mixture was stirred overnight at 60°C. The mixture was concentrated and diluted with water and tert-butyl methyl ether. After stirring for 30 minutes, the aqueous phase was separated, adjusted to approximately pH 3 with 1N HCl, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-2, which was used directly in the next step without purification.

[0294] Step 3: At 0°C under a nitrogen atmosphere, boranetetrahydrofuran complex solution (1.36 L, 1.36 mol, 1.0 M in tetrahydrofuran) was added dropwise to a solution of 119-2 (320 g, 906 mmol) in tetrahydrofuran (2.5 L). The mixture was stirred at room temperature for 4 hours, quenched with methanol (500 mL), and stirred under reflux for 3 hours. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-3, which was used directly in the next step without purification.

[0295] Step 4: At 0°C, Dess-Martin periodinane (445 g, 1.05 mol) was added to a solution of 119-3 (285 g, 840 mmol) in dichloromethane (3.5 L). The mixture was stirred overnight at room temperature, quenched with saturated sodium hyposulfite aqueous solution, and stirred at room temperature for 3 hours. The mixture was filtered, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate aqueous solution and brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-4, which was used directly in the next step without purification.

[0296] Step 5: At -40°C under a nitrogen atmosphere, lithium bis(trimethylsilyl)amide (944 mL, 944 mmol, 1.0 M in tetrahydrofuran) was added dropwise to a solution of 2-(diethoxyphosphoryl)ethyl acetate (211 g, 944 mmol) in tetrahydrofuran (1.5 L). The mixture was stirred at -40°C for 1 hour. Then, a solution of 119-4 (265 g, 786 mmol) in tetrahydrofuran (500 mL) was added dropwise to the reaction mixture at -40°C. The resulting mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-5, which was used directly in the next step without purification.

[0297] Step 6: At room temperature, hydrochloric acid (800 mL, 2.8 mol, 3.5 M in ethyl acetate) was added to a solution of 119-5 (320 g, 786 mmol) in ethyl acetate (500 mL). After stirring at room temperature for 3 hours, the mixture was concentrated and diluted with water and tert-butyl methyl ether. The mixture was stirred at room temperature for 30 minutes. The aqueous phase was separated, the pH was adjusted to approximately 10 with saturated sodium carbonate aqueous solution, and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-6, which was used directly in the next step without purification.

[0298] Step 7: The mixture of 119-6 (225 g, 733 mmol) and 10% Pd / C (11 g) in ethyl acetate (1.2 L) was stirred overnight at room temperature and under a hydrogen atmosphere, then heated to reflux and stirred overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 4) to obtain 119-7.

[0299] Step 8: Under a nitrogen atmosphere at 0°C, boranetetrahydrofuran complex solution (740 mL, 740 mmol, 1.0 M in tetrahydrofuran) was added dropwise to a solution of 119-7 (130 g, 494 mmol) in tetrahydrofuran (1.5 L). The mixture was then stirred at room temperature for 4 hours, quenched with methanol, and stirred under reflux for 3 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-8, which was used directly in the next step without purification.

[0300] Step 9: The mixture of 119-8 (2.5 g, 10 mmol) and 10% Pd / C (200 mg) in methanol (30 mL) was stirred overnight at 45°C under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol = 10 / 1) to obtain 119-9.

[0301] Step 10: A mixture of 11-8 (500 mg, 1.64 mmol), N,N-diisopropylethylamine (636 mg, 4.92 mmol), and chloro(methoxy)methane (265 mg, 3.28 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (100 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 9 / 1) to obtain 119-10.

[0302] Compound 119-11 was prepared from compound 73-6 according to the synthesis process of compound 73-7 in Example 6.

[0303] Step 11: At -5°C, 3-chloroperbenzoic acid (314 mg, 1.82 mmol) was added in several portions to a solution of 119-11 (910 mg, 1.4 mmol) in dichloromethane (20 mL). The mixture was stirred at -5°C for 0.5 hours, diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate aqueous solution and brine, dried over sodium sulfate, filtered, and concentrated to obtain 119-12, which was used directly in the next step without purification.

[0304] Step 12: At -5°C, lithium bis(trimethylsilyl)amide (1.8 mL, 1.0 M, 1.8 mmol in tetrahydrofuran) was added to a solution of 119-9 (325 mg, 2.04 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred for 5 minutes. At -5°C, a solution of 119-12 (909 mg, 1.36 mmol) in tetrahydrofuran (5 mL) was added dropwise to the above mixture. The mixture was stirred at -5°C for 5 minutes. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (aqueous acetonitrile solution containing 0.05% TFA: 15% to 95%) to obtain 119-13.

[0305] 119-13 (421 mg) was purified by SFC (column: REGIS(S,S)WHELK-O1,EtOH / CO2=55 / 45) to obtain 119-13-P1 (179 mg) and 119-13-P2 (200 mg), respectively. 119-13-P1: SFC analysis: 99.5% ee. Retention time 6.05 minutes; Column: REGIS(S,S)WHELK-O1, in CO2 with IPA (0.1% DEA); Pressure: 100 Bar; Flow rate: 1.5 mL / min.

[0306] 119-13-P2: SFC analysis: 98.3% ee. Retention time 7.87 minutes; Column: REGIS(S,S)WHELK-O1, in CO2 with IPA (0.1% DEA); Pressure: 100 Bar; Flow rate: 1.5 mL / min.

[0307] Compound 119 was prepared from compound 119-13-P1 according to the synthesis process of compound 2 in Example 1, and was 2 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] + =617.3; HNMR (400MHz, methanol-d4, ppm): δ 8.31 (s, 1H), 7.77 (dd, J=8.0, 1.2Hz, 1H), 7.40-7.32 (m, 3H), 7.07 (d, J=2.4Hz, 1H), 5.63-5.48 (m, 1H), 4.83-4.80 (m, 1H), 4.73-4.64 (m, 3H), 4.27-4.20 (m, 2H), 4.05-3.80 (m, 5H), 3.50-3.40 (m, 1H), 2.77-2.00 (m, 10H). FNMR (376MHz, methanol-d4, ppm): δ -125.07 (1F), -174.24 (1F).

