Heteroaryl group compounds, methods for producing the same, and uses

Abstract

The present invention provides novel compounds, for example, compounds having formula (I), formula (A), formula (II), formula (III), formula (IV), or formula (V), or pharmacologically acceptable salts thereof. The present invention further provides methods for producing the compounds, as well as methods for inhibiting KRAS, for example, in cancer cells. G12D and / or methods of using said compounds to treat various cancers, such as pancreatic, colorectal, lung or endometrial cancer.

Description

[Technical Field]

[0001] Cross-citation of related applications This application claims priority to the international application filed on 26 August 2020, application number PCT / CN2020 / 111302, and the international application filed on 7 February 2021, application number PCT / CN2021 / 075781, the entire contents of which are incorporated into this application by reference.

[0002] In various embodiments, this disclosure generally relates to novel heteroaryl compounds for inhibiting RAS and / or treating multiple diseases or conditions such as cancer, compositions containing such heteroaryl compounds, methods for producing the same, and methods for using the same. [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, KRASG12D Targeting the mutation is challenging because the pocket is shallow.

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

[0005] In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, methods for their manufacture, and methods of use. Generally, the compounds of the present application 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 application are used for treating various diseases or medical conditions, such as cancer or cancer metastasis.

[0006] In some embodiments, the present disclosure provides compounds of Formula I, Formula A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof. TIFF0007837952000001.tif110166 wherein R 1 , R 2 , R 3 , R 8 , J 1 , J 2 , J 3 , J 4 and J 5 are as defined in the present application.

[0007] Specific embodiments of the present disclosure include one or more compounds of the present disclosure (e.g., formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I- The present invention relates to a pharmaceutical composition comprising any compound of formula 9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any compound of compounds 1-247, or any pharmacologically acceptable salt thereof), and any pharmacologically acceptable excipient. The pharmaceutical composition according to the present application may be 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 (e.g., KRAS G12D). In some embodiments, the method involves administering a therapeutically effective amount of the compounds of the Disclosure (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E) to a subject in need. The treatment comprises administering a therapeutically effective amount of any compound of formula A (e.g., I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any compound of compounds 1-247, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition relating to this application. Diseases or conditions related to RAS, e.g., KRAS G12D, suitable for treatment by this method include those described in this application.

[0009] In some embodiments, a method for treating cancer is provided. In some embodiments, the method involves administering a therapeutically effective amount of the compounds of the Disclosure (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E) to a test subject who needs it. The treatment involves administering a therapeutically effective amount of a compound of formula (I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any compound of compounds 1-247, or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable amount thereof of the pharmaceutical composition of this application. 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., those described in this application). 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 is provided for treating cancer metastasis or tumor metastasis. In some embodiments, the method provides a therapeutically effective amount of the compounds of the Disclosure (e.g., formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E) to a subject who needs it. The treatment involves administering a therapeutically effective amount of any compound of formula 1-247 (I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), or any compound of compounds 1-247 or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of the pharmaceutical composition relating to this application.

[0011] The administration in the present invention 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 a subject with targeted therapies, chemotherapies, therapeutic antibodies, radiation, cell therapy and / or immunotherapy.

[0013] It should be understood that the above summary and the following detailed description are merely illustrative and explanatory, and do not constitute any limitation on the present invention as applied to this application. [Modes for carrying out the invention]

[0014] International application number PCT / CN2020 / 099104, filed by Inventisbio Shanghai Ltd. on June 30, 2020 (the entire contents of which are addressed in this application), describes certain quinazoline compounds as RAS (e.g., KRAS). G12D It is described as a useful pharmaceutical for inhibiting and / or treating multiple diseases or conditions (e.g., cancer). Currently, it has been discovered that the quinazoline core is not necessary for the inhibition of the RAS. In various embodiments, the present application provides novel heteroaryl group compounds, pharmaceutical compositions, methods of production and methods of use.

[0015] compound Some embodiments of this disclosure relate to novel compounds. Compound h in this application may generally be an inhibitor of the KRAS protein (particularly the KRAS G12D mutant protein) and may be used to treat various diseases or conditions described in this application, such as cancer.

[0016] In some embodiments, the present disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof. TIFF0007837952000002.tif3375 Here, J 1 However, CR 9 or N; J 2 However, CR 10 or N; J 3 However, CR 11 or N; J 4 However, CR 12 or N; J 5 However, CR 12A or N; However, J 1 and J 2 At least one of them is N, and J 1 and J 2 If both are N, then J 3 and J 4 and J 5At least one of them is N; Or, J 4 and J 5 These groups may be linked to form a substituted phenyl group or a substituted 5 or 6-membered heteroaryl group, provided that in this case, for example, J 4 and J 5 When linked to form a triazole ring, J 4 and J 5 The bond between them may be a single bond; R 1 However, hydrogen, -(L 1 ) m1 -OR 20 , halogen, -(L 1 ) m1 -NR 30 R 31 -C(O)-NR 30 R 31 , an optionally substituted alkyl group, or an optionally substituted heterocyclic or heteroaryl ring; R 2 However, the ring or ring chain structure is such that, for example, it has a basic functional group having a conjugate acid pKa of about 5 or more, or an acylation derivative thereof (i.e., the basic functional group such as a basic NH is bonded to an acyl group); R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 9 and R 10 However, each can independently be hydrogen, halogen, cyano group, or substituted C 1-4 Alkyl group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C 2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 1-4 Alkoxy group, substituted KarC 3-6A cycloalkyl group, an optionally substituted aryl group, an optionally substituted 4-8 membered heterocyclic group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or an optionally substituted 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S. R 11 , R 12 and R 12A However, each is independent of hydrogen, F, Cl, Br, I, CN, -OH, -C(O)NH2, -NH2, -NH(C 1-6 Alkyl(alkyl group), -N(C) 1-6 (Alkyl group)(C 1-6 Alkyl(alkyl group), -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 group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C 2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 3-6 A cycloalkyl group (e.g., a cyclopropyl group or a cyclobutyl group) may be substituted. 1-4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), may be substituted C 3-6 A cycloalkoxy group (e.g., a cyclopropoxy group or a cyclobutoxy group), a substituted or alternatively substituted 4-7 membered heterocycloalkoxy group; Alternatively, R 12 and R 12A They are linked together to form a 5-7 membered ring structure; and Here, m1 is either 0 or 1, and if m1 is 1, L 1 However, these may be substituted alkylene groups, substituted carbocyclylene groups, or substituted heterocyclylene groups; R 20 However, hydrogen, oxygen protecting groups, and substitutions may be made of C. 1-6It is an alkyl group, an optionally substituted carbon ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle; R 30 and R 31 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 30 and R 31 They may be linked together to form a heterocycle or heteroaryl ring, or R 30 and R 31 One of them is L 1 They form a heterocyclic or heteroaryl ring, which may be substituted with appropriate atoms and any atoms in between.

[0017] Compounds of formula I (including any applicable sub-formulas described herein) may exist in the form of a single enantiomer, a diastereomer, an 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 any applicable sub-formulas described herein) may exist as a mixture of atropisomers in any proportion (including about 1:1). In some embodiments, where applicable, compounds of formula I (including any applicable sub-formulas described herein) may exist as a single enantiomer of isolation, such single enantiomer being essentially free of other enantiomers (e.g., containing less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other enantiomers by weight, HPLC area, or both).

[0018] In some embodiments, J in formula I 1 However, CR 9 Each of the various groups is R 9 This is appropriate, but in equation I, R 9 However, generally, it is H. In some embodiments, J in formula I1 is N. In some embodiments, J in Formula I 2 is CR 10 , for example, CH. In some embodiments, J in Formula I 2 is N. In some embodiments, J in Formula I 3 is CR 11 , for example CH or C-F. In some embodiments, J in Formula I 3 is N. In some embodiments, J in Formula I 4 is CR 12 , for example, CH or C-CN. In some embodiments, J in Formula I 4 is N. In some embodiments, J in Formula I 5 is CR 12A , for example, CH or C-Me. In some embodiments, J in Formula I 5 is N. In some embodiments, J 4 and J 5 may be linked and substituted to form a 5- or 6-membered heteroaryl group, provided that the bond between J 4 and J 5 may be a single bond. For example, in some embodiments, J 4 and J 5 are linked to form a triazole ring, for example, see Formula I-24 below.

[0019] J 1 , J 2 , J 3 , J 4 and J 5 in combination are not particularly limited. For example, in some embodiments, the compound of Formula I can have one of the following sub-formulas. TIFF0007837952000003.tif40166TIFF0007837952000004.tif249166where R 1 , R 2 , R 3 , R 10 , R 11 , R 12 and R 12AHowever, this includes any combination of any of the ones defined in this application.

[0020] In some embodiments, if present, R in formula I (e.g., formulas I-5, I-6, I-8, I-12, or I-14) 10 However, C may be substituted with hydrogen, halogens (e.g., Cl), or 1-3 F atoms. 1-4 The C11 is an alkyl group (e.g., methyl group, ethyl group, CF3, etc.), a cyclopropyl group, a cyclobutyl group, or a 5-membered or 6-membered heteroaryl group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S (e.g., pyrazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, etc.), wherein the heteroaryl group may be substituted with 1-3 substituents, and the substituents may be independently substituted with halogens, CN, or 1-3 F atoms. 1-4 C may be substituted with an alkyl group (e.g., methyl group, ethyl group, CF3, etc.) or one or more substituents independently selected from the group consisting of methyl group, F, OH, and methoxy group. 3-6 Cycloalkyl groups (e.g., cyclopropyl group, cyclobutyl group), and C which may be substituted with 1-3 F 1-4 Selected from the group consisting of alkoxy groups (e.g., methoxy group, ethoxy group, -OCF3, etc.).

[0021] In some embodiments, if present, R in formula I (e.g., formulas I-5, I-6, I-8, I-12, or I-14) 10 However, these are hydrogen, F, Cl, methyl group, ethyl group, isopropyl group, CF3, cyclopropyl group, or cyclobutyl group.

[0022] In some embodiments, if present, R in formula I (e.g., formulas I-5, I-6, I-8, I-12, or I-14) 10 but, The filename is TIFF0007837952000005.tif2950, R 100 However, each time it appears, it may be independently substituted with a halogen, CN, and 1-3 F atoms. 1-4C may be substituted with an alkyl group (e.g., methyl group, ethyl group, CF3, etc.) or one or more substituents independently selected from the group consisting of methyl group, F, OH, and methoxy group. 3-6 Cycloalkyl groups (e.g., cyclopropyl group, cyclobutyl group), and C which may be substituted with 1-3 F 1-4 An alkoxy group (e.g., methoxy group, ethoxy group, -OCF3, etc.); and n is 0, 1, 2, or 3, preferably n is 0, 1, or 2.

[0023] The appropriate R used in formula I (e.g., formulas I-5, I-6, I-8, I-12, or I-14) 10 This further includes those specifically cited in this application.

[0024] In some embodiments, if present, R in formula I (e.g., formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23, or I-24) 11 However, R is 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. For example, in some embodiments, R in formula I (e.g., formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23 or I-24) 11 However, F. In some embodiments, R in formula I (e.g., formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23 or I-24) 11 However, it is Cl. In some embodiments, R in formula I (e.g., formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23 or I-24) 11 However, is a methyl group. In some embodiments, R in formula I (e.g., formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23 or I-24) 11However, it is a cyclopropyl group. In some embodiments, R in formula I (e.g., formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23 or I-24) 11 However, it is hydrogen. The appropriate R used in formula I (for example, formulas I-1, I-3, I-5, I-9, I-10, I-11, I-12, I-13, I-14, I-23 or I-24) 11 This further includes those specifically cited in this application.

[0025] In some embodiments, if present, R in formula I (e.g., formulas I-2, I-4, I-6, I-13, I-14, or I-23) 12 However, the group is 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, R in formula I (e.g., formulas I-2, I-4, I-6, I-13, I-14, or I-23) 12 However, F. In some embodiments, R in formula I (e.g., formulas I-2, I-4, I-6, I-13, I-14, or I-23) 12 However, it is Cl. The appropriate R used in formula I (for example, formulas I-1, I-3, I-5, I-13, I-14 or I-23) 12 This further includes those specifically cited in this application.

[0026] In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, it is hydrogen. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, it is a halogen, for example, Cl. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, C may be substituted. 1-4 Alkyl groups (e.g., methyl group, ethyl group, CHF2, CF3, etc.) are substituted, and C 1-4The alkyl group may generally be substituted with 1-3 independently fluorine atoms, OH groups, and 1-3 fluorine atoms. 1-4 Alkoxy group, cyclopropyl group, cyclobutyl group, CONH(C 1-4 Alkyl(C), CONH2, CON(C 1-4 (Alkyl group)(C 1-4 It is substituted with substituents selected from the group consisting of an alkyl group and a 4-7 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, or S. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, C may be substituted. 3-6 A cycloalkyl group (e.g., a cyclopropyl group or a cyclobutyl group), if substituted, the C 3-6 The cycloalkyl group is generally substituted with 1-3 substituents, and these substituents may be independently substituted with F, OH, a methyl group, a hydroxymethyl group, CHF2, CH2F, CF3, and 1-3 F. 1-4 Selected from the group consisting of alkoxy groups. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, C may be substituted. 1-4 The alkoxy group (e.g., methoxy group, ethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, -O-CH2-CH2-cyclopropyl group, -O-CH2-cyclopropyl group) is substituted, and the C 1-4 The alkoxy group is generally substituted with 1-3 substituents, and these substituents may be independently substituted with F, OH, and 1-3 F atoms. 1-4 Alkyl group, C which may be substituted with 1-3 F 1-4 Alkoxy group, cyclopropyl group, cyclobutyl group, CONH(C 1-4 Alkyl(C), CONH2, CON(C 1-4 (Alkyl group)(C 1-4Selected from the group consisting of a 4-7 membered heterocycle having an alkyl group and one or two independently selected ring-forming heteroatoms from the group consisting of O, N, or S. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, C may be substituted. 3-6 A cycloalkoxy group (for example, a cyclopropoxy group or a cyclobutoxy group), if substituted, the C 3-6 The cycloalkoxy group is generally substituted with 1-3 substituents, and these substituents may be independently substituted with F, OH, methyl group, hydroxymethyl group, CHF2, CH2F, CF3 and 1-3 F. 1-4 Selected from the group consisting of alkoxy groups. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, a 4-7 membered heterocycle may be substituted, for example, the monocyclic 4-7 membered heterocycle relating to this application, and if substituted, the 4-7 membered heterocycle is generally substituted with 1-3 substituents, and the substituents may be independently substituted with F, an oxo group, OH, a methyl group, a hydroxymethyl group, CHF2, CH2F, CF3, and 1-3 F atoms. 1-4 Selected from the group consisting of alkoxy groups. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, the 4-7 member heterocycloalkoxy group may be substituted, and if substituted, the 4-7 member heterocycloalkoxy group is generally substituted with 1-3 substituents, and the substituents may independently be F, an oxo group, OH, a methyl group, a hydroxymethyl group, CHF2, CH2F, CF3, and 1-3 F atoms. 1-4 Selected from the group consisting of alkoxy groups. As used in this application, heterocycloalkoxy group means -OR, where R is the heterocycle as defined herein. In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, -NH2, -NH(C 1-6 Alkyl(alkyl group) or -N(C) 1-6 (Alkyl group)(C 1-6(Alkyl alkyl group) may also be used.

[0027] In some embodiments, when applied, R in formula I 12 and R 12A However, they may be connected to form a 5-7 member ring structure.

[0028] In some embodiments, if present, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A is hydrogen, 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, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, C may be substituted with H or F. 1-4 The alkyl group is, for example, a methyl group. In some embodiments, R in formula I (for example, formulas I-9, I-11, or I-12) 12A However, it is a Cl or a methoxy group. In some embodiments, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, this is an ethyl group or a difluoromethyl group. In some embodiments, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, it is OH. In some embodiments, R in formula I (e.g., formulas I-9, I-11, or I-12) 12A However, C may be substituted with halogens, -OH, or 1-3 F atoms. 1-4 Alkyl group, C which may be substituted with 1-3 F 1-4 C substituted with an alkoxy group or a cyclopropyl group which may be substituted with 1-3 fluorine atoms. 1-4 It is an alkoxy group. In some embodiments, R in formula I (e.g., formula I-9, I-11, or I-12) 12AThe appropriate R used in formula I (e.g., formulas I-9, I-11, or I-12) is Cl, -OH, methoxy group, difluoromethoxy group, ethoxy group, isopropoxy group, -O-CH2-cyclopropyl group, -O-CH2-CH2-cyclopropyl group, -C(O)NHMe, -O-CH2-C(O)NHMe, -O-CH2-CF3, -O-CH2-CHF2, methyl group, CHF2, CF3, ethyl group, isopropyl group, or cyclopropyl group. 12A This further includes those specifically cited in this application.

[0029] In some embodiments, the compound of formula I may have one of the following sub-formulas. TIFF0007837952000006.tif253166TIFF0007837952000007.tif69163In formula, R 1 , R 2 , R 3 and R 10 However, this includes any combination of any of the ones defined in this application.

[0030] Various groups, R in formula I 1 It is appropriate as follows. In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1However, it may be hydrogen. In some embodiments, R in formula I (e.g., subformulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, halogens, such as F or Cl, may also be used. In some embodiments, an appropriate R used in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 This further includes any of those specifically cited in this application.

[0031] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, alkyl groups that may be substituted, for example, C which may be substituted 1-4 It may be an alkyl group. For example, in some embodiments, R in formula I 1 However, C may be substituted with 1-3 Fs. 1-4 It may be an alkyl group. In some embodiments, R in formula I 1 However, it may also be a methyl group, CHF2, or CF3.

[0032] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, -C(O)-NR 30 R 31 For example, CONH(C 1-4 It may be an alkyl group, and the C 1-4 The alkyl group may be substituted. For example, in some embodiments, R in formula I 1 but, TIFF0007837952000008.tif2375 is also acceptable.

[0033] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, -(L 1 ) m1 -OR 20 It may also be the case that, in some embodiments, m1 is 0, i.e., R 1 ga-OR 20 In some embodiments, m1 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, m1 is 1 and L 1 However, C 1-4Alkylene groups, such as -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-, may also be used.

[0034] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 ga-OR 20 And R 20 ga-C 1-6 Alkylene group-R 101 And R 101 NR 32 R 33 A 4-10 membered heterocycle which may be substituted, and the C 1-6 The alkylene group may be substituted, for example, with one or more substituents, and the substituents may independently be F, OH, NR 34 R 35 and C which may be substituted with 1-3 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 32 and R 33 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, a substituted or substituted carbon ring, or a substituted or substituted heterocycle; or, NR 32 R 33 However, it represents a monoalkyl or dialkylamine; or, R 32 and R 33 They may be linked and substituted to form a heterocyclic or heteroaryl ring; R 34 and R 35 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 34 and R 35The linked and substituted heterocyclic rings or heteroaryl rings are formed. In some embodiments, R 20 -C in 1-6 The alkylene group-unit is unsubstituted C 1-4 It is an alkylene group (straight-chain or branched-chain). In some embodiments, R 20 -C in 1-6 The alkylene group-unit may be substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents. 1-4 It is an alkylene group, and the substituent is independently selected from the group consisting of F, -OH, methyl group, ethyl group and CF3. In some embodiments, R 20 -C in 1-6 The alkylene group-unit is C 1-4 The alkylene group is formed by linking two substituents (for example, on homologous carbons) to form a cyclopropyl 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 20 -C in 1-6 The alkylene group-unit is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, TIFF0007837952000009.tif1664 or Selected from the group consisting of TIFF0007837952000010.tif2156. In some embodiments, R 20 -C in 1-6 Alkylene group-unit, The file is TIFF0007837952000011.tif1556. As used in this application, unless otherwise specified, the divalent structure can be linked to the rest of the molecule in either direction. In some embodiments, R 20 ga-CH2-R 101 -CH2-CH2-R 101 -CH2-CH2-CH2-R 101 , TIFF0007837952000012.tif1667 or TIFF0007837952000013.tif2165, R 101 R is defined in this application. In some embodiments, R 20 -C in 1-6 Alkylene group-unit, TIFF0007837952000014.tif1552, R 101 This is defined in this application.

