Pyridazinone or pyridinone compounds, their preparation and use

Abstract

The present application provides novel compounds, such as compounds having the general formula (I) or a pharmacologic acceptable salt thereof, as well as pharmaceutical compositions containing them. The present application further provides methods for preparing the compounds, as well as methods for using the compounds, for example, to treat cancer. TIFF2024532845000410.tif4786

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Application No. PCT / CN2021 / 112906, filed August 17, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates generally to pyridazinone or pyridinone compounds, compositions, syntheses, and methods of use for treating various diseases or conditions herein, such as, for example, cancer. [Background technology]

[0003] Poly(ADP-ribose) polymerase (PARP) is a member of a family of 17 enzymes that regulate fundamental cellular processes. PARP1 inhibitors have been shown to be effective in treating cancers associated with cellular stress caused by DNA damage. Currently, at least four PARP1 inhibitors have been approved, with several others in late-stage development. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in cellular processes such as the response to hypoxia, innate immunity, and regulation of nuclear receptors (Rasmussen, M. et al., Cells 10(3):623). PARP7 inhibition has recently been recognized as a strategy for improving cancer treatment and immunotherapy. Therefore, new PARP inhibitors are needed, for example, to treat various related diseases or conditions. Summary of the Invention

[0004] In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, and methods for their manufacture and use. Generally, the compounds of the present disclosure are PARP inhibitors, particularly PARP7 inhibitors. The compounds and compositions of the present disclosure are used to treat various diseases or conditions of the present disclosure, such as cancer.

[0005] In some embodiments, the present disclosure provides a compound of general formula I, or a pharmaceutically acceptable salt thereof: TIFF2024532845000002.tif46114 Among them, variable R 1 , R 2 , L 1 , L 2 , L 3 , X, Z, ring A, and ring B are as defined herein. In some embodiments, compounds of general formula I are represented by subgeneric formulas of general formula I, such as general formulas I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, I C-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c. In some embodiments, the present disclosure provides a compound selected from the group consisting of any compound disclosed in Table A herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure further provides a compound selected from the group consisting of Compound Nos. 1-353, or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments of the present disclosure include one or more compounds of the present disclosure (e.g., compounds of general formula I (e.g., compounds of general formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, I The present disclosure relates to a pharmaceutical composition comprising any of Compounds 1-353, ...

[0007] Some embodiments relate to methods for treating PARP, particularly PARP7, related diseases or conditions. In some embodiments, the methods include administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of general formula I (e.g., general formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1 The method includes administering to a subject a therapeutically effective amount of any of the compounds disclosed in Table A herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure, to a subject in need of a therapeutically effective amount of a compound disclosed in Table A herein, or a pharmaceutical composition according to the present disclosure.

[0008] In some embodiments, the method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of general formula I (e.g., general formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1 or ID-1-c), Compound Nos. 1-353, any compound disclosed in Table A herein or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition according to the present disclosure. In some embodiments, the cancer may be breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (upper aerodigestive tract cancer), urinary tract cancer, or colon cancer. In some embodiments, the cancer is associated with aberrant PARP7 expression and / or activity.

[0009] Administration in the methods of the present application is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrathoracic, intrathecal, and parenteral.

[0010] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy. In some embodiments, the combination therapy includes administering to the subject an immunotherapy such as an anti-PD-1, anti-PDL-1 antibody, anti-CTLA-4, and / or anti-4-1BB antibody.

[0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] As detailed herein, the present disclosure is based, in part, on the discovery that certain novel compounds can be PARP7 inhibitors useful in the treatment of various diseases or conditions, such as cancer. In various embodiments, the present disclosure provides novel compounds, compositions, methods of manufacture, and uses related to this discovery.

[0013] compound Some embodiments of the present disclosure relate to novel compounds that are generally PARP inhibitors, and in particular PARP7 inhibitors, and are useful for treating various diseases or conditions, such as those disclosed herein, e.g., cancer.

[0014] In some embodiments, the present disclosure provides a compound of general formula I, or a pharmaceutically acceptable salt thereof: TIFF2024532845000003.tif46118 where, Z is N or C, preferably N; R 1 But hydrogen, halogen, CN, OR 10 , S.R. 11 , S(O)R 12 , S(O)2R 13, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbocyclyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclyl group; R 2 But hydrogen, halogen, CN, OR 10 , S.R. 11 , S(O)R 12 , S(O)2R 13 , N.R. 14 R 15 , an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbocyclyl group, an optionally substituted phenyl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclyl group; L 1 and L 2 are independently a single bond, O, S, S(O), S(O)2, NR 16 , C(O), C(O)O, C(O)NR 16 , OC(O)NR 16 , S(O)NR 16 , N.R. 17 C(O)NR 16 , N.R. 17 S(O)NR 16 , an optionally substituted alkylene group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted heteroalkylene group, an optionally substituted carbocyclylene group, an optionally substituted heterocyclylene group, an optionally substituted phenylene group or an optionally substituted heteroarylene group, and preferably, L 1 and L 2 is not a single bond at the same time, X is a single bond, C(O), G 1 -C(O)-G 2 , S(O), S(O)2 or G 1 -S(O)2-G 2 Among them, G 1 and G 2 are each independently a single bond, O, NH, or optionally substituted C 1-4 an alkylene group or an optionally substituted C 1-4a heteroalkylene group, or G 1 and G 2 are linked together with the atoms therebetween to form an optionally substituted 4- to 7-membered ring structure, Ring A is an optionally substituted carbocycle or heterocycle, L 3 single bond, O, S, S(O), S(O)2, NR 16 , may be replaced by C 1-4 an alkylene group or an optionally substituted C 1-4 is a heteroalkylene group, Ring B is an optionally substituted aryl or heteroaryl ring; Alternatively, R 1 and R 2 are linked together with the atoms therebetween to form an optionally substituted ring structure; Alternatively, R 2 and L 1 are linked together with the atoms therebetween to form an optionally substituted ring structure; Or, L 1 and L 2 are linked together with the atoms therebetween to form an optionally substituted ring structure; Alternatively, R 1 , R 2 and L 1 are linked together with the atoms therebetween to form an optionally substituted ring structure; Or, L 3 is a single bond, ring A and ring B together represent an optionally substituted cyclic structure having one ring or at least two rings, for example, a bicyclic structure; where: Each R 10 , R 11 , R 12 and R 13 each occurrence is independently selected from the group consisting of hydrogen, an optionally substituted alkyl group, an optionally substituted carbocyclyl group, or an optionally substituted heterocyclyl group; and Each R 14 , R 15 , R 16 and R 17Each occurrence of is independently selected from the group consisting of hydrogen, a nitrogen protecting group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group.

[0015] In some embodiments, compounds of general formula I (including any possible subgeneric formulas according to the present disclosure) can have stereoisomers. In these embodiments, compounds of general formula I can exist in the form of a single enantiomer, diastereomer, and / or geometric isomer (if applicable) or a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). For example, in some embodiments, compounds of general formula I (including any applicable subgeneric formulas according to the present disclosure), if applicable, can exist as an isolated single enantiomer essentially free of other enantiomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or an undetectable amount of other enantiomers by weight, by HPLC area, or both). In some embodiments, where applicable, compounds of general formula I (including any applicable subgeneric formulas according to the present disclosure) can have an enantiomeric excess ("ee") of greater than 60%, e.g., greater than 80% ee, greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, greater than 99% ee, or can exist as a single enantiomer with no detectable other enantiomer.

[0016] Generally, in general formula I, Z is N. Therefore, compounds of general formula I can generally be identified as having general formula I-1. TIFF2024532845000004.tif46102 Among them, variable R 1 , R 2 , L 1 , L 2 , L 3 , X, ring A and ring B include any combination of the definitions as per any of the present disclosure.

[0017] In some embodiments, in general formula I, Z can be C.

[0018] In some embodiments, R in general formula I 1 (For example, any applicable subgeneric formula according to this disclosure, e.g., I-1, IB, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b or ID-1-c) is hydrogen. 1 is hydrogen, then R 2 But it's not hydrogen.

[0019] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 1 is a halogen, for example, F, Cl or Br.

[0020] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 1 But it is CN.

[0021] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 1 may be replaced by C 1-6 In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an alkyl group. 1 may be replaced by C 2-6In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is an alkenyl group. 1 may be replaced by C 2-6 In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an alkynyl group. 1 may be replaced by C 3-8 For example, in some preferred embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is a carbocyclyl group. 1 may be replaced by C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 In some embodiments, R 1 But C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 cycloalkyl groups, each of which may be independently substituted with F, OH, oxo, 1-3 F, 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 For example, in some embodiments, R 1 C, which may be substituted with 1-3 F 1-4 alkyl groups, such as methyl, ethyl, isopropyl, CHF, CF, etc. In some embodiments, R 1 But C 2-4 In some embodiments, R is an alkynyl group, such as a C alkynyl group. 1 But C 3-6 A cycloalkyl group is, for example, cyclopropyl.

[0022] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 1 But, OR 10 Among them, R 10is as defined herein. For example, in some embodiments, R in general formula I 1 But, OR 10 Among them, R 10 But hydrogen, C 1-4 Alkyl group or C 3-6 Cycloalkyl groups, among which C 1-4 Alkyl group or C 3-6 cycloalkyl groups independently optionally substituted with F, OH, oxo, 1-3 F; 1-4 C optionally substituted with alkyl group and 1-3 F 1-4 For example, in some embodiments, R 1 may be OCH3. In some embodiments, R 1 C, which may be substituted with 1-3 F 1-4 It may also be an alkoxy group, for example, OCH2CF2H.

[0023] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 1 But, SR 11 Among them, R 11 is as defined herein. For example, in some embodiments, R in general formula I 1 But, SR 11 Among them, R 11 But hydrogen, C 1-4 Alkyl group or C 3-6 Cycloalkyl groups, among which C 1-4 Alkyl group or C 3-6 cycloalkyl groups independently optionally substituted with F, OH, oxo, 1-3 F; 1-4 C optionally substituted with alkyl group and 1-3 F 1-4 For example, in some embodiments, R 1 However, it may also be SCH3.

[0024] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 1 But S(O)R 12 or S(O)2R 13 R 12 and R 13 is as defined herein. For example, in some embodiments, R 12 or R 13 But hydrogen, C 1-4 Alkyl group or C 3-6 It may be a cycloalkyl group, among which C 1-4 Alkyl group or C 3-6 cycloalkyl groups independently optionally substituted with F, OH, oxo, 1-3 F; 1-4 C optionally substituted with alkyl group and 1-3 F 1-4 It may be substituted with one or more (eg, 1 to 3) substituents selected from the group consisting of alkoxy groups.

[0025] In any embodiment according to the present disclosure, unless specifically stated otherwise or conflicting with the context, R in general formula I 1 (For example, any applicable subgeneric formula according to this disclosure, e.g., I-1, IB, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, I C-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b or ID-1-c) is hydrogen, CH3, ethyl, isopropyl, cyclopropyl, CN, OCH3, SCH3, CF3, F, Cl, Br, CF2H, TIFF2024532845000005.tif1455 or, It can also be TIFF2024532845000006.tif1676 or OCH2CF2H.

[0026] In some specific embodiments, the compound of general formula I is characterized by having the general formula I-2. TIFF2024532845000007.tif47107 Among them, variable R 2 , L 1 , L 2 , L 3 , X, Ring A and Ring B include any combination of the definitions as per any of the present disclosure.

[0027] In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c) 2 may also be hydrogen.

[0028] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 may be replaced by C 1-6 In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) may be an alkyl group. 2 may be replaced by C 2-6 In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is an alkenyl group. 2 may be replaced by C 2-6 In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an alkynyl group.2 may be replaced by C 3-8 It is a carbocyclyl group.

[0029] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 But C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 cycloalkyl groups, each of which is independently (1) halogen (preferably F) or CN, (2) OH, (3) NG 3 G 4 , (4) Oxo, (5) G 5 and (6) O.G. 5 and is substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: 3 and G 4 are independently hydrogen or G 5 Among them, G 5 is as defined herein. In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to this disclosure) 2 But C 1-4 alkyl groups, which are independently (1) F, (2) OH, and (6) OG 5 and optionally substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: 5 is as defined herein. In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to this disclosure) 2 But C 2-4 Alkenyl group or C 2-4 alkynyl groups, each independently selected from (1) F and (5) G 5 and optionally substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: 5 is as defined herein. In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to this disclosure) 2 But C3-6 cycloalkyl groups, which are independently (1) F, (2) OH, (5) G 5 and (6) O.G. 5 and optionally substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: 5 is as defined herein. In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A (iv) a 4-8 membered heterocyclyl group having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B or (v) 1-5 (e.g., 1, 2, or 3) G B is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them G A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; and G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 It is to be noted that the term "N(C 1-4 alkyl group)(C 1-4 In the alkyl group, two C 1-4 The alkyl groups may be the same or different. In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A1 (iv) a 4-6 membered monocyclic heterocyclyl group having 1-2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B1or (v) 1-5 (e.g., 1, 2, or 3) G B1 is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them G A1 represents independently F; oxo; C optionally substituted with 1-3 F; 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; and G B1 represents independently each time a halogen (preferably F, Cl, or Br); CN; C optionally substituted with 1 to 3 F; 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Among them, G C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 1-4 an alkyl group, or (ii) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 3-6is a cycloalkyl group, Among them G A2 represents independently F; oxo; C optionally substituted with 1-3 F; 1-3 Alkyl group (preferably methyl); OH; NH; NH(C 1-3 alkyl group), preferably NHCH; N(C 1-3 alkyl group)(C 1-3 alkyl group), preferably N(CH3)2; or C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy).

[0030] For example, in some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 may be replaced by C 1-4 alkyl groups, such as methyl, methoxymethyl, CF, etc. In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 2 may be replaced by C 2-4 In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is an alkenyl group. 2 may be replaced by C 2-4 Alkynyl groups, for example TIFF2024532845000008.tif2075, etc. In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 2 may be replaced by C 3-6 A cycloalkyl group is, for example, cyclopropyl.

[0031] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 But NR 14 R 15 Among them, R 14 and R 15 is as defined herein. For example, in some embodiments, R 14 and R 15are independently (i) hydrogen, (ii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 1-4 (iii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 3-6 a cycloalkyl group, and (iv) 1-5 (e.g., 1, 2, or 3) G A 4-8 membered heterocyclyl groups each having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with Among them, G A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; Among them, G C Each time it represents, it may be independently substituted by F, OH, 1-3 F, C 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 It is an alkoxy group. In some embodiments, R 14 and R 15 are independently (i) hydrogen, (ii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 1-4 (iii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 3-6 a cycloalkyl group, and (iv) 1-5 (e.g., 1, 2, or 3) G A1 4-6 membered monocyclic heterocyclyl groups each having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with Among them, G A1 represents independently F; oxo; C optionally substituted with 1-3 F; 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 For example, in some embodiments, R in general formula I is an alkoxy group. 2 However, NH2;NH(C 1-4 alkyl group); or N(C 1-4 alkyl group)(C 1-4 In some specific embodiments, R in general formula I is 2 is NH2 or NHCH3.

[0032] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 may be an optionally substituted heterocyclyl group.