[0308] Compound 120 was prepared from compound 119-13-P2 according to the synthesis process of compound 2 in Example 1, and was 2 equivalents of TFA salt. LCMS(ESI,m / z): [M+H] + =617.3; HNMR (400MHz, methanol-d4, ppm): δ 8.31 (s, 1H), 7.77 (dd, J=8.0, 1.6Hz, 1H), 7.41-7.32 (m, 3H), 7.07 (d, J=2.4Hz, 1H), 5.63-5.48 (m, 1H), 4.83-4.78 (m, 1H), 4.76-4.64 (m, 3H), 4.27-4.20 (m, 2H), 4.05-3.81 (m, 5H), 3.50-3.39 (m, 1H), 2.77-2.01 (m, 10H). FNMR (376MHz, methanol-d4, ppm): δ -125.09 (1F), -174.22 (1F). JPEG0007860003000100.jpg98166

[0309] Step 1: Pd / C (10%, 20g) was added to a solution of methyl 5-hydroxypyridine-3-carboxylate (100g, 653 mmol) in AcOH (1L). The reaction mixture was stirred at 70°C for 72 hours at 50 psi H2. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 50-1, which was used directly in the next step without purification.

[0310] Step 2: N-ethyl-N-isopropyl-propa-2-amine (253 g, 1.96 mol) and benzylchloroformate (167 g, 1.3 mol) were added to a solution of 50-1 (104 g, 653 mmol) in dichloromethane (1 L). The mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain 50-2.

[0311] Step 3: At -78°C, DMSO (13.3g, 170.5 mmol, 12.1 mL) was added dropwise to a DCM (50 mL) solution of oxalyl chloride (10.8 g, 85.2 mmol). The mixture was stirred at -78°C for 0.5 hours. At -78°C, a 50-2 (5 g, 17.1 mmol) dichloromethane (20 mL) solution was added to the mixture, and the resulting mixture was stirred at -78°C for 2 hours. Then TEA (25.9 g, 255.7 mmol, 35.7 mL) was added, and the mixture was stirred for a further 0.5 hours at -78°C. The mixture was raised to room temperature and stirred overnight. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to obtain 50-3.

[0312] Step 4: At 0°C, N-ethyl-N-(trifluorosulfanyl)ethylamine (4.81 g, 29.9 mmol) was added to a solution of 50-3 (2.9 g, 9.96 mmol) in dichloromethane (30 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was inclined over ice water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain 50-4.

[0313] Step 5: Pd / C (10%, 340 mg) and Pd(OH)2 (20%, 170 mg) were added to a solution of 50-4 (1.7 g, 5.4 mmol) in MeOH (20 mL). The mixture was stirred overnight at room temperature under an H2 atmosphere. The reaction mixture was filtered and concentrated to obtain 50-5, which was used directly in the next step without purification.

[0314] Step 6: A mixture of 50-5 (0.9 g, 5.0 mmol), TEA (1.52 g, 15.1 mmol), and Boc2O (1.6 g, 7.5 mmol) in dichloromethane (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain 50-6.

[0315] Step 7: LiAlH4 (679 mg, 17.9 mmol) was added to a 10 mL solution of 50-6 (1 g, 3.6 mmol) in THF. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with water, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2 to ethyl acetate) to obtain 50-7.

[0316] Compound 50-8 was prepared from compounds 50-7 and 2-5 according to the synthesis process of compound 2-6 in Example 1.

[0317] Compound 50 was prepared from compound 50-8 according to the synthesis process of compound 2 in Example 1. LCMS(ESI,m / z): [M+H] + =598.2; HNMR(400MHz, methanol-d4, ppm): δ 7.95(s,1H),7.74(d,J=8.3Hz,1H),7.40(t,J=7.3Hz,1H),7.28-7.15(m,3H),7.02(d,J=2.4Hz,1H),4.57-4 .30(m,4H),3.69-3.58(m,4H),3.05-2.94(m,2H),2.50-2.18(m,6H),2.15-2.10(m,1H),1.93-1.63(m,5H). JPEG0007860003000101.jpg77166

[0318] Step 1: At -15°C under a nitrogen atmosphere, n-butyllithium (38 mL, 60 mmol, 1.6 M in hexane) was added dropwise to a mixture of 1-bromo-3-chloro-2,4-difluorobenzene (11.35 g, 50 mmol) and furan (6.8 g, 100 mmol) in toluene (200 mL) over 0.5 hours. The mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and filtered. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by reverse HPLC (aqueous solution of acetonitrile containing 0.1% TFA: 10% to 95%) to obtain 125-1.

[0319] Step 2: At 80°C, the solution of 125-1 (3.5 g, 17.8 mmol) in concentrated HCl (500 mL) and ethanol (40 mL) was stirred for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 50 / 1) to obtain 125-2.

[0320] Step 3: At room temperature under a nitrogen atmosphere, the mixture of 125-2 (1.2 g, 6.1 mmol), N,N-diisopropylethylamine (3.93 g, 30.5 mmol), and a 4 Å molecular sieve (1.2 g) in dichloromethane (25 mL) was stirred for 10 minutes. Then, trifluoroacetic anhydride (2.1 g, 7.3 mmol) was added at -40°C, and the mixture was stirred at -40°C for 10 minutes. The reaction mixture was quenched with water and filtered. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 50 / 1) to obtain 125-3.

[0321] Step 4: At 80°C, a mixture of 125-3 (1.9 g, 5.8 mmol), bis(pinacolato)diborone (2.2 g, 8.7 mmol), potassium acetate (2.26 g, 23 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (844 mg, 1.15 mmol) in dimethyl sulfoxide (40 mL) was stirred for 2 hours. The mixture was then filtered, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 10% to 95%) to obtain 125-4.

[0322] Compound 125-5 was prepared according to the synthesis process of compound 11 in Example 3.

[0323] Compound 125 was prepared according to the synthesis process of Compound 2 in Example 1, and was 3 equivalents of TFA salt. LCMS(ESI,m / z): [M+H] +=628.2; HNMR(400MHz,methanol-d4,ppm): δ 8.17-8.11(m,1H),8.07(dd,J=9.2,5.6Hz,1H),7.94(d,J=1.6Hz,1H),7.68-7.63(m,1H),7.51(t,J=8.8Hz,1H),7.45(d,J=7.2Hz,1H) ,5.67-5.44(m,1H),4.79-4.60(m,4H),4.28-4.19(m,2H),4.04-3.79(m,5H),3.49-3.40(m,1H),2.76-2.51(m,2H),2.45-2.06(m,8H). FNMR (376 MHz, methanol-d4, ppm): δ -111.22 (1F), -123.64 (1F). JPEG0007860003000102.jpg100166

[0324] Step 1: At 0°C under a nitrogen atmosphere, 150 mL of anhydrous THF solution of benzoyl isothiocyanate (36.4 g, 223.2 mmol) was added to 150 mL of anhydrous THF solution of 5-fluoro-2-methoxyphenylamine (30.0 g, 212.5 mmol). After addition, the mixture was heated to room temperature and stirred for 3 hours. Then, 216.8 mL of NaOH solution was added, and the resulting mixture was stirred overnight at 80°C. The mixture was concentrated and filtered. The filtered cake was washed with cold hexane to obtain 112-1, which was used directly in the next step without purification.