[0035] R 101 However, generally speaking, NR 32 R 33 Alternatively, it is a 4-10 membered heterocycle having 1-3 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, which may be substituted. Generally, the heterocycle is a saturated heterocycle which may be substituted.

[0036] In some embodiments, R 101 NR 32 R 33 And R 32 and R 33 However, C may be hydrogenated or substituted independently. 1-4 Alkyl groups, such as methyl, ethyl, and isopropyl groups. 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 application, 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, and include, for example, N(CH3)2 and N(CH3)(C2H5). Other similar expressions should be understood in the same way. In some embodiments, R 101 NR 32 R 33 And R 32 and R 33 One of them is hydrogen or a substituted C 3-6 It is a cycloalkyl group, R32 and R 33 Another of these is defined in this application, and for example, in some embodiments, R 32 and R 33 The other one inside is hydrogen, which may be substituted with C. 3-6 Cycloalkyl groups or C 1-4 Alkyl group, for example, methyl group. In some embodiments, R 101 NR 32 R 33 , R 32 and R 33 One of them is a 4-8 membered heterocycle which may have hydrogen or be substituted, for example, a heterocycle having 1 or 2 heteroatoms independently selected from the group consisting of O and N, preferably the ring has one or less oxygen atoms and R 32 and R 33 Another of these is defined in this application, and for example, in some embodiments, R 32 and R 33 The other one inside is hydrogen or C 1-4 Alkyl group, for example, methyl group. In some embodiments, R 101 NR 32 R 33 And R 32 and R 33 One of them is hydrogen or C 1-4 It is an alkyl group, R 32 and R 33 The other one inside is C 1-30 It may be an alkyl group. For example, in some embodiments, R 101 However, NH(C 1-30 Alkyl(alkyl group) or N(C) 1-4 (Alkyl group)(C 1-30 Alkyl(alkyl group), for example, N(CH3)(C 1-30 (Alkyl alkyl group) may also be used.

[0037] In some embodiments, R 101 NR 32 R 33 , R 32 and R 33However, together with the N that is linked with them, they may form a 4-8 member monocyclic heterocycle which may be substituted, and which has one or two ring-forming heteroatoms, for example, 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 NR 32 R 33 And R 32 and R 33 However, together with the N that connects them, they form a ring selected from the following group. TIFF0007837952000015.tif26166 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 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S, 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. The substituent can also be linked to any available position on the ring, for example, including an available ring-forming nitrogen atom.

[0038] In some embodiments, R 101 NR 32 R 33 And R 32 and R 33 However, together with N which is connected to them, they form a ring TIFF0007837952000016.tif2370 is formed, which may be substituted with one or more (e.g., 1 or 2) substituents, the substituents of which may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with alkoxy groups, oxo groups, acyl groups, amides, esters, or 1-3 fluorine groups. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(C) 1-4 (Alkyl group)(C 1-4 The group consists 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. For example, in some embodiments, the piperazine ring may have a substituent linked to one of its ring-forming nitrogen atoms, and the substituent is C 1-4 Alkyl groups, acyl groups, for example, -C(O)(C 1-30 Alkyl alkyl groups), esters (for example, -C(O)-O-(C 1-30 Alkyl alkyl groups, or amides, for example, -C(O)-NH(C 1-30 Alkyl(alkyl group) or -C(O)-N(C 1-4 (Alkyl group)(C 1-30 It may be an alkyl group. For example, in some embodiments, R 101 but, TIFF0007837952000017.tif3592 or TIFF0007837952000018.tif3183 is also acceptable.

[0039] In some embodiments, R 101 However, it may 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, bridged, 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, and the monocyclic or dicyclic form may be substituted, for example, with one or more (e.g., one or two) substituents, and the substituents may be independently F, -(CH2) x-OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 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. The monocyclic or bicyclic formula is connected to -C via any available position. 1-6 R is linked to the alkylene group portion. 20 This can form a two-ring structure. In the case of the two-ring structure, the connection point may be on either of the two rings, and may include bridging atoms and bridge atoms where applicable.

[0040] For example, in some embodiments, R 101 However, it may also be a monoring selected from the group consisting of the following: TIFF0007837952000019.tif24164 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 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(C) 1-4 (Alkyl group)(C 1-4The substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4-6 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.

[0041] In some embodiments, R 101 However, it may also be a biringual structure selected from the group consisting of the following: TIFF0007837952000020.tif70159 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 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S, 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. To clarify further, the linking point of the two spiro-dicyclic structures described above may be a ring atom derived from a cyclobutyl group or an azetidine or pyrrolidine ring. In some embodiments, the linking point is a ring atom derived from a cyclobutyl group, for example, on a carbon not adjacent to the spirocenter. In some embodiments, R 101However, the structure may be a bridging bicyclic structure, for example, a bridging bicyclic structure containing one or two independently selected ring-forming heteroatoms from the group consisting of nitrogen and oxygen, for example, a bridging bicyclic structure having one ring-forming nitrogen, or a bridging bicyclic structure having one ring-forming nitrogen and one ring-forming oxygen, or a bridging bicyclic structure having two ring-forming nitrogens, among which the bridging bicyclic system may be, for example, a [2,2,1], [2,2,2], [3,1,1], or [3,2,1] bridging bicyclic system. The bridging bicyclic structure may be substituted, for example, with one or more (e.g., 1, 2, or 3) substituents, the substituents being independently selected from the group consisting of F, methyl group, ethyl group, isopropyl group, cyclopropyl group, -N(CH3)2, -OH, and -OCH3.

[0042] In some embodiments, R 101 However, NH2, NH(C 1-30 Alkyl(CH3), N(CH3)(C 1-30 (Alkyl alkyl group), TIFF0007837952000021.tif2087TIFF0007837952000022.tif3087 or TIFF0007837952000023.tif3063 is also acceptable.

[0043] Any R 101 However, any of the -Cs described in this application 1-6 Combined with the alkylene group portion, R 1 ga-OR 20 Formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I- 3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) R 20It can be applied to R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B). 1 but, The group consisting of TIFF0007837952000024.tif144166 may also be selected. Alternatively, R 1 but, The filename is TIFF0007837952000025.tif2778.

[0044] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, the methoxy group, TIFF0007837952000026.tif1871NH2, NH(CH3) or N(CH3)2 may also be used.

[0045] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000027.tif99166 or TIFF0007837952000028.tif34103 is also acceptable.

[0046] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, It could also be TIFF0007837952000029.tif1780, R 101 However, NH2, NH(C 1-30 Alkyl(CH3), N(CH3)(C 1-30 (Alkyl alkyl group), TIFF0007837952000030.tif35166 or The filename is TIFF0007837952000031.tif34106.

[0047] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 Also, -OR 20 It may be R 20 However, C may be substituted. 3-6 It is a carbocyclic or 4-10 membered heterocyclic ring. Oxygen can be linked to the carbocyclic or heterocyclic ring via any available linkage point, but generally not via a heteroatom or a carbon atom adjacent to a heteroatom. In some embodiments, R20 However, the monocyclic 4-8 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of N, O, and S, or the condensed, bridged, 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 form may be substituted, for example, with one or more (e.g., one or two) substituents, and the substituents may be independently F, -(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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 embodiments, R 20 However, it is a 4-8 member monocyclic saturated ring having one ring-forming heteroatom and a ring-forming nitrogen. For example, in some embodiments, R 20 However, it is a monocyclic saturated ring selected from the group consisting of the following: TIFF0007837952000032.tif2396 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 1-3 fluorines.1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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.

[0049] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 Also, -OR 20 It may be R 20 However, it is an aryl group or heteroaryl ring that may be substituted.

[0050] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, they may be selected from the following group: TIFF0007837952000033.tif46119

[0051] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 Also, -(L 1 ) m1 -NR 30 R 31 It may also be the case that, in some embodiments, m1 is 0, i.e., R 1 However, NR 30 R 31 In some embodiments, m1 is 1 and L 1 However, C may be substituted. 1-6 Alkylene group, substituted KilC 3-6 The group may be a carboxycyclylene group or a substituted 3-7 membered heterocyclylene group. For example, in some embodiments, m1 is 1 and L1 is C 1-4 Alkylene groups, such as -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-, may also be used.

[0052] For example, in some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, NR 30 R 31 or -C 1-6 Alkylene group-NR 30 R 31 It may also be R 30 and R 31However, hydrogen may be substituted on C independently. 1-6 An alkyl group, or a substituted heterocycle; or, R 30 and R 31 However, together with N which is linked together with them, they form a substituted heterocycle having one or two ring-forming heteroatoms, or R 30 and R 31 One of them is the aforementioned C 1-6 The alkylene group forms a CH2 unit and any of the atoms between them, and a substituted heterocyclic or heteroaryl ring having one or two ring-forming heteroatoms. In some embodiments, R 30 and R 31 One of these is a substituted 4-8 member monocyclic saturated heterocycle, for example, a heterocycle 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 4-8 member 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 -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 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 4-8 membered monocyclic saturated heterocycle has one ring-forming heteroatom, which is a ring-forming nitrogen atom (e.g., azetidine, pyrrolidine, piperazine, etc.). Generally, the linking point is not the ring-forming nitrogen atom or a carbon atom adjacent to the ring-forming nitrogen. In some embodiments, R 30 and R 31 The other one inside is a hydrogen or substituted C 1-6 Alkyl alkyl groups, for example, C 1-4 Alkyl groups, such as methyl, ethyl, or isopropyl groups.

[0053] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, -C 1-6 Alkylene group-NR 30 R 31 It may be R 30 and R 31 However, together with N which is connected to them, they form a ring selected from the following group. TIFF0007837952000034.tif25160 Each of them may be substituted, for example, with one or more (e.g., 1 or 2) substituents, the substituents independently being F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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.

[0054] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, -C 1-6 Alkylene group-NR 30 R 31 It may be R 30 C 1-6 The CH2 unit of the alkylene group and any of the atoms between them together form a ring selected from the group consisting of the following (R 31 It forms (showing). TIFF0007837952000035.tif22155 Each of them may be substituted, for example, with one or more (e.g., 1 or 2) substituents, where the substituents are independently F,-(CH2) x-OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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, R 31 ga-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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) p -Cyclopropyl group, -(CH2) p -Cyclobutyl group, or -(CH2) p -A 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S, where x is 1, 2, or 3, and p is 0, 1, 2, or 3.

[0055] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000036.tif44166 is also acceptable.

[0056] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 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, bridged, or spiro-dicyclic 6-10 membered heterocycle having 1 to 3 independently selected ring-forming heteroatoms from the group consisting of N, O, and S, where the monocyclic or bicyclic form may be substituted. In some embodiments, R 1 However, the 4-8 member monocyclic saturated heterocycle may be substituted, for example, a 4-8 member monocyclic saturated heterocycle 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 4-8 member 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 -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), x is 0, 1, 2, or 3, 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, -(CH2)-N(CH3)2, -N(CH3)2, -OH, and -OCH3. In some embodiments, the 4-8 membered monocyclic saturated heterocycle has one ring-forming heteroatom and one ring-forming nitrogen atom (e.g., azetidine, pyrrolidine, piperazine, etc.).

[0057] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, it may be a substituted condensed, bridging, or spiro-dicyclic 6-10 membered heterocycle, having 1 to 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 TIFF0007837952000037.tif69147, Each of them may be substituted, for example, with one or more (e.g., 1 or 2) substituents, and the substituents may independently be F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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 data may be selected from the group consisting of TIFF0007837952000038.tif75129. In some embodiments, R 1The bridging bicyclic structure may also be a bridging bicyclic structure containing one or two independently selected ring-forming heteroatoms from the group consisting of nitrogen and oxygen, for example, a bridging bicyclic structure having one ring-forming nitrogen, or a bridging bicyclic structure having one ring-forming nitrogen and one ring-forming oxygen, or a bridging bicyclic structure having two ring-forming nitrogens, where the bridging bicyclic system may be, for example, a [2,2,1], [2,2,2], [3,1,1], or [3,2,1] bridging bicyclic system. The bridging bicyclic structure may be substituted, for example, with one or more (for example, one, two, or three) substituents, where the substituents are independently selected from the group consisting of F, methyl group, ethyl group, isopropyl group, cyclopropyl group, -N(CH3)2, -OH, and -OCH3.

[0058] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 However, it can have the structure of an F-1. TIFF0007837952000039.tif3567 Here, R 13 and R 14 However, each time it appears, it independently of hydrogen or C 1-4 It is an alkyl group, q is an integer between 0 and 6, R 15 , R 16 , R 36 and R 37 However, together with the carbon and nitrogen atoms in between, they form a substituted 6-10 membered condensed bicyclic structure.

[0059] Generally, q is 1-3. In some embodiments, q is 1. In some embodiments, q is 2. R 13 and R 14 However, it is generally 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. In some embodiments, R 13 and R 14 However, each time it appears, it is always hydrogen.

[0060] In some embodiments, R 15 , R 16 , R 36 and R 37 However, together with the carbon and nitrogen atoms in between, they form a substituted 6-10 member condensed bicyclic structure, and the 6-10 member condensed bicyclic structure is Selected from the group consisting of TIFF0007837952000040.tif70153, 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 1-3 fluorine atoms. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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.

[0061] In some embodiments, R 15 , R 16 , R 36 and R 37 However, together with the carbon and nitrogen atoms in between TIFF0007837952000041.tif2168 is formed, and it may be replaced by one or two rings. In some embodiments, TIFF0007837952000042.tif1965 may be substituted with one or more (e.g., one or two) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorine atoms. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(C) 1-4 The substituents are selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4-6 membered heterocycle having one or two ring-forming heteroatoms independently selected 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. In some embodiments, only one pyrrolidine ring is substituted, for example, by a single fluorine atom.

[0062] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, Selected from the group consisting of TIFF0007837952000043.tif2596.

[0063] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000044.tif2268 or It can have the structure of TIFF0007837952000045.tif2275, G 10 However, it is an amino group, a monoalkylamino group, a dialkylamino group, or a 4-10 membered heterocycle, preferably G 10 If the compound is a heterocycle, the heterocycle has ring-forming nitrogen bonded to the carbonyl group of the compound so as to form a carbamic acid ester. The stereochemistry of the compound is not particularly limited and may be any of the four possible stereoisomers or any proportion thereof. For example, in some embodiments, R 1 but, TIFF0007837952000046.tif21139 or It could also be TIFF0007837952000047.tif1969, G 10 However, as defined in this application, R 1 but, TIFF0007837952000048.tif27159 or It could also be TIFF0007837952000049.tif2267, G 10 However, as defined in this application. In some embodiments, G 10 However, NH2, NH(C 1-30 Alkyl(alkyl group) or N(C) 1-4 (Alkyl group)(C 1-30 (Alkyl alkyl group) may also be used. In some embodiments, G 10 However, NH2, NH(C 1-30 Alkyl(alkyl group) or N(CH3)(C1-30 (Alkyl alkyl group) may also be used. In some embodiments, G 10 However, it may also be a 4-7 member monocyclic heterocycle having one or two independently ring-forming heteroatoms that are N, O, or S. For example, in some embodiments, G 10 but, TIFF0007837952000050.tif2373 or It may also be TIFF0007837952000051.tif2066. For example, in some embodiments, R 1 but, TIFF0007837952000052.tif26158 or It may also be TIFF0007837952000053.tif2579. In some embodiments, R 1 but, It may also be TIFF0007837952000054.tif2581. In some embodiments, R 1 but, It may also be TIFF0007837952000055.tif1566. In some embodiments, R 1 but, It may also be TIFF0007837952000056.tif2782. In some embodiments, R 1 but, TIFF0007837952000057.tif3082 is also acceptable.

[0064] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000058.tif1977 or The structure of TIFF0007837952000059.tif2177 may be present. The stereochemistry of the portion is not particularly limited and may be any of the four possible stereoisomers or any proportion thereof. For example, in some embodiments, R 1 but, It may also be TIFF0007837952000060.tif2169. In some embodiments, R 1 but, It may also be TIFF0007837952000061.tif2078. In some embodiments, R 1 but, It may also be TIFF0007837952000062.tif1864. In some embodiments, R 1 but, It may also be TIFF0007837952000063.tif2069. In some embodiments, R 1 but, It may also be TIFF0007837952000064.tif2074. In some embodiments, R 1 but, It may also be TIFF0007837952000065.tif2073. In some embodiments, R 1 but, It may also be TIFF0007837952000066.tif2170. In some embodiments, R 1 but, TIFF0007837952000067.tif2167 is also acceptable.

[0065] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000068.tif96166 and The group consisting of TIFF0007837952000069.tif3198 may also be selected.

[0066] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 (1) C may be substituted with 1-3 F 1-6 C substituted with alkoxy groups, such as methoxy groups and (2)hydroxyl groups. 1-6 (3) C substituted with an alkoxy group, for example, a hydroxyethoxy group. 1-6 C substituted with an alkoxy group, for example, a methoxyethoxy group, or (4) an amino group or an alkylamino group. 1-6 An alkoxy group may be used, for example, an N,N-dimethylaminoethoxy group. For example, in some embodiments, R in formula I 1 However, the methoxy group, TIFF0007837952000070.tif1398 or TIFF0007837952000071.tif1469 is also acceptable.

[0067] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 Also, NH2, NH(C1-6 Alkyl(alkyl group) or N(C) 1-6 (Alkyl group)(C 1-6 It may be an alkyl group. For example, in some embodiments, R in formula I 1 However, NH2, NH(CH3), or N(CH3)2 may also be used.

[0068] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000072.tif2667 is also acceptable.

[0069] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 1 but, TIFF0007837952000073.tif1969 is also acceptable.

[0070] In some specific embodiments, R in formula I 1However, a compound of formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B, or I-6-B) may have one of the following formulas. In formula TIFF0007837952000074.tif114166, q1 is 1 or 2, and q2 is 0, 1 or 2, R 110 However, each time it appears, it is independently either F or a hydroxyl group; and J 1 , J 2 , J 3 , J 4 , J 5 , R 2 and R 3 However, it includes any of the following as defined herein, and is specifically limited by sub-formulas of formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B). In some embodiments, q2 in formula I-19 is 0. In some embodiments, q2 in formula I-19 is 1, and R 110 The group is either F or a hydroxyl group. The "trans" designation in formula I-16 means that the F substitution is in the trans position relative to the ether bond. To avoid any ambiguity, formula I-16 includes single stereoisomers (enantiomers, etc.) and mixtures of stereoisomers in any proportion (including racemic mixtures). In some embodiments, compounds of formula I-16 may have structural formulas I-16-E1 or I-16-E2. TIFF0007837952000075.tif43166, J 1 , J2 , J 3 , J 4 , J 5 , R 2 and R 3 However, this includes any of the formulas defined herein, and is specifically limited by the subformulas of formula I. In some embodiments, the compound of formula I-16-E1 or I-16-E2 may be present primarily as the enantiomer (with respect to the two chiral centers shown in the stereochemical diagram), and may have other enantiomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable, for example, by weight, HPLC area, or both. The enantiomers, such as stereoisomers, can typically be separated by chiral HPLC, as illustrated in this application.

[0071] Various bases are R of formula I 2 Suitable as such, and containing any of the groups listed in the specific compounds of this application. Generally, R in formula I 2 However, it does not contain Michael addition acceptors, such as α-β unsaturated carbonyl group structural moieties. In some embodiments, R 2 However, -(L 2 ) m2 -R 102 It may also be shown as such, where m2 is 0-3, generally 0 or 1, and m2 is not 0, for example, when m2 is 1, L 2 However, each time it appears, it is independently CH2, O, NH or NCH3, and R 102 However, the heterocycle or heteroaryl ring may be substituted, for example, a heterocycle or heteroaryl ring having one or two ring-forming nitrogen atoms. For clarity, when the heterocycle or heteroaryl ring is said to have one or two ring-forming nitrogen atoms, the heterocycle or heteroaryl ring may contain other ring-forming heteroatoms, for example, ring-forming oxygen or ring-forming sulfur atoms. However, in some embodiments, the heterocycle or heteroaryl ring has only the ring-forming nitrogen atoms as ring-forming heteroatoms. In some embodiments, m2 is 0. In some embodiments, m2 is 1.