[0033] For example, in some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 is an optionally substituted 4-10 membered heterocyclyl group having 1-3 ring-forming heteroatoms, each independently selected from the group consisting of N, O, and S, which may be saturated or partially unsaturated and may include fused, spiro, or bridged ring systems. In some embodiments, the 4-10 membered heterocyclyl group is a 4-6 membered monocyclic heterocycle. In some embodiments, the 4-10 membered heterocyclyl group is a 6-10 membered fused, spiro, or bridged bicyclic heterocycle. A fused bicyclic heterocycle may include a ring in which one ring is an aryl or heteroaryl group, provided that the bicyclic heterocycle is not entirely aromatic. Typically, the 4-10 membered heterocyclyl group ring contains 1-3 ring-forming heteroatoms, e.g., one or two ring-forming heteroatoms, each independently O, N, or S. When substituted, the 4-10 membered heterocyclyl group typically contains 1-5 (e.g., 1, 2 or 3) GA wherein G A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; Among them, G C represents, independently, F, OH, C, which may be substituted with 1-3 F 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 In some embodiments, the 4- to 10-membered heterocyclyl group may be a 4- to 8-membered monocyclic or bicyclic (fused, spiro, or bridged bicyclic) heterocyclyl group having 1-3 ring-forming heteroatoms, e.g., 1 or 2 ring-forming heteroatoms (each of which is independently selected from the group consisting of N, O, and S). For example, in some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to this disclosure) 2 is a spiro bicyclic heterocyclyl group, for example a 6-membered spiro bicyclic ring, for example TIFF2024532845000009.tif23736-membered fused bicyclic rings, for example, TIFF2024532845000010.tif2462 or a seven-membered spiro bicyclic ring, e.g. TIFF2024532845000011.tif2577 or In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) may be 2 is a monocyclic 4-7 membered heterocycle, for example, TIFF2024532845000013.tif1752 or TIFF2024532845000014.tif2058, which may be substituted with one or more (e.g., one or two) substituents according to the present disclosure, for example, the substituents may each independently be halogen (preferably F); CN; OH; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); and C optionally substituted with 1-3 F 1-4 alkyl groups. In some embodiments, the substituents can each independently be selected from the group consisting of F, CN, NH(CH), N(CH), CHF, and methyl.

[0034] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 But, OR 10 R 10 is as defined herein. For example, in some embodiments, R 10 (i) 1-5 (e.g., 1, 2, or 3) G A3 may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A3 may be substituted with C 3-6 a cycloalkyl group, or (iii) 1-5 (e.g., 1, 2, or 3) G A3 a 4- to 8-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms, each independently selected from the group consisting of N, O, and S, optionally substituted with A3 is as defined herein. In some embodiments, R in general formula I (e.g., any applicable subgeneral formula according to this disclosure) 2 However, NHR 15 R 15 is as defined herein. For example, in some embodiments, R 15 (i) 1-5 (e.g., 1, 2, or 3) G A3 may be substituted with C 1-4(ii) 1-5 (e.g., 1, 2, or 3) G A3 may be substituted with C 3-6 a cycloalkyl group, or (iii) 1-5 (e.g., 1, 2, or 3) G A3 a 4- to 8-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms, each independently selected from the group consisting of N, O, and S, optionally substituted with A3 is as defined herein. 10 and R 15 In the definition of G A3 each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 alkyl group; 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 Alkenyl groups; 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 Alkynyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 an alkoxy group; or 1-5 (e.g., 1, 2, or 3) G C3 It may be a 3-8 membered ring optionally substituted with; Among them, G C3 represents, independently, (1) F, Cl, OH, or CN; (2) C optionally substituted with 1-3 F; 1-4 (3) a 3-4 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with 1-3 substituents independently selected from the group consisting of F, OH, CN, or methyl; or (4) a C having 1 or 2 heteroatoms independently selected from O, N, or S, optionally substituted with 1-3 F. 1-4Heteroalkyl groups. Unless otherwise specifically stated or conflicting with the context, the term "3-8 membered ring" as used herein is understood to include monocyclic and bicyclic (fused, spiro, or bridged) rings having 3-8 ring-forming atoms, which may be saturated, partially unsaturated, or aromatic, and which may contain one or more ring-forming heteroatoms, independently N, O, or S, in which the ring-forming carbon, N, or S atoms may be oxidized, e.g., in the form of C(=O), N-oxide, SO, or SO. Other membered rings should be understood in the same way. Examples of 3-8 membered rings include, but are not limited to, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, 5- or 6-membered heteroaryl groups, such as pyrazole, etc. C having one or two heteroatoms, independently O, N, or S, may be oxidized, e.g., in the form of C(=O), N-oxide, SO, or SO. Other membered rings should be understood in the same way. Examples of 3-8 membered rings include, but are not limited to, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, 5- or 6-membered heteroaryl groups, e.g., pyrazole, etc. C having one or two heteroatoms, independently O, N, or S. 1-4 Non-limiting examples of heteroalkyl groups include C 1-4 Alkoxy group, NH(C 1-4 alkyl group), N(C 1-3 alkyl group)(C 1-3 alkyl group) (wherein each C 1-3 alkyl groups independently selected, provided that the total number of carbon atoms is 4 or less, optionally substituted with hydroxy or NH 1-4 C optionally substituted with alkyl or methoxy 1-3 C, optionally substituted with alkyl group, NMe2 1-2 Contains alkyl groups and the like.

[0035] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to this disclosure), R 2 is as defined herein OR 10 ,for example, TIFF2024532845000015.tif3496 or The file is TIFF2024532845000016.tif2763.

[0036] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to this disclosure), R 2NHR as defined herein 15 ,for example, TIFF2024532845000017.tif35166 or TIFF2024532845000018.tif2562.

[0037] In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) 2 but 1-5 (e.g., 1, 2, or 3) G A3 a 4- to 10-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms, each independently selected from the group consisting of N, O and S, optionally substituted with Among them, G A3 each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 alkyl group; 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 Alkenyl groups; 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 Alkynyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 an alkoxy group; or 1-5 (e.g., 1, 2, or 3) G C3 is a 3-8 membered ring optionally substituted with; Among them, G C3 represents, independently, (1) F, Cl, OH, or CN; (2) C optionally substituted with 1-3 F; 1-4(3) a 3-4 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with 1-3 substituents independently selected from the group consisting of F, OH, CN, or methyl; or (4) a C having 1 or 2 heteroatoms independently selected from O, N, or S, optionally substituted with 1-3 F. 1-4 For example, in some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) is a heteroalkyl group. 2 are 4-8 membered monocyclic or bicyclic (fused, spiro or bridged bicyclic) heterocyclyl groups each having one or two ring-forming heteroatoms independently selected from the group consisting of N, O and S, for example: TIFF2024532845000019.tif19108 or It may be TIFF2024532845000020.tif2592, and it may contain 1-2 G A3 For example, in some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to this disclosure) may be substituted with 2 but, TIFF2024532845000021.tif1897 or TIFF2024532845000022.tif86166 or In some embodiments, R in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) may be a substituted azetidine selected from the group consisting of: 2 and optionally substituted spiro bicyclic rings having an azetidine ring, such as TIFF2024532845000024.tif56164 or It could also be TIFF2024532845000025.tif2782.

[0038] In any embodiment according to the present disclosure, unless otherwise specifically stated or conflicting in context, R in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c) 2 But hydrogen, CH3, CF3, TIFF2024532845000026.tif875NH2, NHCH3, TIFF2024532845000027.tif50165 or TIFF2024532845000028.tif17102; or R 2 but, TIFF2024532845000029.tif55166 or TIFF2024532845000030.tif2388; or R 2 but, TIFF2024532845000031.tif29117 or TIFF2024532845000032.tif29107; or R 2 but, TIFF2024532845000033.tif54166 or TIFF2024532845000034.tif26116; or R 2 but, TIFF2024532845000035.tif3172 or TIFF2024532845000036.tif2566; or R 2 is cyclopropyl.

[0039] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to this disclosure), R 1 and R 2 are linked together with the atoms between them to form an optionally substituted ring structure. For example, in some embodiments, compounds of general formula I can be identified as having the general formula IA. TIFF2024532845000037.tif50111 wherein ring C represents an optionally substituted ring structure, such as an optionally substituted benzene ring, an optionally substituted heteroaryl ring, an optionally substituted carbocyclic ring, or a heterocyclic ring; and wherein variable L 1 , L 2 , L 3 , X, ring A and ring B include any combination of any of the definitions described herein. Generally, ring C is an optionally substituted benzene ring or heteroaryl ring.

[0040] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to the present disclosure), L 1 and R 2 are linked together with the atoms between them to form an optionally substituted ring structure. For example, in some embodiments, compounds of general formula IB can be identified as having the general formula IB. TIFF2024532845000038.tif48110 wherein ring D represents an optionally substituted ring structure, such as an optionally substituted benzene ring, an optionally substituted heteroaryl ring, an optionally substituted carbocyclic ring or a heterocyclic ring; and wherein variable R 1 , L 2 , L 3 , X, ring A and ring B include any combination of any of the definitions described herein. Generally, ring D is an optionally substituted carbocycle or heterocycle.

[0041] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to this disclosure), R 1 , R 2 and L 1are linked together with the atoms between them to form an optionally substituted ring structure: wherein rings C and D each independently represent an optionally substituted ring structure, such as an optionally substituted benzene ring, an optionally substituted heteroaryl ring, or an optionally substituted carbocyclic or heterocyclic ring; and wherein variable L 2 , L 3 , X, ring A, and ring B include any combination of any of the definitions described herein. Generally, ring C and ring D are not both aromatic rings. For example, generally, ring C is an optionally substituted benzene ring or heteroaryl ring, and ring D is an optionally substituted carbocyclic or heterocyclic ring.

[0042] In some embodiments, R 1 and R 2 , R 2 and L 1 , or R 1 , R 2 and L 1 However, they do not form rings with each other.

[0043] In some embodiments, in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), R 1 and R 2are linked together with the atoms therebetween to form an optionally substituted benzene ring or an optionally substituted 5- or 6-membered heteroaryl ring having 1 to 3 ring-forming heteroatoms each independently selected from the group consisting of N, O, and S. Therefore, in such embodiments, ring C in general formula IA or, where applicable, in general formula IAa, may be an optionally substituted benzene ring or an optionally substituted 5- or 6-membered heteroaryl ring having 1 to 3 ring-forming heteroatoms each independently selected from the group consisting of N, O, and S.

[0044] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to this disclosure), R 1 and R 2 are connected together with the atoms therebetween and an optionally substituted benzene ring, TIFF2024532845000040.tif1883. In some embodiments, R 1 and R 2 are linked together with the atoms therebetween to form an optionally substituted pyridine ring, for example: TIFF2024532845000041.tif1997. Unless otherwise stated, either of the two attachment points of the pyridinyl fragment may be attached to the carbonyl group in general formula I. For example, in some embodiments, the top attachment point of the pyridinyl fragment is attached to the carbonyl group in general formula I, see e.g., general formula IA-2. In some embodiments, the bottom attachment point of the pyridinyl fragment is attached to the carbonyl group in general formula I, see e.g., compound 126. It is understood that terms such as top, bottom, etc. refer to the relative positions depicted. In some embodiments, R 1 and R 2 are linked together with the atoms therebetween to form an optionally substituted pyrrole ring, for example: TIFF2024532845000042.tif2276. Similarly, unless otherwise stated, either of the two attachment points of the pyrrole group fragment may be attached to the carbonyl group in general formula I. When substituted, the benzene ring or a 5- or 6-membered heteroaryl ring, e.g., pyridine or pyrrole ring, generally contains 1-5 (e.g., 1, 2, or 3) G B wherein G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 It is an alkoxy group. In some embodiments, when substituted, a benzene ring or a 5- or 6-membered heteroaryl ring, such as a pyridine or pyrrole ring, is substituted with 1-5 (e.g., 1, 2, or 3) G B1 wherein GB1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group; OH; 1-3 G C1 may be substituted with C 3-6 Cycloalkyl group; 1-3 G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with 1 to 3 F; or a C 1-4 an alkoxy group; C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, when substituted, a benzene ring or a 5- or 6-membered heteroaryl ring, such as a pyridine or pyrrole ring, may contain 1-5 (e.g., 1, 2, or 3) G B3 wherein G B3 each time represents, independently, F, Cl, Br, CN, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 alkyl group, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 alkenyl group, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 Alkynyl group, OH, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 3-6 cycloalkyl groups, 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with NH, NH(C 1-4 alkyl group), N(C 1-4 alkyl group)(C 1-4 alkyl group), 1-5 (e.g., 1, 2, or 3) GC3 may be substituted with C 1-4 Alkoxy group, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 3-6 cycloalkoxy group, 1-5 (e.g., 1, 2, or 3) G C3 a 4-6 membered heterocycloalkoxy group optionally substituted with, or 1-5 (e.g., 1, 2, or 3) G C3 is an optionally substituted 5- or 6-membered heteroaryl group; Among them, G C3 represents, independently, (1) F, Cl, OH, or CN; (2) C optionally substituted with 1-3 F; 1-4 (3) a 3-4 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with 1-3 substituents that are independently F, OH, CN, or methyl; or (4) a C having 1 or 2 heteroatoms that are independently O, N, or S, optionally substituted with 1-3 F. 1-4 It is a heteroalkyl group.

[0045] In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to this disclosure), R 1 and R 2 are connected together with the atoms between them to form a benzene ring, TIFF2024532845000043.tif1973, which may be independently substituted with F, Cl, or 1-3 F. 1-4 In some embodiments, in general formula I (e.g., any applicable subgeneric formula according to the present disclosure), R 1 and R 2 are connected together with the atoms between them to form a benzene ring, TIFF2024532845000044.tif1985, which may be independently substituted with F, Cl, or 1-3 F. 1-4 Alkyl groups, cyclopropyl, cyclobutyl, TIFF2024532845000045.tif16113CN, TIFF2024532845000046.tif18116 and TIFF2024532845000047.tif2156 and may be substituted with one or more (for example, 1-5 or 1-3, more preferably 1 or 2) substituents selected from the group consisting of:

[0046] In some specific embodiments, in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), R 1 and R 2 are linked together with the atoms therebetween to form a ring structure selected from the group consisting of: TIFF2024532845000048.tif51165 or forming a cyclic structure selected from the group consisting of: TIFF2024532845000049.tif69166 wherein the apex linkage of the fragment connects to the carbonyl group in general formula I.

[0047] In some embodiments, the compound of general formula I can be characterized as having the following general formula IA-1, IA-2, or IA-3: TIFF2024532845000050.tif140110 where, Variable L 1 , L 2 , L 3 wherein X, ring A and ring B include any combination of the definitions described herein; and j is 0, 1, 2 or 3; and R 3 each occurrence independently represents a halogen (preferably F, Cl, or Br), CN, 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group, OH, 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups, 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with NH, NH(C 1-4 alkyl group), N(C 1-4 alkyl group)(C 1-4 alkyl group), 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy group, 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group, or 1-5 (e.g., 1, 2, or 3) G C is a 4-6 membered heterocycloalkoxy group optionally substituted by Among them, G C represents, independently, F, OH, C, which may be substituted with 1-3 F 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 is an alkoxy group, or R 3 each time represents, independently, F, Cl, Br, CN, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 alkyl group, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 alkenyl group, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 2-4 Alkynyl group, OH, 1-5 (e.g., 1, 2, or 3) G C3may be substituted with C 3-6 cycloalkyl groups, 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with NH, NH(C 1-4 alkyl group), N(C 1-4 alkyl group)(C 1-4 alkyl group), 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 1-4 Alkoxy group, 1-5 (e.g., 1, 2, or 3) G C3 may be substituted with C 3-6 cycloalkoxy group, 1-5 (e.g., 1, 2, or 3) G C3 a 4-6 membered heterocycloalkoxy group optionally substituted with, or 1-5 (e.g., 1, 2, or 3) G C3 is an optionally substituted 5- or 6-membered heteroaryl group; Among them, G C3 represents, independently, (1) F, Cl, OH, or CN; (2) C optionally substituted with 1-3 F; 1-4 (3) a 3-4 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with 1-3 substituents independently selected from the group consisting of F, OH, CN, or methyl; or (4) a C having 1 or 2 heteroatoms independently selected from O, N, or S, optionally substituted with 1-3 F. 1-4 is a heteroalkyl group, Alternatively, in general formula IA-1 or IA-3, R 3 One example of L 1 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure. For example, in some embodiments, R 3 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group; OH; 1-3 G C1 may be substituted with C 3-6 Cycloalkyl group; 1-3 GC1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with 1 to 3 F; or a C 1-4 and may be an alkoxy group; C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 In some embodiments, R is an alkoxy group (preferably, methoxy). 3 represents, independently, F, Cl, C which may be substituted with 1-3 F 1-4 The alkyl group may be cyclopropyl or cyclobutyl.