[0325] Step 2: At 0°C, Br2 (35.0 g, 219.1 mmol) was added dropwise to a solution of 112-1 (43.0 g, 214.7 mmol) in CHCl3 (900 mL). After stirring at 0°C for 0.5 hours, the mixture was heated and refluxed for 2 hours. The mixture was then cooled, filtered, and the filtered cake was washed with cold hexane to obtain 112-2, which was used directly in the next step without purification.

[0326] Step 3: At 0°C, BBr3 (1M dichloromethane solution, 312.8 mL) was added dropwise to a solution of 112-2 (20.0 g, 100.9 mmol) in dichloromethane. The mixture was raised to room temperature and stirred overnight. The reaction was quenched with methanol at 0°C. The mixture was then filtered, and the filtered cake was washed with cold dichloromethane to obtain 112-3, which was used directly in the next step without purification.

[0327] Step 4: At room temperature, Boc2O (45.8 g, 209.8 mmol) was added to a mixture of 112-3 (16.8 g, 91.2 mmol), Et3N (19.4 g, 191.5 mmol), and DMAP (557.2 mg, 4.6 mmol) in dichloromethane (280 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated and dissolved again in methanol (180 mL). MeONa (5.4 M MeOH solution, 25 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain 112-4, which was used directly in the next step without purification.

[0328] Step 5: At 0°C, Tf2O (27.4 g, 97.1 mmol) was added to a solution of 112-4 (23.0 g, 80.9 mmol) and pyridine (12.8 g, 161.8 mmol, 13.0 mL) in dichloromethane (60 mL). The mixture was stirred at 0°C for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 112-5.

[0329] Step 6: At 80°C, the mixture of 112-5 (18.0 g, 43.2 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (87.8 g, 345.8 mmol), KOAc (12.7 g, 129.7 mmol), and Pd(PPh3)4 (10.0 g, 8.65 mmol) in 1,4-dioxane (240 mL) was stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 10% to 95%) to obtain 112-6.

[0330] Compound 112-7 was prepared from compound 73-6 according to the synthesis process of compound 73-7 in Example 6.

[0331] Compound 112-9 was prepared according to the synthesis process of compound 119-13 in Example 19.

[0332] Step 7: Bromo(trimethyl)silane (0.2 mL) was added to a solution of 112-9 (60 mg, 0.074 mmol) in acetonitrile / N,N-dimethyl amide (1 mL / 0.5 mL). The mixture was stirred at room temperature for 6 hours. The mixture was then diluted with dichloromethane and washed sequentially with saturated sodium bicarbonate aqueous solution, water, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) and preparative HPLC (acetonitrile aqueous solution containing 0.1% TFA: 5% to 95%) to obtain 112, which was 3 equivalents of the FA salt. LCMS (ESI, m / z): [M+H] +=607.3; HNMR(400MHz,methanol-d4,ppm): δ 8.47(s,3H),8.26(s,1H),7.33(dd,J=8.8,5.6Hz,1H),7.02(t,J=8.8Hz,1H),5.51-5.37(m,1H), 4.53-4.44(m,4H),4.03-3.95(m,2H),3.90-3.45(m,5H),3.28-3.22(m,1H),2.60-1.86(m,10H). JPEG0007860003000103.jpg69166

[0333] Compound 143-4 was prepared according to the synthesis process of compound 112-6 in Example 22.

[0334] Compound 143-5 was prepared from Compound 2-5 and Compound 119-9 according to the synthesis process of Compound 2-6 in Example 1.

[0335] Compound 143 was prepared from compound 143-5 according to the synthesis process of compound 2 in Example 1, and was 0.29 equivalents of the FA salt. LCMS(ESI,m / z): [M+H] + =666.1; HNMR(400MHz, methanol-d4, ppm): δ 8.34(s,0.29H),7.96(s,1H),7.54-7.48(m,1H),7.39-7.34(m,1H),5.61-5.40(m,1H),4.74-4.64(m,2H),4.61-4.54(m,2H),4.1 9-4.10(m,2H),3.92-3.71(m,5H),3.42-3.35(m,1H),2.70-2.46(m,2H),2.43-2.34(m,1H),2.33-2.22(m,2H),2.17-2.01(m,5H). JPEG0007860003000104.jpg74166

[0336] Compound 121-3 was prepared from compound 2-2 according to the synthesis process of compound 73-5 in Example 6.

[0337] Step 1: Tetra(triphenylphosphino)palladium (337 mg, 0.29 mmol) was added to a stirred mixture of 121-3 (1 g, 2.92 mmol) and (5-(tributylstanyl)thiazole-2-yl)carbamate tert-butyl (1.43 g, 2.92 mmol) in 1,4-dioxane (30 mL) under nitrogen. The resulting mixture was stirred at 85°C for 16 hours. After cooling to room temperature, the mixture was filtered and the filtered cake was washed with 1,4-dioxane. The combined organic layer was concentrated to obtain 121-4.

[0338] Compound 121-5 was prepared from compounds 121-4 and 11-9 according to the synthesis process of compound 73-7 in Example 6.

[0339] Step 2: TEA (13 mg, 0.13 mmol) and Boc2O (24 mg, 0.11 mmol) were added to a stirred mixture of 121-5 (10 mg, 0.020 mmol) and DMAP (2.7 mg, 0.022 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 121-6.

[0340] Compound 121 was prepared from compound 121-6 according to the synthesis process of compound 73 in Example 6. LCMS(ESI,m / z): [M+H] + =570.1; HNMR (400MHz, methanol-d4, ppm): δ 8.35 (s, 1H), 8.21 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.37-7.29 (m, 3H), 6.99 (s, 1H), 3.96-3.88 (m, 1H), 3.75-3.70 (m, 1H), 3.08 (s, 3H), 2.80-2.73 (m, 2H), 2.19-2.09 (m, 2H), 2.09-1.95 (m, 2H), 1.60-1.56 (m, 1H). FNMR (376MHz, methanol-d4, ppm): δ -123.65 (1F). JPEG0007860003000105.jpg65166

[0341] At room temperature, a mixture of 73-5 (500.00 mg, 0.82 mmol), TEA (249.12 mg, 2.46 mmol, 0.34 mL), and Pd(dppf)Cl2 (120.14 mg, 0.16 mmol) in methanol (15 mL) was stirred for 5 hours using a carbon monoxide balloon. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 122-1.

[0342] Compound 122-2 was prepared from compounds 122-1 and 119-10 according to the synthesis process of compound 73-7 in Example 6.