[0072] In some embodiments, m2 is 0 and R 102 It has a 4-10 membered heterocycle in which one or two ring-forming nitrogen atoms may be substituted. For example, in some embodiments, R 102 However, selected from the group consisting of the following ring structures, TIFF0007837952000076.tif27142 Each of these may be replaced, G 4 ga-(L 3 ) m3 -NH2, -(L 3 ) m3 -NH(C 1-4 It is an alkyl group, and m3 is 0 or 1, and if m3 is 1, L 3 C 1-4 These are alkylene groups (for example, methylene groups, ethylene groups, propylene groups, isopropylene groups, etc.), Or, G 4 However, it links with one substituent on the ring to form a 4-6 membered heterocycle having one or two ring-forming nitrogen atoms. In some embodiments, each of the ring structures described above may be substituted with 1-3 (usually 1 or 2) substituents, and the substituents independently form C 1-4 C substituted with alkyl groups (e.g., methyl group, ethyl group, etc.) and fluorine. 1-4 C substituted with alkyl groups (e.g., CHF2, CH2F, or CF3) or hydroxyl groups 1-4 C substituted with alkyl or alkoxy groups 1-4 C substituted with alkyl groups or cyano groups 1-4 The substituents are selected from the group consisting of alkyl groups and CONH2, or two substituents combine to form an oxo group, an imino group, or a ring structure (preferably a 3-5 membered ring, such as a cyclopropyl group or a cyclobutyl ring). The substitution can occur at any available position on the ring, including the ring-forming nitrogen atom.

[0073] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 102 or R 2 but, Selected from the group consisting of TIFF0007837952000077.tif192166 or, TIFF0007837952000078.tif2989 or TIFF0007837952000079.tif3172 (for example, Selected from the group consisting of TIFF0007837952000080.tif3285), or, TIFF0007837952000081.tif31108 or Selected from the group consisting of TIFF0007837952000082.tif2870.

[0074] In some embodiments, m2 is 1, L 2 CH 2 or NH and R 102 It is a substituted 4-10 membered heterocycle having one or two ring-forming nitrogen atoms. For example, in some embodiments, m2 is 1 and L 2 However, it is CH2 or NH, and R 102 However, 4-8 membered heterocycles may be substituted, such as monocyclic saturated 4-8 membered rings, and these may be substituted. For example, in some embodiments, m2 is 1 and L 2 However, it is CH2 or NH, and R 102 but, Selected from the group consisting of TIFF0007837952000083.tif2597, These may each be substituted, for example, with 1-3 (generally 1 or 2) substituents, and the substituents may independently be C 1-4 C substituted with alkyl groups (e.g., methyl group, ethyl group, etc.) and fluorine. 1-4 C substituted with alkyl groups (e.g., CF3) or hydroxyl groups 1-4 C substituted with alkyl or alkoxy groups 1-4 C substituted with alkyl groups or cyano groups 1-4 A substituent is selected from the group consisting of alkyl groups and CONH2, or two substituents combine to form an oxo group, an imino group, or a ring structure. The substitution can occur at any available position on the ring, including the ring-forming nitrogen atom.

[0075] In some embodiments, in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), R 2 but, Selected from the group consisting of TIFF0007837952000084.tif25106.

[0076] In some embodiments, in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), R 2 Also, -(L 2 ) m2 -R 102 It may also be the case that m2 is 0 or 1, and if m2 is 1, L 2 is CH2, O, NH or NCH3, and R 102 However, C may be substituted. 3-7 A carbon ring (e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.), an optionally substituted phenyl group, or an optionally substituted 5-membered or 6-membered heteroaryl ring, each having at least one nitrogen-containing substituent, for example, NH2, NH(C 1-4 Alkyl(alkyl group) or N(C) 1-4 (Alkyl group)(C 1-4 It has an alkyl group. In some embodiments, m2 is 1. In some embodiments, m2 is 0 and R 2 However, C 3-7 The carbon ring may be a phenyl group or a 5- or 6-membered heteroaryl group ring, each having at least one nitrogen-containing substituent, for example, a substituent containing basic nitrogen, e.g., NH2, NH(C) 1-4 Alkyl(alkyl group) or NH(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 TIFF0007837952000085.tif24105.

[0077] In some embodiments, in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), R 2 However, it can have the structure of the F-2. TIFF0007837952000086.tif4872 Here, G 1 However, CR 17 or N; G 2 and G 3 However, each time they appear, they become independent, CR 18 R 19 , O or NR 38 And, however, G 2 and G 3 At least one example of NR 38 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. 18 R 19 , O or NR 38 And, however, A 1 and A 2 At least one of them is O or NR 38 Instead, Here, R 17 , R 18 or R 19 However, each time it appears, it is independently replaced by hydrogen, F, -OH, or C which may be substituted. 1-6 It is an alkyl group, or R 18 and R 19 However, together with the carbon atoms linked to them, they link to form an oxo group, an imino group, or a ring; and, R 38However, each time it appears, it may independently be a hydrogen atom, a nitrogen protecting group, or a substituted C atom. 1-6 It is an alkyl group.

[0078] In some embodiments, G in F-2 1 However, it is N.

[0079] In some embodiments, G in F-2 1 However, CR 17 In some embodiments, R 17 However, hydrogen, F, -OH or C 1-6 Alkyl groups (e.g., methyl group, ethyl group, etc.) may be used, and they may be substituted, for example, F, -OH, methoxy group, etc. Generally, G 1 CR 17 If R 17 That is hydrogen.

[0080] A in the F-2 1 and A 2 However, independently, the linker may be a carbon-based linker, an oxygen-based linker, or a nitrogen-based linker. Generally, A in F-2 1 and A 2 However, independently, combined or CR 18 R 19 It may also be A 1 and A 2 One of them is a bond. In some embodiments, A 1 and A 2 However, both are bonds, and therefore, both bridging points are directly G 1 It connects to A. In some embodiments, A 1 and A 2 One of them is CR 18 R 19 And R 18 and R 19 However, independently, hydrogen, F, -OH or C 1-6 It may also be an alkyl group (for example, a methyl group, an ethyl group, etc.), and the C 1-6 The alkyl group may be substituted, for example, with F, -OH, a methoxy group, etc. In some embodiments, A1 and A 2 One of them is CR 18 R 19 And R 18 and R 19 However, together with the carbon atoms linked to them, they form an oxo group, an imino group, or a ring (for example, a cyclopropyl group), for example, A 1 However, C=O, C=NH, etc. may also be used. In some embodiments, A 1 and A 2 However, each of them is selected independently. 18 R 19 And R 18 and R 19 A is defined in this application. 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 CH 2 , A 1 and A 2 Another is C=O or C=NH. In some embodiments, A 1 and A 2 However, in all cases, C=O.

[0081] In some embodiments, G in F-2 2 However, each time they appear, they become independent, CR 18 R 19 In such embodiments, G 3 At least one example of NR 38 In some embodiments, G 2 However, it may be the same each time it appears. In some embodiments, G 2 However, it may differ each time it appears, or some G 2 In some embodiments, G 2 However, each time they appear, they become independent, CR 18 R 19 It may be R 18 and R 19 However, independently, hydrogen, F, -OH or C 1-6It may also be an alkyl group (for example, a methyl group, an ethyl group, etc.), and the C 1-6 The alkyl group may be substituted, for example, with F, -OH, a methoxy group, etc. In some embodiments, G 2 One or two examples are CR 18 R 19 It may be R 18 and R 19 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 might be C=O or C=NH.

[0082] In some embodiments, G 2 One or two examples are O or NR 38 This is also acceptable. Generally, one or fewer G 2 However, this is the part of the complex atom system, for example, O or NR 38 G 2 Other examples include, independently, CR 18 R 19 That is the case.

[0083] In some embodiments, G in F-2 3 However, each time they appear, they become independent, CR 18 R 19 In such embodiments, G 3 At least one example of NR 38 In some embodiments, G 3 However, it may be the same each time it appears. In some embodiments, G 3 However, it may be different each time it appears, or G 3 Some parts may be the same, while others may be different. In some embodiments, G 3 However, each time they appear, they become independent, CR 18 R 19 It may be R 18 and R 19 However, independently, hydrogen, F, -OH or C 1-6It may also be an alkyl group (for example, a methyl group, an ethyl group, etc.), and the C 1-6 The alkyl group may be substituted, for example, with F, -OH, a methoxy group, etc. In some embodiments, G 3 One or two examples are CR 18 R 19 It may be R 18 and R 19 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 might be C=O or C=NH.

[0084] In some embodiments, G 3 One or two examples are O or NR 38 This is also acceptable. Generally, one or fewer G 3 However, this is the part of the complex atom system, for example, O or NR 38 G 3 Other examples include, independently, CR 18 R 19 That is the case.

[0085] Generally, F-2 has 1, 2, or 3 G 2 (For example, as defined in this application), i.e., n1 is 1, 2, or 3. In some embodiments, F-2 is 1, 2, or 3 G 3 This includes (for example, those defined in this application), i.e., n2 is 1, 2, or 3.

[0086] As stated in this application, all G 2 and G 3 Among them, at least one example is NR 38 In some embodiments, all G 2 and G 3 One example, namely all G 2 and G 3 One of the G 2 or one G 3 However, NR 38For example, in some embodiments, all G 2 and G 3 In the middle, one G 2 or one G 3 NR 38 And R 38 However, hydrogen or C 1-4 It is an alkyl group (for example, a methyl group). In some embodiments, R 38 However, each time it appears, it independently produces hydrogen, a nitrogen protecting group (for example, as described above in this application), or C 1-6 It may also be an alkyl group (for example, a methyl group, an ethyl group, an isopropyl group, etc.), and the C 1-6 The alkyl group may be substituted, for example, with 1, 2, or 3 substituents, and the substituents may independently be F, -OH, a protected hydroxyl group, an oxo group, NH2, a protected amino group, or NH(C) 1-4 Alkyl group) or its protected derivative group, 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 3-7 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 be independently F, -OH, oxo group (for example, if applicable), C 1-4 C substituted with alkyl groups, cyclopropyl groups, and fluorine 1-4 Alkyl (e.g., CF3), C 1-4 C substituted with alkoxy groups and fluorine 1-4 Selected from the group consisting of alkoxy groups.

[0087] In some embodiments, the compound of formula I is characterized by having formula I-20, I-21, or I-22. The variables in formula TIFF0007837952000087.tif124166 are defined in this application and J 1 , J 2 , J 3 , J 4 , J 5 , R 1 , R 3 , R 38 , G 2 and n1 include any of the sub-formulas of formula I as defined herein (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I This includes those described in detail in -17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B). For example, in some embodiments, n1 is 1, 2 or 3, and each G 2 However, CH2 may also be used. In some embodiments, R 38 However, hydrogen may also be used.

[0088] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 2 but, TIFF0007837952000088.tif39129 or Selected from the group consisting of TIFF0007837952000089.tif3165. In some embodiments, R in formula I 2 too, TIFF0007837952000090.tif2966 is also acceptable.

[0089] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 2 but, TIFF0007837952000091.tif31105 or Selected from the group consisting of TIFF0007837952000092.tif2779, preferably, The filename is TIFF0007837952000093.tif2876.

[0090] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 2 but, TIFF0007837952000094.tif2974 or TIFF0007837952000095.tif3275 (for example, It is TIFF0007837952000096.tif3377).

[0091] In some specific embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 2 but, TIFF0007837952000097.tif31108 or The filename is TIFF0007837952000098.tif2771.

[0092] In this application, R applied to formula I 3 Various bases of are described. In some embodiments, formula I (e.g., subformulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-1 9, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I -9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 However, it may be a phenyl group or a 5 or 6-membered heteroaryl group, such as a pyridyl group, and may be substituted. In some embodiments, R 3 However, the phenyl group may be substituted with one or more (generally 1-3) substituents, and the substituents may be independently substituted with F, Cl, Br, I, -OH, or C. 1-4Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, -CH2CH2-CN, CF2H, or CF3), may be substituted with C 2-4 Alkenyl group, substitution in Container C 2-4 Selected from the group consisting of an alkynyl group (e.g., an ethynyl group or a propargyl 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 with C 2-4 Alkenyl group, substitution in Container C 2-4 The substituent is selected from the group consisting of an alkynyl group (e.g., an ethynyl group or a propargyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or less of the substituents are OH, -NH2, protected -OH, or protected -NH2. For example, in some embodiments, R 3 but, TIFF0007837952000099.tif2685 or It may also be TIFF0007837952000100.tif2890. In some embodiments, R 3 but, TIFF0007837952000101.tif2678 is also acceptable.

[0093] In some embodiments, R in formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 may be a naphthyl group, which may be substituted, for example, with one or more (generally 1-3) substituents, and the substituents are independently selected from the group consisting of F, Cl, Br, I, -OH, C 1-4 alkyl group (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 of the substituents is OH, -NH2, protected -OH, or protected -NH2. In some embodiments, R 3 is as follows. TIFF0007837952000102.tif3986 Here, 1) G B is OH, G A is H, and G C and G D are independently H, F, Cl, CN, C 1-4 alkyl group which may be substituted with 1-3 fluorines, for example, methyl group, ethyl group or CF3, and preferably G D is H, F or methyl group; 2) G C is Cl, methyl group, ethyl group, ethynyl group or CN, G A is H, G B is H or OH, and G D is H, F, Cl, CN, C 1-4 alkyl group which may be substituted with 1-3 fluorines, for example, methyl group, ethyl group or CF3, and preferably GD is an H, F or methyl group; or 3) G A Cl is G B is H, F or methyl group, G C and G D The C atoms may be independently substituted with H, F, Cl, CN, or 1-3 fluorine atoms. 1-4 The alkyl group is, for example, a methyl group, an ethyl group, or CF3, and preferably G C and G D These are independently H, F, or a methyl group.

[0094] In some embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I- 19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R in I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 However, it may be a substituted naphthyl group, for example, a naphthyl group substituted with one or more (generally 1-3) 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 Container C 2-4 Selected from the group consisting of an alkynyl group (e.g., an ethynyl group or a propargyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or less of the substituents are OH, -NH2, protected -OH, or protected -NH2. In some embodiments, R 3 but, TIFF0007837952000103.tif3372, G C and G D The C atoms may be independently substituted with H, F, Cl, CN, or 1-3 fluorine atoms. 1-4 Alkyl groups, for example, methyl group, ethyl group or CF3, cyclopropyl group or C 2-4 An alkynyl group (e.g., an ethynyl group or a propargyl group), preferably G D is H, F or a methyl group. In some embodiments, G is in F-3-A. C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, G D However, H, F, Cl, CN, and C may be substituted with 1-3 fluorine atoms. 1-4 Alkyl group, for example, methyl group, ethyl group or CF3. In some embodiments, G in F-3-A. 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, R 3 but, TIFF0007837952000104.tif4274, G C and G D The C atoms may be independently substituted with H, F, Cl, CN, or 1-3 fluorine atoms. 1-4 Alkyl groups, for example, methyl group, ethyl group or CF3, cyclopropyl group or C 2-4 An alkynyl group (e.g., an ethynyl group or a propargyl group), preferably G D is H, F or methyl group, G A1 However, each time it appears, it is independently a halogen (e.g., F or Cl), OH, CN, cyclopropyl group, or a substituted C. 1-4 Alkyl alkyl group, or optionally substituted C 1-4 It is an alkoxy group and k is 1, 2, or 3. Note that G in F-1-B A1 However, they may be substituted at any available position on the naphthylene ring, preferably one or two G A1 However, it is adjacent to the OH group. In some embodiments, in F-3-B, G CHowever, 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 1-3 fluorine atoms. 1-4 Alkyl groups, such as methyl groups, ethyl groups, or CF3. In some embodiments, in F-3-B, G C However, it is Cl, methyl group, ethyl group, ethynyl group or CN, G D However, it is H or F. In some embodiments, k is 1 and G A1 It is adjacent to the OH group, and G A1 However, C may be substituted with F, Cl, CN, or 1-3 fluorine atoms. 1-4 It is an alkyl group. In some embodiments, k is 2 and there are two G A1 All of them are adjacent to the OH group, and each G A1 However, independently, C may be substituted with F, Cl, CN, or 1-3 fluorine atoms. 1-4 It is an alkyl group.

[0095] In some embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-1 9, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I -9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 However, it may be a substituted naphthyl group, for example, a naphthyl group that may be substituted with one or more substituents (generally 1-4, more generally 1-3), 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 with C 2-4 Alkenyl group, substitution in Container C2-4 An alkynyl group (e.g., ethynyl group or propargyl group), optionally substituted C 1-4 An alkoxy group (e.g., methoxy group, ethoxy group, etc.), optionally substituted C 3-5 A cycloalkyl group, e.g., cyclopropyl group, optionally substituted C 3-5 Selected from the group consisting of a cycloalkoxy group, -NH2, -CN, protected -OH, and protected -NH2.

[0096] In some embodiments, R in formula I 3 is TIFF0007837952000105.tif4089, and G C and G D are independently H, F, Cl, CN, C optionally substituted with 1 - 3 fluorines 1-4 An alkyl group, e.g., methyl group, ethyl group or CF3, cyclopropyl group or C 2-4 An alkynyl group (e.g., ethynyl group or propargyl group), preferably, G D is H, F or methyl group, and G A1 is, each time it appears, independently a halogen (e.g., F or Cl), OH, CN, cyclopropyl group, C optionally substituted 1-4 An alkyl group, or C optionally substituted 1-4 An alkoxy group, and k is 0, 1, 2 or 3. In addition, when present, G in F - 3 - C A1 may be substituted at any available position of the naphthylene ring, preferably, one or two G A1 are adjacent to the NH2 group. In some embodiments, in F - 3 - C, G C is Cl, methyl group, ethyl group, ethynyl group, propargyl group, or CN, and G D is H, F, Cl, CN, C optionally substituted with 1 - 3 fluorines 1-4 An alkyl group, e.g., methyl group, ethyl group or CF3. In some embodiments, in F - 3 - C, G C is Cl, methyl group, ethyl group, ethynyl group or CN, and G Dis H or F. In some embodiments, k is 0. In some embodiments, k is 1 and G A1 It is adjacent to the NH2 group, and G A1 However, C may be substituted with F, Cl, CN, or 1-3 fluorine atoms. 1-4 It is an alkyl group. In some embodiments, k is 2 and there are two G A1 Both are adjacent to the NH2 group, and each G A1 However, independently, C may be substituted with F, Cl, CN, or 1-3 fluorine atoms. 1-4 It is an alkyl group.

[0097] In some embodiments, R in formula I 3 but, TIFF0007837952000106.tif3989, G C and G D However, independently, H, F, Cl, CN, and C may be substituted with 1-3 fluorine atoms. 1-4 C may be substituted with alkyl groups, such as a methyl group, an ethyl group, or CF3, with 1-3 fluorine atoms. 1-4 Alkoxy groups (e.g., methoxy group, ethoxy group, difluoromethoxy group, etc.), cyclopropyl group, or C 2-4 An alkynyl group (for example, an ethynyl group or a propargyl group), preferably G D is H, F or methyl group, G A1 However, each time it appears, it is independently a halogen (e.g., F or Cl), OH, CN, cyclopropyl group, or a substituted C. 1-4 Alkyl alkyl group, or optionally substituted C 1-4 It is an alkoxy group and k is 0, 1, 2, or 3. If present, G in F-3-D A1 However, they may be substituted at any available position on the naphthylene ring, preferably one or two G A1 However, adjacent to the OH group. In some embodiments, in F-3-D, G C However, the group is Cl, methyl group, ethyl group, methoxy group, ethoxy group, difluoromethoxy group, ethynyl group, propargyl group or CN, G DC may be substituted with H, F, Cl, CN, or 1-3 fluorines. 1-4 Alkyl group, for example, methyl group, ethyl group or CF3. In some embodiments, G in F-3-D C is Cl, methyl group, ethyl group, ethynyl group or CN, and G D is H or F. In some embodiments, k is 0. In some embodiments, k is 1 and G A1 It is adjacent to the OH group, and G A1 However, C may be substituted with F, Cl, CN, or 1-3 fluorine atoms. 1-4 It is an alkyl group. In some embodiments, k is 2 and there are two G A1 All of them are adjacent to the OH group, and each G A1 However, independently, C may be substituted with F, Cl, CN, or 1-3 fluorine atoms. 1-4 It is an alkyl group.