[0048] In some embodiments according to general formulas IA-1 through IA-3, j is 0.

[0049] In some embodiments according to general formulas IA-1 to IA-3, j is 1 and R 3 is as defined herein. In some embodiments, when j is 1, R 3 are respectively located at the ortho position of the carbonyl in general formulas IA-1 to IA-3. In some specific embodiments, when j is 1, R 3 C optionally substituted with F, Cl, 1-3 F 1-4 In some specific embodiments, when j is 1, R 3 but, TIFF2024532845000051.tif1259CN, TIFF2024532845000052.tif19122 or The file is TIFF2024532845000053.tif2069.

[0050] In some embodiments, in general formula IA-1 or IA-3, R 3 One example of L 1may be linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure, typically a 5- to 7-membered carbocyclic or heterocyclic ring.

[0051] In some embodiments, the compound of general formula I is characterized by having the general formula IA-1, wherein R 3 One example of L 1 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure, for example, a 5- or 6-membered ring structure containing 1 or 2 ring-forming heteroatoms each independently selected from the group consisting of N, O, and S.

[0052] For example, in some embodiments, a compound of general Formula I can be characterized as having the general formula IA-1-a: TIFF2024532845000054.tif5094 where, Variable R 3 , L 2 , L 3 , wherein X, ring A and ring B include any combination of the definitions described herein; j is 0, 1 or 2; and R 3A hydrogen, 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group, 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkyl group or 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms, each independently selected from the group consisting of N, O and S, optionally substituted with Among them, G C Each time it represents, it may be independently substituted by F, OH, 1-3 F, C 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 In some embodiments, R 3A C optionally substituted with hydrogen, 1-3 F 1-4Alkyl group, or C 3-6 It is a cycloalkyl group.

[0053] In some embodiments according to general formula IA-1-a, j is 0.

[0054] In some embodiments according to general formula IA-1-a, j is 1 and R 3 is as defined herein. In some specific embodiments according to general formula IA-1-a, when j is 1, R 3 C optionally substituted with F, Cl, 1-3 F 1-4 In some specific embodiments according to general formula IA-1-a, when j is 1, R 3 but, TIFF2024532845000055.tif1360CN, TIFF2024532845000056.tif22124 or The file is TIFF2024532845000057.tif2061.

[0055] Some embodiments of the present disclosure relate to compounds of the general formula IB according to the present disclosure. In some embodiments, in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, or ID-3-a), R 2 and L 1are linked together with the atoms therebetween to form a 5-7 membered heterocyclyl group having one or two optionally substituted heteroatoms, each independently selected from the group consisting of O, N, and S. Thus, in such embodiments, ring D in general formula IB or, where applicable, in general formula IAa, may be an optionally substituted 5-7 membered heterocyclyl group having one or two heteroatoms, each independently selected from the group consisting of O, N, and S. In some embodiments, the 5-7 membered heterocyclyl group has one heteroatom selected from the group consisting of N, S, and O. In some embodiments, the 5-7 membered heterocyclyl group has only one heteroatom, which is O or N. When substituted, the 5-7 membered heterocyclyl group generally has, independently, (1) halogen (preferably F) or CN, (2) OH, (3) NG3G 4 , (4) Oxo, (5) G 5 , (6) OG 5 , (7)(C 1-4 Alkylene group)-G 5 and (8)(C 1-4 Heteroalkylene group)-G 5 and is substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: where: G 3 and G 4 are independently hydrogen or G 5 and G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A (iv) a 4-8 membered heterocyclyl group having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with Bor (v) 1-5 (e.g., 1, 2, or 3) G B is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them, G A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; and G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G Crepresents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 It is an alkoxy group.

[0056] In some embodiments, when substituted, the 5-7 membered heterocyclyl group is substituted with one or more (e.g., 1-5 or 1-3) substituents independently selected from the group consisting of: (1) F; (2) oxo; (3) G 5 ;(4)(C 1-4 Alkylene group)-G 5 , and (6)(C 1-4 Heteroalkylene group)-G 5 , Among them, G 5 is as defined herein. For example, in some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A1 (iv) a 4-6 membered monocyclic heterocyclyl group having 1-2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B1 or (v) 1-5 (e.g., 1, 2, or 3) G B1 is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them G A1 represents independently F; oxo; C optionally substituted with 1-3 F; 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4is an alkoxy group; and G B1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Among them, G C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 1-4 an alkyl group, or (ii) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 3-6 is a cycloalkyl group: Among them G A2 represents independently F; oxo; C optionally substituted with 1-3 F; 1-3 Alkyl group (preferably methyl); OH; NH; NH(C 1-3 alkyl group), preferably NHCH; N(C 1-3 alkyl group)(C 1-3 alkyl group), preferably N(CH3)2; or C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, when substituted, the 5-7 membered heterocyclyl group is independently selected from F, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 an alkyl group, and 1-5 (e.g., 1, 2, or 3) G B and phenyl groups optionally substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F. 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 cycloalkyl groups; B is as defined herein. For example, in some embodiments, G B But every time you express it, G B1 which may be independently substituted with F; Cl; Br; CN; or 1-3 F. 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 an alkoxy group; C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy).

[0057] In some specific embodiments, the compound of general formula I is characterized by having the general formula IB-1, IB-2, or IB-3. TIFF2024532845000058.tif149105 where, Variable R 1 , L 2 , L 3 wherein X, ring A and ring B include any combination of the definitions described herein; m is 0, 1, 2, 3, or 4; and R 4 Each time, (1) F, (2) OH, (3) NG are expressed independently. 3 G 4 , (4) Oxo, (5) G 5 , (6) OG 5 , (7)(C 1-4 Alkylene group)-G 5 , or (8)(C 1-4 Heteroalkylene group)-G 5 and where: G 3 and G 4 are independently hydrogen or G 5 and G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A (iv) a 4-8 membered heterocyclyl group having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B or (v) 1-5 (e.g., 1, 2, or 3) G B is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them, G Aeach occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; and G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Alternatively, in general formula IB-2 or IB-3, R 4 One example of R1 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure; Alternatively, R 4 Two examples of the following are linked together with the atoms between them to form an optionally substituted 3- to 6-membered ring structure; Alternatively, R 4 One example of L 2 are linked together with the atoms therebetween to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A1 (iv) a 4-6 membered monocyclic heterocyclyl group having 1-2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B1 or (v) 1-5 (e.g., 1, 2, or 3) G B1 is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them G A1 represents independently F; oxo; C optionally substituted with 1-3 F; 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; and G B1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Among them, G C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 1-4 an alkyl group, or (ii) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 3-6 is a cycloalkyl group, Among them G A2 represents independently F; oxo; C optionally substituted with 1-3 F; 1-3 Alkyl group (preferably methyl); OH; NH; NH(C 1-3 alkyl group), preferably NHCH; N(C 1-3 alkyl group)(C 1-3 alkyl group), preferably N(CH3)2; or C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, R 4 represents, independently, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 alkyl group or 1-5 (e.g., 1, 2, or 3) G B a phenyl group optionally substituted with G Drepresents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F. 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 cycloalkyl groups; B is as defined above. In some specific embodiments, R 4 Each time it appears, it independently represents a methyl group, a phenyl group, TIFF2024532845000059.tif1968 or, TIFF2024532845000060.tif1968. In some embodiments, R 4 may be linked to the ring-forming N in general formula IB-2 or IB-3, wherein R 4 is as defined herein.

[0058] In some embodiments according to general formulas IB-1 through IB-3, m is 0.

[0059] In some embodiments according to general formulas IB-1 to IB-3, m is 1 and R 4 is as defined herein. For example, in some embodiments, m is 1 and R 4 but 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 alkyl group or 1-5 (e.g., 1, 2, or 3) G B a phenyl group optionally substituted with G D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups3-6 cycloalkyl groups; B is as defined herein. For example, in some embodiments, m is 1 and R 4 but 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 In some embodiments, R 4 is methyl, methoxymethyl, cyclopropylmethyl, etc. In some embodiments, m is 1 and R 4 phenyl group or 1-3 G B phenyl groups substituted with G B is as defined herein. In some embodiments, G B is G as defined in this application. B1 and each occurrence of is independently selected from F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 an alkoxy group; C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 In some specific embodiments, R is an alkoxy group (preferably, methoxy). 4 Each time it appears, it independently represents a methyl group, a phenyl group, TIFF2024532845000061.tif1873 or, The file is TIFF2024532845000062.tif2176.

[0060] As will be apparent to those skilled in the art, R 4 may be linked to a ring-forming nitrogen atom in general formulae IB-1 to IB-3.

[0061] In some embodiments, the compounds of general formulas IB-1 to IB-3 are characterized by having the general formula IB-1-E1, IB-1-E2, IB-2-E1, IB-2-E2, IB-3-E1, or IB-3-E2. TIFF2024532845000063.tif135166, wherein the variables include any combination of any of the definitions associated with the corresponding general formulae IB-1 through IB-3 described herein. In some embodiments, a compound according to general formula IB-1-E1, IB-1-E2, IB-2-E1, IB-2-E2, IB-3-E1, or IB-3-E2 can exist primarily as the depicted stereoisomer about the depicted chiral center, e.g., free of or essentially free of the corresponding other enantiomer about the depicted chiral center. However, in some embodiments, a compound according to general formula IB-1-E1, IB-1-E2, IB-2-E1, IB-2-E2, IB-3-E1, or IB-3-E2 can exist as a mixture, in any proportion, with the corresponding other enantiomer about the depicted chiral center, e.g., a racemic mixture.

[0062] In some embodiments, in general formula IB-3, R 4 One example of R 1 may be linked together with the atoms therebetween to form the following ring structure: TIFF2024532845000064.tif2693R A may be halogen or substituted C 1-4 Alkyl or optionally substituted C 3-6and n is 0, 1, or 2, wherein the apical attachment point of the fragment is attached to the carbonyl group in formula IB-3. As used herein, when a substituent or variable is referred to as being linked together with another substituent or variable and the atoms therebetween to form a ring structure, the following options are included: when a pair of substituents or variables is attached to two different atoms, one or two remaining hydrogens on the two atoms to which the pair of substituents or variables is attached are eliminated to form the particular ring structure. For example, R 4 and R 1 When an optionally substituted phenyl group is formed from 4 The ring structure formed by eliminating the remaining hydrogen on the atom connecting to form a bond may be a benzene ring. Other similar situations described herein should be understood in the same way.

[0063] In some embodiments according to general formulas IB-1 to IB-3, R 4 One example of L 2 may be linked together with the atoms between them to form an optionally substituted 3- to 6-membered ring structure. In such embodiments, the 3- to 6-membered ring structure is typically a non-aromatic ring structure, such as a cycloalkyl group, e.g., cyclopropyl. For example, in some embodiments, compounds of general formula IB-1-E1 or IB-1-E2, respectively, are characterized by having one of the following general formulas: TIFF2024532845000065.tif97104, where m is 0, 1, 2, or 3, and the variable R 1 , R 4 , L 3 , X, ring A and ring B include any combination of the definitions described herein.

[0064] In some embodiments according to general formulas IB-1 to IB-3, R 4 Two examples of R may be linked together with the atom between them to form an optionally substituted 3- to 6-membered ring structure. As will be understood by those skilled in the art, two R 4are linked to form a ring, the ring formed is a spiro ring; two R 4 When two R are linked to form a ring, the ring formed is a fused ring. 4 When the link to form a ring, the ring system formed is a fused or bridged ring system. Generally, in these embodiments, the 3-6 membered ring structure formed is a non-aromatic ring structure, such as a cycloalkyl group or a heterocyclyl group.

[0065] Generally, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 and L 2 are independently a single bond, O, S, S(O), S(O)2, NR 16 , C(O), C(O)O, C(O)NR 16 , OC(O)NR 16 , S(O)NR 16 , N.R. 17 C(O)NR 16 , N.R. 17 S(O)NR 16 , may be replaced by C 1-4 Alkylene group, optionally substituted C 2-4 Alkenylene group, optionally substituted C 2-4 Alkynylene group, optionally substituted C 1-4 Heteroalkylene group, optionally substituted C 3-8 a carbocyclylene group, an optionally substituted 4- to 10-membered heterocyclylene group, an optionally substituted phenylene group, or an optionally substituted 5- or 6-membered heteroarylene group, preferably L 1 and L 2 are not both single bonds.

[0066] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, or ID-3-a) 1is an optionally substituted 4-10 membered heterocyclylene group having 1-3 ring-forming heteroatoms, each independently selected from the group consisting of O, N, and S. For example, in some embodiments, L in general formula I 1 is an optionally substituted 5- or 6-membered monocyclic heterocyclylene group having one or two ring-forming heteroatoms, each independently selected from the group consisting of N, O, and S. Suitable 5- or 6-membered monocyclic heterocyclylene groups include any one of the definitions described herein. For example, in some embodiments, the 5- or 6-membered monocyclic heterocyclylene group may be a saturated monocyclic ring, such as a pyrrolidine, piperidine, or morpholine ring. In some embodiments, L in general formula I 1 is an optionally substituted 6-10 membered fused, spiro or bridged bicyclic heterocyclylene group having one or two ring-forming heteroatoms, each independently selected from the group consisting of N, O and S. In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a or ID-3-a) 1 is an optionally substituted ring selected from the group consisting of: TIFF2024532845000066.tif30129

[0067] For example, in some specific embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, or ID-3-a) 1 but, It could also be TIFF2024532845000067.tif27111.

[0068] In some specific embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, or ID-3-a) 1 but, It could also be TIFF2024532845000068.tif26125.

[0069] In some specific embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, or ID-3-a) 1 but, It could also be TIFF2024532845000069.tif22123.

[0070] L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, or ID-3-a) 1 is an optionally substituted 4- to 10-membered heterocyclylene group according to the present disclosure, the 4- to 10-membered heterocyclylene group generally independently contains: (1) halogen (preferably F or Cl) or CN; (2) OH; (3) NG 3 G 4 , (4) Oxo, (5) G 5 , (6) OG 5 , (7)(C 1-4 Alkylene group)-G 5 and (8)(C 1-4 Heteroalkylene group)-G 5 and optionally substituted with one or more (e.g., 1-5 or 1-3) substituents selected from the group consisting of: 3 and G 4 are independently hydrogen or G 5 and G 5is as defined herein. For example, in some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A (iv) a 4-8 membered heterocyclyl group having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B or (v) 1-5 (e.g., 1, 2, or 3) G B is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them, G A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; and G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G Ca 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 It is an alkoxy group. In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A1 (iv) a 4-6 membered monocyclic heterocyclyl group having 1-2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B1 or (v) 1-5 (e.g., 1, 2, or 3) G B1 is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them G A1 represents independently F; oxo; C optionally substituted with 1-3 F; 1-4 Alkyl group; OH; NH2; NH(C1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; and G B1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Among them, G C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy).