[0343] Compound 122-4 was prepared from compound 122-2 according to the synthesis process of compound 119-13 in Example 19.

[0344] Step 2: To a solution of 122-4 (40 mg, 0.05 mmol) in tetrahydrofuran / methanol (3 mL / 1 mL), sodium hydroxide solution (1 mL, 2 mmol, 2 M) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was oxidized with 1 M hydrochloric acid to pH 4-5 and then extracted with dichloromethane. The combined organic layer was concentrated to obtain 122-5.

[0345] Step 3: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (25 mg, 0.067 mmol), DIPEA (17 mg, 0.14 mmol), and methylamine hydrochloride (5 mg, 0.067 mmol) were added to a solution of 122-5 (35 mg, 0.045 mmol) in dimethylformamide (2 mL). The mixture was stirred at room temperature for 1 hour and reacted. The mixture was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 10% to 60%) to obtain 122-6.

[0346] Compound 122 was prepared according to the synthesis process of Compound 2 in Example 1, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] + =649.2; HNMR (400MHz, methanol-d4, ppm): δ 7.95 (s, 1H), 7.72-7.70 (m, 1H), 7.35-7.27 (m, 3H), 6.96 (d, J=2.4Hz, 1H), 5.60-5.47 (m, 1H), 4.79-4.62 (m, 4H), 4.24 (s, 2H), 4.02-3.81 (m, 5H), 3.48-3.41 (m, 1H), 2.72-2.56 (m, 5H), 2.44-2.29 (m, 3H), 2.19-2.08 (m, 5H). FNMR (376MHz, methanol-d4, ppm): δ -126.92 (1F), -174.36 (1F). JPEG0007860003000106.jpg96166

[0347] Step 1: At 0°C, 60% by weight of NaH (in mineral oil) (8.13 g, 203 mmol) was added in several portions to a solution of 6-bromo-4-methylpyridine-2-amine (10 g, 53 mmol) in DMF (150 mL). The resulting mixture was stirred at room temperature for 1 hour. Then, 4-methoxybenzyl chloride (18.3 g, 117 mmol) was added, and the mixture was stirred at this temperature for 2 hours. After quenching with saturated NH4Cl solution, the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 142-1.

[0348] Step 2: Under a nitrogen atmosphere at 110°C, the mixture of 142-1 (1 g, 2.3 mmol), hexabutylditin (4.1 g, 7.1 mmol), Pd2(dba)3 (215 mg, 0.23 mmol), tricyclohexylphosphine (131 mg, 0.46 mmol), and lithium chloride (492 mg, 11.7 mmol) in 1,4-dioxane (20 mL) was stirred for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 142-2.

[0349] Step 3: KF (11.27 g, 194.01 mmol) was added to a DMA (120 mL) solution of 2-5 (4.08 g, 8.06 mmol). The mixture was stirred at 120°C for 12 hours. The mixture was tilted to H2O and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 142-3.

[0350] Step 4: In N2, LiCl (108.19 mg, 2.55 mmol), CuI (61.7 mg, 0.32 mmol), and Pd(PPh3)4 (235.84 mg, 0.20 mmol) were added to the solutions of 142-3 (500 mg, 1.02 mmol) and 142-2 (1.04 g, 1.63 mmol) in dioxane (10 mL). The solutions were stirred at 120 °C for 10 hours and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 142-4.

[0351] Step 5: TsOH·H2O (108 mg, 0.56 mmol) and n-iodosucciimide (609 mg, 2.71 mmol) were added to a solution of 142-4 (410 mg, 0.54 mmol) in DMF (10 mL). The resulting solution was stirred at 0°C for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 142-5.

[0352] Step 6: In N2, 2,2-difluoro-2-fluorosulfonylmethyl acetate (706.96 mg, 3.68 mmol) was added to a DMA (5 mL) solution of 142-5 (130 mg, 0.15 mmol) and CuI (336.41 mg, 1.77 mmol). The solution was stirred at 90°C for 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 142-6.

[0353] Step 7: At 0°C, in N2, NaH (60% in oil, 8.5 mg, 0.35 mmol) was added to a solution of 119-9 (48.7 mg, 0.3 mmol) in THF (5 mL). The solution was stirred at 25°C for 1 hour, and a solution of 142-6 (101 mg, 0.12 mmol) in 2 mL of THF was added. The solution was stirred at 25°C for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 142-7.

[0354] Compound 142 was prepared according to the synthesis process of Compound 2 in Example 1, and was 0.46 equivalents of the FA salt. LCMS(ESI,m / z): [M+H] +=624.0; HNMR(400MHz,methanol-d4,ppm): δ 8.41(s,0.46H),7.90(s,1H),6.61(s,1H),5.65-5.45(m,1H),4.64-4.59(m,4H),4.16-4.01(m ,2H),3.98-3.81(m,5H),3.49-3.46(m,1H),2.69(s,3H),2.56-2.21(m,5H),2.16-1.99(m,5H). JPEG0007860003000107.jpg62166

[0355] Step 1: At -50°C, a solution of 1,3-dibromo-5-fluoro-2-iodobenzene (5 g, 13 mmol) and 2-methylfuran (3.2 g, 39 mmol) in toluene (50 mL) was added dropwise to a solution of 2.5 M n-BuLi in THF (5.7 mL, 14 mmol). The resulting solution was slowly heated to room temperature and stirred for 1 hour. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to obtain 137-1.

[0356] Step 2: Potassium azodicarboxylate (2.34 g, 12.06 mmol) was added to a solution of 137-1 (1.03 g, 4.02 mmol) in MeOH (50 mL) at room temperature, shielded from light. The mixture was stirred, and simultaneously, a solution of glacial acetic acid (1.82 mL) in MeOH (30 mL) was added dropwise. The resulting mixture was stirred at room temperature for 15 minutes. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 137-2, which was used directly in the next step without purification.

[0357] Step 3: The mixture of 137-2 (800 mg crude) in a 12N HCl aqueous solution (20 mL) was stirred in a sealed tube at 95°C for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to obtain 137-3.

[0358] Step 4: A mixture of 137-3 (600 mg, 2.52 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (960 mg, 3.78 mmol), Pd(dppf)Cl2 (187 mg, 0.25 mmol), and KOAc (750 mg, 7.65 mmol) in 1,4-dioxane (15 mL) was degassed three times with N2 and stirred at 90°C for 5 hours. The mixture was cooled and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to obtain 137-4.