[0098] In some embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-1 9, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I -9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 However, it may be a bicyclic heteroaryl group (e.g., a benzothiazolyl group, an indazolyl group, or an isoquinolinyl group), and it may be substituted, for example, with one or more (generally 1-3) substituents, and the substituents may be independently substituted with F, Cl, Br, I, -OH, C 1-4 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, CH2-CH2-CN, CF2H or CF3), may be substituted C 2-4 Alkenyl group, substitution in Container C 2-4The substituent is selected from the group consisting of an alkynyl group (e.g., an ethynyl group or a propargyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, one or less of the substituents are OH, -NH2, protected -OH, or protected -NH2. For example, in some embodiments, R 3 but, TIFF0007837952000107.tif37123, where q3 is 0, 1 or 2, 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 with C 2-4 Alkenyl group, substitution in Container C 2-4 The group is an alkynyl group (e.g., an ethynyl group or a propargyl group), a cyclopropyl group, -NH2, -CN, a protected -OH, and a 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 or a propargyl group), a cyclopropyl group, CH2CH2-CN, CF2H, CF3, or -CN.

[0099] Formula I (e.g. sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-1 3, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I- Appropriate R used for 21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B)3 However, the present application further includes any of those bases, which are given in specific examples. In some embodiments, formula I (e.g., sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-1 9, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I -9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, The data may be selected from the group consisting of TIFF0007837952000108.tif156155.

[0100] In some embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-1 9, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I -9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, The group consisting of TIFF0007837952000109.tif53166 may also be selected.

[0101] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, The data may be selected from the group consisting of TIFF0007837952000110.tif2499.

[0102] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000111.tif2975 is also acceptable.

[0103] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000112.tif2985 is also acceptable.

[0104] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000113.tif2481 is also acceptable.

[0105] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000114.tif2571 is also acceptable.

[0106] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000115.tif2972 is also acceptable.

[0107] In some preferred embodiments, formula I (for example, sub-formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000116.tif2777 is also acceptable.

[0108] In some specific embodiments, Equation I (for example, sub-equations I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000117.tif30133TIFF0007837952000118.tif28123 or TIFF0007837952000119.tif2774 is also acceptable.

[0109] In some specific embodiments, Equation I (for example, sub-equations I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000120.tif29122 or TIFF0007837952000121.tif2882 is also acceptable.

[0110] In some specific embodiments, Equation I (for example, sub-equations I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I -19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, R at I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B) 3 but, TIFF0007837952000122.tif28110 or TIFF0007837952000123.tif2263 is also acceptable.

[0111] In some embodiments, the present disclosure provides exemplary embodiments 1-57, as follows: Embodiment 1. Compound represented by formula I-9: TIFF0007837952000124.tif3769 or its pharmacologically acceptable salt. Here, the variable R 1 , R2 , R 3 , R 11 , and R 12A However, this application includes any combination of those relating to formula I-9. Embodiment 2.R 11 A compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein F is present. Embodiment 3.R 12A A compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is H. Embodiment 4.R 12A However, C may be substituted with halogens, -OH, or 1-3 F atoms. 1-4 Alkyl group, C which may be substituted with 1-3 F 1-4 C may be substituted with 1-3 F groups that are substituted with alkoxy or cyclopropyl groups. 1-4 A compound according to Embodiment 1 or 2, which is an alkoxy group, or a pharmaceutically acceptable salt thereof. Embodiment 5.R 12A The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is Cl, -OH, methoxy group, difluoromethoxy group, ethoxy group, isopropoxy group, -O-CH2-cyclopropyl group, -O-CH2-CH2-cyclopropyl group, -C(O)NHMe, -O-CH2-C(O)NHMe, -O-CH2-CF3, -O-CH2-CHF2, methyl group, CHF2, CF3, ethyl group, isopropyl group, or cyclopropyl group. Embodiment 6. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that formula I-9 has one of the following sub-formulas. TIFF0007837952000125.tif163165 Embodiment 7.R 1 A compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound is H. Embodiment 8.R 1 C may be replaced by 1-3 F 1-4 A compound according to any of Embodiments 1-6, which is an alkyl group, or a pharmaceutically acceptable salt thereof. Embodiment 9.R 1A compound according to any of Embodiments 1-6, wherein the compound is a methyl group or CHF2, or a pharmaceutically acceptable salt thereof. Embodiment 10.R 1 but, A compound according to any of Embodiments 1-6, selected from the group consisting of TIFF0007837952000126.tif147166, or a pharmaceutically acceptable salt thereof. Embodiment 11.R 1 but, A compound according to any of Embodiments 1-6, selected from the group consisting of TIFF0007837952000127.tif45119, or a pharmaceutically acceptable salt thereof. Embodiment 12.R 1 but, A compound according to any of Embodiments 1-6, selected from the group consisting of TIFF0007837952000128.tif91119, or a pharmaceutically acceptable salt thereof. Embodiment 13.R 1 but, A compound according to any of Embodiments 1-6, selected from the group consisting of TIFF0007837952000129.tif75139, or a pharmaceutically acceptable salt thereof. Embodiment 14.R 1 but, A compound according to any of Embodiments 1-6, selected from the group consisting of TIFF0007837952000130.tif25103, or a pharmaceutically acceptable salt thereof. Embodiment 15.R 1 but, A compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000131.tif2577. Embodiment 16.R 1 but, A compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000132.tif2067. Embodiment 17.R 1 but, TIFF0007837952000133.tif2472 or Selected from the group consisting of TIFF0007837952000134.tif2385, G 10 However, it is an amino group, a monoalkylamino group, a dialkylamino group, or a 4-10 membered heterocycle, preferably G 10 If the compound is heterocyclic, the compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, having a ring-forming nitrogen bonded to the carbonyl group of the portion to form the heterocyclic carbamic acid ester. Embodiment 18.G 10 However, NH2, NH(C 1-30 Alkyl(CH3), N(CH3)(C 1-30 (Alkyl alkyl group), TIFF0007837952000135.tif2274 or The compound described in Embodiment 17, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000136.tif1964. Embodiment 19.R 1 but, TIFF0007837952000137.tif95166 and A compound according to any of Embodiments 1-6, selected from the group consisting of TIFF0007837952000138.tif30157, or a pharmaceutically acceptable salt thereof. Embodiment 20.R 1 However, C may be substituted with 1-3 Fs. 1-6 C substituted with alkoxy groups, such as methoxy or hydroxyl groups. 1-6 Alkoxy groups, for example, hydroxyethoxy groups, C substituted with alkoxy groups 1-6 C substituted with an alkoxy group, such as a methoxyethoxy group, or an amino group or alkylamino group. 1-6 A compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound is an alkoxy group, for example, a dimethylaminoethoxy group. Embodiment 21.R 1 However, NH2, NH(C 1-6 Alkyl(alkyl group) or N(C) 1-6 (Alkyl group)(C 1-6A compound according to any of Embodiments 1-6, which is an alkyl group, or a pharmaceutically acceptable salt thereof. Embodiment 22.R 1 However, the methoxy group, TIFF0007837952000139.tif1467 A compound according to any of Embodiments 1-6, which is NH2, NH(CH3) or N(CH3)2, or a pharmaceutically acceptable salt thereof. Embodiment 22.R 1 ga-OR 20 And R 20 ga-C 1-6 Alkylene group-R 101 And R 101 However, NR 32 R 33 A 4-10 membered heterocycle which may be substituted, and the C 1-6 The alkylene group may be substituted, for example, with one or more substituents, and the substituents may independently be F, OH, NR 34 R 35 and C which may be substituted with 1-3 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 32 and R 33 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, a substituted or substituted carbon ring, or a substituted or substituted heterocycle; or, NR 32 R 33 R represents a monoalkyl or dialkylamine; or, 32 and R 33 They may be linked and substituted to form a heterocyclic or heteroaryl ring; R 34 and R 35 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 34 and R 35 A compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, which forms a heterocyclic or heteroaryl ring that may be linked and substituted. Embodiment 23.R 20 ga-CH2-R 101 -CH2-CH2-R 101 -CH2-CH2-CH2-R 101 , TIFF0007837952000140.tif1466 or The compound described in Embodiment 22, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000141.tif2082. Embodiment 24.R 20 but The compound described in Embodiment 22, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000142.tif1373. Embodiment 25.R 101 However, NH2, NH(C 1-30 Alkyl(CH3), N(CH3)(C 1-30 (Alkyl alkyl group), TIFF0007837952000143.tif26114TIFF0007837952000144.tif3281 or The compound described in any of Embodiments 22-24, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000145.tif3183. Embodiment 26.R 1 but, A compound according to any of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000146.tif1970. Embodiment 27.R 2 but, A compound according to any of Embodiments 1-26, selected from the group consisting of TIFF0007837952000147.tif191159, or a pharmaceutically acceptable salt thereof. Embodiment 28.R 2 but, A compound according to any of Embodiments 1-26, selected from the group consisting of TIFF0007837952000148.tif2789, or a pharmaceutically acceptable salt thereof. Embodiment 29.R 2 but, A compound according to any of Embodiments 1-26, selected from the group consisting of TIFF0007837952000149.tif2699, or a pharmaceutically acceptable salt thereof. Embodiment 30.R 2 but, TIFF0007837952000150.tif38127 or The compound described in any of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000151.tif2966. Embodiment 31.R 2 but, A compound according to any of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000152.tif2777. Embodiment 32.R 2 but, A compound according to any of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000153.tif2970. Embodiment 33.R 2 but, TIFF0007837952000154.tif2767 or TIFF0007837952000155.tif3173 (for example, A compound according to any of Embodiments 1-26, or a pharmaceutically acceptable salt thereof (TIFF0007837952000156.tif3274). Embodiment 34.R 2 but, TIFF0007837952000157.tif3096 or The compound described in any of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000158.tif2584. Embodiment 35.R 3 but, A compound according to any of Embodiments 1-34, selected from the group consisting of TIFF0007837952000159.tif156153, or a pharmaceutically acceptable salt thereof. Embodiment 36.R3 but, A compound according to any of Embodiments 1-34, selected from the group consisting of TIFF0007837952000160.tif53163, or a pharmaceutically acceptable salt thereof. Embodiment 37.R 3 but, The compound described in any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000161.tif2887. Embodiment 38.R 3 but, A compound according to any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000162.tif2874. Embodiment 39.R 3 but, TIFF0007837952000163.tif2668 or The compound described in any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000164.tif2476. Embodiment 40.R 3 but, A compound according to any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000165.tif2668. Embodiment 41.R 3 but, A compound according to any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, which is TIFF0007837952000166.tif2772. Embodiment 42.R 3 but, TIFF0007837952000167.tif2889TIFF0007837952000168.tif29166 or The compound described in any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000169.tif2686. Embodiment 43.R 3 but, TIFF0007837952000170.tif29124 or The compound described in any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000171.tif2791. Embodiment 44.R 3 but, TIFF0007837952000172.tif28101 or The compound described in any of Embodiments 1-34, or a pharmaceutically acceptable salt thereof, is TIFF0007837952000173.tif2266. Embodiment 45. Compound represented by formula I-11: TIFF0007837952000174.tif3777 or its pharmacologically acceptable salt. Here, the variable R 1 , R 2 , R 3 , R 11 , and R 12A However, this application includes any combination of those relating to formula I-11. Embodiment 46.R 11 However, F is the compound described in Embodiment 45, or a pharmaceutically acceptable salt thereof. Embodiment 47.R 12A However, the compound described in Embodiment 44 or 45, or a pharmaceutically acceptable salt thereof, is any of those defined in Embodiments 3-5. Embodiment 48.R 1 However, the compounds described in any of Embodiments 44-47, or a pharmaceutically acceptable salt thereof, are any of those defined in Embodiment 7-26. Embodiment 49.R 2 However, the compounds described in any of Embodiments 44-48, or a pharmaceutically acceptable salt thereof, are any of those defined in Embodiments 27-34. Embodiment 50.R 3 However, the compounds described in any of Embodiments 44-49, or a pharmaceutically acceptable salt thereof, are any of those defined in Embodiments 35-44. Embodiment 51. A compound represented by the following formula: TIFF0007837952000175.tif254157 or its pharmacologically acceptable salt. In the formula, the variable R 1 , R 2 , R 3 , R 11 , R 12 and R 12A However, this application includes any combination of those relating to each formula. Embodiment 52. If present, R 11 However, F is the compound described in Embodiment 51, or a pharmaceutically acceptable salt thereof. Embodiment 53. If present, R 12A However, the compound described in Embodiment 51 or 52, or a pharmaceutically acceptable salt thereof, is any of those defined in Embodiments 3-5. Embodiment 54.R 12 The compound according to Embodiment 51 or 52, or a pharmaceutically acceptable salt thereof, wherein the compound is 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. Embodiment 55.R 1 However, the compounds described in any of Embodiments 51-54, or a pharmaceutically acceptable salt thereof, are any of those defined in Embodiment 7-26. Embodiment 56.R 2 However, the compounds described in any of Embodiments 51-55, or pharmaceutically acceptable salts thereof, are any of those defined in Embodiments 27-34. Embodiment 57.R 3 However, the compounds described in any of Embodiments 51-56, or pharmaceutically acceptable salts thereof, are any of those defined in Embodiments 35-44.

[0112] In some embodiments, the present disclosure provides compounds of formula A or pharmaceutically acceptable salts thereof. TIFF0007837952000176.tif3487 Here, R 8However, hydrogen may be substituted into C 1-6 Alkyl group (e.g., methyl group), or may be substituted C 3-10 It is a cycloalkyl group, and R 1 , R 2 , R 3 , J 1 , J 2 and J 3 However, the present application includes any combination of those relating to formula I (for example, its sub-formulas). To avoid ambiguity, if a variable in formula A is described in this application as having or containing any of the definitions relating to formula I, then that variable may have or contain the definition of a variable having the same sign, for example, R in formula A. 2 However, in this application, R relating to formula A 2 It should be understood that the definition of has or may include. Other similar expressions in this application should be understood in the same way. The appropriate J used in formula A. 1 , J 2 and J 3 The definition of also includes any combination of those relating to formula I (or its sub-formulas) in this application. For example, in some embodiments, if present, R in formula A 11 The group is hydrogen, 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, J 1 However, it is CH or N. In some embodiments, J 2 However, it is either CH or N.

[0113] Compounds of formula A (including any applicable sub-formula described herein) may exist in the form of a single enantiomer, a diastereomer, an 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 A (including any applicable sub-formula described herein) may exist as a mixture of atropisomers in any proportion (including about 1:1). In some embodiments, where applicable, compounds of formula A (including any applicable sub-formula described herein) may exist as a single enantiomer of isolation, such single enantiomer being essentially free of other enantiomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other enantiomers by weight, HPLC area, or both).

[0114] In some embodiments, the compound of formula A is characterized by having formula A-1. TIFF0007837952000177.tif3882R 1 , R 2 , R 3 , R 11 and R 8 However, this application includes any combination of those relating to formula I (e.g., its sub-formulas). For example, in some embodiments, R 8 However, it is hydrogen. In some embodiments, R 8 However, C may be substituted. 1-6 It is an alkyl group (e.g., a methyl group), and a suitable substituent is C in this application. 1-6 Includes any of the alkyl groups.

[0115] In some embodiments, R in formula A (e.g., formula A-1) 1However, 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, bridged, or spirodicyclic 6-10 membered heterocycle having 1 to 3 independently selected ring-forming heteroatoms from the group consisting of N, O, and S, where the monocyclic or bicyclic form may be substituted. For example, in some embodiments, R in formula A (e.g., formula A-1) 1 but, It is TIFF0007837952000178.tif68148, Each of them may be substituted with one or more (e.g., one or two) substituents, and the substituents independently are F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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.

[0116] In some embodiments, R in formula A (e.g., formula A-1) 1 ga-OR 20 And R 20 ga-C 1-6 Alkylene group-R 101 And R 101NR 32 R 33 Alternatively, it is a 4-10 membered heterocycle which may be substituted, Said C 1-6 The alkylene group may be substituted, for example, with one or more substituents, and the substituents may independently be F, OH, N R 34 R 35 and C which may be substituted with 1-3 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 32 and R 33 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, a substituted or substituted carbon ring, or a substituted or substituted heterocycle; or, NR 32 R 33 R represents a monoalkyl or dialkylamine; or, 32 and R 33 They may be linked and substituted to form a heterocyclic or heteroaryl ring; and R 34 and R 35 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 34 and R 35 These groups may be linked together to form a heterocyclic or heteroaryl ring, which may also be substituted. Appropriate "-C" 1-6 Alkylene group-" and R 101 However, R defined in formula I (including sub-formulas) in this application 20 This includes any of those having the same corresponding notation relating to the same. For example, in some embodiments, the "-C 1-6 The alkylene group - is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, TIFF0007837952000179.tif1880 or The filename is TIFF0007837952000180.tif1961. In some embodiments, R101 However, the 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, bridged, 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, where the monocyclic or bicyclic ring may be substituted. In some embodiments, R 101 However, it is a monoring selected from the group consisting of the following: Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 membered heterocycle having one or two ring-forming heteroatoms independently selected from the group consisting of N, O, and S, 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. In some embodiments, R 101 However, it is a biringual equation selected from the group consisting of the following: TIFF0007837952000182.tif71151 Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(C) 1-4 (Alkyl group)(C 1-4The substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4-6 membered heterocycle having one or two ring-forming heteroatoms independently selected from the group consisting of N, O, 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.

[0117] In some embodiments, R in formula A (e.g., formula A-1) 1 but, Selected from the group consisting of TIFF0007837952000183.tif2390.

[0118] Generally, R in equation A 2 However, it does not contain Michael addition acceptors, such as the α-β unsaturated carbonyl group structural moiety. In some embodiments, R in formula A 2 However, -(L 2 ) m2 -R 102 It can be shown that m2 is 0-3, generally 0 or 1, and m2 is not 0, for example, if m2 is 1, L 2 However, each time it appears, it is independently CH2, O, NH or NCH3, and R 102 However, it may be a substituted 4-10 membered heterocycle or heteroaryl ring, for example, a heterocycle or heteroaryl ring having one or two ring-forming nitrogen atoms. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, R in formula A (e.g., formula A-1) 2 ga-(L 2 ) m2 -R 102 And, m2 is either 0 or 1, and if m2 is 1, L 2 is CH2, O, NH or NCH3, R 102 However, it is a substituted 4-10 membered heterocyclic ring or heteroaryl ring having one or two ring-forming nitrogen atoms.

[0119] Appropriate R102 However, this application includes any of the formulas I (for example, any of its sub-formulas). In some embodiments, R 102 However, it is a substituted 4-10 membered heterocycle having one or two ring-forming nitrogen atoms. In some embodiments, R in formula A (e.g., formula A-1) 102 or R 2 but, Selected from the group consisting of TIFF0007837952000184.tif190161, or, TIFF0007837952000185.tif2799 or TIFF0007837952000186.tif3197 (for example, Selected from the group consisting of TIFF0007837952000187.tif3182), or, TIFF0007837952000188.tif3299 or Selected from the group consisting of TIFF0007837952000189.tif2766.

[0120] The appropriate R used in equation A (for example, equation A-1) 3 However, this includes either those relating to Formula I in this application or those given as specific examples in this application. For example, in some embodiments, R in Formula A (e.g., Formula A-1) 3 The substituent is a phenyl group, a pyridyl group, a naphthyl group, or a bicyclic heteroaryl group (e.g., a benzothiazolyl group, an indazolyl group, or an isoquinolinyl group), and each of these may be substituted, for example, by 1 to 3 substituents, where the substituents are independently F, Cl, Br, I, -OH, C 1-4 Selected 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, R in formula A (e.g., formula A-1) 3 but, TIFF0007837952000190.tif143136TIFF0007837952000191.tif150166 or Selected from the group consisting of TIFF0007837952000192.tif2283.