[0071] In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 1-4 an alkyl group, or (ii) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 3-6 is a cycloalkyl group, Among them G A2 represents independently F; oxo; C optionally substituted with 1-3 F; 1-3 Alkyl group (preferably methyl); OH; NH; NH(C 1-3 alkyl group), preferably NHCH; N(C 1-3 alkyl group)(C 1-3alkyl group), preferably N(CH3)2; or C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, the 4- to 10-membered heterocyclylene group is optionally substituted with one or more (e.g., 1-5 or 1-3) substituents, each of which is independently selected from halogen (preferably F or Cl), CN, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 alkyl group, or 1-5 (e.g., 1, 2, or 3) G D and preferably, the substituents are each independently F or 1-5 (e.g., 1, 2, or 3) G. D may be substituted with C 1-4 alkyl groups, among which G D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 It is a cycloalkyl group.

[0072] In some specific embodiments, the compound of general formula I is characterized by having the general formula IC-1, IC-2, or IC-3. TIFF2024532845000070.tif130110 where, Variable R 1 , R 2 , L 2 , L 3 wherein X, ring A and ring B include any combination of the definitions described herein; g is 0, 1, 2, 3, or 4; and R 5 each time it appears, it independently represents (1) halogen (preferably F or Cl) or CN, (2) OH, (3) NG 3G 4 , (4) Oxo, (5) G 5 , (6) OG 5 , (7)(C 1-4 Alkylene group)-G 5 and (8)(C 1-4 Heteroalkylene group)-G 5 Selected from the group consisting of: 3 and G 4 are independently hydrogen or G 5 and G 5 is as defined herein; Alternatively, R 5 One example of R 2 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure; Alternatively, R 5 Two examples of the following are linked together with the atom between them to form an optionally substituted 5- to 7-membered ring structure; Alternatively, R 5 One example of L 2 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure. 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A (iv) a 4-8 membered heterocyclyl group having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B or (v) 1-5 (e.g., 1, 2, or 3) G B is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them, G Aeach occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group; and G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 It is an alkoxy group. In some embodiments, G 5each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 1-4 (ii) 1-5 (e.g., 1, 2, or 3) G A1 may be substituted with C 3-6 (iii) 1-5 (e.g., 1, 2, or 3) G A1 (iv) a 4-6 membered monocyclic heterocyclyl group having 1-2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with B1 or (v) 1-5 (e.g., 1, 2, or 3) G B1 is a 5- or 6-membered heteroaryl group having 1 to 3 ring-forming heteroatoms, optionally substituted with Among them G A1 represents independently F; oxo; C optionally substituted with 1-3 F; 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; and G B1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Among them, G C1represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy). In some embodiments, G 5 each time represents, independently, (i) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 1-4 an alkyl group, or (ii) 1-5 (e.g., 1, 2, or 3) G A2 may be substituted with C 3-6 is a cycloalkyl group, Among them G A2 represents independently F; oxo; C optionally substituted with 1-3 F; 1-3 Alkyl group (preferably methyl); OH; NH; NH(C 1-3 alkyl group), preferably NHCH; N(C 1-3 alkyl group)(C 1-3 alkyl group), preferably N(CH3)2; or C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy).

[0073] In some embodiments according to general formulas IC-1 to IC-3, R 5 each occurrence independently represents a halogen (preferably F or Cl), CN, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 an alkyl group, or 1-5 (e.g., 1, 2, or 3) G D and preferably, each independently, F or 1-5 (e.g., 1, 2, or 3) G. D may be substituted with C 1-4 alkyl groups, among which G D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 In some embodiments, R 5 represents, independently, F or C each time 1-4 An alkyl group, for example, methyl.

[0074] In some embodiments according to general formulas IC-1 through IC-3, g is 0.

[0075] In some embodiments according to general formulas IC-1 to IC-3, g is 1 or 2, wherein R 5 is as defined herein. For example, in some embodiments, g is 1 or 2 and R 5 each occurrence independently represents a halogen (preferably F or Cl), CN, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 an alkyl group, or 1-5 (e.g., 1, 2, or 3) G D and preferably, each independently, F or 1-5 (e.g., 1, 2, or 3) G. D may be substituted with C 1-4 alkyl groups, among which G D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 In some embodiments, R 5 represents, independently, F or C each time 1-4 An alkyl group, for example, methyl.

[0076] L in general formula IC-12 -X-(Ring A)-L 3 The -(Ring B) moiety can be linked to the morpholine ring at the adjacent ring-forming nitrogen or the adjacent ring-forming oxygen. For example, in some embodiments, a compound of general formula IC-1 can have the general formula IC-1-E1, IC-1-E2, IC-1-E3, or IC-1-E4. TIFF2024532845000071.tif104165, wherein the variables in the general formulas include any combination of any of the definitions described herein for general formula IC-1. In some embodiments, compounds according to general formulas IC-1-E1 through IC-1-E4 can exist primarily as the depicted stereoisomer, e.g., free of or essentially free of the corresponding enantiomer for the depicted chiral centers. However, in some embodiments, compounds according to general formulas IC-1-E1 through IC-1-E4 can exist as a mixture, e.g., a racemic mixture, with the corresponding enantiomer for the depicted chiral centers in any proportion.

[0077] Similarly, L in general formula IC-2 2 -X-(Ring A)-L 3 The -(Ring B) moiety can be linked to the pyrrolidine ring at adjacent or non-adjacent ring-forming nitrogens. For example, in some embodiments, a compound of general formula IC-2 can have general formula IC-2-E1, IC-2-E2, IC-2-E3, or IC-2-E4. TIFF2024532845000072.tif101166, wherein the variables in the general formulas include any combination of any of the definitions described for general formula IC-2 herein. In some embodiments, compounds according to general formulas IC-2-E1 through IC-2-E4 can exist primarily as the depicted stereoisomer, e.g., free of or essentially free of the corresponding enantiomer for the depicted chiral centers. However, in some embodiments, compounds according to general formulas IC-2-E1 through IC-2-E4 can exist as a mixture, e.g., a racemic mixture, with the corresponding enantiomer for the depicted chiral centers in any proportion.

[0078] L in General Formula IC-3 2 -X-(Ring A)-L 3 The -(Ring B) moiety can be linked to the piperidine ring at adjacent or non-adjacent ring-forming nitrogens. For example, in some embodiments, a compound of general formula IC-2 can have general formula IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4. TIFF2024532845000073.tif100163, wherein the variables in the general formulas include any combination of any of the definitions described herein for general formula IC-3. In some embodiments, compounds according to general formulas IC-3-E1 through IC-3-E4 can exist primarily as the depicted stereoisomer, e.g., free of or essentially free of the corresponding enantiomer for the depicted chiral centers. However, in some embodiments, compounds according to general formulas IC-3-E1 through IC-3-E4 can exist as a mixture, e.g., a racemic mixture, with the corresponding enantiomer for the depicted chiral centers in any proportion.

[0079] In some embodiments according to general formulas IC-1 to IC-3, R 5 One example of R 2are linked together with the atoms between them to form an optionally substituted 5- to 7-membered ring structure. For example, in some embodiments, R 5 is attached next to the nitrogen atom and R 2 and the atoms therebetween join together to form an optionally substituted 5- to 7-membered ring structure.

[0080] In some embodiments according to general formulas IC-1 to IC-3, R 5 and the atom between them can be linked together to form an optionally substituted 5- to 7-membered ring structure, such as an optionally substituted phenyl group or an optionally substituted pyridinyl. For example, in some embodiments, a compound of general formula IC-1 (e.g., IC-1-E1, IC-1-E2, IC-1-E3, or IC-1-E4) is characterized by having the general formula IC-1-a: TIFF2024532845000074.tif49116 where, Variable R 1 , R 2 , L 2 , L 3 , X, ring A and ring B include any combination of the definitions described in any of the present applications, including any definition shown in general formula IC-1-E1, IC-1-E2, IC-1-E3, or IC-1-E4; R G each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 is an alkoxy group; Alternatively, R G each time it appears, it independently represents a halogen (preferably F, Cl, or Br); CN; OH; NH; G A4 ;OG A4 ;NHG A4 ;N(C 1-4 alkyl group)(G A4 );COG A4 ;SO2G A4 ;CONHG A4 ;CON(C 1-4 alkyl group)(G A4 );NHCOG A4 ; or N(C 1-4 Alkyl group)COG A4 and; Among them, G A4 represents, independently, (1) 1-5 (e.g., 1, 2, or 3) G C4 may be substituted with C 1-4 (2) 1-5 (e.g., 1, 2, or 3) G C4 may be substituted with C 2-4 alkenyl group; (3) 1-5 (e.g., 1, 2, or 3) G C4 may be substituted with C 2-4 (4) an alkynyl group having one or two heteroatoms, which are independently N, O, or S; 1-4 Heteroalkyl groups (wherein S, if present, may be oxidized as SO or SO), where C 1-4The heteroalkyl group may be 1-5 (e.g., 1, 2, or 3) G C4 (6) 1-5 (e.g., 1, 2, or 3) G C4 may be substituted with C 3-6 cycloalkyl groups; (7) 1-5 (e.g., 1, 2, or 3) G C4 (8) a 4-6 membered heterocyclyl group having 1-3 ring-forming heteroatoms, each independently selected from the group consisting of N, O, and S, each of which may be substituted with 1-5 (e.g., 1, 2, or 3) G C4 is a phenyl group or a 5- or 6-membered heteroaryl group, optionally substituted with Among them, G C4 each time it appears, it independently represents (a) halogen (e.g., F, Cl), OH, oxo (where applicable), or CN; (b) C optionally substituted with 1-3 F; 1-4 (c) a 3-4 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with 1-3 substituents that are independently F, OH, CN, or methyl; or (d) a C having 1 or 2 heteroatoms that are independently O, N, or S, optionally substituted with 1-3 F. 1-4 heteroalkyl groups (in which S, if present, may be oxidized as SO or SO); and g1 is an integer selected from the group consisting of 0, 1, 2 or 3, preferably 0 or 1. For clarity, and as will be appreciated by those skilled in the art, R G The -L group, if present, is attached to the phenyl portion of the bicyclic ring. 2 -X-(Ring A)-L 3 The residue of - (Ring B) should be linked to the bicyclic oxazine moiety.

[0081] In some embodiments according to general formula IC-1-a, g1 is 0.

[0082] In some embodiments according to general formula IC-1-a, gl is 1, wherein R Gis as defined herein, and preferably, in this case, R G is linked to the para position of the oxygen atom or the para position of the nitrogen atom, for example, the compound can have a structure according to general formula IC-1-a1 or IC-1-a2. TIFF2024532845000075.tif46166

[0083] In some embodiments, gl is 1 and R G is halogen (preferably F or Cl), CN, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 an alkyl group, or 1-5 (e.g., 1, 2, or 3) G D and preferably R G is F, Cl, CN, cyclopropyl, or 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 alkyl groups, among which G D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 In some embodiments, R G is F, Cl, CN, cyclopropyl or C 1-4 In some embodiments, R G C, which may be substituted with 1-3 F 1-4 In some embodiments, R G But C 2-4 Alkynyl groups, for example TIFF2024532845000076.tif1589. In some embodiments, R GC with one or two heteroatoms that are independently N, O, or S 1-4 Heteroalkyl groups (wherein S, if present, may be oxidized as SO or SO), where C 1-4 The heteroalkyl group may be 1-5 (e.g., 1, 2, or 3) G C4 may be substituted with, for example, R G but, TIFF2024532845000077.tif1983 or, TIFF2024532845000078.tif1585. In some embodiments, R G But C 3-6 a cycloalkyl group, e.g., cyclopropyl, and 1-5 (e.g., 1, 2, or 3) G C4 may be substituted with, for example, R G is cyclopropyl or TIFF2024532845000079.tif1888. In some embodiments, R G but 1-5 (e.g., 1, 2, or 3) G C4 a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms each independently selected from the group consisting of N, O and S, which may be substituted with, for example, TIFF2024532845000080.tif2490. In some embodiments, R G Each of these has 1-5 (e.g., 1, 2, or 3) G C4 and optionally substituted 5- or 6-membered heteroaryl groups, such as TIFF2024532845000081.tif2286. In some embodiments, R G But CONHG A4 ,for example, TIFF2024532845000082.tif2570 or TIFF2024532845000083.tif2168. In some embodiments, R G However, NHCOG A4 ,for example, TIFF2024532845000084.tif2268.

[0084] In some embodiments, R G represents, independently, F, Cl, CN, C optionally substituted with 1-3 F 1-4 alkyl groups (e.g., CHF2), cyclopropyl, TIFF2024532845000085.tif40166 or TIFF2024532845000086.tif2368.

[0085] In some embodiments according to general formulas IC-1 to IC-3, R 5 One example of L 2 may be linked together with the atoms therebetween to form an optionally substituted 5-7 membered ring structure, for example, cyclopropyl.

[0086] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 is a single bond, and preferably, L 1 is a single bond, L 2 is never a single bond.

[0087] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 is S(O), S(O)2, C(O), C(O)O, C(O)NR 16 , OC(O)NR 16 , S(O)NR 16 , N.R. 17 C(O)NR 16 , or NR 17 S(O)NR 16 Among them, R 16 and R 17 is as defined herein. For example, in some embodiments, R 16 and R 17 are independently hydrogen or optionally substituted C 1-4 It is an alkyl group.

[0088] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 is a linear or branched, optionally substituted alkylene group, for example, an optionally substituted C 1-4 It is an alkylene group.

[0089] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 may be a linear or branched, optionally substituted alkenylene group, for example, optionally substituted C 2-4 It is an alkenylene group.

[0090] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 may be a linear or branched, optionally substituted alkynylene group, for example, optionally substituted C 2-4 It is an alkynylene group.

[0091] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 is a straight-chain or branched, optionally substituted heteroalkylene group, for example, optionally substituted C 1-4 It is a heteroalkylene group.

[0092] In some embodiments, L1 in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted cycloalkylene group, e.g., an optionally substituted C3-6 cycloalkylene group.

[0093] In some embodiments, L 1 in general formula I (eg, any applicable subgeneral formula according to the present disclosure) is an optionally substituted phenylene group.

[0094] In some embodiments, L1 in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted heteroarylene group, for example, an optionally substituted 5- or 6-membered heteroarylene group having 1-3 ring-forming heteroatoms, each independently selected from the group consisting of O, N, and S.

[0095] In some embodiments, L in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is O, S, or NR, where R is hydrogen or optionally substituted C. 1-4 It may be an alkyl group, for example, methyl.

[0096] In some specific embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 1 However, it may also be O.

[0097] In some embodiments, the general formula I (e.g., any applicable subgeneric formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC- In the formula (IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4), L2 is a single bond, and preferably, when L2 is a single bond, L1 is not also a single bond.

[0098] In some embodiments, L2 in general formula I (e.g., any applicable subgeneric formula according to this disclosure) is S(O), S(O)2, C(O), C(O)O, C(O)NR16, OC(O)NR16, S(O)2NR16, NR17C(O)NR16, or NR17S(O)2NR16, where R16 and R17 are as defined herein. For example, in some embodiments, R16 and R17 are independently hydrogen or optionally substituted C 1-4 It is an alkyl group.

[0099] In some embodiments, L2 in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted alkylene group, which may be linear or branched, such as an optionally substituted C 1-4 Alkylene groups such as methylene and ethylene.

[0100] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted alkenylene group, which may be linear or branched, such as an optionally substituted C 2-4 It is an alkenylene group.

[0101] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted alkynylene group, which may be linear or branched, such as an optionally substituted C 2-4 It is an alkynylene group.

[0102] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is a linear or branched, optionally substituted heteroalkylene group, such as an optionally substituted C 1-4 It is a heteroalkylene group.

[0103] In some embodiments, L2 in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted cycloalkylene group, e.g., an optionally substituted C3-6 cycloalkylene group.