[0359] Compound 137 was prepared from compounds 137-4 and 143-5 according to the synthesis process of compound 2 in Example 1. LCMS(ESI,m / z): [M+H] + =608.3; HNMR (400MHz, methanol-d4, ppm): δ 7.98(s,1H),7.82(d,J=8.4Hz,1H),7.70(dd,J=9.2,2.4Hz,1H),7.43(t,J= 7.6Hz,1H),7.25(d,J=7.2Hz,1H),7.15-7.12(m,1H),5.60-5.50(m,1H),4. 79-4.73(m,2H),4.68-4.65(m,3H),4.28-4.19(m,2H),3.95-3.81(m,4H),3 .46-3.43(m,1H),2.75-2.50(m,2H),2.41-2.28(m,3H),2.19-2.00(m,8H). FNMR (376 MHz, methanol-d4, ppm): δ -119.34 (1F), -123.09 (1F), -174.26 (1F). JPEG0007860003000108.jpg69166

[0360] Step 1: Potassium hydroxide solution (12M, 3mL, 36 mmol) was added to a solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (2.6g, 10 mmol) in water (16mL). The reaction mixture was stirred at 80°C for 1.5 hours. The mixture was oxidized with 1M hydrochloric acid to pH=3 and then extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 123-1, which was used directly in the next step without purification.

[0361] Step 2: Concentrated sulfuric acid (2.6 mL) was added to a methanol (30 mL) solution of 123-1 (2.5 g, 10 mmol). The reaction mixture was stirred at 70°C for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 123-2, which was used directly in the next step without purification.

[0362] Step 3: At 0°C, acetyl chloride (0.78 g, 10 mmol) was added to a solution of 123-2 (1.9 g, 6.9 mmol) and triethylamine (2.1 g, 20.6 mmol) in dichloromethane (60 mL). The mixture was stirred at 0°C for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 123-3, which was used directly in the next step without purification.

[0363] Step 4: Stannous chloride (5.3 g, 28 mmol) was added to a solution of 123-3 (2.1 g, 69 mmol) in ethyl acetate (60 mL). The reaction mixture was stirred at 60°C for 3 hours. The mixture was based to pH=8 with aqueous sodium bicarbonate and then filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 123-4, which was used directly in the next step without purification.

[0364] Step 5: Selectfluor (2.43 g, 6.8 mmol) was added to a solution of 123-4 (1.8 g, 6.25 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was based to pH=8 with aqueous sodium bicarbonate and then extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 123-5.

[0365] Step 6: Potassium carbonate (496 mg, 3.6 mmol) was added to a methanol (10 mL) solution of 123-5 (550 mg, 1.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was oxidized to pH=5 with 1 M hydrochloric acid and then extracted with ethyl acetate. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 123-6.

[0366] Step 7: Cesium carbonate (1.1 g, 3.4 mmol) was added to a solution of 123-6 (450 mg, 1.7 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature for 10 minutes, after which iodoethane (265 mg, 1.7 mmol) was added. The mixture was stirred at 0°C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 123-7.

[0367] Compound 123 was prepared from compound 123-7 according to the synthesis process of compound 2 in Example 1. LCMS(ESI,m / z): [M+H] +=636.3; HNMR(400MHz,methanol-d4,ppm): δ 7.72-7.69(m,1H),7.33-7.25(m,3H),7.06(s,1H),6.94(t,J=2.0Hz,1H),5.60-5.45(m,1H),4.69-4.53(m ,4H),4.24-3.22(m,2H),4.15-3.70(m,7H),3.47-3.42(m,1H),2.67-2.18(m,10H),1.12(t,J=7.2Hz,3H). JPEG0007860003000109.jpg126166

[0368] Step 1: A mixture of 6-methoxy-3,4-dihydronaphthylene-1(2H)-one (50 g, 280 mmol) and O-methylhydroxyamine hydrochloride (28 g, 336 mmol) in ethanol (500 mL) and pyridine (33 g, 420 mmol) was stirred at room temperature for 2 hours. The mixture was concentrated to obtain an oily substance. The oily substance was dissolved in dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate aqueous solution, and brine, dried over sodium sulfate, filtered, and concentrated to obtain 146-1, which was used directly in the next step without purification.

[0369] Step 2: A mixture of 146-1 (25 g, 120 mmol), palladium(II) acetate (1.3 g, 6 mmol), and n-bromosucciimide (21 g, 120 mmol) in acetic acid (400 mL) was stirred at 80°C for 1 hour. The solution was inverted into water and filtered. The filtered cake was dried to obtain 146-2, which was used directly in the next step without purification.

[0370] Step 3: The suspension of 146-2 (18 g, 80 mmol) in concentrated hydrochloric acid (100 mL) and dioxane (150 mL) was stirred under reflux for 1 hour. The mixture was concentrated, the residue was dissolved in ethyl acetate, washed with 1NNaOH, water, and brine (150 mL), concentrated, and the crude product was obtained. The product was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 146-3.

[0371] Step 4: Concentrated sulfuric acid (0.1 mL) was added to a mixture of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanbis(tetrafluoroborate) (8.14 g, 23 mmol) and 146-3 (5.1 g, 20 mmol) in methanol (80 mL). The mixture was stirred at 50 °C for 5 hours under an N2 atmosphere. The mixture was concentrated, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was polished with petroleum ether / ethyl acetate (10 / 1) to obtain 146-4.

[0372] Step 5: The mixture of 146-4 (4.63 g, 16.96 mmol) and pyridium tribromide (5.97 g, 18.66 mmol) in acetonitrile (46 mL) was stirred at 60°C under an N2 atmosphere for 30 minutes. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was polished with petroleum ether / ethyl acetate (10 / 1) to obtain 146-5.

[0373] Step 6: The mixture of 146-5 (5.4 g, 15.38 mmol) and lithium bromide (2.94 g, 33.85 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100°C under an N2 atmosphere for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was polished with petroleum ether / ethyl acetate (10 / 1) to obtain 146-6.

[0374] Step 7: At 0°C under an N2 atmosphere, trifluoroformic anhydride (16.2 g, 57.6 mmol) was added dropwise to a mixture of 146-6 (12.96 g, 48 mmol) and pyridine (11.4 g, 144 mmol) in dichloromethane (150 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 8 / 1) to obtain 146-7.

[0375] Step 8: Under an N2 atmosphere, triisopropylsilylacetylene (12.3 g, 67.5 mmol), diisopropylamine (45.5 g, 450 mmol), CuI (855 mg, 4.5 mmol), and bis(triphenylphosphin)chloropalladium(II) (1.58 g, 2.25 mmol) were added to the mixture of 146-7 (18 g, 45 mmol) in N,N-dimethylformamide (300 mL). The mixture was stirred at 50 °C for 16 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to obtain 146-8.