[0121] In some embodiments, the present disclosure provides compounds of formula II or pharmaceutically acceptable salts thereof. TIFF0007837952000193.tif3983 Here, J 1 However, CR 9 or N; J 3 However, CR 11 or N; J 4 However, CR 12 or N; J 5 However, CR 12A or N; Or, J 4 and J 5 These groups may be linked to form a substituted phenyl group or a substituted 5-membered or 6-membered heteroaryl group, provided that in this case, for example, J 4 and J 5 When linked to form a triazole ring, J 4 and J 5 The bond between them may be a single bond; R 1 However, hydrogen may be substituted into C 1-6 Alkyl group, optionally substituted carbon ring, optionally substituted aryl group, -(L 1 ) m1 -OR 20 ,-(L 1 ) m1 -NR 30 R 31 -C(O)-NR 30 R 31 , or may be substituted, heterocyclic or heteroaryl rings; R 2However, these ring or ring-chain structures are ring or ring-chain structures having a basic functional group whose conjugate acid has a pKa of about 6 or more, or their acylation derivatives (i.e., the basic functional group, such as a basic NH, bonded to an acyl group); R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 9 However, hydrogen, halogen, cyano group, or substitution C may be present. 1-4 Alkyl group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C 2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 1-4 Alkoxy group, substituted KarC 3-6 A cycloalkyl group, an optionally substituted aryl group, an optionally substituted 4-8 membered heterocyclic group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or an optionally substituted 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S. R 11 , R 12 and R 12A However, each time they appear, they are all independently hydrogen, F, Cl, Br, I, CN, -OH, -C(O)NH2, -NH2, -NH(C 1-6 Alkyl(alkyl group), -N(C) 1-6 (Alkyl group)(C 1-6 Alkyl(alkyl group), -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 group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C -2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 3-6 Cycloalkyl groups (e.g., cyclopropyl group, cyclobutyl group) may be substituted. 1-4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), may be substituted C3-6 A cycloalkoxy group (e.g., a cyclopropoxy group or a cyclobutoxy group), an optionally substituted 4-7 membered heterocyclic ring, or an optionally substituted 4-7 membered heterocycloalkoxy group; or R 12 and R 12A They are linked together to form a 5-7 membered ring structure; and Here, m1 is either 0 or 1, and if m1 is 1, L 1 However, these may be substituted alkylene groups, substituted carbocyclylene groups, or substituted heterocyclylene groups; R 20 However, hydrogen, oxygen protecting groups, and substitutions may be made of C. 1-6 It is an alkyl group, a substituted or possibly substituted carbon ring, a substituted or possibly substituted aryl group, a substituted or possibly substituted aryl group, a substituted or possibly substituted heteroaryl group, or a substituted or possibly substituted heterocycle; R 30 and R 31 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 30 and R 31 They may be linked and substituted to form a heterocyclic or heteroaryl ring; or, R 30 and R 31 One of them is L 1 It forms a heterocycle or heteroaryl ring, which may be substituted with the appropriate atoms and any of the atoms in between.

[0122] Compounds of formula II (including any applicable sub-formula described herein) may exist in the form of a single enantiomer, a diastereomer, an 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 applicable sub-formula described herein) 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 applicable sub-formula described herein) may exist as a single enantiomer of isolation, such single enantiomer being essentially free of other atropisomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other enantiomers by weight, HPLC area, or both).

[0123] The appropriate R used in Equation II 2 and R 3 The base includes any combination of those relating to Formula I (e.g., its sub-formulas) in this application. To avoid ambiguity, if it is stated that a variable in Formula II has or includes any definition relating to Formula I in this application, then that variable may have or include the definition of a variable bearing the same sign, for example, R in Formula II. 2 However, in this application, R relating to formula I 2 It should be understood that it has or may include the definition of . Other similar expressions in this application should be understood in the same way. The appropriate J used in Formula II 1 , J 3 , J 4 and J 5 The definition of also includes any combination of those relating to Formula I (or its sub-formulas) in this application. For example, in some embodiments, if present, R in Formula II 11is hydrogen, 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, if present, R in formula II 12 is hydrogen, 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, if present, R in formula II 12A However, the group is hydrogen, 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, for example, hydrogen, Cl or methyl group. In some embodiments, if present, R in formula II 12A However, these are hydrogen, a methyl group, Cl, or a methoxy group. In some embodiments, J 4 and J 5 These may be linked together to form a 5-membered or 6-membered heteroaryl group, however, in this case, J 4 and J 5 The bond between them may be a single bond. For example, in some embodiments, J 4 and J 5 These link together to form a triazole ring.

[0124] In some embodiments, the compound of formula II may have one of the following sub-formulas. TIFF0007837952000194.tif145166In formula, R 1 , R 2 , R 3 , R 11 and R 12 However, it includes any combination of those defined in this application.

[0125] In some embodiments, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 1 However, -C 1-6Alkylene group-R 101 A substituted alkyl group having the formula R 101 However, NR 32 R 33 Alternatively, it is a 4-10 membered heterocycle which may be substituted, Said C 1-6 The alkylene group may be substituted, for example, with one or more substituents, and the substituents may independently be F, OH, NR 34 R 35 , and C which may be substituted with 1-3 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 32 and R 33 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, a substituted or substituted carbon ring, or a substituted or substituted heterocycle; or, NR 32 R 33 R represents a monoalkyl or dialkylamine; or, 32 and R 33 They may be linked and substituted to form a heterocyclic or heteroaryl ring; and R 34 and R 35 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 34 and R 35 These groups may be linked together to form a heterocyclic or heteroaryl ring, which may also be substituted. Appropriate "-C" 1-6 Alkylene group-" and R 101 However, this includes any of those having the same corresponding notation relating to R20 as defined in this application by formula I (e.g., any of its sub-formulas). For example, in some embodiments, the "-C 1-6 The alkylene group - is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, TIFF0007837952000195.tif1577 or This is TIFF0007837952000196.tif1973. In some embodiments, R 101 However, the 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, bridged, 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, where the monocyclic or bicyclic ring may be substituted. In some embodiments, R 101 However, it is a monoring selected from the group consisting of the following: Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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 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. In some embodiments, R 101 However, it is a biringual equation selected from the group consisting of the following: Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(C) 1-4 (Alkyl group)(C 1-4The substituent is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a 4-6 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.

[0126] In some embodiments, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 1 ga-C 1-6 Alkylene group-NR 30 R 31 And R 30 and R 31 However, hydrogen may be substituted on C independently. 1-6 It is an alkyl group or a substituted heterocycle; or, R 30 and R 31 However, together with N which is linked together with them, they form a substituted heterocycle having one or two ring-forming heteroatoms, or R 30 and R 31 One of them is the aforementioned C 1-6 The CH2 units of the alkylene group and any of the atoms between them form a substituted heterocyclic or heteroaryl ring having one or two ring-forming heteroatoms.

[0127] In some embodiments, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 1 ga-C 1-6 Alkylene group-NR 30 R 31 And, R 30 However, C 1-6 The CH2 unit of the alkylene group and any of the atoms between them together form a ring selected from the group consisting of the following (R 31 (Indicating formation:) TIFF0007837952000199.tif25163 Each of them may be substituted with one or more (e.g., 1 or 2) substituents, the substituents independently being F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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, R 31 ga-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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) p -Cyclopropyl group, -(CH2) p -Cyclobutyl group, or -(CH2) p-(a 4-6 membered heterocycle having 1 or 2 independently selected ring-forming heteroatoms from the group consisting of O, N, and S), x is 1, 2, or 3, preferably 2 or 3, and p is 0, 1, 2, or 3.

[0128] In some embodiments, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 1 ga-C 1-6 Alkylene group-NR 30 R 31 And, R 30 and R 31 However, together with N which are connected to them, they form a ring selected from the following group, TIFF0007837952000200.tif26161 Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents independently are F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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.

[0129] In some specific embodiments, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 1 but, Selected from the group consisting of TIFF0007837952000201.tif2293.

[0130] The appropriate R used in equation II (for example, equations II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 2 However, this includes either those relating to Formula I in this application or those given as specific examples in this application. Generally, R in Formula II 2 However, it does not contain Michael addition acceptors, such as α-β unsaturated carbonyl group structural moieties. For example, in some embodiments, formula R is used in II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8). 2 but, Selected from the group consisting of TIFF0007837952000202.tif193162 or, TIFF0007837952000203.tif2977 or TIFF0007837952000204.tif3171 (for example, Selected from the group consisting of TIFF0007837952000205.tif3383), or, TIFF0007837952000206.tif31105 or Selected from the group consisting of TIFF0007837952000207.tif2666.

[0131] The appropriate R used in equation II (for example, equations II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 3However, this includes either those relating to Formula I in this application or those given as specific examples in this application. For example, in some embodiments, R in Formula II (e.g., Formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 3 The group is a phenyl group, a pyridyl group, a naphthyl group, or a bicyclic heteroaryl group (e.g., a benzothiazolyl group, an indazolyl group, or an isoquinolinyl group), and each of these may be substituted with 1 to 3 substituents, the substituents independently being F, Cl, Br, I, -OH, C 1-4 Selected 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, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 3 However, the naphthyl group may be substituted with one or more (generally 1-3) 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 Container C 2-4 R is selected from the group consisting of an alkynyl group (e.g., an ethynyl group or a propargyl group), a cyclopropyl group, -NH2, -CN, a protected -OH, and a protected -NH2. In some embodiments, R in formula II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) 3 but, TIFF0007837952000208.tif246166TIFF0007837952000209.tif55154 or Selected from the group consisting of TIFF0007837952000210.tif22106.

[0132] In some embodiments, the present disclosure provides compounds of formula III or pharmaceutically acceptable salts thereof. TIFF0007837952000211.tif3374 Here, J 1 However, CR 9 or N; J 3 However, CR 11 or N; J 4 However, CR 12 or N; R 1 However, hydrogen, -(L 1 ) m1- Ure 20 , halogen, -(L 1 ) m1 -NR 30 R 31 -C(O)-NR 30 R 31 , an optionally substituted alkyl group, or an optionally substituted heterocyclic or heteroaryl ring; R 2 However, these ring or ring-chain structures are ring or ring-chain structures having a basic functional group whose conjugate acid has a pKa of about 6 or more, or their acylation derivatives (i.e., the basic functional group, such as a basic NH, bonded to an acyl group); R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 9 However, hydrogen, halogen, cyano group, or substitution C may be present. 1-4 Alkyl group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C 2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 1-4 Alkoxy group, substituted KarC 3-6A cycloalkyl group, an optionally substituted aryl group, an optionally substituted 4-8 membered heterocyclic group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or an optionally substituted 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S. R 11 and R 12 However, each time they appear, they appear independently as F, Cl, Br, I, CN, -OH, -C(O)NH2, -NH2, -NH(C 1-6 Alkyl(alkyl group), -N(C) 1-6 (Alkyl group)(C 1-6 Alkyl(alkyl group), -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 group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C -2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 3-6 A cycloalkyl group (e.g., a cyclopropyl group or a cyclobutyl group) may be substituted. 1-4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), may be substituted C 3-6 A cycloalkoxy group (e.g., a cyclopropoxy group or a cyclobutoxy group), a substituted or alternatively substituted 4-7 membered heterocycloalkoxy group; and Here, m1 is either 0 or 1, and if m1 is 1, L 1 However, these may be substituted alkylene groups, substituted carbocyclylene groups, or substituted heterocyclylene groups; R 20 However, hydrogen, oxygen protecting groups, and substitutions may be made of C. 1-6 It is an alkyl group, an optionally substituted carbon ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle; R 30 and R31 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 30 and R 31 They may be linked and substituted to form a heterocyclic or heteroaryl ring; or, R 30 and R 31 One of them is L 1 It forms a heterocycle or heteroaryl ring, which may be substituted with the appropriate atoms and any of the atoms in between.

[0133] Compounds of formula III (including any applicable sub-formulas relating to this application) may exist in the form of a single enantiomer, a diastereomer, an 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, compounds of formula III (including any applicable sub-formulas relating to this application) 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 applicable sub-formulas relating to this application) may exist as a single enantiomer of isolation, such single enantiomer being essentially free of other enantiomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other enantiomers by weight, HPLC area, or both).

[0134] The appropriate R used in Equation III 1 , R 2 and R 3 The base includes any of those having the same corresponding notation for formula I (e.g., its sub-formulas) in this application. The appropriate J used in formula III. 1 and J 3 The definition further includes any combination of those relating to Formula I (or its sub-formulas) in this application. For example, in some embodiments, if present, R in Formula III 11is 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, if present, R in formula III 11 However, it is hydrogen. In some embodiments, if present, R in formula III 11 is Br. In some embodiments, if present, R in Equation III 9 However, it is hydrogen. In some embodiments, if present, R in formula III 12 However, these are hydrogen, 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.

[0135] In some embodiments, the compound of formula III may have any of the following sub-formulas. TIFF0007837952000212.tif69166 formula, R 1 , R 2 , R 3 and R 11 However, it includes any combination of those defined in this application.

[0136] For example, in some embodiments, R in formula III (e.g., sub-formulas III-1, III-2, III-1-A, or III-2-A) 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, bridged, or spirodicyclic 6-10 membered heterocycle having 1 to 3 independently selected ring-forming heteroatoms from the group consisting of N, O, and S, where the monocyclic or bicyclic form may be substituted.

[0137] In some embodiments, R in formula III (e.g., sub-formulas III-1, III-2, III-1-A, or III-2-A) 1 but, Selected from the group consisting of TIFF0007837952000213.tif69146, Each of them may be substituted with one or more (e.g., one or two) substituents, and the substituents independently are F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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.

[0138] In some embodiments, R in formula III (e.g., sub-formulas III-1, III-2, III-1-A, or III-2-A) 1 ga-OR 20 And R 20 ga-C 1-6 Alkylene group-R 101 And R 101 NR 32 R 33 Alternatively, it is a 4-10 membered heterocycle which may be substituted, C 1-6 The alkylene group may be substituted, for example, with one or more substituents, and the substituents may independently be F, OH, NR 34 R 35 , and C which may be substituted with 1-3 fluorines 1-4Selected from the group consisting of alkyl groups, or two substituents of an alkylene group linked together to form a ring; R 32 and R 33 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, a substituted or substituted carbon ring, or a substituted or substituted heterocycle; or, NR 32 R 33 R represents a monoalkyl or dialkylamine; or, 32 and R 33 They may be linked and substituted to form a heterocyclic or heteroaryl ring; and, R 34 and R 35 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 34 and R 35 These groups may be linked together to form a heterocyclic or heteroaryl ring, which may also be substituted. Appropriate "-C" 1-6 Alkylene group-" and R 101 However, R defined in formula I (including sub-formulas) in this application 20 This includes any of those having the same corresponding notation. For example, in some embodiments, "-C 1-6 The alkylene group - is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, TIFF0007837952000214.tif1677 or This is TIFF0007837952000215.tif2068. In some embodiments, R 101 However, it 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, bridged, 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, where the monocyclic or bicyclic form may be substituted. In some embodiments, R 101 However, it is a monoring selected from the group consisting of the following: Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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 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. In some embodiments, R 101 However, it is a biringual equation selected from the group consisting of the following: Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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.

[0139] In some embodiments, R in formula III (e.g., sub-formulas III-1, III-2, III-1-A, or III-2-A) 1 but, Selected from the group consisting of TIFF0007837952000218.tif2276.

[0140] In some embodiments, R in formula III (e.g., sub-formulas III-1, III-2, III-1-A, or III-2-A) 1 but, The filename is TIFF0007837952000219.tif2692.

[0141] The appropriate R used in equation III (e.g., equations III-1, III-2, III-1-A, or III-2-A) 1 However, this includes either those relating to Formula I in this application or those given as specific examples in this application.

[0142] R used in equation III (for example, equations III-1, III-2, III-1-A, or III-2-A) 2 However, this includes either those relating to Formula I in this application or those given as specific examples in this application. Generally, R in Formula III 2 However, it does not contain Michael addition acceptors, such as α-β unsaturated carbonyl group structural moieties. In some embodiments, R in formula III (e.g., subformulas III-1, III-2, III-1-A or III-2-A) 2 ga-(L 2 ) m2- R 102 And, m2 is either 0 or 1, and if m2 is 1, L 2 is CH2, O, NH or NCH3 R 102 However, it is a substituted 4-10 membered heterocyclic ring or heteroaryl ring having one or two ring-forming nitrogen atoms.

[0143] Appropriate R 102 However, this application includes any of the formulas I (for example, any of its sub-formulas). In some embodiments, R 102However, it is a substituted 4-10 membered heterocycle having one or two ring-forming nitrogen atoms. In some embodiments, R in formula III (e.g., subformulas III-1, III-2, III-1-A or III-2-A) 102 or R 2 but, Selected from the group consisting of TIFF0007837952000220.tif195164 or, TIFF0007837952000221.tif2688 or TIFF0007837952000222.tif3171 (for example, Selected from the group consisting of TIFF0007837952000223.tif3282) or, TIFF0007837952000224.tif31113 or Selected from the group consisting of TIFF0007837952000225.tif2761.

[0144] The appropriate R used in Equation III (e.g., Sub-Equations III-1, III-2, III-1-A, or III-2-A) 3 However, this includes either those relating to Formula I in this application or those given as specific examples in this application. For example, in some embodiments, R in Formula III (e.g., sub-formulas III-1, III-2, III-1-A or III-2-A) 3 The substituents are a phenyl group, a pyridyl group, a naphthyl group, or a bicyclic heteroaryl group (e.g., a benzothiazolyl group, an indazolyl group, or an isoquinolinyl group), and each of these may be substituted, for example, by 1 to 3 substituents, where the substituents are independently F, Cl, Br, I, -OH, C 1-4 Selected 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, R in formula III (e.g., subformulas III-1, III-2, III-1-A or III-2-A) 3However, the naphthyl group may be substituted with one or more (generally 1-3) 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 with C 2-4 Alkenyl group, substitution in Container C 2-4 R is selected from the group consisting of an alkynyl group (e.g., an ethynyl group or a propargyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, R in formula III (e.g., subformulas III-1, III-2, III-1-A, or III-2-A) 3 but, TIFF0007837952000226.tif238166TIFF0007837952000227.tif52153 or Selected from the group consisting of TIFF0007837952000228.tif2378.

[0145] In some embodiments, the disclosure provides compounds of formula IV or V, or pharmaceutically acceptable salts thereof. TIFF0007837952000229.tif38102 Here, J 1 However, CR 9 or N; J 2 However, CR 10 or N; J 3 However, CR 11 or N; J 4 However, CR 12 or N; J 5 However, CR 12A or N; Or, J 4 and J 5 These groups may be linked to form a substituted phenyl group or a substituted 5-membered or 6-membered heteroaryl group, provided that in this case, for example, J4 and J 5 When linked to form a triazole ring, J 4 and J 5 The bond between them may be a single bond; R 1 However, hydrogen, -(L 1 ) m1- Ure 20 , halogen, -(L 1 ) m1 -NR 30 R 31 -C(O)-NR 30 R 31 , an optionally substituted alkyl group, or an optionally substituted heterocyclic or heteroaryl ring; R 2 However, these ring or ring-chain structures are ring or ring-chain structures having a basic functional group whose conjugate acid has a pKa of about 6 or more, or their acylation derivatives (i.e., the basic functional group, such as a basic NH, bonded to an acyl group); R 3 However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R 9 and R 10 However, each time it appears, it may be independently a hydrogen atom, a halogen, a cyano group, or a substituted C. 1-4 Alkyl group (e.g., methyl group, ethyl group, CF3, etc.), may be substituted C 2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 1-4 Alkoxy group, substituted KarC 3-6 A cycloalkyl group, an optionally substituted aryl group, an optionally substituted 4-8 membered heterocyclic group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or a 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from the group consisting of N, O, and S. R 11 , R 12 and R 12A However, each time they appear, independently, F, chloro, Cl, I, CN, -OH, -C(O)NH2, -NH2, -NH(C 1-6 Alkyl(alkyl group), -N(C)1-6 (Alkyl group)(C 1-6 Alkyl(alkyl group), -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.), may be substituted. 2-4 Alkenyl group, substitution in Container C 2-4 Alkynyl group, substituted KiC 3-6 A cycloalkyl group (e.g., a cyclopropyl group or a cyclobutyl group) may be substituted. 1-4 Alkoxy groups (e.g., methoxy group, ethoxy group, -O-CH2-cyclopropyl group), may be substituted C 3-6 A cycloalkoxy group (e.g., a cyclopropoxy group or a cyclobutoxy group), a substituted or alternatively substituted 4-7 membered heterocycloalkoxy group; Alternatively, R 12 and R 12A They are linked together to form a 5-7 membered ring structure; and, Here, m1 is either 0 or 1, and if m1 is 1, L 1 However, these may be substituted alkylene groups, substituted carbocyclylene groups, or substituted heterocyclylene groups; R 20 However, hydrogen, oxygen protecting groups, and substitutions may be made of C. 1-6 It is an alkyl group, an optionally substituted carbon ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle; R 30 and R 31 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 30 and R 31 They may be linked and substituted to form a heterocyclic or heteroaryl ring; or, R 30 and R 31 One of them is L 1It forms a heterocycle or heteroaryl ring, which may be substituted with the appropriate atoms and any of the atoms in between.