[0104] In some embodiments, L2 in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is an optionally substituted heterocyclylene group, for example, an optionally substituted 4-10 membered (e.g., 3-8 membered or 5-8 membered) heterocyclylene group having 1-3 ring-forming heteroatoms, each independently selected from the group consisting of O, N, and S.

[0105] In some embodiments, L2 in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is an optionally substituted phenylene group, where, when substituted, the phenylene group is generally optionally substituted with 1-5 (e.g., 1, 2, or 3) GB; Among them, G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G C represents independently F; OH; C optionally substituted with 1-3 F; 1-4alkyl group; or C optionally substituted with 1-3 F 1-4 It is an alkoxy group. In some embodiments, the phenylene group generally comprises 1-5 (e.g., 1, 2, or 3) G B1 wherein G B1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 Alkoxy groups, among which G C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy).

[0106] In some specific embodiments, the general formula I (e.g., any applicable subgeneric formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2 ...2, IB-2-E2, IB-2-E2, IB-2-E2, IB-2-E2, IB-2-E2, IB-2-E B-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC -1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4) 2may be a phenylene group selected from the group consisting of: TIFF2024532845000087.tif49166 and TIFF2024532845000088.tif1968

[0107] In some embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 2 is an optionally substituted heteroarylene group, for example, an optionally substituted 5- or 6-membered heteroarylene group having 1 to 3 ring-forming heteroatoms, each independently selected from the group consisting of O, N, and S. When substituted, the heteroarylene group generally has 1 to 5 (e.g., 1, 2, or 3) G B may be substituted with Among them, G B each occurrence independently represents a halogen (preferably F, Cl, or Br); CN; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 alkyl group; OH; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkoxy groups; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 3-6 a cycloalkoxy group; or 1-5 (e.g., 1, 2, or 3) G C is an optionally substituted 4-6 membered heterocycloalkoxy group; Among them, G Crepresents independently F; OH; C optionally substituted with 1-3 F; 1-4 alkyl group; or C optionally substituted with 1-3 F 1-4 It is an alkoxy group. In some embodiments, the heteroarylene group comprises 1-5 (e.g., 1, 2, or 3) G B1 wherein G B1 represents independently F; Cl; Br; CN; C optionally substituted with 1-3 F 1-4 Alkyl group;OH;C 3-6 cycloalkyl groups; 1-5 (e.g., 1, 2, or 3) G C1 a 4- to 6-membered monocyclic heterocyclyl group having 1 to 2 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with ; NH; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or C optionally substituted with 1-3 F 1-4 Alkoxy groups, among which G C1 represents independently F; OH; C optionally substituted with 1-3 F; 1-3 an alkyl group (preferably methyl); or a C optionally substituted with 1-3 F 1-3 It is an alkoxy group (preferably methoxy).

[0108] In some specific embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) 2 but, TIFF2024532845000089.tif2171 or, It could also be TIFF2024532845000090.tif1973.

[0109] In some embodiments, L2 in general formula I (eg, any applicable subgeneral formula according to this disclosure) can be O.

[0110] In some embodiments, L in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is a C having 1 or 2 heteroatoms, each independently selected from the group consisting of O, S, and N. 1-4 For example, in some embodiments, L in general formula I may be a C 1-4 It may also be a heteroalkylene group. In some specific embodiments, L in general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4) 2 but, TIFF2024532845000091.tif1481 ​​or, It could also be TIFF2024532845000092.tif1381.

[0111] In some embodiments, the compound of general formula I is characterized by having the general formula ID-1, ID-2, or ID-3. TIFF2024532845000093.tif147110 where, Variable R 1 , R 2 , L 1 , L 3 wherein X, ring A and ring B include any combination of the definitions described herein; h is 0, 1 or 2, and R 6each time represents, independently, F, Cl, Br, CN, 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group, OH, cyclopropyl, cyclobutyl, 1-5 (e.g., 1, 2, or 3) G C a 4- to 6-membered heterocyclyl group having 1 to 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with NH, NH(C 1-4 alkyl group), N(C 1-4 alkyl group)(C 1-4 alkyl group), or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 is an alkoxy group, Among them, G C represents, independently, F, OH, C, which may be substituted with 1-3 F 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 is an alkoxy group; Alternatively, R 6 One example of L 1 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure. In some embodiments, R 6 Each time it represents F, Cl, C which may be substituted with 1-3 F 1-4 It is an alkyl group, or cyclopropyl.

[0112] Generally, in general formulas ID-1 to ID-3, L1 is O, S, NH, or NCH3. In some specific embodiments, in general formulas ID-1 to ID-3, L1 is O.

[0113] In some embodiments according to general formulas ID-1 to ID-3, h is 0.

[0114] In some embodiments according to general formulas ID-1 to ID-3, h is 1 and R6 is as defined herein. For example, in some embodiments, R6, each time it occurs, can be selected from the group consisting of F, Cl, C, optionally substituted with 1-3 F. 1-4 It is an alkyl group, or cyclopropyl.

[0115] In embodiments according to general formulas ID-1 to ID-3, the X-(ring A)-L3-(ring B) moiety is generally 1 is linked to a phenylene group or a pyridinylene group at the meta position. For example, in some embodiments, the compounds of general formulas ID-1 to ID-3 are each characterized by having one of the following general formulas: TIFF2024532845000094.tif155117, where variable R 1 , R 2 , R 6 , h, L 1 , L 3 , X, ring A, and ring B include any combination of any of the definitions described for general formulas ID-1 to ID-3 herein. For example, in some embodiments, L 1 is O and the compound has one of the following general formulas: TIFF2024532845000095.tif156117, where variable R 1 , R 2 , R 6 , h, L 3 , X, ring A and ring B include any combination of any of the definitions described for general formulae ID-1 to ID-3 in this application.

[0116] In some embodiments according to general formulas ID-1 to ID-3, R 6 One example of L 1 are linked together with the atoms therebetween to form an optionally substituted 5- to 7-membered ring structure. For example, in some embodiments, the compound of general formula ID-1 is characterized by having the following general formula ID-1-c: TIFF2024532845000096.tif49108, wherein h is 0 or 1, and the variables R1, R2, R6, L3, X, ring A, and ring B include any combination of the definitions described herein. As will be apparent to one skilled in the art, in general formula ID-1-c, R6 and -X-(ring A)-L3-(ring B) are both connected to a benzene ring.

[0117] Generally, general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a 2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC -3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), where X is C(O).

[0118] However, in some embodiments, X in general formula I (e.g., any applicable subgeneric formula according to this disclosure) can be G1-C(O)-G2, where G1 and G2 are as defined herein. For example, in some embodiments, G1 and G2 can each independently be a single bond, O, NH, or an optionally substituted C(O)-C ... 1-4 Alkylene groups, such as methylene, or optionally substituted C 1-4 In some embodiments, G is a heteroalkylene group. 1 and G 2are linked to form an optionally substituted 4- to 7-membered ring, typically with each ring-forming heteroatom independently being O or N, for example, forming a lactam ring or an imidazolinone ring. For example, in some embodiments, X in general formula I (e.g., any applicable subgeneral formula according to the present disclosure) is TIFF2024532845000097.tif2474 or It could also be TIFF2024532845000098.tif2168.

[0119] In some embodiments, X in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is G 1 -S(O)2-G 2 wherein G 1 and G 2 is as defined herein. For example, in some embodiments, G 1 and G 2 are each independently a single bond, O, NH, or optionally substituted C 1-4 Alkylene groups, such as methylene, or optionally substituted C 1-4 In some embodiments, G is a heteroalkylene group. 1 and G 2 are linked to form an optionally substituted 4- to 7-membered ring, which generally has one or two ring-forming heteroatoms, each independently O or N, other than the S atom derived from the SO2 group.

[0120] In some embodiments, X in general formula I (eg, any applicable subgeneral formula according to this disclosure) can be S(O) or S(O) 2 .

[0121] In some embodiments, X in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is It may be TIFF2024532845000099.tif2292 or S(O)2.

[0122] General Formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2 Ring A in -E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c) is typically an optionally substituted 4- to 7-membered monocyclic heterocyclyl group having one or two ring heteroatoms independently selected from the group consisting of N, O, and S, preferably at least one ring heteroatom is N. For example, in some embodiments, ring A in general formula I may be a saturated 4- or 6-membered heterocyclic ring having one or two ring heteroatoms, e.g., one or two ring nitrogens, such as a pyrrolidine ring or a piperazine ring, which may be substituted. When substituted, a 4-7 membered monocyclic heterocyclyl group typically contains 1-5 (e.g., 1, 2 or 3) G A where G is substituted A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 an alkoxy group; Crepresents, independently, F, OH, C, which may be substituted with 1-3 F 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 In some embodiments, when substituted, the 4-7 membered monocyclic heterocyclyl group is substituted with 1-5 (e.g., 1, 2, or 3) G A where G is substituted A each occurrence is independently F; oxo; methyl; OH; NH; NH(CH); N(CH) or methoxy. In some embodiments, the 4-7 membered monocyclic heterocyclyl group is unsubstituted.

[0123] In some embodiments, general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E In the formulas (ID-1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), ring A is an optionally substituted 6- to 10-membered fused, spiro, or bridged bicyclic heterocyclyl group having one or two ring-forming heteroatoms (preferably, at least one ring-forming heteroatom is N), each independently selected from the group consisting of N, O, and S. When substituted, the 6- to 10-membered fused, spiro, or bridged bicyclic heterocyclyl group may have one to five (e.g., one, two, or three) G A where G is substituted Aeach occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 an alkoxy group; C Each time it represents, it may be independently substituted by F, OH, 1-3 F, C 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 In some embodiments, when substituted, the 6-10 membered fused, spiro, or bridged bicyclic heterocyclyl group has 1-5 (e.g., 1, 2, or 3) G A where G is substituted A each occurrence is independently F; oxo; methyl; OH; NH; NH(CH); N(CH) or methoxy. In some embodiments, the 6-10 membered fused, spiro or bridged bicyclic heterocyclyl group is unsubstituted.

[0124] In some specific embodiments, ring A in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is optionally substituted: In some specific embodiments, ring A in general formula I (e.g., any applicable subgeneric formula according to the present disclosure) is optionally substituted: TIFF2024532845000101.tif2868. When substituted, the piperazine or pyrrolidine generally has 1-5 (e.g., 1, 2, or 3) G A where G is substituted A each occurrence independently represents halogen (preferably F) or CN; oxo; 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4Alkyl group; OH; NH2; NH(C 1-4 alkyl group);N(C 1-4 alkyl group)(C 1-4 alkyl group); or 1-5 (e.g., 1, 2, or 3) G C may be substituted with C 1-4 an alkoxy group; C Each time it represents, it may be independently substituted by F, OH, 1-3 F, C 1-4 C optionally substituted with alkyl group or 1-3 F 1-4 For example, in some embodiments, piperazine or pyrrolidine may have 1-5 (e.g., 1, 2, or 3) G groups. A wherein G A each time it occurs, it is independently F; oxo; methyl; OH; NH; NH(CH); N(CH) or methoxy. In some embodiments, when substituted, two substituents of piperazine or pyrrolidine are joined together with the atoms between them to form a 3-4 membered ring, e.g., cyclopropyl, and the piperazine or pyrrolidine further comprises 1-3 G A wherein G A is as defined above, for example, ring A is TIFF2024532845000102.tif3386 or TIFF2024532845000103.tif3386, and its top or bottom connection point is L 3 - may be connected to ring B, preferably at the bottom connection point L 3 - linked to ring B. In some embodiments, the piperazine or pyrrolidine is unsubstituted.

[0125] In some specific embodiments, the general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a 1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC- 3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), ring A is The file is TIFF2024532845000104.tif3384.

[0126] Generally, general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, I C-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC -3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), L 3 is a single bond. Generally, in these embodiments, Ring A is linked to Ring B at a ring-forming nitrogen atom.

[0127] In some embodiments, ring A is L 3 (Whether it is O, NH or N(C 1-4 and L is connected to ring B via a group (which may be an alkyl group), 3 is not linked to a ring-forming heteroatom of ring A or ring B.

[0128] General Formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3

[0033] Ring B in formula I (ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c) is typically an optionally substituted 5- or 6-membered heteroaryl group having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S. For example, in some embodiments, ring B in formula I is an optionally substituted pyridine, pyrazine, thiazole, thiadiazole, or pyrimidine. In some embodiments, when substituted, the 5- or 6-membered heteroaryl group is typically optionally substituted with 1-3 substituents, which are independently selected from F, Cl, Br, CN, C, optionally substituted with 1-3 F. 1-4 C optionally substituted with alkyl group, OH, cyclopropyl, cyclobutyl, or 1-3 F 1-4In some embodiments, when substituted, the 5- or 6-membered heteroaryl group may be substituted with 1-3 (preferably 1) substituents independently selected from the group consisting of: (1) F, Cl, Br, OH, or CN; (2) C optionally substituted with 1-3 F; 1-4 (3) C optionally substituted with hydroxy 1-4 (4) cyclopropyl or cyclobutyl, each optionally substituted with one or two substituents independently selected from F, methyl, CN, or OH; (5) C, optionally substituted with one to three F groups. 2-4 Alkynyl group; (6) C having one or two heteroatoms independently selected from the group consisting of O and N, optionally substituted with 1-3 F; 1-4 In some embodiments, when substituted, the 5- or 6-membered heteroaryl group is optionally substituted with one or two substituents (preferably one substituent), and the substituents are independently selected from F, Cl, CN, C, optionally substituted with 1-3 F. 1-4 It is selected from the group consisting of an alkyl group (e.g., CHF2 or CF3), or cyclopropyl.

[0129] In some specific embodiments, the general formula I (e.g., any applicable subgeneral formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a 1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC- Ring B in 3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c) is TIFF2024532845000105.tif2979 or TIFF2024532845000106.tif2096, or ring B may be TIFF2024532845000107.tif32166, or ring B is TIFF2024532845000108.tif32102 or The file is TIFF2024532845000109.tif1972.

[0130] In some embodiments according to general formula I, L 3 When L is a single bond, ring A and ring B together can represent an optionally substituted cyclic structure having one ring or at least two rings, e.g., a bicyclic structure. For example, in some embodiments, ring A and ring B together are an optionally substituted monocyclic aromatic or heteroaromatic ring, in other words, one of rings A and B is absent. In some embodiments, ring A and ring B together form an optionally substituted cyclic structure having at least two rings, e.g., a bicyclic ring, e.g., a bicyclic heteroaryl group or heterocyclic ring. In some embodiments, L3 is a single bond, and where applicable, ring A and ring B together form an optionally substituted cyclic structure, such as an optionally substituted piperidine, piperazine or fused tetrahydrotriazolopyrimidine ring, e.g., TIFF2024532845000110.tif3088 or, Showing TIFF2024532845000111.tif3088.

[0131] The combinations of variables in each general formula of the present application are not particularly limited and include any applicable combinations exemplified in the specific compounds shown in the present application, such as those shown in the Examples section or Table A of the present application.

[0132] In some embodiments, any applicable general formula according to the present disclosure, e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2 , IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC -X-(ring A)-L in -3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c 3 -(Ring B) is TIFF2024532845000112.tif34157 or In some preferred embodiments, -X-(ring A)-L in any applicable general formula according to the present disclosure may be 3 -(Ring B) is It could also be TIFF2024532845000114.tif3067.