[0376] Step 9: At -78°C, under an N2 atmosphere, boron tribromide (14.6 mL, 29.2 mmol, 2 M in dichloromethane) was added dropwise to a mixture of 146-8 (10.6 g, 24.4 mmol) in dichloromethane (150 mL). The mixture was stirred at 0°C for 3 hours. The reaction was quenched with ice water. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 6 / 1) to obtain 146-9.

[0377] Step 10: A mixture of 146-9 (8.89 g, 19 mmol), bis(pinacolate)diborone (9.65 g, 38 mmol), potassium acetate (5.59 g, 57 mmol), tris(dibenzylacetone)dipalladium (870 mg, 0.95 mmol), and tricyclohexylphosphine (532 mg, 1.9 mmol) in dioxane (100 mL) was stirred at 105 °C under an N2 atmosphere for 10 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 8 / 1) to obtain 146-10.

[0378] Compound 146-11 was prepared from compounds 146-10 and 143-5 according to the synthesis process of compounds 11-12 in Example 3.

[0379] Step 11: Cesium fluoride (31 mg, 0.2 mmol) was added to a solution of 146-11 (18 mg, 0.02 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred at 50°C for 1 hour under a N2 atmosphere. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 146-12, which was used directly in the next step without purification.

[0380] Step 12: At room temperature, 146-12 obtained in the previous step was dissolved in 0.75 M ethyl acetate HCl (2.7 mL). The mixture was stirred at 50°C for 1 hour under a N2 atmosphere. The mixture was concentrated, and the residue was purified by preparative HPLC (aqueous solution of acetonitrile containing 0.05% TFA: 5% to 95%) to obtain 146. It was 3 equivalents of the TFA salt. LCMS (ESI, m / z): [M+H] + =634.3; HNMR (400MHz, methanol-d4, ppm): δ 7.90-7.84 (m,2H), 7.34-7.30 (m,2H), 7.03 (s,1H), 5.62-5.48 (m,1H), 4.80-4.73 (m,1H), 4.71-4.62 (m,3H), 4.27-4.24 (m,2H), 4.03-3.81 (m,5H), 3.47-3.44 (m,1H), 3.28 (s,1H), 2.73-2.55 (m,2H), 2.45-2.34 (m,3H), 2.24-2.09 (m,5H). FNMR (376MHz, methanol-d4, ppm): δ -115.53(1F),-123.83(1F),-174.41(1F). JPEG0007860003000110.jpg99166

[0381] Compound 154-1 was prepared from compound 121-3 according to the synthesis process of compounds 2-5 in Example 1.

[0382] Compound 154-2 was prepared from compounds 154-1 and 146-10 according to the synthesis procedure for compound 73-7 in Example 6.

[0383] Compound 154-3 was prepared from compound 154-2 according to the synthesis process of compound 73-1 in Example 6.

[0384] Compound 154-4 was prepared from compound 154-3 according to the synthesis process of compound 119-13 in Example 19.

[0385] Compound 154-4 (646 mg) was purified by SFC (column: DAISEL CHIRALPAK IC, EtOH / n-hexane / CO2) to obtain 154-4-P1 (275 mg) and 154-4-P2 (318 mg), respectively. 154-4-P1: SFC analysis: >99% ee; Retention time: 4.91 minutes; Column: Daicel CHIRALPAK® IC, in CO2 with n-hexane / EtOH (0.2% DEA); Pressure: 100 Bar; Flow rate: 1.0 mL / min. 154-4-P2: SFC analysis: >99% ee; Retention time: 5.73 minutes; Column: Daicel CHIRALPAK® IC, in CO2 with n-hexane / EtOH (0.2% DEA); Pressure: 100 Bar; Flow rate: 1.0 mL / min.

[0386] Compound 154 was prepared from compound 154-4-P1 according to the synthesis process of compound 146 in Example 29. LCMS(ESI,m / z): [M+H] + =634.3; HNMR(400MHz,methanol-d4,ppm): δ 7.90-7.84(m,2H),7.35-7.30(m,2H),7.04-7.03(m,1H),5.61-5.49(m,1H),4.77-4.64(m,4H), 4.26-4.24(m,2H),4.03-3.83(m,5H),3.49-3.42(m,1H),3.28-3.27(m,1H),2.74-2.10(m,10H).

[0387] Compound 155 was prepared from compound 154-4-P2 according to the synthesis process of compound 146 in Example 29. LCMS(ESI,m / z): [M+H] + =634.3; HNMR(400MHz,methanol-d4,ppm): δ 7.90-7.84(m,2H),7.35-7.30(m,2H),7.03(d,J=2.4Hz,1H),5.63-5.49(m,1H),4.83-4.74(m,1H),4.73-4.61(m,3H),4.30 -4.21(m,2H),4.05-3.81(m,5H),3.48-3.41(m,1H),3.27(s,1H),2.74-2.53(m,2H),2.45-2.29(m,3H),2.23-2.02(m,5H). JPEG0007860003000111.jpg92166

[0388] Compound 152-1 was prepared from compounds 73-6 and 146-10 according to the synthesis process of compound 73-7 in Example 6.

[0389] Compound 152-2 was prepared from compound 152-1 according to the synthesis process of compound 73-1 in Example 6.

[0390] Compound 152-3 was prepared from compound 152-2 according to the synthesis process of compound 119-13 in Example 19.

[0391] Compound 152-3 (441 mg) was purified by SFC (column: DAISELCHIRALPAK® MIC, MeOH (0.2% DEA) / CO2) to obtain 152-3-P1 (221 mg) and 152-3-P2 (206 mg), respectively. 152-3-P1: SFC analysis: >99% ee; Retention time: 1.68 minutes; Column: DAISELCHIRALPAK(registered trademark) IC, methanol (0.1% DEA) in CO2; Pressure: 100 Bar; Flow rate: 1.5 mL / min. 152-3-P2: SFC analysis: >99% ee; Retention time: 2.20 minutes; Column: DAISELCHIRALPAK(registered trademark) IC, methanol (0.1% DEA) in CO2; Pressure: 100 Bar; Flow rate: 1.5 mL / min.

[0392] Compound 152 was prepared from compound 152-3-P1 according to the synthesis process of compound 146 in Example 29, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] + =625.3; HNMR (400MHz, methanol-d4, ppm): δ 8.30(s,1H),7.92-7.88(m,1H),7.40-7.33(m,2H),7.14(d,J=2.4Hz,1H),5.63-5.50(m,1H),4.83-4.66(m,4H),4.32-4.21(m,2H),4.05-3.83(m,5H),3.49-3.42(m,1H),3.37-3.34(m,1H),2.78-2.53(m,2H),2.49-2.28(m,3H),2.25-2.03(m,5H). FNMR (376MHz, methanol-d4, ppm): δ -111.06(1F),-124.88(1F),-174.27(1F).