[0146] Compounds of formula IV or V (including, for example, any applicable sub-formula as described herein) may exist in the form of a single enantiomer, a diastereomer, an 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 IV or V (including any applicable sub-formula as described herein) may exist as a mixture of atropisomers in any proportion (including about 1:1). In some embodiments, where applicable, compounds of formula IV or V (including any applicable sub-formula as described herein) may exist as a single enantiomer of isolation, such single enantiomer being essentially free of other enantiomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other enantiomers, by weight, HPLC area, or both).

[0147] The appropriate R used in formula IV or V 1 , R 2 and R 3 The base includes any combination of those having the same corresponding notation relating to formula I (e.g., its sub-formulas) in the present application. 1 , J 2 , J 3 , J 4 and J 5 The definition further includes any combination of those relating to formula I (or its sub-formulas) in this application. For example, in some embodiments, J 1 and J 2 However, N is present. In some embodiments, if present, R in formula IV or V. 9 However, it is hydrogen. In some embodiments, J in formula V 3 However, CR 11 , R 11However, these are 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.

[0148] In some embodiments, the compound of formula IV or V may have one of the following sub-formulas. TIFF0007837952000230.tif38166In formula, R 1 , R 2 , R 3 , R 11 , R 12 and R 12A However, it includes any combination of those defined in this application.

[0149] For example, in some embodiments, if present, R in equation V (e.g., sub-equation V-1) 11 However, these are hydrogen, F, Cl, or a methyl group. In some embodiments, if present, R in formula IV (e.g., sub-formula IV-1) 12 The group is hydrogen, 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, if present, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 12A is hydrogen, 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, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 12A However, C may be substituted with H or F. 1-4 It may be an alkyl group, for example, a methyl group. In some embodiments, R in formula IV or V (for example, sub-formula IV-1 or V-1) 12A However, it may be Cl or a methoxy group. In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 12AHowever, it may be an ethyl group or a difluoromethyl group. In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 12A However, it is OH. The appropriate R used in formula IV or V (for example, sub-formula IV-1 or V-1) 12A This further includes those specifically cited in this application.

[0150] In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 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, bridged, or spirodicyclic 6-10 membered heterocycle having 1 to 3 independently selected ring-forming heteroatoms from the group consisting of N, O, and S, wherein the monocyclic or bicyclic form may be substituted.

[0151] In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 1 but, Selected from the group consisting of TIFF0007837952000231.tif70146, Each of them may be substituted with one or more (e.g., one or two) substituents, and the substituents independently are F,-(CH2) x -OH,-(CH2) x -1-3 fluorine atoms may be substituted for C 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 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 4-6 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of O, N, and S), 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.

[0152] In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 1 ga-OR 20 And R 20 ga-C 1-6 Alkylene group-R 101 And R 101 NR 32 R 33 Alternatively, it is a 4-10 membered heterocycle which may be substituted, Said C 1-6 The alkylene group may be substituted, for example, with one or more substituents, and the substituents may independently be F, OH, NR 34 R 35 and C which may be substituted with 1-3 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 32 and R 33 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, a substituted or substituted carbon ring, or a substituted or substituted heterocycle; or, NR 32 R 33 R represents a monoalkyl or dialkylamine; or, 32 and R 33 They may be linked and substituted to form a heterocyclic or heteroaryl ring; and, R 34 and R 35 However, independently, hydrogen, nitrogen protecting group, and substituted C may be present. 1-6 It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R 34 and R 35These groups may be linked together to form a heterocyclic or heteroaryl ring, which may also be substituted. Appropriate "-C" 1-6 Alkylene group-" and R 101 However, R defined in formula I (including sub-formulas) in this application 20 This includes any of those having the same corresponding notation. For example, in some embodiments, "-C 1-6 The alkylene group - is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, TIFF0007837952000232.tif1771 or This is TIFF0007837952000233.tif2163. In some embodiments, R 101 However, the monocyclic 4-8 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of N, O, and S, or the condensed, bridged, 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, where the monocyclic or bicyclic form may be substituted. In some embodiments, R 101 However, it is a monoring selected from the group consisting of the following: TIFF0007837952000234.tif22152 Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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 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. In some embodiments, R 101 However, it is a biringual equation selected from the group consisting of the following: Each of them may be substituted with one or more (e.g., 1 or 2) substituents, and the substituents may be independently substituted with F, -OH, and 1-3 fluorines. 1-4 C may be substituted with an alkoxy group, an oxo group, or 1-3 fluorines. 1-4 Alkyl alkyl groups, NH2, NH(C 1-4 Alkyl(C)(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 4-6 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.

[0153] In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 1 but, Selected from the group consisting of TIFF0007837952000236.tif2182.

[0154] In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 1 but, The filename is TIFF0007837952000237.tif2599.

[0155] The appropriate R used in equation IV or V (e.g., sub-equation IV-1 or V-1) 1 However, this includes either those relating to Formula I in this application or those given as specific examples in this application.

[0156] The appropriate R used in equation IV or V (e.g., sub-equation IV-1 or V-1) 2 However, this includes either those relating to Formula I in this application or those given as specific examples in this application. Generally, R in Formula IV or V (e.g., sub-formula IV-1 or V-1)2 However, it does not contain Michael addition acceptors, such as α-β unsaturated carbonyl group structural moieties. In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 2 ga-(L 2 ) m2- R 102 And, m2 is either 0 or 1, and if m2 is 1, L 2 CH 2 , O, NH or NCH3, R 102 However, it is a substituted 4-10 membered heterocyclic ring or heteroaryl ring having one or two ring-forming nitrogen atoms.

[0157] Appropriate R 102 However, this application includes any of the formulas I (for example, any of its sub-formulas). In some embodiments, R 102 However, it is a substituted 4-10 membered heterocycle having one or two ring-forming nitrogen atoms. In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 102 or R 2 but, Selected from the group consisting of TIFF0007837952000238.tif192163 or, TIFF0007837952000239.tif2672 or TIFF0007837952000240.tif2975 (for example, Selected from the group consisting of TIFF0007837952000241.tif3272), or, TIFF0007837952000242.tif32102 or Selected from the group consisting of TIFF0007837952000243.tif2465.

[0158] The appropriate R used in equation IV or V (e.g., sub-equation IV-1 or V-1) 3However, this includes either those relating to Formula I in this application or those given as specific examples in this application. For example, in some embodiments, R in Formula IV or V (e.g., sub-formula IV-1 or V-1) 3 The substituents are a phenyl group, a pyridyl group, a naphthyl group, or a bicyclic heteroaryl group (e.g., a benzothiazolyl group, an indazolyl group, or an isoquinolinyl group), and each of these may be substituted, for example, by 1 to 3 substituents, where the substituents are independently F, Cl, Br, I, -OH, C 1-4 Selected 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, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 3 However, the naphthyl group may be substituted with one or more (generally 1-3) 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 with C 2-4 Alkenyl group, substitution in Container C 2-4 R is selected from the group consisting of an alkynyl group (e.g., an ethynyl group or an alkynyl group), a cyclopropyl group, -NH2, -CN, protected -OH, and protected -NH2. In some embodiments, R in formula IV or V (e.g., sub-formula IV-1 or V-1) 3 but, TIFF0007837952000244.tif254165TIFF0007837952000245.tif55158 or Selected from the group consisting of TIFF0007837952000246.tif2492.

[0159] In some embodiments, the disclosure further provides compounds selected from the group consisting of compound numbers 1-247, or pharmaceutically acceptable salts thereof. TIFF0007837952000247.tif196155TIFF0007837952000248.tif233166TIFF0007837952000249.tif227166TIFF0007837952000250.tif235166TIFF000 7837952000251.tif215166TIFF0007837952000252.tif217166TIFF0007837 952000253.tif229166TIFF0007837952000254.tif217166TIFF00078379520 00255.tif220166TIFF0007837952000256.tif221166TIFF0007837952000257.tif241166TIFF0007837952000258.tif237166TIFF0007837952000259.t if239166TIFF0007837952000260.tif228166TIFF0007837952000261.tif233166TIFF0007837952000262.tif200166TIFF0007837952000263.tif170166

[0160] Exemplary synthesis and identification of compound numbers 1-247 are shown in the Examples section. When specific compound number 1-247 is indicated as “trans”, for example, in the exemplary synthesis of such a compound shown in the Examples section, the compound may be prepared in racemic form, isolated into two enantiomers including the enantiomer depicted, or, according to this disclosure, one or two of these two enantiomers can be prepared by chiral synthesis.

[0161] In some embodiments, to the extent applicable, the types of compounds in this disclosure do not include any compounds specifically manufactured and disclosed prior to this disclosure.

[0162] 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.

[0163] The following method for synthesizing formula I is illustrative, and those skilled in the art can synthesize compounds of formulas A, II, III, IV, or V in the same manner by using appropriate synthetic starting materials or intermediates. In some embodiments, including those shown in the Examples section, the Disclosure further provides synthetic methods and synthetic intermediates for producing compounds of formulas I, A, II, III, IV, or V, as shown in the scheme of the Application.

[0164] As shown in Scheme 1, compounds of formula I can generally be synthesized by a series of coupling reactions. In some embodiments, compound S-1 is R 2 It can be coupled with supply unit S-2. 2 Depending on the properties, such coupling can be performed with or without a transition metal catalyst. In some embodiments, generally, in a non-protonate solvent, under basic conditions, R 2 -M 2 Lg 1 Lg can be substituted to form OC or NC bonds, producing compound S-3. 1 However, the detaching group relating to this application may be a halogen (e.g., Cl). In some embodiments, M 2 However, it is hydrogen. Subsequently, compound S-3 can be converted to formula I by reaction with S-4. R in S-4 1 -M 1 Generally, these include -OH or -NH functional groups, for example M 1 It may also be hydrogen, which reacts with S-3 to form a leaving group Lg 2 It can be substituted to form an OC or NC bond. Leaving group Lg 2 However, halogens (e.g., Cl) or other detaching groups relating to this application, such as methyl sulfoxide, methyl sulfone, etc., may also be used. Other coupling sequences are also appropriate. For example, in some embodiments according to Scheme 1, R 1 R 2The group can be introduced first before the other group is introduced. Exemplary reaction conditions for converting the compound of formula S-1 to the compound of formula I are shown in the Examples section. The variable R in formulas S-1, S-2, S-3 and S-4 of Scheme 1. 1 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 and J 5 This includes those defined in formula I above (e.g., any of the subformulas of formula I), and, where applicable, any of the protected derivative groups. When using a synthetically protected group, for example, R protected with S-3. 2 When using the group, those skilled in the art will understand that the synthesis sequence includes a deprotection step, for example, coupling with S-4 to synthesize the compound of formula I. TIFF0007837952000264.tif96128

[0165] The compounds of formula I may be prepared by a slightly different coupling sequence. For example, as shown in scheme 2, the synthesis may involve coupling the compound at S-5 with S-4 to form the compound at S-6. 1 -M 1 Generally, these include -OH or -NH functional groups, for example M 1 It may also be hydrogen, which reacts with S-5 to form a leaving group Lg 2 It can be substituted to form an OC or NC bond. Leaving group Lg 2 However, halogens or other detaching groups related to this application may also be used, such as methyl sulfoxide, methyl sulfone, etc. Subsequently, the compound of S-6 is the compound of S-7, R 3 -M 3 It reacts with to provide the compound of formula I. Generally, Lg in S-6 compounds 3 It is first activated by the release group, and then further R 3 -M 3 It can react with to produce the compound of formula I. For example, in some embodiments, Lg at S-63 This is a hydroxyl group or a protected hydroxyl group, which is first converted to a detaching group, such as a halogen anion or a sulfonate ion, such as a trifluoromethanesulfonate ion, and then to the S-7 compound, R 3 -M 3 Cross-coupling reactions can be carried out with M. Generally, 3 However, hydrogen, metals (for example, Zn 2+ ), may be a boronic acid or ester, tributyltin, etc., and the cross-coupling is generally a transition metal-catalyzed coupling reaction, for example, the palladium-catalyzed coupling reaction mentioned in this application. Other coupling sequences are also appropriate. For example, in some embodiments according to Scheme 2, R 3 R 1 It can be introduced before the introduction of the base. In some embodiments, Lg 2 R 1 It may be a suitable precursor of a detaching group for coupling with feeder S-4. For example, in some embodiments, Lg 2 However, it may also be -S-Me, which is first oxidized to -S(O)-Me or -S(O)2Me, and then further reacts with S-4 to form R 1 A group can be introduced. Exemplary reaction conditions for converting the S-5 compound to the compound of formula I are shown in the Examples section, see, for example, Example 2. The variable R in formulas S-4, S-5, S-6 and S-7 of Scheme 2. 1 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 and J 5 However, it includes any of the groups defined by formula I above (e.g., any sub-formula of formula I), and, if applicable, any of the protected derivative groups (e.g., if applicable). When using a group protected in synthesis, for example, R protected by S-6. 2 When using the group, those skilled in the art will understand that the synthesis sequence includes a deprotection step, for example, coupling with S-7 to synthesize the compound of formula I. TIFF0007837952000265.tif100166

[0166] Suitable coupling partners, for example, S-1, S-2, S-4, S-5, or S-7, can be manufactured by methods known in the art or by methods relating to this disclosure, see, for example, the Examples section.

[0167] 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, such as those from Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others can be prepared by following the procedures described in the references, or obvious modifications thereof, such as in *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 any of these documents.

[0168] Pharmaceutical composition Specific embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0169] The pharmaceutical composition may optionally contain pharmacologically acceptable excipients. In some embodiments, the pharmaceutical composition may contain compounds of the present disclosure (e.g., formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I The compound comprises (I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compounds 1-247, or pharmacologically acceptable salts thereof), and pharmacologically acceptable excipients. The 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, Remington's *The Science and Practice of Pharmacy*, 21, discloses prior art for each excipient used to prepare pharmaceutical compositions and for the manufacture of the same. st See Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005, which is incorporated herein by reference).

[0170] The pharmaceutical composition may contain one or more of the compounds of the Disclosure. For example, in some embodiments, the pharmaceutical composition may contain, for example, a therapeutically effective amount of formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9- The compounds include those of formula D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compound numbers 1-247, or pharmaceutically acceptable salts thereof. In any embodiment of the present application, the pharmaceutical composition may include, for example, a therapeutically effective amount of a compound selected from the group consisting of any of the compounds represented by compound number 1-247, or a pharmaceutically acceptable salt thereof.

[0171] 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.

[0172] In some embodiments, the pharmaceutical composition can be prepared for oral administration. Oral formulations can be expressed in individual units such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound, and can be expressed as powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for producing 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.

[0173] 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). The parenteral preparation may be, for example, an aqueous solution, a suspension or an emulsion. Excipients for the manufacture of parenteral preparations 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.

[0174] In some embodiments, the pharmaceutical composition is prepared into an inhalation formulation. The inhalable formulation is prepared, for example, as a nasal spray, dry powder, or aerosol 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 spray may further contain propellants such as chlorofluorocarbons and unsubstituted volatile volatile hydrogen compounds such as butane and propane.

[0175] The pharmaceutical composition may contain various amounts of the compound of the Disclosure depending on various factors such as the intended use, efficacy, and selectivity of the compound. In some embodiments, the pharmaceutical composition may contain a therapeutically effective amount of the compound of the Disclosure (e.g., formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I- The compounds include those of formula 9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of the compounds 1-247, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used in this application, the therapeutically effective dose of a compound in this disclosure means an effective dose for treating the disease or condition relating to this application, 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.

[0176] 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.

[0177] 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).

[0178] 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.

[0179] 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., formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I- The present invention provides a method comprising contacting a compound of formula 9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compound numbers 1-247, or a pharmaceutically acceptable salt thereof. 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.

[0180] 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 compounds of the present disclosure (e.g., formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9- The present invention provides a method comprising contacting a compound of formula E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compound numbers 1-247, or a pharmaceutically acceptable salt thereof.

[0181] 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 compounds of the present disclosure (e.g., formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9- The present invention provides a method comprising contacting a compound of formula E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compound numbers 1-247, or a pharmaceutically acceptable salt thereof.

[0182] 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., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9 The present invention provides a method comprising contacting a compound of formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8), formula III (e.g., formula III-1, III-2, III-1-A, or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compound numbers 1-247, 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.

[0183] In some embodiments, the present disclosure is a method for treating cancer in a test subject, wherein the test subject is given a therapeutically effective amount of one or more compounds of the present disclosure ((e.g., formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-1 6, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A , I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I- The present invention provides a method comprising administering any of the compounds of formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8), formula III (e.g., formula III-1, III-2, III-1-A, or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), compound number 1-247, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of the pharmaceutical composition relating to the present invention. In some embodiments, the cancer is pancreatic cancer, lung cancer, colorectal cancer, endometrial cancer, appendiceal cancer, bile duct cancer, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, or hematological malignancies. In some embodiments, the examinee is KRAS G12D , HRAS G12D and / or NRAS G12D It has mutations.

[0184] 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 (for example, compounds of formula I (for example, formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I- The present invention provides a method comprising administering a therapeutically effective amount of a compound of formula 9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any of compound numbers 1-247, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition relating to the present invention.

[0185] 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 present invention. In some embodiments, the method provides a therapeutically effective amount of the compound of the present disclosure to a test subject (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9 The treatment involves administering any of the compounds of formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8), formula III (e.g., formula III-1, III-2, III-1-A, or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), compound numbers 1-247, or any pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition relating to this application.

[0186] In some embodiments, a method for treating cancer, wherein an effective amount of any compound disclosed (e.g., formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, The present invention provides a method comprising administering a pharmaceutical composition containing any of the compounds of formula I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), compound numbers 1-247, or a pharmaceutically acceptable salt thereof, or 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).

[0187] 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 to, a) determining whether the test subject has a Ras mutation; and b) if the test subject is determined 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., formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, The present invention provides a method comprising administering any of the compounds of formula I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), compound numbers 1-247, or any pharmaceutically acceptable salt thereof) or a pharmaceutical composition relating to the present application. 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.

[0188] 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 G12D mutation in KRAS, HRAS and / or NRAS, e.g., KRAS G12D To determine whether the test-taker has a mutation, and to determine if the test-taker has KRAS, HRAS and / or NRAS G12DIf a patient is determined to have a mutation, for example, the KRAS G12D mutation, the test subject will be required to take at least one of the compounds of this disclosure in an effective therapeutic dose (e.g., formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19, I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E, I-9-F, The present invention provides a method comprising administering a pharmaceutical composition comprising any of the compounds of formula I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), formula A (e.g., formula A-1), formula II (e.g., formula II-1, II-2, II-3, II-4, II-5, II-6, II-7 or II-8), formula III (e.g., formula III-1, III-2, III-1-A or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), compound numbers 1-247, or any pharmaceutically acceptable salt thereof, or at least one compound of the present disclosure.

[0189] 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, tau cell lymphoma, and Fahrenheit macroglobulinemia.

[0190] 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.

[0191] 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; gemcitabine; capecitabine; and any pharmacokinetically acceptable salts, acids, or derivatives of the above.

[0192] Appropriate chemotherapeutic cell modulators also 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).

[0193] 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, or zosuquidar.

[0194] The compounds of this disclosure can also 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 also 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.

[0195] 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.

[0196] The administration described herein 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.

[0197] 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.

[0198] definition Furthermore, it should be understood that all components and their combinations maintain an appropriate compound value.

[0199] It should be understood that specific embodiments of the variable parts relating to this application may be the same as or different from other specific embodiments bearing the same reference numeral.

[0200] The appropriate atoms or groups used in the variables herein are selected independently. The definitions of the variables may be combined. For example, in formula I, R 1 , R 2 , R 3 , J 1 , J 2 , J 3 , J4 and J 5 The definition of any one of the following in R in equation I 1 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 and J 5 This may be combined with any of the other definitions contained herein. Such combinations have also been devised and are within the scope of the present invention.