[0133] In some specific embodiments, -X-(ring A)-L in any applicable general formula according to the present disclosure 3 -(Ring B) special feature, TIFF2024532845000115.tif3377, in which ring B is TIFF2024532845000116.tif30166 or In some specific embodiments, -X-(ring A)-L in any applicable general formula according to the present disclosure 3 -(Ring B) special feature, TIFF2024532845000118.tif3365 structure: wherein ring B is TIFF2024532845000119.tif31166 or TIFF2024532845000120.tif31101, for example, -X-(ring A)-L 3 -(Ring B) is In some specific embodiments, -X-(ring A)-L in any applicable general formula according to the present disclosure 3 -(Ring B) is TIFF2024532845000122.tif3775 or, TIFF2024532845000123.tif3569, wherein ring B is TIFF2024532845000124.tif32166 or In some specific embodiments, -X-(ring A)-L in any applicable general formula according to the present disclosure 3 -(Ring B) special feature, TIFF2024532845000126.tif39101 or TIFF2024532845000127.tif3877, in which ring B is TIFF2024532845000128.tif31106 or The file is TIFF2024532845000129.tif2061.

[0134] The present disclosure provides the following exemplary embodiments according to subgeneral formulae of general formula I of the present disclosure: Embodiment 1. Compounds of the general formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, Compound IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, or a pharmaceutically acceptable salt thereof. Embodiment 2. General formula I-1, IB, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-2-E1, IB-2-E2, IB-1-E1-a, IB-1-E2-a, IB-3-E1 , IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2 -E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, where R1 is hydrogen, CH3, ethyl, isopropyl, cyclopropyl, CN, OCH3, SCH3, CF3, F, Cl, Br, CF2H, TIFF2024532845000130.tif1379 or, TIFF2024532845000131.tif1790, or R1 is OCH2CF2H, or a pharmaceutically acceptable salt thereof. Embodiment 3. R in general formula I-1, I-2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c 2 But hydrogen, CH3, CF3, TIFF2024532845000132.tif1063NH2, NHCH3, TIFF2024532845000133.tif50166 or TIFF2024532845000134.tif1890; Alternatively, R 2but, TIFF2024532845000135.tif56166 or TIFF2024532845000136.tif2392; Alternatively, R 2 but, TIFF2024532845000137.tif30110 or TIFF2024532845000138.tif2673; Alternatively, R 2 but, TIFF2024532845000139.tif56166 or TIFF2024532845000140.tif2884; Alternatively, R 2 but, TIFF2024532845000141.tif3277 or TIFF2024532845000142.tif2564; Alternatively, R2 is cyclopropyl. 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof. Embodiment 4. General formula I-1, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, I R 1 and R 2 are joined together with the atoms therebetween to form a ring structure selected from the group consisting of: TIFF2024532845000143.tif44154 or forming a ring structure selected from the group consisting of: TIFF2024532845000144.tif63159, wherein the top linkage of the fragment is linked to the carbonyl group in the corresponding general formula The compound of embodiment 1 or a pharmaceutically acceptable salt thereof. Embodiment 5. In the general formula I-1, I-2, IA, IA-1, IA-2 or IA-3, L 1 is an optionally substituted ring selected from the group consisting of: or a pharmaceutically acceptable salt thereof. TIFF2024532845000145.tif27113 or TIFF2024532845000146.tif2677 Embodiment 6. When the optionally substituted ring is substituted, it is substituted with one or more (e.g., 1-5 or 1-3) substituents, each of which is independently selected from halogen (preferably F or Cl), CN, 1-5 (e.g., 1, 2, or 3) G D may be substituted with C 1-4 an alkyl group, or 1-5 (e.g., 1, 2, or 3) G D cyclopropyl, optionally substituted by G D represents independently F; OH; C optionally substituted with 1-3 F; 1-4 Alkoxy group; C optionally substituted with 1-3 F 3-6 a cycloalkoxy group; or a C optionally substituted independently with F, OH, and 1-3 F 1-4 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups 3-6 The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R is a cycloalkyl group. Embodiment 7. When the optionally substituted ring is substituted, it is substituted with one or two substituents, each of which is independently F or methyl; or in general formula IC-1-a, g1 is 1 and R G is F, Cl, CN, cyclopropyl or C 1-4 is an alkyl group, preferably R Gis located at the para position of the oxygen atom; or in general formula IC-1-a1 or IC-1-a2, R G C optionally substituted with F, Cl, CN, 1-3 F 1-4 Alkyl groups, cyclopropyl groups, TIFF2024532845000147.tif42164 or TIFF2024532845000148.tif2578 or a pharmaceutically acceptable salt thereof. Embodiment 8. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted ring is selected from the group consisting of: TIFF2024532845000149.tif25100Embodiment 8. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted ring is selected from the group consisting of: TIFF2024532845000150.tif2399Embodiment 9. In the general formula I-1, I-2, IA, IA-1, IA-2, IA-3, ID-1, ID-2, ID-3, ID-1-a, ID-2-a or ID-3-a, L 1 The compound of any of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein is O, S, NH, or NCH3. Embodiment 10. In the general formula I-1, I-2, ID-1, ID-2, ID-3, ID-1-a, ID-2-a or ID-3-a, R 2 and L 1 or a pharmaceutically acceptable salt thereof. Embodiment 11. When the optionally substituted 5-7 membered heterocyclyl group is substituted with one ring-forming heteroatom, it is independently methyl, phenyl, TIFF2024532845000151.tif1892 or, TIFF2024532845000152.tif1892, or a pharmaceutically acceptable salt thereof. Embodiment 12. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC- 1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, I C-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4, L 2 is a single bond (i.e., X is directly connected to L 1 12. The compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof. Embodiment 13. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1 , IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC- 2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4, L 2 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein: is a phenylene group selected from the group consisting of: TIFF2024532845000153.tif46159 and TIFF2024532845000154.tif1985 Embodiment 14. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1 -a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3- E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC -1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4, L 2 but, TIFF2024532845000155.tif1287 or TIFF2024532845000156.tif1287 or a pharmaceutically acceptable salt thereof. Embodiment 15. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC- 1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, I C-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4, L 2 but, TIFF2024532845000157.tif2090 or, TIFF2024532845000158.tif2090, or a pharmaceutically acceptable salt thereof. Embodiment 16. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC- 1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, I C-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, or IC-3-E4, L 2 But C 1-4 12. The compound of any of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein the alkylene group is preferably methylene or ethylene. Embodiment 17. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1 -E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC- 17. The compound of any of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein X is C(O) in: ID-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c. Embodiment 18. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB- 1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC- 3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC -3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, where X is TIFF2024532845000159.tif2498 or S(O)2, or a pharmaceutically acceptable salt thereof. Embodiment 19. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB- 1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC- 3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC- In 3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, ring A is TIFF2024532845000160.tif2874 or, TIFF2024532845000161.tif2662, which is substituted as described herein, for example, where ring A is TIFF2024532845000162.tif3198 or, 19. The compound of any of embodiments 1-18, wherein the compound is TIFF2024532845000163.tif3198, or a pharmaceutically acceptable salt thereof. Embodiment 20. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB- 1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC -3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, I C-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, L 3 20. The compound of any of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein is a single bond. Embodiment 21. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB- 1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC -3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, I C-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, L 320. The compound of any of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein is O, NH, or NCH3. Embodiment 22. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E 2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein in IC-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, Ring B is an optionally substituted 5- or 6-membered heteroaryl group selected from the group consisting of pyridine, pyrazine, thiazole, thiadiazole, and pyrimidine, wherein the appropriate substituents are as described herein. Embodiment 23. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB- 1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC- 3, IC-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC- In 3-E3, IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, ring B is TIFF2024532845000164.tif2670 or TIFF2024532845000165.tif1968; or ring B is TIFF2024532845000166.tif31158, or ring B is TIFF2024532845000167.tif3078 or TIFF2024532845000168.tif1875 or a pharmaceutically acceptable salt thereof. Embodiment 24. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1- E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, I C-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3 , IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, -X-(Ring A)-L 3 -(Ring B) is TIFF2024532845000169.tif36145 or, 17. The compound of any of embodiments 1-16, which is TIFF2024532845000170.tif3497 or any of those exemplified in the Examples or a compound in Table A, or a pharmaceutically acceptable salt thereof. Embodiment 25. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1- E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, I C-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3 , IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, -X-(Ring A)-L 3 -(Ring B) is TIFF2024532845000171.tif3586 structure, wherein ring B is TIFF2024532845000172.tif30158 or 17. The compound of any of embodiments 1-16, wherein the compound is TIFF2024532845000173.tif3073, or a pharmaceutically acceptable salt thereof. Embodiment 26. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1- E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, I C-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3 , IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, -X-(Ring A)-L 3 -(Ring B) is TIFF2024532845000174.tif3070 structure, in which ring B is TIFF2024532845000175.tif27144 or TIFF2024532845000176.tif2763 For example, -X-(ring A)-L 3 -(Ring B) is 17. The compound of any of embodiments 1-16, wherein the compound is TIFF2024532845000177.tif3075, or a pharmaceutically acceptable salt thereof. Embodiment 27. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1- E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, I C-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3 , IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, -X-(Ring A)-L 3 -(Ring B) is TIFF2024532845000178.tif3494 or TIFF2024532845000179.tif3494, wherein ring B is TIFF2024532845000180.tif31158 or 17. The compound of any of embodiments 1-16, wherein the compound is TIFF2024532845000181.tif2970, or a pharmaceutically acceptable salt thereof. Embodiment 28. General formula I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1- E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, I C-1-E1, IC-1-E2, IC-1-E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3 , IC-3-E4, ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c, -X-(Ring A)-L 3 -(Ring B) is TIFF2024532845000182.tif34104 or TIFF2024532845000183.tif34104, wherein ring B is TIFF2024532845000184.tif2791 or 17. The compound of any of embodiments 1-16, wherein the compound is TIFF2024532845000185.tif1770, or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the present disclosure further provides a compound selected from Table A below, a deuterated analog thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. TIFF2024532845000186.tif232166TIFF2024532845000187.tif217166TIFF2024532845000188.tif223166TIFF2024532845000189.t if225166TIFF2024532845000190.tif217166TIFF2024532845000191.tif225166TIFF2024532845000192.tif220166TIFF20245328450 00193.tif218166TIFF2024532845000194.tif211166TIFF2024532845000195.tif229166TIFF2024532845000196.tif214166TIFF202 4532845000197.tif217166TIFF2024532845000198.tif215166TIFF2024532845000199.tif212166TIFF2024532845000200.tif100166

[0136] In some embodiments, where applicable, the compounds set forth in Table A can exist as a single enantiomer having an enantiomeric excess ("ee") of greater than 60%, e.g., greater than 80% ee, greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, greater than 99% ee, or with no detectable other enantiomer. In some embodiments, where applicable, the compounds set forth in Table A can exist as a mixture of stereoisomers in any proportion, e.g., a racemic mixture.

[0137] In some embodiments, where applicable, the classes of compounds in this disclosure exclude any compounds that have been specifically made and disclosed prior to this disclosure.

[0138] Synthesis method In view of the present disclosure, one of ordinary skill in the art can readily synthesize the compounds of the present disclosure. Exemplary syntheses are provided in the Examples section.

[0139] The following synthetic methods of general formula I are illustrative: In some embodiments, the present disclosure provides synthetic methods and synthetic intermediates for making compounds of general formula I, such as those shown in the reaction schemes herein. TIFF2024532845000201.tif94166

[0140] As shown in Scheme 1, compounds of formula I can generally be synthesized by coupling S-1 with S-2, followed by deprotection if necessary. Generally, S-1 is a compound having a leaving group Lg 1 , for example, a halogen, such as Cl, which reacts with S-2, for example, T 1 is hydrogen or metal, and L 1 -T 1 may have a nucleophilic functional group (e.g., OH, NH, SH, etc.) that can react with S-1 to form the required linkage shown in S-3. In some embodiments, Pg in S-1 may be 1 is a protecting group, e.g., SEM (2-(trimethylsilyl)ethoxymethyl), and the synthesis of general formula I can be carried out by 1 In some embodiments, Pg in S-1 must be deprotected from S-3. 1 may be hydrogen, in which case S-3 is a compound of general formula I. In some embodiments, R 1 and / or R 2 may be different from the corresponding moiety in general formula I, in which case further functionalization of S-3 provides the target compound of general formula I. For example, in some embodiments, R 1 and / or R 2 may also be a leaving group, which, when appropriate, may be reacted to form a different R 1 and / or R 2 A group can be introduced. Exemplary reaction conditions for converting compounds of S-1 and S-2 to compounds of general formula I are shown in the Examples section. Where applicable, the variable R in general formulas S-1, S-2, and S-3 of Scheme 1 1 , R 2 , L 1 , L 2 , L3 , X, Z, ring A and ring B include any of the definitions above associated with general formula I (eg, any subgeneric formula of general formula I) and protected derivatives thereof.

[0141] In accordance with the present disclosure, as will be apparent to those skilled in the art, compounds of general formula I can be synthesized by different coupling strategies. For example, as shown in Scheme 2, S-4 can be coupled with S-5 under appropriate conditions to form L in S-3. 1 -L 2 Linkage formation followed by optional deprotection (Pg 1 is a protecting group) and / or further functionalization to provide the desired compounds of general formula I. For example, in some embodiments, L 1 -T 2 is optionally L 1 , R 1 , R 2 When a ring structure is formed between R 1 and R 2 and S-5 together can have a nucleophilic functional group (e.g., OH, NH, SH, etc.) that can react with S-5 to form the necessary linkage shown in S-3, 3 But, L 2 indicates the precursor of L 1 -T 2 reacts with the L required in S-3 1 -L 2 For example, in some embodiments, the L 1 -L 2 Consolidation is OC 1-4 In some embodiments, L 1 -T 2 may contain an OH group, and T 3 C 1-4 Alkylene group -Lg 2 or vinyl group, where Lg 2 is a leaving group, e.g., a halogen, e.g., Cl, and when it reacts, S-3 becomes OC 1-4Linkages containing alkylene groups or O-ethylene can be provided. Exemplary reaction conditions for converting compounds of S-4 and S-5 to compounds of general formula I are shown in the Examples section. Where applicable, the variable R in general formulas S-4, S-5, and S-3 of Scheme 2 1 , R 2 , L 1 , L 2 , L 3 , X, Z, ring A and ring B include any of the definitions above associated with general formula I (eg, any subgeneric formula of general formula I) and protected derivatives thereof. TIFF2024532845000202.tif96166

[0142] Similarly, for example, as shown in Scheme 3, S-6 can be coupled with S-7 under appropriate conditions to form the X linkage in S-3, followed by deprotection (Pg 1 is a protecting group) and / or further functionalization to provide the desired compounds of general formula I. For example, in some embodiments, L 2 -T 4 is optionally L 1 and L 2 When a ring structure is formed between L 1 together with an X donor that can react with S-7 to form the necessary linkage shown in S-3, wherein T 5 represents hydrogen. For example, in some embodiments, the linking X may be a C(=O) group, and in some embodiments, L 2 -T 4 may contain a COOH group, and the ring AT 5 reacts with COOH under appropriate conditions to provide the linkage X of C(=O) in S-3. Exemplary reaction conditions for converting compounds of S-6 and S-7 to compounds of general formula I are shown in the Examples section. Where applicable, the variable R in general formulas S-6, S-7, and S-3 of Scheme 3 1 , R 2 , L 1 , L 2 , L 3, X, Z, ring A and ring B include any of the definitions above associated with general formula I (eg, any subgeneric formula of general formula I) and protected derivatives thereof. TIFF2024532845000203.tif98166

[0143] As will be apparent to those skilled in the art, Pg in S-1, S-4 or S-6 1 is a protecting group, alternative protection strategies for masking the "amide" functionality can also be used. For example, in Schemes 1, 2, or 3, instead of S-1, S-4, or S-6, TIFF2024532845000204.tif39109 or TIFF2024532845000205.tif39109 can be used to provide S-3 and the corresponding portion of general formula I. Pg in S-1', S-4' or S-6' 3 Generally, it may be a group that can generate the "C(O)-NH" functional group in general formula I during a hydrolysis reaction. For example, in some embodiments, Pg 3 may be Cl or an alkoxy group, for example, methoxy or ethoxy.