[0393] Compound 153 was prepared from compound 152-3-P2 according to the synthesis process of compound 146 in Example 29, and was a 3-equivalent TFA salt. LCMS(ESI,m / z): [M+H] + =625.3; HNMR (400MHz, methanol-d4, ppm): δ 8.29(s,1H),7.92-7.88(m,1H),7.40-7.33(m,2H),7.15(d,J=2.4Hz,1H),5.63-5.50(m,1H),4.85-4.67(m,4H),4.32-4.21(m,2H),4.08-3.82(m,5H),3.53-3.42(m,1H),3.37-3.34(m,1H),2.78-2.53(m,2H),2.49-2.28(m,3H),2.25-2.03(m,5H). FNMR (376MHz, methanol-d4, ppm): δ -111.09(1F),-124.84(1F),-174.25(1F). JPEG0007860003000112.jpg68166

[0394] Compound 167-1 was prepared from 1,3-dibromo-2,5-difluorobenzene and benzophenone imine according to the synthesis process of compound 11-2 in Example 3.

[0395] Step 1: A mixture of sodium sulfate (46.3 g, 326.16 mmol), hydroxyamine hydrochloride (9.92 g, 142.70 mmol), and chloral hydrate (10.12 g, 61.16 mmol) in water (200 mL) was stirred at room temperature for 0.5 hours. Then, a solution of 167-1 (16 g, ~40.77 mmol) in ethanol (28 mL), water (16 mL), and concentrated hydrochloric acid (7 mL) was added to the above mixture. The reaction mixture was stirred mechanically at 60 °C for 16 hours. The mixture was cooled to room temperature and then filtered. The filtered cake was slurryed with petroleum ether / ethyl acetate (240 mL / 40 mL) to obtain 167-2.

[0396] Step 2: At 60°C, 167-2 (7.75 g, 27.88 mmol) was dissolved in sulfuric acid (70 mL). The reaction mixture was then stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature and slowly inclined into ice water. The precipitate obtained by filtration was collected, washed with water, and dried under vacuum. The filtered cake was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2 / 1) to obtain 167-3.

[0397] Step 3: At 0°C, 30% hydrogen peroxygen aqueous solution (11.81 g, 104.20 mmol) was added to 94 mL of 2N sodium hydroxide aqueous solution of 167-3 (5.46 g, 20.84 mmol), and the mixture was stirred at room temperature for 4 hours. The pH of the mixture was adjusted to 8 with concentrated hydrochloric acid. The resulting rice-colored precipitate was filtered to obtain 167-4.

[0398] Step 4: The solution of 167-4 (4.07 g, 16.15 mmol) in sulfuryl chloride (50 mL) was stirred at 45°C for 1 hour. The mixture was concentrated and dissolved in acetone (50 mL). The mixture was treated with ammonium thiocyanate (1.35 g, 17.77 mmol), and then stirred at room temperature for 1 hour. The reaction mixture was diluted with water and filtered to obtain 167-5.

[0399] Step 5: At room temperature, the mixture of 167-5 (4.32 g, 14.75 mmol) in methanol (60 mL) was added to a solution of sodium hydroxide (1.18 g, 29.5 mmol) in water (45 mL) and iodomethane (4.19 g, 29.5 mmol), and then stirred for 1 hour. The reaction mixture was turned to water, the pH was adjusted to 6 with 2N hydrochloric acid aqueous solution, filtered, and washed with water. The filtered cake was made into a slurry with methanol (20 mL) to obtain 167-6.

[0400] Step 6: At 0°C, sodium hydride (456 mg, 60%, 11.41 mmol) was added to a solution of methanol (313 mg, 9.78 mmol) in N,N-dimethylformamide (10 mL), and the reaction was stirred at 0°C for 0.5 hours. The reaction mixture was then treated in several portions with 167-6 (1 g, 3.26 mmol) and stirred at room temperature for 16 hours. The mixture was diluted with water, and the pH was adjusted to approximately 3 with 2N hydrochloric acid. The mixture was filtered to obtain 167-7.

[0401] Compound 167 was prepared from compound 167-7 and 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl according to the synthesis process of compound 154 in Example 30, and was 3 equivalents of the TFA salt. LCMS(ESI,m / z): [M+H] +=630.3; HNMR(400MHz,methanol-d4,ppm): δ 7.87-7.83(m,1H),7.34-7.29(m,2H),7.13(d,J=2.4Hz,1H),6.90(d,J=4.8Hz,1H),5.60-5.46(m,1H),4.74-4.62(m,2H),4.57-4.29(m,2 H),4.22-4.18(m,2H),4.04-3.64(m,8H),3.50-3.37(m,1H),3.35-3.31(m,1H),2.75-2.53(m,2H),2.51-2.26(m,3H),2.22-1.98(m,5H). FNMR (400 MHz, methanol-d4, ppm): δ -111.51 (1F), -140.39 (1F), -174.26 (1F).

[0402] According to this disclosure, those skilled in the art can synthesize the compounds of this disclosure. Representative other compounds synthesized by similar processes / methods described in the following Examples section, and their identification data, are shown in Table 1 below. JPEG0007860003000113.jpg241166JPEG0007860003000114.jpg241166JPEG0007860003000115.jpg227166JPEG000 7860003000116.jpg243166JPEG0007860003000117.jpg224166JPEG0007860003000118.jpg242166JPEG0007860003 000119.jpg244166JPEG0007860003000120.jpg221166JPEG0007860003000121.jpg229166JPEG0007860003000122. jpg243166JPEG0007860003000123.jpg228166JPEG0007860003000124.jpg225166JPEG0007860003000125.jpg24216 6JPEG0007860003000126.jpg233166JPEG0007860003000127.jpg220166JPEG0007860003000128.jpg224166JPEG00 07860003000129.jpg239166JPEG0007860003000130.jpg239166JPEG0007860003000131.jpg242166JPEG0007860003 000132.jpg244166JPEG0007860003000133.jpg242166JPEG0007860003000134.jpg235166JPEG0007860003000135. jpg243166JPEG0007860003000136.jpg241166JPEG0007860003000137.jpg243166JPEG0007860003000138.jpg19166

[0403] Biological Example 1. Cell assay Recombinant KRAS G12D Ba / F3 parent cells were transfected using lentivirus, followed by a 1ug / mL promycin screen and IL3 depletion to determine Ba / F3_KRAS G12DCells (KYinno, China) were generated. The cells were cultured at 37°C in a 5% CO2 air atmosphere in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. 5 × 10⁶ cells were placed per well. 3 The compound was inoculated into a 96-well plate at a specific density and incubated overnight. Serially diluted compounds were added to each well. Cells were treated with the compound for 3 days, after which cell proliferation was assessed using the Glo reagent (Promega #G7572). Luminescence signals were then collected using a Tecan Spar plate reader. The formula for calculating inhibition rate is: Inhibition rate % = 100 * (control - well) / (control - blank). IC = Bottom value + (Top value - Bottom value) / (1 + 10^((LogIC50 - X) * HillSlope))). 50 The cell growth inhibition rate was calculated.