[0201] Definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are determined according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described herein. Furthermore, general principles of organic chemistry, and specific functional parts and reactivity, are based on Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito, 1999; and 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 This disclosure is described in Edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0202] 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 application may be in the form of individual enantiomers, diastereomers, atropisomers, or geometric isomers, or in the form of stereoisomeric mixtures, including racemic mixtures and mixtures 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 present disclosure further encompasses the compounds relating to the present application as individual isomers that do not essentially contain other isomers, or as mixtures of various isomers, including racemic mixtures. In embodiments of the present application, unless otherwise specified, when stereochemistry is described, the compound exists primarily as the described stereoisomer with respect to a particular chiral center or axial chirality, 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.

[0203] The compounds of this disclosure may have atropisomers. In any embodiment relating to this application, where applicable, the compounds of this disclosure may exist as a mixture of atropisomers in any proportion. In some embodiments, where applicable, the compounds may exist as a single isolated atropisomer and contain essentially no other atropisomers (e.g., in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable by weight, HPLC area, or both). The Examples section shows some exemplary isolated atropisomers of the compounds of this disclosure. As will be understood by those skilled in the art, when rotation is restricted around a single bond (e.g., a single bond of a biaryl group), the compounds may exist as a mixture of atropisomers, and each single atropisomer may be isolated.

[0204] When specifying a range of values, it is intended to include each value and sub-range within that range. For example, "C 1-6 " refers to 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 It is intended to include

[0205] As used in this application, the terms “compounds of the disclosure” or “compounds of the present invention” mean the compounds of formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-23, I-24, I-15, I-16, I-16-E1, I-16-E2, I-17, I-18, I-19) , I-20, I-21, I-22, I-1-A, I-2-A, I-3-A, I-4-A, I-5-A, I-6-A, I-9-A, I-9-B, I-9-C, I-9-D, I-9-E , I-9-F, I-9-G, I-10-A, I-2-B, I-2-C, I-4-B or I-6-B), Formula A (e.g., Formula A-1), Formula II (e.g., Formula II-1, II-2, II- This means any compound of formula III (e.g., II-4, II-5, II-6, II-7, or II-8), formula III (e.g., formula III-1, III-2, III-1-A, or III-2-A), formula IV (e.g., formula IV-1), formula V (e.g., formula V-1), any compound number 1-247, its isotopically labeled compound (e.g., a deuterium analog in which one of its hydrogen atoms is substituted with a deuterium atom, and the abundance of that deuterium atom is higher than its natural abundance), its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), geometric isomers, atropisomers, tautomers, conformosomers, and / or pharmacoposityal salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). To avoid any ambiguity, compound number 1-247 or compound 1-247 refers to the compounds designated as integers 1, 2, 3, ..., 247 as described herein, for example, see the title compound of Example 1-82 and Table 1. For convenience of explanation, synthetic starting materials or intermediates may be designated as a single integer (compound number) followed by a single "-" and an additional numerical value, e.g., 66-1, 66-2, etc., as will be seen in detail in the Examples. Such designations of synthetic starting materials or intermediates should not be confused with compounds that use only an integer and do not have a "-" and an additional numerical value. Hydrates and solvates of the compounds of this disclosure are recognized as compositions of this disclosure, in which the compound is coupled with water or a solvent, respectively.In some embodiments, the compounds of the present disclosure may be any of those defined in claims 1-77 of the application. In some embodiments, the compounds of the present disclosure may be any of those defined in exemplary embodiments 1-44 of the application. In some embodiments, the compounds of the present disclosure may be any of those defined in exemplary embodiments 45-57 of the application.

[0206] 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, 14 C, 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.

[0207] As used in this application, the phrases “administer” a compound, “administer” a compound, or other variations thereof, mean to provide a compound or a prodrug of a compound to an individual in need of treatment.

[0208] As used in this application, 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 1-10It 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. 1-4 It is an alkyl group. As used in this application, 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-restrictive linear alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0209] As used in this application, 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.

[0210] As used in this application, the term “alkynyl group” means a linear or branched fatty hydrocarbon containing one or more, for example, 1-3 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 2-4These are alkynyl groups. Non-exclusive exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0211] As used in this application, the term “alkoxy group” means, when used alone or as part of another group, the formula OR a1 It means the base of R a1 However, it is an alkyl group. As used in this application, the term “cycloalkoxy group” means a group of the formula OR when used alone or as part of another group. a1 It means the base of R a1 However, it is a cycloalkyl group.

[0212] As used in this application, 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.

[0213] 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"). 3-10 The 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 point is on the carbocyclic, 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.

[0214] In some embodiments, the “carbocyclic group” is fully saturated and is also called a cycloalkyl group. In some embodiments, the cycloalkyl group can have 3 to 10 ring-forming carbon atoms ("C"). 3-10 (Cycloalkyl group). In preferred embodiments, the cycloalkyl group is monocyclic.

[0215] "Heterocyclic group" or "heterocyclic" means a 3- to 10-membered non-aromatic cyclic group ("3-10-membered heterocyclic group") having a ring-forming carbon atom and 1-4 ring-forming heteroatoms (each heteroatom 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, such as a bicyclic system ("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 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 on a heterocyclic group, and in this case, the number of ring members still represents the number of ring members in the heterocyclic system.

[0216] 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 (also referred to in this application as a 5,6-dicyclic 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 (also referred to in this application as a 6,6-dicyclic heterocycle) that condenses with an exemplary aryl ring includes, but is not limited to, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, and the like.

[0217] 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 ("C6 aryl group"; e.g., a phenyl group). In some embodiments, an aryl group has 6 ring-forming carbon atoms ("C6 aryl group"; e.g., a phenyl group). In some embodiments, an 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 condensation 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.

[0218] 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.

[0219] 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 (each heteroatom 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" includes a ring system formed by the fusion of the heteroaryl ring defined above with one or more carbocyclic or heterocyclic groups, 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 fusion 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. In dicycloheteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl group, quinolinyl group, cabazolyl group, etc.), the linking point may be in either ring, i.e., a ring with a heteroatom (e.g., a 2-indolyl group) or a ring without a heteroatom (e.g., a 5-indolyl group).

[0220] 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.

[0221] 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.

[0222] 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.

[0223] The terms "substitutable" groups, such as substituted alkyl groups, substituted alkenyl groups, substituted alkynyl groups, substituted carbocyclic groups, substituted heterocyclic groups, substituted aryl groups, and substituted heteroaryl groups, mean the unsubstituted or substituted groups, respectively. Generally, the term "substituted," whether preceding or otherwise, means that at least one hydrogen atom on a group (e.g., a carbon or nitrogen atom) is substituted with a permissible substituent, and the substitution thereon produces a stable compound, such as a compound that is not subject to spontaneous transformation (e.g., rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a "substituted" group has substituents at one or more substituted positions, and if multiple positions of any given structure are substituted, the substituents may be the same or different at each position. The substituents may, as necessary, be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents.

[0224] Unless otherwise explicitly 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).

[0225] In some embodiments, the "may be substituted" alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic groups in this application may be unsubstituted, or 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 3-7 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 1-4Selected from the group consisting of alkoxy groups. In some embodiments, the "may be substituted" aryl or heteroaryl group in this application may be unsubstituted, or may be substituted with 1, 2, 3, or 4 substituents, the substituents independently being F, Cl, -OH, -CN, 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), -S(=O)(C 1-4 Alkyl(alkyl group), -SO2(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 3-7 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 alkyl group, C 1-4 Alkoxy groups and fluorine-substituted C 1-4 Selected from the group consisting of alkoxy groups.

[0226] Exemplary carbon substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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, and 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 dd Substituted with;X -However, it is a counterion; Alternatively, two gem hydrogen atoms 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, and 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, and 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;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, and 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 , -SSRee -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, C 6-10Selected 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 Substituents may link together to form =O or =S; 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, and 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 1-6 Alkyl(2,-N(C) 1-6Alkyl(2,-N(C) 1-6 (Alkyl)3 + X - , -NH(C 1-6 (Alkyl group)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(alkyl group), -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 group)2,-OC(=O)NH(C 1-6 Alkyl(alkyl group), -NHC(=O)(C 1-6 Alkyl(alkyl group), -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 1-6 Alkyl(2), -NHC(=NH)NH2, -NHSO2(C1-6 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 link together to form =O or =S; X - This is a counterion.

[0227] 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 two 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.

[0228] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0229] 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 the group consisting of R aa and R bb However, it is as defined in this application.

[0230] 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 )R 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)(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 5-14 member 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, and 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 R aa , R bb , R cc and R dd However, it is defined as described above.

[0231] In some embodiments, the substituent on the nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups are well known in the art and are incorporated by reference in Protectivegroups in Organic Synthesis, TW Greene 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-butoxycarbonyl (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.

[0232] 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 application. In some embodiments, the oxygen atom substituent on the oxygen atom is an oxygen protecting group (also called a hydroxyl group protecting group). Oxygen protecting groups are well known in the art and are incorporated into this application by reference in Protectivegroups in Organic Synthesis, TW Greene and PGMWuts, 3 rd This includes those described in detail in edition, John Wiley & Sons, 1999. Exemplary oxygen-protecting groups include, but are not limited to, 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] As used in this Application, the term “examinee” (or “patient” as used in this Application) means an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation, or experimentation.

[0237] As used in this application, 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 application, 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 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 or have a disease or condition recurrence, but who has not experienced a recurrence or relapse of the disease or condition. The term “treatment” and its synonyms mean administering a therapeutically effective amount of the compound relating to this application to a test subject who requires such treatment.

[0238] As used in this application, the singular forms "a," "an," and "the" include plurals unless explicitly stated otherwise or the context clearly indicates otherwise.

[0239] The term "and / or" as used in phrases such as "A and / or B" in this application 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).

[0240] The titles and subtitles are used solely for convenience or formal compliance purposes and are not intended to limit the featured technology, nor are they related to the interpretation of the description of the featured technology. In various embodiments, features described under one title or subtitle of this disclosure may be combined with features described under other titles or subtitles. Furthermore, not all features under a single title or subtitle are necessarily used together in the embodiments.

[0241] 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 carried out 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. Example 1 Synthesis of Compound 20 TIFF0007837952000266.tif121166

[0242] Step 1: 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 at 95°C for 2 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 = 10 / 1) to obtain 20-1.

[0243] Step 2: A mixture of 20-1 (1.48 g, 7.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (2.86 g, 11.25 mmol), potassium acetate (1.47 g, 15 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (549 mg, 0.75 mmol) in 1,4-dioxane (50 mL) was stirred at 100 °C for 7 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 = 5 / 1) to obtain 20-2.

[0244] Step 3: The mixture of 20-2 (2 g, 8.16 mmol) and methanol (4 mL) in concentrated hydrochloric acid (12 mL) was stirred at 65°C for 2 hours. The mixture was diluted with water, based to pH ~5 with solid NaOH, and extracted with ethyl acetate. The aqueous layer was concentrated and the residue was washed with dichloromethane containing 10% methanol. The combined organic layer was concentrated and the residue was purified by reverse-face HPLC (acetonitrile and 0.05% TFA aqueous solution: 0% to 5%) to obtain 20-3.

[0245] Step 4: A mixture of 20-3 (980 mg, 3.54 mmol) and a 4.5 M aqueous solution of KHF2 (4.4 mL, 19.8 mmol) in methanol (10 mL) was stirred at room temperature for 0.5 hours. The mixture was concentrated, the residue was washed with hot acetone (80 mL), and filtered. The filtrate was concentrated, and the residue was polished with ethyl ether. The suspension was then filtered, and the filtrate cake was dried to obtain 20-4.

[0246] Step 5: Pd(dppf)Cl2 (2.7g, 3.69mmol) was added to a mixture of 2,6-dichloro-5-fluoronicotinic acid (10g, 47.6mmol), (2-fluorophenyl)boronic acid (12.3g, 71.5mmol), and saturated NaHCO3 aqueous solution (150mL) in 300mL of dimethyl ether (DME). The mixture was stirred at 70°C for 16 hours under a nitrogen atmosphere. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The aqueous layer was oxidized with concentrated hydrochloric acid to pH ~1 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The residue was polished with dichloromethane, filtered, and the filtered cake was dried to obtain 20-5.

[0247] Step 6: To a solution of ethyl 3-oxobutanoate (4.97 g, 38.2 mmol) in dimethyl ether (250 mL), t-BuOK (11.4 g, 102.0 mmol) was added. The mixture was stirred at room temperature for 1 hour. Cu(OAc)2 (1.86 g, 10.2 mmol) and 20-5 (7.7 g, 25.5 mmol) were added, and the resulting mixture was stirred at 100°C under a nitrogen atmosphere for 24 hours. The mixture was diluted with water, oxidized to pH ~2 with 1 M HCl, 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 (dichloromethane / methanol = 10 / 1) to obtain 20-6.

[0248] Step 7: Ethyl chloroformate (2.63 mL, 27.74 mmol) was added dropwise to a solution of 20-6 (4.45 g, 13.86 mmol) and triethylamine (7.7 mL, 55.35 mmol) in tetrahydrofuran (40 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at this temperature for 1 hour, then aqueous ammonia (28%, 12 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. 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 silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 20-7.

[0249] Step 8: A solution of 20-7 (466 mg, 1.70 mmol) in PhPOCl2 (5 mL) was stirred at 110°C under a nitrogen atmosphere for 3 hours. The mixture was cooled and diluted with ethyl acetate. The mixture 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 = 10 / 1) to obtain 20-8.

[0250] Step 9: A mixture of 20-8 (100 mg, 0.32 mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl (204 mg, 0.96 mmol), and DIPEA (0.33 mL, 1.90 mmol) in DMSO (3 mL) was stirred at 90°C for 18 hours. The mixture was cooled and diluted with ethyl acetate. The mixture 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 = 2 / 1) to obtain 20-9.

[0251] Step 10: A mixture of 20-9 (134 mg, 0.27 mmol), 2-(dimethylamino)ethane-1-ol (75 mg, 0.85 mmol), NaOt-Bu (95 mg, 0.99 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), and BINAP (17.6 mg, 0.028 mmol) in toluene (4 mL) was stirred at 110°C for 6 hours under a nitrogen atmosphere. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 20-10.

[0252] Step 11: A suspension of 20-10 (63 mg, 0.12 mmol) in acetonitrile (3.5 mL) was added dropwise to a solution of NBS (22 mg, 0.12 mmol) in acetonitrile (0.5 mL) at -35°C. After stirring for 2 minutes, the mixture was quenched with water and extracted with ethyl acetate. 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 (dichloromethane / methanol = 20 / 1) to obtain 20-11.

[0253] Step 12: A mixture of 20-11 (52 mg, 0.084 mmol), 20-4 (90 mg, 0.27 mmol), Pd(dtbpf)Cl2 (11 mg, 0.017 mmol), and K3PO4 (62 mg, 0.29 mmol) in DMF (0.5 mL) and a drop of water was stirred at 90°C for 1 hour under a nitrogen atmosphere. The mixture was concentrated, and the residue was purified by reverse-face HPLC (acetonitrile and 0.05% TFA aqueous solution: 5% to 70%) to obtain 20-12.

[0254] Step 13: 0.5 mL of TFA was added to a 3 mL solution of 20-12 (5 mg, 0.0076 mmol) of dichloromethane. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC (acetonitrile and 0.05% TFA aqueous solution: 5% to 70%) to obtain 3 equivalents of TFA salt 20. LCMS (ESI, m / z): [M+H] + =557.4; 1 1H NMR (400 MHz, methanol-d4, ppm): δ 8.51(d,J=4.4Hz,1H),8.38(d,J=10.0Hz,1H),8.29(d,J=6.8Hz,1H),7.75-7. 72(m,1H),7.51-7.48(m,2H),7.28-7.20(m,2H),4.81-4.74(m,2H),3.78-3.73 (m,2H),3.60-3.50(m,2H),3.43(d,J=12Hz,2H),3.30-3.28(m,2H),2.83(s,6H ),2.38-2.29(m,2H),2.14-2.09(m,2H),2.04-1.99(m,1H),1.12-0.98(m,4H). Example 2 Synthesis of Compound 43 TIFF0007837952000267.tif195166

[0255] 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 43-1.

[0256] Step 2: LiHMDS (655 mL, 655 mmol in 1.0 M tetrahydrofuran) was added to a solution of 43-1 (49 g, 311.8 mmol) and 3-chloro-2-chloromethylpropa-1-ene (100 g, 800 mmol) in tetrahydrofuran (200 mL) at -40 °C under a nitrogen atmosphere. 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 (from petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 43-2.

[0257] Step 3: To a tetrahydrofuran (1 L) solution of sodium hydride (2.72 g, 68.1 mmol), a tetrahydrofuran (100 mL) solution of 43-2 (13.6 g, 55.35 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The mixture was then heated under reflux and stirred for 9 hours. The mixture was cooled to 0°C, quenched 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 (from petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 43-3.

[0258] 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 43-3 (9.0 g, 43.15 mmol) in acetonitrile (245 mL) and dichloromethane (245 mL). 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, then 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 (from petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 43-4.

[0259] Step 5: Sodium borohydride (475 mg, 12.55 mmol) was added in multiple portions to a methanol (100 mL) solution of 43-4 (10.6 g, 50.2 mmol) at 0°C under a nitrogen atmosphere, 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 43-5.

[0260] Step 6: Diethylaminosulfur trifluoride (4.1 g, 2.35 mmol) was added to a solution of 43-5 (4.8 g, 22.6 mmol) in dichloromethane (50 mL) at -78 °C. The mixture was stirred at room temperature for 5 hours, 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 (from petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 43-6.

[0261] Step 7: To a solution of lithium aluminum hydride (1.25 g, 33 mmol) in tetrahydrofuran (33 mL), a solution of 43-6 (2.36 g, 11 mmol) in tetrahydrofuran (10 mL) was added under a nitrogen atmosphere at 0°C. The mixture was stirred under reflux for 2 hours and then cooled to 0°C. Water (1.3 mL), 15% NaOH aqueous 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 43-7.

[0262] Step 8: 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 then filtered, and the filtrate was inverted into water. The mixture was filtered again, and the filtrate cake was dried to obtain 43-8.

[0263] Step 9: 43-8 (31.3 g, 89 mmol) in a 200 mL solution of dioxane was mixed with 100 mL of 4N HCl. The mixture was stirred at room temperature for 1 hour. The suspension was then filtered, and the filtered cake was dried to obtain 43-9.

[0264] Step 10: A suspension of 43-9 (78.8 g, 350 mmol) in concentrated hydrochloric acid (350 mL) and water (175 mL) was added to a solution of sodium nitrite (25.4 g, 367.5 mmol) in water (51 mL) within 30 minutes at 0°C. The reaction mixture was added to a solution of CuCl (41.6 g, 420 mmol) in concentrated hydrochloric acid (131 mL) and water (175 mL) within 1 hour at room temperature. 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 43-10.

[0265] Step 11: The mixture of 43-10 (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 n-heptane to obtain 43-11.

[0266] Step 12: At room temperature, a solution of bromine (97.9 g, 613.1 mmol) in acetic acid (470 mL) was added to a solution of 43-11 (49.5 g, 278.7 mmol) in acetic acid (200 mL). The mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtered cake was washed with acetic acid (120 mL) and then suspended in 20% sodium hydroxide (600 mL). The mixture was stirred at room temperature for 20 minutes and filtered. The solid was dissolved in dichloromethane, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain 43-12.

[0267] Step 13: Sodium nitrite (13.0 g, 188.1 mmol) was added in multiple portions at 5°C to a solution of 43-12 (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, 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 43-13.

[0268] Step 14: Sodium borohydride (8.17 g, 216.15 mmol) was added in multiple portions at 5°C to a suspension of 43-13 (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 (from petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 43-14.

[0269] Step 15: A mixture of 43-14 (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 a nitrogen 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 (from petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 43-15.

[0270] Step 16: Pivaloyl chloride (24 g, 200 mmol) was added dropwise to a solution of 2,6-dichloropyridine-4-amine (27 g, 166 mmol) and triethylamine (50 g, 500 mmol) in dichloromethane (260 mL) under a nitrogen atmosphere at 0°C. After stirring at room temperature for 5 hours, the mixture was washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was polished with methyl tert-butyl ether to obtain 43-16.