[0144] Suitable coupling partners, e.g., S-1, S-2, S-4, S-5, S-6, S-7, S-1', S-4', or S-6', can be prepared by methods known in the art or according to the present disclosure (see, e.g., the Examples section).

[0145] As will be apparent to those skilled in the art, some functional groups may require common protecting groups to prevent undesired reactions. Suitable protecting groups for each functional group and suitable conditions for protecting and deprotecting specific functional groups are known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis" (4th ed., P.G.M.Wuts, T.W. Greene, John Wiley, 2007) and the references cited therein. Reagents for the reactions of the present invention are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, some reagents are commercially available, such as those sold by Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and supplements (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 available updated versions of any of these publications, or obvious modifications thereof.

[0146] Pharmaceutical Composition Some embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0147] The pharmaceutical composition may optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure and a pharmaceutically acceptable excipient. Pharmacologically acceptable excipients are well known in the art. Non-limiting examples of suitable excipients include, for example, sealants or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavor enhancers, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. Further, the prior art of each excipient and its preparation for preparing pharmaceutical compositions is disclosed in Remington's The Science and Practice of Pharmacy, 21 st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005, which is incorporated herein by reference).

[0148] A pharmaceutical composition can include any one or more compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition can include, for example, a therapeutically effective amount of a compound of general formula I (e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC The pharmaceutical composition may comprise a compound of formula (I), (II), (III), (IV ...

[0149] Pharmaceutical compositions can further be prepared to be administered by any known route of administration, including, but not limited to, oral administration, parenteral administration, inhalation administration, and the like.

[0150] In some embodiments, pharmaceutical compositions can be prepared for oral administration. Oral formulations can be presented as discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound; 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 preparing oral administration compositions are well known in the art. Non-limiting examples of suitable excipients include 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, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcellulose, isopropanol, saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, and the like. 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, stearic fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofuryl alcohol, triglycerides, water and mixtures thereof.

[0151] In some embodiments, the pharmaceutical composition is prepared in a dosage form for parenteral administration (e.g., intravenous injection or infusion, subcutaneous injection, or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for the manufacture of parenteral formulations are well known in the art. Non-limiting examples of 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.

[0152] In some embodiments, the pharmaceutical composition is prepared as an inhalable formulation. The inhalable formulation is prepared, for example, as a nasal spray, dry powder, or aerosol that can be administered using a metered-dose inhaler. Excipients for the manufacture of inhalable formulations are well known in the art. Non-limiting examples of suitable excipients include lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, and mixtures thereof. Sprays can further contain propellants such as chlorofluorocarbons and unsubstituted volatile hydrocarbon compounds such as butane and propane.

[0153] Pharmaceutical compositions can contain varying amounts of the compounds of the present disclosure, depending on various factors such as the intended use, efficacy, and selectivity of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used in this disclosure, a therapeutically effective amount of a compound of the present disclosure means an amount effective to treat a disease or condition according to the present disclosure, which depends on the subject 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 compound's efficacy (e.g., inhibition of PARP7), its clearance rate, and whether it is used in combination with other drugs.

[0154] For veterinary use, the compounds of the present disclosure can be administered in an appropriately acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0155] In some embodiments, all components necessary for the treatment of a PARP7-related disease can be packaged into a kit, using a compound of the present disclosure, either alone or in combination with another therapeutic or interventional agent conventionally used to treat such disease. Specifically, in some embodiments, the present invention provides kits for therapeutic intervention of a disease, comprising a compound of the present disclosure, a packaged drug set, including buffers and other ingredients for preparing the drug in a usable format, and / or a device for delivering such a drug, and / or any other agent for co-treatment with the compound of the present disclosure, and / or instructions for treating the disease in the drug package. These instructions can be fixed on any tangible medium, such as a printed paper, or a computer-readable magnetic or optical medium, or instructions referencing a remote computer data source (e.g., a World Wide Web page accessible via the Internet).

[0156] Treatment method The compounds of the present disclosure are useful for inhibiting the activity of PARP, particularly PARP7, in cells or subjects in need of enzyme inhibition. The compounds of the present disclosure are useful as therapeutically active agents for the treatment and / or prevention of diseases or conditions associated with PARP, particularly PARP7.

[0157] As described in WO2021 / 087018A1, WO2021 / 087025A1, and WO2019 / 212937, overexpression and / or activation of PARP7 has been shown to play a role in cancer cells evading the host immune system through suppression of type I interferon and T cell-mediated antitumor immunity. For example, it has been reported that PARP7 knockout in a mouse melanoma cell line increases the proliferation and activation of co-cultured T cells. Thus, PARP7 inhibition can activate T cell-mediated tumor killing.

[0158] Furthermore, a PARP7 inhibitor is currently undergoing Phase I clinical trials in patients with advanced or metastatic solid tumors. ClinicalTrials.gov ID: NCT04053673. As detailed in the clinical trial description, cancer cells use PARP7 to hide from the immune system, signaling the immune system to stop sending signals (type 1 interferons) that would otherwise kill the cells. According to the ClinicalTrials.gov description, the PARP7 inhibitor being tested (RBN2397) has been shown to inhibit tumor growth in animal models and block the "don't kill" signals tumors send to evade the immune system. These and other evidences further support the use of PARP7 inhibitors for the treatment of various diseases associated with abnormal PARP7 expression and / or activity.

[0159] In some embodiments, the disclosure provides a method for inhibiting PARP7, comprising contacting PARP7 with an effective amount of one or more compounds of the disclosure, e.g., compounds of general formula I (e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, I and / or a compound of any of the compounds numbered 1-353, any compound disclosed in Table A herein, or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the disclosure provides a method for inhibiting PARP7 in a cell (e.g., a cancer cell), comprising combining the cell with an effective amount of one or more compounds of the disclosure, e.g., compounds represented by general formula I (e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, The present invention provides a method for treating a cancer cell with a compound of the formula (I), (II), (III), (IV ... In some embodiments, the cancer cells are blood, breast, central nervous system, endometrial, kidney, colon, lung, esophagus, ovary, pancreas, prostate, stomach, head and neck (upper aerodigestive tract), urinary tract, colon, and / or other cells.

[0161] In some embodiments, the present disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present disclosure, e.g., compounds of general formula I (e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2-E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, and administering to a subject a compound of formula (I) or (II) of formula (II) or (II) (ID-1, ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), any compound of formula (I), or any compound disclosed in Table A of the present application, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (upper aerodigestive tract cancer), urinary tract cancer, or colon cancer. In some embodiments, the cancer is a hematopoietic malignancy such as leukemia and lymphoma. Examples of lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma. Examples of leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).In some embodiments, the cancer may be liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, digestive tumors, head and neck cancer (upper aerodigestive tract cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and / or uterine cancer. In some embodiments, the cancer may be multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive tract cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and / or breast cancer. In some embodiments, the cancer is associated with aberrant expression or activity of PARP7.

[0162] In some preferred embodiments, the compounds of the disclosure for the methods of the present application have a PARP7 IC50 or anti-proliferative IC50 of less than 100 nM when measured according to Biometric Examples A or B herein. In some preferred embodiments, the compounds of the disclosure for the methods of the present application are selected from the compounds according to Examples 1-353 having a PARP7 IC50 or anti-proliferative IC50 level designated "A" or "B," preferably "A," and are set forth in Tables 2 and / or 3 herein.

[0163] PARP7-associated conditions that can be treated with the methods of the present application also include those in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, which are characterized by overexpression or increased activity of PARP7.

[0164] The compounds of the present disclosure may be used as monotherapy or combination therapy. In some embodiments, combination therapy includes treating a subject with targeted therapeutic agents, chemotherapeutic or other anti-cancer agents, therapeutic antibodies, radiation therapy, cell therapy, anti-tumor and anti-viral vaccines, cytokine therapy, kinase inhibitors, epigenetic or signal transduction inhibitors, immune enhancers, immunosuppressants, and / or immunotherapy. In some embodiments, the compounds of the present disclosure may also be co-administered to a subject in need thereof with an additional pharmaceutically active compound, either simultaneously or sequentially in any order. The compounds of the present disclosure may be used in combination with any known therapeutic agent. In some embodiments, the compounds of the present disclosure may be used in combination with radiation therapy, hormone therapy, cell therapy, surgery, and / or immunotherapy, as known to those skilled in the art.

[0165] The compounds of the present disclosure can be used in combination with a variety of chemotherapeutic agents currently known in the art. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, antiangiogenic agents, 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 range of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosphosphamide (CYTOXANTM); alkylsulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenediamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylolomelamine. ethylenimines and methylamelamines; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine dichloromethyl hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Aclacinomycins, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, keramicin, lo Antibiotics such as dolubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; florinic acid Folic acid supplements such as aceglatone, aldophosphamide glycosides, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfomithine, elliptinium acetate, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenametPirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex; razoxane; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes such as paclitaxel and docetaxel; retinoic acid; esperamicin; capecitabine; and pharmacologically acceptable salts, acids, or derivatives of any of the above.

[0166] In some embodiments, compounds of the present disclosure can be used in combination with antihormonal agents, which act to regulate or inhibit hormone action on tumors, such as, for example, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY Antiestrogens such as 117018, onapristone, and toremifene (Fareston); and antiandrogens 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); the topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0167] In some embodiments, the compounds or pharmaceutical compositions of the present disclosure are administered in combination with commonly prescribed anti-cancer drugs, such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, Avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor drug, antitumor herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, afatinib 2992 (BIBW 2992), biricoda, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle nonspecific antitumor drug, dichloroacetic acid, discordermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, India Locarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome Inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford VV), swainsonine, talaporfin, tariquidar, tegafur uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uracil mustard, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0168] The compounds of the present disclosure can also be used in combination with VEGF or VEGFR inhibitors, or VEGFR kinase inhibitors. VEGFR kinase inhibitors and other anti-angiogenic inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0169] The compounds of the present disclosure may also be used in combination with inhibitors of FGFR inhibitors.

[0170] The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more agents selected from EGFR inhibitors, CDK 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 imids (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs).

[0171] In some embodiments, compounds of the present disclosure can also be used in combination with immunotherapies such as PD-1 and PD-L1 antagonists, such as anti-PD-1 or anti-PDL-1 antibodies, or anti-CTLA-4 or anti-4-1BB antibodies, etc. 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), disclose exemplary anti-PD-1 or anti-PDL-1 antibodies and methods of use thereof, each of which is expressly incorporated herein by reference.

[0172] Exemplary immunotherapies that can be used in combination with a compound or composition of the disclosure include pembrolizumab (Keytruda®), nivolumab (Opdivo®), Yervoy™ (pilimumab) or tremelimumab (anti-CTLA-4), galiximab (anti-B7.1), M7824 (bifunctional anti-PD-L1 / TGF-β Trap fusion protein), AMP224 (anti-B7DC), BMS-936559 (anti-B7-H1), MPDL3280A (anti-B7-H1), MEDI-570 (anti-ICOS), AMG 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).

[0173] Exemplary immunotherapies that can be used in combination with the compounds or compositions of the present disclosure further include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0174] Non-limiting useful additional reagents that can be used in combination with the compounds or compositions of the present disclosure further include anti-EGFR antibodies and small molecule EGFR inhibitors, such as cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, osimertinib, etc. Non-limiting useful additional reagents further include CDK inhibitors, such as CDK4 / 6 inhibitors, such as seliciclib, UCN-01, P1446A-05, palbociclib (PD-0332991), abemaciclib, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965, etc. Non-limiting examples of useful additional reagents include MEK inhibitors, such as trametinib (Mekinist®), CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0175] Other useful agents that can be used in combination with the compounds or compositions of the present disclosure include those described in the combination therapy section of WO2021 / 087018A1, WO2021 / 087025A1, or WO2019 / 212937.

[0176] The administration of the present disclosure is not limited to a particular route of administration. For example, in some embodiments, the mode of administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the mode of administration is oral.

[0177] Dosage regimens, including dosage, can vary and be adjusted depending on the subject 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.

[0178] definition It should be understood that all moieties and combinations thereof maintain the appropriate chemical value.

[0179] It should be understood that a specific embodiment of a variable portion according to the present disclosure may be the same as or different from another specific embodiment having the same reference number.

[0180] Suitable atoms or groups used for the variables in the present disclosure are independently selected. The variable definitions may be combined. For example, in Formula I, R 1 , R 2 , L 1 , L 2 , L 3 , X, Z, ring A, and ring B, 1 , R 2 , L 1 , L 2 , L 3 , X, Z, ring A and ring B. Such combinations are also contemplated and are within the scope of the present invention.

[0181] Definitions of specific functional groups and chemical terms are discussed in more detail below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover), and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0182] The compounds of the present disclosure can contain one or more asymmetric centers and / or axial chirality and therefore can exist in various isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds of the present disclosure can be in the form of a single enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), SFC, and the formation and crystallization of chiral salts; alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, 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 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds of the present disclosure as single isomers essentially free of other isomers or as mixtures of various isomers, including racemic mixtures.In embodiments of the present disclosure, unless otherwise stated, when stereochemistry is specifically depicted for a particular chiral center or axial asymmetry, it is understood that the compound exists primarily as the described stereoisomer, with less than 20%, less than 10%, less than 5%, less than 1%, or an undetectable amount of other stereoisomers, e.g., by weight, HPLC area or SFC area, or both. For example, it should be understood that the compound can exist as a single enantiomer with an enantiomeric excess ("ee") of greater than 80%, e.g., greater than 90% ee, greater than 95% ee, greater than 98% ee, greater than 99% ee, or with no detectable other enantiomers. According to the present disclosure, one skilled in the art can determine the presence and / or amount of stereoisomers by methods including determination by chiral HPLC or SFC. It should be noted that for any compound of the present disclosure in which the stereochemistry is specifically depicted in the present disclosure, the corresponding racemic or stereoisomeric mixtures thereof in any proportions are also encompassed within the scope of the present disclosure, and such racemic or stereoisomeric mixtures are also compounds of the present disclosure.

[0183] When a range of values ​​is stated, it is intended to encompass each value and subrange 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 is intended to encompass.

[0184] As used in this disclosure, the term "compound of the disclosure" or "compound of the invention" refers to a compound of general formula I (e.g., I-1, I-2, IA, IB, IAa, IA-1, IA-2, IA-3, IA-1-a, IB-1, IB-2, IB-3, IB-1-E1, IB-1-E2, IB-1-E1-a, IB-1-E2-a, IB-2-E1, IB-2 -E2, IB-3-E1, IB-3-E2, IC-1, IC-1-a, IC-1-a1, IC-1-a2, IC-2, IC-3, IC-1-E1, IC-1-E2, IC-1- E3, IC-1-E4, IC-2-E1, IC-2-E2, IC-2-E3, IC-2-E4, IC-3-E1, IC-3-E2, IC-3-E3, IC-3-E4, ID-1 , ID-2, ID-3, ID-1-a, ID-2-a, ID-3-a, ID-1-b, ID-2-b, ID-3-b, or ID-1-c), any compound numbered 1-353, any compound set forth in Table A of the present disclosure, its isotopically labeled compounds (e.g., deuterium analogs in which one hydrogen atom is replaced with a deuterium atom and the abundance of the deuterium atom is higher than its natural abundance), its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), geometric isomers, atropisomers, tautomers, conformers, and / or pharmacologically acceptable salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). For the avoidance of doubt, Compound No. 1-353 or Compound 1-353 refers to compounds described in the present disclosure labeled as integers 1, 2, 3, ..., 353, e.g., with reference to the title compounds in the Examples and Table 1. For convenience of description, synthetic starting materials or intermediates may be labeled with an integer (Compound No.) followed by "-" and additional numbers, such as 1-1, 1-2, etc., with reference to the Examples for details. Such synthetic starting material or intermediate labels should not be confused with compounds labeled with only the integer, excluding the "-" and additional numbers. Some of Compound 1-353 refer to enantiomers separated by the SFC method, e.g., as described in the Examples section.The absolute stereochemistry of these separated enantiomers has not been determined. If the assumed stereochemistry of these separated enantiomers described in the Examples section is incorrect, one skilled in the art would understand that the correct stereochemistry should be the enantiomer opposite the assumed one. Regardless, these separated enantiomers can also be characterized by their retention times in the chiral SFC methods described herein and their biological activity, such as inhibition of PARP7. It is clear that the corresponding racemic mixtures of these separated enantiomers are also compounds of the present disclosure. Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure in which the compounds are combined with water or solvent, respectively. In some embodiments, the compounds of the present disclosure refer to any of the compounds described in claims 1-86 herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present disclosure refer to any of the compounds according to exemplary embodiments 1-28 herein, or a pharmaceutically acceptable salt thereof.