[0404] Table 2 below shows IC 50 The levels are indicated as I, II, or III, where I is IC. 50 The value is less than 500 nM; II is IC 50 This means the value is between 500nM and 5000nM; III is IC 50 This means the value exceeds 5000 nM.

[0405] JPEG0007860003000139.jpg98166JPEG0007860003000140.jpg178166

[0406] Biological Example 2. KRAS G12D Protein binding measurement Recombinant human KRAS by temperature-dependent fluorescence (TdF) measurement G12DProtein binding affinity was analyzed. TdF measurements were performed using a 96-well real-time fluorescence plate reader (ABI 7500 or Roche LightCycler 480). The fluorescent dye Sypro Orange (Sigma) was used to monitor the folded-unfolded conversion of the protein. Protein-compound binding was measured by the change in unfolded conversion temperature (ΔTm) obtained with and without the compound. Each reaction sample was treated with 6 μM KRAS in 20 μL of reaction buffer (25 mM HEPES pH 7.5, 150 mM NaCl, 10 mM MgCl2). G12D The sample consisted of a protein, a 10 μM compound, and a Sypro orange dye (in 1% DMSO). The sample plate was heated from 30°C to 95°C at a heating rate of 0.5%, and the fluorescence count was read once every 0.4°C using a CY3 channel tuned to the excitation and emission wavelengths of Sypro Orange (λex 470 nm; λem 570 nm). The degree of fluorescence shift of the protein in the presence and absence of the compound was used to determine the binding affinity (K). d The value was calculated.

[0407] In Table 2 below, K d The levels are listed as I, II, or III, where I is K d The value means less than or equal to 500 nM; II is K d This means the value is between 500 nM and 5000 nM; III is K d This means the value exceeds 5000 nM.

[0408] JPEG0007860003000141.jpg178166JPEG0007860003000142.jpg213166

[0409] The summary and abstract sections may describe one or more exemplary embodiments of the invention as conceived by the inventors and are therefore not intended to limit the scope of the invention and the appended claims in any way.

[0410] The present invention has been described above with the help of functional components that describe the implementation of specific functions and their relationships. The boundaries of these functional components are arbitrarily defined in this disclosure for the convenience of explanation. Other boundaries may be defined if they allow for the proper performance of the specified functions and their relationships.

[0411] With respect to aspects of the present invention described as a genus, all individual species are considered separately from distinct aspects of the present invention. Where an aspect of the present invention is described as "including" a feature, the embodiment is also considered to "consist of" or "essentially consist of" that feature.

[0412] The foregoing description of specific embodiments fully reveals the general nature of the invention, so that others can readily modify and / or adapt them to various uses, such as specific embodiments, for their respective applications by applying knowledge within the scope of the art, without excessive experimentation and without deviating from the general concept of the invention. Accordingly, such adaptations and modifications are intended to be within the meaning and scope of equivalents of the disclosed embodiments based on the teachings and guidance presented herein. The words or terms in this disclosure are for illustrative purposes only, not limitation, and it should be understood that the words or terms in this disclosure are to be interpreted by those skilled in the art in accordance with the teachings and guidance.

[0413] The scope and breadth of the present invention should not be limited by any of the exemplary embodiments described above.

[0414] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0415] All publications, patents, and patent applications described herein are incorporated by reference to the same extent as any individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. If any meaning or definition of a term in this document conflicts with the meaning or definition of the same term in any document incorporated by reference, the meaning or definition assigned to that term in this document shall prevail.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, Here, G １ However, N is; G ２ and G ３ each time they appear independently, CR １１ R １２ or NR ２０ whereas, G ２ and G ３ at least one example of which is NR ２０ where; n1 and n2 are independent integers of 1, 2, 3, or 4; A １ and A ２ However, each can be independent, combined, or CR １１ R １２ And; R １ However, -OR ３０ And among them, R ３０ ga-C １～６ Alkilen-R １０１ And among them, R １０１ but, These are two rings selected from the group consisting of, Each of these may be substituted with one or more substituents, and the substituents may be independently substituted with F, -OH, or 1 to 3 fluorines. １～４ C may be substituted with an alkoxy group, an oxo group, or one to three fluorines. １～４ Alkyl, NH ２ NH(C １～４ Alkyl alkyl group), N (C １～４ (Alkyl alkyl group) (C １～４ Selected from the group consisting of 4- to 6-membered heterocycles having an alkyl group, a cyclopropyl group, a cyclobutyl group, and one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S; R ３ However, (1) a phenyl group, a pyridyl group, a naphthyl group, or a bicyclic heteroaryl group, each of which may be substituted with one to three substituents, and the substituents are independently F, Cl, Br, I, -OH, C １～４ Alkyl alkyl, CF ３ , -NH ２ (2) A naphthyl group which may be substituted with one or more substituents, wherein the substituents are independently F, Cl, Br, I, -OH, and C １～４ C, which may be alkyl or substituted. ２～４ Alkenyl group, substitution may be C ２～４ Alkynyl group, cyclopropyl group, -NH ２ Selected from the group consisting of , and -CN, R １００ However, each time they appear, independently, F, Cl, CN, -OH, -C(O)NH(C) １～６ C (alkyl group), or substituted C １～４ It is an alkoxy group, and m is 0, 1, 2, or 3; Among them, R １１ and R １２ However, it is hydrogen; R ２０ However, it is hydrogen. A compound or a pharmacologically acceptable salt thereof.

2. Part in Equation I but, Selected from the group consisting of, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ３０ -C １～６ Alkylene - Unit is -CH ２ -ien-CH ２ -CH ２ -ien-CH ２ -CH ２ -CH ２ - Selected from the group consisting of, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ but, or That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R １００ However, each time they appear, independently, F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH ２ -Cyclopropyl group, -C(O)NHMe, or CF ３ That is, The compound according to claim 1.

6. m is 2, and there are two R １００ However, all of them are R ３ Located in the ortho position of the base, The compound according to claim 1.

7. R ３ but, Selected from the group consisting of, Alternatively, R ３ but, Selected from the group consisting of, The compound according to claim 1.

8. Selected from the group consisting of the following compounds: The compound according to claim 1.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9 for use in the treatment of cancer in examinees.

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