[0271] Step 17: To a solution of 43-16 (13 g, 53 mmol) in tetrahydrofuran (150 mL), n-butyllithium (2.5 M, 53 mL, 132.5 mmol) was added dropwise at -78°C under a nitrogen atmosphere. The mixture was stirred at -78°C for 3 hours. At -78°C under a nitrogen atmosphere, N,N-dimethylformamide (11.6 g, 159 mmol) was added to the above mixture. The mixture was stirred at -78°C for 0.5 hours. The reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic layer 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 / dichloromethane = 3 / 1) to obtain 43-17.

[0272] Step 18: To a solution of diisopropylamine (8.67 g, 85.8 mmol) in tetrahydrofuran (150 mL), n-butyllithium (34.3 mL, 85.8 mmol) was added dropwise at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 0.5 hours. To the above mixture, a solution of tert-butyl acetate (9.95 g, 85.8 mmol) in tetrahydrofuran (50 mL) was added dropwise at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 0.5 hours, and then a solution of 43-17 (9 g, 33 mmol) in tetrahydrofuran (100 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 0.5 hours, then quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic layers were 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 / dichloromethane = 3 / 1) to obtain 43-18.

[0273] Step 19: The mixture of 43-18 (12.5 g, 32 mmol) in dioxane (75 mL) and concentrated hydrochloric acid (75 mL) was stirred at 100°C for 2 hours. The mixture was cooled, inverted into water, filtered, the filtered cake was washed with water, and polished with acetonitrile to obtain 43-19.

[0274] Step 20: N-chlorosucciimide (15.3 g, 115 mmol) was added to a solution of 43-19 (4.9 g, 23 mmol) in N,N-dimethylformamide (60 mL). The mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. Further addition of N-chlorosucciimide (15.3 g, 115 mmol) was made, and the mixture was stirred at 100°C for 5 hours. The mixture was cooled, 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 ethyl acetate to obtain 43-20.

[0275] Step 21: A mixture of 43-20 (1.24 g, 5 mmol), N,N-diisopropylethylamine (1.94 g, 15 mmol), and 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (1.59 g, 7.5 mmol) in dimethyl sulfoxide (30 mL) was stirred at 90°C for 3 hours under a nitrogen atmosphere. The mixture was cooled, 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 ethyl acetate to obtain 43-21.

[0276] Step 22: A mixture of 43-21 (636 mg, 1.5 mmol), 43-7 (477 mg, 3 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (94 mg, 0.15 mmol), sodium tert-butoxide (576 mg, 6 mmol), and tri(dibenzalacetone)dipalladium (69 mg, 0.075 mmol) in dioxane (20 mL) was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The mixture was cooled, 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 reverse-face HPLC (acetonitrile and 0.05% TFA aqueous solution: 15% to 95%) to obtain 43-22.

[0277] Step 23: Cesium carbonate (325 mg, 1 mmol) and N,N-bis(trifluoromethanesulfonyl)aniline (357 mg, 1 mmol) were added to a 10 mL solution of 43-22 (273 mg, 0.5 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, then 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 reverse-face HPLC (with acetonitrile and 0.05% TFA aqueous solution: 15% to 95%) to obtain 43-23.

[0278] Step 24: A mixture of 43-23 (102 mg, 0.15 mmol), 43-15 (91 mg, 0.3 mmol), sodium carbonate (64 mg, 0.6 mmol), and tetra(triphenylphosphin)palladium (17 mg, 0.015 mmol) in 1,4-dioxane / water (3 mL / 0.6 mL) was stirred under a nitrogen atmosphere at 100 °C under microwave conditions for 0.3 hours. The mixture was concentrated, and the residue was purified by reverse-face HPLC (acetonitrile and 0.05% TFA aqueous solution: 25% to 95%) to obtain 43-24.

[0279] Step 25: A solution of 43-24 (20 mg, 0.028 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (1.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC (acetonitrile and 0.05% TFA aqueous solution: 15% to 95%) to obtain 3 equivalents of TFA salt 43. LCMS (ESI, m / z): [M+H] + =608.3; 1 ¹H NMR (400 MHz, methanol-d4, ppm): δ 8.42 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.38-7.29 (m, 3H), 7.02 (d, J=2.0 Hz, 1H), 6.87 (s, 1H), 5.63-5.50 (m, 1H), 4.66-4.53 (m, 2H), 4.22-3.42 (m, 10H), 2.75-2.00 (m, 10H). Example 3 Synthesis of Compound 10 TIFF0007837952000268.tif80166

[0280] Step 1: 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 at 95°C for 2 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 10⁻¹.

[0281] Step 2: To a solution of 2,6-dichloronicotinic acid (4.5 g, 20 mmol) in dichloromethane (50 mL) at room temperature, one drop each of N,N-dimethylformamide and oxalichloride (5.0 g, 40 mmol) were added dropwise. The resulting mixture was stirred at 70°C for 30 minutes, then cooled and concentrated to obtain 10⁻², which was used in the next step without purification.

[0282] Step 3: 2-methyl-2-isothiouronium sulfate (7 g, 37 mmol) was added in multiple portions at room temperature to a 30 mL aqueous solution of sodium hydroxide (3.6 g, 90 mmol), followed by the addition of a 50 mL solution of tetrahydrofuran (4.9 g, 20 mmol) of 10-2. The resulting mixture was stirred at room temperature for 30 minutes, then 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 hexane to obtain 10-3.

[0283] Step 4: A solution of 10-3 (4 g, 13.4 mmol) in DMAc (50 mL) was stirred at 0°C under a nitrogen atmosphere for 24 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 polished with petroleum ether / ethyl acetate (5 / 1) and filtered. The filtered cake was dried to obtain 10-4.

[0284] Step 5: To a solution of 10-4 (400 mg, 1.53 mmol) in acetonitrile (20 mL) at room temperature, DIEA (296 mg, 2.3 mmol) and phosphoryl chloride (285 mg, 1.84 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour, then cooled to -10°C, and DIEA (296 mg, 2.3 mmol) and 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (342 mg, 1.53 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, then 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 (dichloromethane to dichloromethane / methanol = 10 / 1) to obtain 10-5.

[0285] Step 6: Oxone (3.3 g, 5.4 mmol) was added to a 20 mL solution of 10-5 (500 mg, 1.13 mmol) of dichloromethane. The mixture was stirred at room temperature for 3 days. The suspension was then filtered, and the filtrate was concentrated. The residue was purified by pre-TLC (petroleum ether / ethyl acetate = 1 / 1) to obtain 10-6.

[0286] Step 7: A solution of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (173 mg, 1.23 mmol) in THF (5 mL) was added with NaH (60%, 49 mg, 1.23 mmol) under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, after which 10-6 (200 mg, 0.40 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then quenched with saturated ammonium chloride (20 mL) 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 (dichloromethane / methanol = 10 / 1) to obtain 10-7.

[0287] Step 8: A mixture of 10-7 (10 mg, 0.018 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthylene-2-ol (10 mg, 0.036 mmol), Na2CO3 (8 mg, 0.072 mmol), and Pd(PPh3)4 (2 mg, 0.0018 mmol) in 1,4-dioxane / water (2 mL / 0.2 mL) was stirred at 105 °C under microwave conditions for 1 hour. The mixture was cooled and trifluoroacetic acid (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC (acetonitrile and 0.05% TFA aqueous solution: 5% to 45%) to obtain 3 equivalents of the TFA salt 10. LCMS (ESI, m / z): [M+H] + =557.3; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.62(s,1H),7.43-7.39(m,2H),7.33(d,J=8.0Hz,1H),7.28(d,J=2.4Hz,1H),7.22-7.13(m,2H),4.79-4.78(m,2 H),4.63(s,2H),4.23(s,2H),3.92(d,J=14.0Hz,2H),3.66-3.63(m,2H),3.25-3.24(m,2H),2.32-2.06(m,12H). Example 4 Synthesis of Compound 2 TIFF0007837952000269.tif29118

[0288] Compound 2-1 was prepared according to the coupling method used to synthesize compound 10 in Example 3.

[0289] Compound 2, a 3-equivalent TEA salt, was prepared according to the synthesis method of compound 10 in Example 3. LCMS(ESI,m / z):[M+H] + =541.3; 1H NMR (400 MHz, methanol-d4, ppm): δ 8.63(s,1H),8.04(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,1H),7.65-7.61(m,1H),7.56-7.52(m,2H),7.52-7.44(m,2H),4.7 9-4.78(m,2H),4.63(s,2H),4.24(s,2H),3.98-3.88(m,2H),3.67-3.61(m,2H),3.25-3.24(m,2H),2.32-2.06(m,12H). Example 5 Synthesis of Compound 60 TIFF0007837952000270.tif114166

[0290] Step 1: A mixture of 10-1 (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. It was dried over an organic layer of Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 9 / 1) to obtain 60-1.

[0291] Step 2: To a solution of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (5.32 g, 20 mmol) in tetrahydrofuran (50 mL), aqueous ammonia (28%, 14 mL) was added at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 60-2, which was used directly in the next step without purification.

[0292] Step 3: A mixture of 60-2 (3.95 g, 16 mmol), N,N-diisopropylethylamine (3.1 g, 24 mmol), and 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (4.07 g, 19.2 mmol) in dimethyl sulfoxide (20 mL) was stirred at 50°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 60-3, which was used directly in the next step without purification.

[0293] Step 4: To a solution of 60-3 (846 mg, 2 mmol) in tetrahydrofuran (20 mL), lithium aluminum hydride (228 mg, 6 mmol) was added in multiple portions at 0°C under a nitrogen atmosphere. The mixture was stirred at this temperature for 2 hours. The reaction was quenched with sodium sulfate decahydrate. The suspension was then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 2) to obtain 60-4.

[0294] Step 5: A mixture of 60-4 (534 mg, 1.4 mmol) and manganese dioxide (2.4 g, 28 mmol) in trichloromethane (20 mL) was stirred at 50°C for 2 hours under a nitrogen atmosphere. The suspension was then filtered and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 60-5.

[0295] Step 6: Piperidine (187 mg, 2.2 mmol) and methyl cyanoacetate (163 mg, 1.65 mmol) were added to a solution of 60-5 (417 mg, 1.1 mmol) in ethanol (10 mL) at room temperature. The mixture was stirred under reflux for 16 hours. The mixture was concentrated, and the residue was purified by reverse-face HPLC (acetonitrile and 0.05% TFA aqueous solution: 25% to 95%) to obtain 60-6.

[0296] Step 7: Trifluoromethane anhydride (338 mg, 1.2 mmol) was added to a solution of 60-6 (342 mg, 0.8 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (10 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 60-7.

[0297] Step 8: A mixture of 60-7 (280 mg, 0.5 mmol), 60-1 (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 (5 / 1, 6 mL) was stirred at 95°C under microwave conditions for 30 minutes. The mixture was cooled, diluted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (from petroleum ether to petroleum ether / ethyl acetate = 1 / 2) to obtain 60-8.

[0298] Step 9: 3-chloroperbenzoic acid (51 mg, 0.25 mmol) was added to a 10 mL solution of 60-8 (150 mg, 0.25 mmol) of dichloromethane at room temperature. The mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 60-9, which was used directly in the next step without purification.

[0299] Step 10: Dissolve 60-9 obtained in the previous step in anhydrous tetrahydrofuran (10 mL) and treat with 43-7 (119 mg, 0.75 mmol). Add bis(trimethylsilyl)lithium amide (0.5 mL, 0.5 mmol, 1 M tetrahydrofuran solution) dropwise to the mixture under a nitrogen atmosphere at 0°C, and stir the reaction at 0°C for 30 minutes. Dilute the mixture with ethyl acetate and wash with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-face HPLC (with acetonitrile and 0.05% TFA aqueous solution: 20% to 95%) to obtain 60-10.

[0300] Step 11: Water (0.4 mL) and concentrated hydrochloric acid (0.4 mL) were added to a solution of 1,4-dioxane (0.8 mL) of 60-10 (46 mg, 0.065 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative HPLC (acetonitrile and 0.05% TFA aqueous solution: 5% to 95%) to obtain 3 equivalents of TFA salt 60. LCMS (ESI, m / z): [M+H] + =566.3; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.98(s,1H),7.79-7.76(m,1H),7.59-7.56(m,1H),7.47-7.43(m,1H),7.34-7.33(m,1H),7.29-7.23(m,2H),5.63-5.4 9(m,1H),4.89-4.83(m,2H),4.73-4.65(m,2H),4.24(s,2H),4.02-3.85(m,5H),3.49-3.42(m,1H),2.74-2.03(m,10H). 19 1F NMR (376 MHz, methanol-d4, ppm): δ -174.24 (1F). Example 6 Synthesis of Compound 6 TIFF0007837952000271.tif131150

[0301] Step 1: A mixture of 1-bromo-8-chloronaphth...

Claims

1. A compound of formula I-9 or formula I-11, or a pharmaceutically acceptable salt thereof, Here, R １ ga-(L １ ) ｍ１ -OR ２０ , halogen, -(L １ ) ｍ１ -NR ３０ R ３１ , or a heterocyclic or heteroaryl ring which may be substituted; R ２ is -(L ２ ) ｍ２ - R １０２ and m2 is either 0 or 1, and if m2 is 1, L ２ However, CH ２ , O, NH, or NCH ３ And, R １０２ However, it is a substituted 4-10 membered heterocycle or heteroaryl ring having one or two ring-forming nitrogen atoms; R ３ However, it is an optionally substituted aryl group or an optionally substituted heteroaryl group. R １１ However, hydrogen, F, Cl, Br, I, CN, -OH, -C(O)NH ２ , -C(O)NH(C １－６ Alkyl alkyl group), -C(O)N(C １－６ (Alkyl alkyl group) (C １－６ C (alkyl group), which may be substituted. １－４ Alkyl group, cyclopropyl group, cyclobutyl group, may be substituted C １－４ It is an alkoxy group, a cyclopropoxy group, or a cyclobutoxy group; R １２Ａ is F, Cl, Br, I, CN, -OH, -C(O)NH ２ , -C(O)NH(C １－６ Alkyl alkyl group), -C(O)N(C １－６ (Alkyl alkyl group) (C １－６ C (alkyl group), which may be substituted. １－４ Alkyl group, cyclopropyl group, cyclobutyl group, may be substituted C １－４ It is an alkoxy group, a cyclopropoxy group, or a cyclobutoxy group; and, Here, m1 is 0 or 1, and if m1 is 1, L １ However, these are optionally substituted alkylene groups, optionally substituted carbocyrene groups, and optionally substituted heterocyclene groups; R ２０ However, hydrogen, oxygen protecting groups, and substituted C may be present. １－６ It is an alkyl group, a substituted or possibly substituted carbon ring, a substituted or possibly substituted aryl group, a substituted or possibly substituted heteroaryl group, or a substituted or possibly substituted heterocycle; R ３０ and R ３１ However, independently, hydrogen, nitrogen protecting groups, and substituted C may be present. １－６ It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R ３０ and R ３１ They may be linked and substituted to form a heterocyclic or heteroaryl ring, or R ３０ and R ３１ One of them is L １ They form a heterocycle or heteroaryl ring which may be substituted together with the appropriate atoms and any of the atoms in between. A compound, or a pharmacologically acceptable salt thereof.

2. R １１ However, hydrogen, F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH ２ -Cyclopropyl group, -C(O)NHMe, CF ３ , methyl group, ethyl group, isopropyl group, or cyclopropyl group The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １２Ａ However, F, Cl, -CN, -OH, methoxy group, ethoxy group, -O-CH ２ -Cyclopropyl group, -C(O)NHMe, CF ３ , a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group, or R １２Ａ However, Cl, -OH, methoxy group, difluoromethoxy group, ethoxy group, isopropoxy group, -O-CH ２ -Cyclopropyl group, -O-CH ２ -CH ２ -Cyclopropyl group, -C(O)NHMe, -O-CH ２ -C(O)NHMe, -O-CH ２ -CF ３ , -O-CH ２ -CH ２ methyl group, CHF ２ CF ３ , an ethyl group, an isopropyl group or a cyclopropyl group, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R １ ga- OR ２０ And R ２０ ga-C １－６ Alkilen-R １０１ And R １０１ NR ３２ R ３３ Alternatively, it is a 4-10 membered heterocycle which may be substituted, C １－６ The alkylene group may be substituted with one or more substituents, and the substituents may independently be F, OH, NR ３４ R ３５ and C which may be substituted with 1-3 fluorines １－４ Selected from the group consisting of alkyl groups, or two substituents of the alkylene group linked together to form a ring; R ３２ and R ３３ However, independently, hydrogen, nitrogen protecting groups, and substituted C may be present. １－６ It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R ３２ and R ３３ They may be linked and substituted to form a heterocyclic or heteroaryl ring; and, R ３４ and R ３５ However, independently, hydrogen, nitrogen protecting groups, and substituted C may be present. １－６ It is an alkyl group, an optionally substituted carbon ring, or an optionally substituted heterocycle; or R ３４ and R ３５ These may be linked and substituted to form a heterocycle or heteroaryl ring. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. R １ but, and Alternatively, R １ but, And, Alternatively, R １ However, the methoxy group, NH ２ NH(CH ３ ), or N (CH ３ ) ２ And, Alternatively, R １ but, or And, Alternatively, R １ is And R １０１ However, NH ２ NH(C １－３０ Alkyl alkyl group), N(CH ３ ) (C １－３０ (Alkyl alkyl group), or That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. R １ However, it has an F-1 structure Here, R １３ and R １４ each independently appears as hydrogen or a C １－４ alkyl group, q is an integer between 0 and 6, R １５ , R １６ , R ３６ and R ３７ However, together with the carbon and nitrogen atoms in between, they form a substituted 6-10 membered condensed bicyclic structure. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R １ but, Selected from the group consisting of, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ２ ga-(L ２ ) ｍ２ -R １０２ And, R １０２ However, the monocyclic 4-8 membered heterocycle having one or two independently selected ring-forming heteroatoms from the group consisting of N, O, and S, or the condensed, bridged, 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 form may be substituted. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. R ２ but, And, Here, G １ However, CR １７ or N; G ２ and G ３ However, each time it appears, it becomes independent, CR １８ R １９ , O or NR ３８ And, however, G ２ and G ３ At least one example of NR ３８ And; n1 and n2 are independent integers of 1, 2, 3, or 4; A １ and A ２ However, each independently, combined, CR １８ R １９ , O or NR ３８ And, however, A １ and A ２ At least one of them is O or NR ３８ Instead, Here, R １７ , R １８ or R １９ However, each time it appears, it is independently replaced by hydrogen, F, -OH, or a substituted C. １－６ It is an alkyl group, or R １８ and R １９ However, together with the carbon atoms linked to them, they link to form an oxo group, an imino group, or a ring; and, R ３８ However, each time it appears, it may independently be replaced by hydrogen, a nitrogen protecting group, or a substituted C. １－６ It is an alkyl group. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. R ２ but, or Selected from the group consisting of R ２ but That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. 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 1 to 3 substituents, and the substituents are independently F, Cl, Br, I, -OH, C １－４ Alkyl alkyl, CF ３ , -NH ２ -CN, protected -OH and protected -NH ２ (2) A naphthyl group which may be substituted with one or more (generally 1-3) substituents, wherein the substituents may be independently F, Cl, Br, I, -OH, or 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 -CN, protected -OH and protected -NH ２ Selected from the group consisting of, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ３ but, Selected from the group consisting of, Alternatively, R ３ but, Selected from a group consisting of Alternatively, R ３ but, or and Alternatively, R ３ but, or and Alternatively, R ３ but, or That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. A compound selected from the group consisting of the following compound numbers 81, 85, 87, 89, 90, 93, 95, 99, 102, 103, 105, 106, 113-128, 130-139, 141-154, and 157-247, or a pharmacokinetically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in (1) a method for suppressing KRAS mutant proteins in cancer cells; (2) a method for treating cancer in a test subject; (3) a method for suppressing cell population proliferation; (4) a method for treating a disease or condition mediated by Ras (KRAS, HRAS, and / or NRAS) mutant proteins in a test subject in need; or (5) a method for suppressing cancer metastasis or tumor metastasis.

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