[0185] The compounds of the present disclosure can exist in isotopically labeled or isotopically enriched forms containing one or more atoms having an atomic mass or mass number different from that most abundantly found in nature. Isotopes can 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 Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0186] As used in this disclosure, the phrase "administration" of a compound, "administering" a compound, or other variations thereof, means providing a compound or a prodrug of a compound to an individual in need of treatment.

[0187] As used in this disclosure, the term "alkyl group," when used alone or as part of another group, means a straight-chain or branched-chain aliphatic saturated hydrocarbon. In some embodiments, an alkyl group is a group having 1 to 12 carbon atoms (i.e., C 1~12 alkyl group) or a specified number of carbon atoms (i.e., a C alkyl group, e.g., a methyl group; a C alkyl group, e.g., an ethyl group; a C alkyl group, e.g., a propyl group or an isopropyl group, etc.). In one embodiment, the alkyl group is a straight-chain C 1~10 In another embodiment, the alkyl group is a branched C 3~10 In another embodiment, the alkyl group is a straight-chain C 1~6 In another embodiment, the alkyl group is a branched C 3~6 In another embodiment, the alkyl group is a straight-chain C 1~4 In one embodiment, the alkyl group is a C 11 group selected from the group consisting of methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl. 1~4 It is an alkyl group. As used in this disclosure, the term "alkylene group," when used alone or as part of another group, means a divalent group derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH-CH-CH-CH-, -CH-CH-CH-, -CH-CH-, and the like.

[0188] As used in this disclosure, the term "alkenyl group," when used alone or as part of another group, means a straight- or branched-chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, an alkenyl group is a C 2~6 In another embodiment, the alkenyl group is C 2~4Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl groups.

[0189] As used herein, the term "alkynyl group," when used alone or as part of another group, refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, e.g., one to three, carbon-carbon triple bonds. In one embodiment, an alkynyl group has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C 2~6 In another embodiment, the alkynyl group is C 2~4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0190] As used in this disclosure, the term "alkoxy group" when used alone or as part of another group refers to a group of the formula OR a1 wherein R a1 is an alkyl group as defined herein. As used in this disclosure, the term "cycloalkoxy group" when used alone or as part of another group refers to a group of the formula OR a1 wherein R a1 is a cycloalkyl group as defined herein. As used in this disclosure, the term "heterocycloalkoxy group" when used alone or as part of another group refers to a group of the formula OR a1 wherein R a1 is a heterocyclyl group as defined herein.

[0191] As used herein, the term "haloalkyl group," when used alone or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In preferred embodiments, the haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a C1~4 It is a haloalkyl group.

[0192] Unless otherwise specified, as used in this disclosure, the term "heteroalkyl group," when used alone or as part of another group, refers to a stable straight- or branched-chain alkyl group having, for example, 2 to 14 carbons, e.g., 2 to 10 carbons in the chain, one or more of which are replaced by a heteroatom selected from the group consisting of S, O, P, and N, wherein the nitrogen, phosphorus, and sulfur atoms may be oxidized and the nitrogen heteroatom may be quaternized. The heteroatoms S, O, P, and N may be located at any interior position of the heteroalkyl group or at the position which connects the alkyl group to the remainder of the molecule. For example, C 1-4Heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, and -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups such as -O-CH2-CH3, and C1 heteroalkyl groups such as O-CH3. Similarly, the term "heteroalkylene group," when used alone or as part of another group, means a divalent radical derived from a heteroalkyl group, for example, but not limited to, -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also be located at either chain terminus or at both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene group linking groups, the direction depicted in the general formula of the linking group does not imply any orientation of the linking group. When referring to a "heteroalkyl group," followed by a specific heteroalkyl group (e.g., -NR'R'', etc.), it is understood that the terms heteroalkyl group and -NR'R'' are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are recited for clarity. Thus, the term "heteroalkyl group" as used herein should not be construed as excluding specific heteroalkyl groups, such as -NR'R''.

[0193] A "carbocyclyl group" or "carbocycle", when used alone or as part of another group, refers to a ring system having 3 to 10 ring-forming carbon atoms ("C 3-10"Carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group having 0 heteroatoms and 0 heteroatoms. A carbocyclyl group can be monocyclic ("monocyclic carbocyclyl") or bicyclic ("bicyclic carbocyclyl"), including fused, bridged, or spiro ring systems, and can be saturated or partially unsaturated. A "carbocyclyl" also includes ring systems in which a carbocycle, as defined above, is fused to one or more aryl or heteroaryl groups, in which the point of attachment is at the carbocycle, and in which case the number of carbons still represents the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamantyl, cyclopentenyl, and cyclohexenyl.

[0194] In some embodiments, a "carbocyclyl group" is fully saturated and is also referred to as a cycloalkyl group. In some embodiments, a cycloalkyl group can have from 3 to 10 ring-forming carbon atoms ("C 3-10 In a preferred embodiment, the cycloalkyl group is a monocyclic ring.

[0195] The terms "heterocyclyl group" or "heterocycle," when used alone or as part of another group, refer to a 3- to 10-membered non-aromatic ring system having ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms, each heteroatom independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl group"). Where applicable, heterocyclyl groups or heterocycles having a different ring size from the 3- to 10-membered heterocyclyl group are designated by the different ring size designation. One of ordinary skill in the art will recognize that such heterocyclyl groups having a different ring size are also non-aromatic ring systems having ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms, each heteroatom independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, for example, the point of attachment may be at a carbon or nitrogen atom, where valency is permitted. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl groups") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl groups"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl groups" also include ring systems comprising a heterocycle, as defined above, fused with one or more carbocyclic groups, wherein the point of attachment is at the carbocyclic or heterocyclic ring, and ring systems comprising a heterocycle, as defined above, fused with one or more aryl or heteroaryl groups, wherein the point of attachment is at the heterocyclic ring, and in which case the number of ring members still refers to the number of ring members in the heterocyclic ring system.

[0196] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl groups. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrole-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolane, oxathiolane, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl groups. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, 1,4-dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to in the present disclosure as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolyl groups, isoindolyl groups, dihydrobenzofuryl groups, dihydrobenzothienyl groups, benzoxazolinonyl groups, etc. Exemplary 6-membered heterocyclyl groups (also referred to in the present disclosure as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl groups, tetrahydroisoquinolinyl groups, etc.

[0197] An "aryl group," when used alone or as part of another group, refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared by the ring array) of 6 to 14 carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring-forming carbon atoms (a "C aryl group"; e.g., a phenyl group). In some embodiments, an aryl group has 10 ring-forming carbon atoms (a "C 10 aryl groups"; e.g., naphthyl groups, e.g., 1-naphthyl and 2-naphthyl groups. In some embodiments, aryl groups have 14 ring-forming carbon atoms ("C 14 "Aryl group" (e.g., anthryl group). "Aryl group" also includes ring systems comprising an aryl ring, as defined above, fused to one or more carbocyclic or heterocyclic groups, in which the radical or point of attachment is on the aryl ring, and in which the number of carbon atoms still refers to the number of carbon atoms in the aromatic ring system.

[0198] An "aralkyl group," when used alone or as part of another group, is an alkyl group substituted with one or more aryl groups, preferably one aryl group. Examples of aralkyl groups include benzyl groups, phenethyl groups, and the like. When an aralkyl group is described as being optionally substituted, either the alkyl portion or the aryl portion of the aralkyl group may be substituted.

[0199] A "heteroaryl group," when used alone or as part of another group, is a group having a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared by the ring array) of ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms, each heteroatom being independently selected from the group consisting of nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl group"). Where applicable, heteroaryl groups having ring sizes different from the 5- to 10-membered heteroaryl group are designated by the different ring size designation. Those skilled in the art will recognize that heteroaryl groups having such different ring sizes also include 4n+2 aromatic ring systems (e.g., 6 or 10 π-electrons shared by the ring array) having ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms (wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur), where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heteroaryl groups containing one or more nitrogen atoms, for example, the point of attachment may be a carbon or nitrogen atom, where valency permits. Bicyclic heteroaryl groups contain one or more heteroatoms in one or both rings. The term "heteroaryl group" includes ring systems comprising a heteroaryl ring, as defined above, fused with one or more carbocyclic or heterocyclic groups, wherein the point of attachment is at the heteroaryl ring, and in this case, the number of ring members still represents the number of ring members in the heteroaryl ring system. The term "heteroaryl" also includes ring systems formed by condensing a heteroaryl ring, as defined above, with one or more aryl groups, wherein the point of attachment is at the aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the condensed (aryl / heteroaryl) ring system. Among these, in dicycloheteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbozolyl, etc.), the point of attachment can be at either ring, i.e., at a heteroatom ring (e.g., 2-indolyl) or at a ring without a heteroatom (e.g., 5-indolyl).

[0200] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, piperazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl groups, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl groups. Exemplary 5,6-dicycloheteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzoisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl groups. Exemplary 6,6-dicycloheteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, 2,3-phthalazinyl, and quinazolinyl groups.

[0201] A "heteroaralkyl group," when used alone or as part of another group, is an alkyl group substituted with one or more heteroaryl groups, preferably one heteroaryl group. Where a heteroaralkyl group is described as being optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl group may be substituted.

[0202] As is generally understood by those skilled in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene groups are the corresponding divalent radicals of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.

[0203] "Optionally substituted" groups, such as optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, refer to the respective unsubstituted or substituted groups. Generally, the term "substituted," whether preceded by the term "optionally," refers to a group in which at least one hydrogen atom present in the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent where the substitution produces a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituent may be the same or different at each position. The substituent may be a carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituent, as appropriate.

[0204] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain unchanged, or essentially unchanged, for a period of time sufficient to permit use of the compound for the purposes described in this disclosure (e.g., therapeutic administration to a subject).

[0205] In some embodiments, an "optionally substituted" alkyl, alkenyl, alkynyl, carbocyclyl, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclyl group in the present disclosure can be unsubstituted or substituted with 1, 2, 3, or 4 substituents, wherein the substituents are independently F, Cl, -OH, a protected hydroxy group, an oxo group (where applicable), NH, a protected ammonia group, NH(C 1~4 alkyl group) or a protected derivative thereof, N(C 1~4 alkyl group)(C 1~4 alkyl group), C 1~4 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 cycloalkoxy group, a phenyl group, a 5- or 6-membered heteroaryl group containing one, two, or three ring-forming heteroatoms independently selected from the group consisting of O, S, and N, and a 3- to 7-membered heterocyclic group containing one or two ring-forming heteroatoms independently selected 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 is optionally substituted with one, two, or three substituents, which are independently selected from F, —OH, oxo group (if applicable), C 1~4 Alkyl group, fluorine-substituted C 1~4 Alkyl groups (e.g., CF3), C 1~4 Alkoxy and fluorine-substituted C 1~4In some embodiments, an "optionally substituted" aryl or heteroaryl group in the present disclosure can be unsubstituted or substituted with 1, 2, 3, or 4 substituents, wherein the substituents are independently selected from the group consisting of F, Cl, -OH, -CN, NH, a protected ammonia group, NH(C 1~4 alkyl group) or a protected derivative thereof, N(C 1~4 alkyl group)(C 1~4 alkyl group), -S(=O)(C 1~4 alkyl group), -SO2(C 1~4 alkyl group), C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 3~6 a cycloalkoxy group, a phenyl group, a 5- or 6-membered heteroaryl group containing 1, 2, or 3 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, and a 3- to 7-membered heterocyclic group containing 1 or 2 ring-forming heteroatoms independently selected 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 is optionally substituted with 1, 2, or 3 substituents, and the substituents are independently selected from F, —OH, oxo group (if applicable), C 1~4 Alkyl group, fluorine-substituted C 1~4 Alkyl group, C 1~4 Alkoxy and fluorine-substituted C 1~4 The alkoxy group is selected from the group consisting of:

[0206] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SRaa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)Raa ,-P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Carbocyclyl group, 3-14 membered heterocyclyl group, C 6-14 and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R ddsubstituted with a group; - is the counterion; Alternatively, two gem hydrogens on a carbon atom can be bonded to the groups =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 is replaced by; R aa Each instance of C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups and 5- to 14-membered heteroaryl groups, or two R aa groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently hydrogen, -OH, -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)SRcc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups and 5- to 14-membered heteroaryl groups, or two R bb groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; - is the counterion; R cc Each instance of is independently hydrogen, C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups and 5- to 14-membered heteroaryl groups, or two R cc groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each example of is independently a 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 )Rff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2,-NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C3~10 Carbocyclic group, 3- to 10-membered heterocyclic group, C 6~10 aryl groups, and 5-10 membered heteroaryl groups, wherein 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 or two gem R dd The substituents may be linked to form =O or =S; - is the counterion; R ee Each instance of C 1~6 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 aryl groups, 3- to 10-membered heterocyclic groups, and 3- to 10-membered heteroaryl groups, wherein 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 a group; R ff Each instance of is independently hydrogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 Carbocyclic group, 3- to 10-membered heterocyclic group, C 6~10 aryl groups and 5-10 membered heteroaryl groups, or two R ff groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 Alkyl group, -ON(C 1-6 alkyl group)2, -N(C 1-6 alkyl group)2, -N(C 1-6 alkyl group)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 group), -N(OH)(C 1-6 alkyl group), -NH(OH), -SH, -SC 1-6 Alkyl group, -SS(C 1-6 alkyl group), -C(=O)(C 1-6 alkyl group), -CO2H, -CO2(C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO2(C 1-6 alkyl group), -C(=O)NH2, -C(=O)N(C 1-6 alkyl group)2, -OC(=O)NH(C 1-6 alkyl group), -NHC(=O)(C 1-6 alkyl group), -N(C 1-6 alkyl group)C(=O)(C 1-6 alkyl group), -NHCO2(C 1-6 alkyl group), -NHC(=O)N(C 1-6 alkyl group)2, -NHC(=O)NH(C 1-6 alkyl group), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl group), -OC(=NH)(C 1-6 alkyl group), -OC(=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 alkyl group)2, -C(=NH)NH(C 1-6 alkyl group), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl group)2, -OC(NH)NH(C 1-6alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl group), -NHC(=NH)NH, -NHSO(C 1-6 alkyl group), -SO2N(C 1-6 alkyl group)2, -SO2NH(C 1-6 alkyl group), -SO2NH2, -SO2C 1-6 Alkyl group, -SO2OC 1-6 Alkyl group, -OSO2C 1-6 Alkyl group, -SOC 1-6 Alkyl group, -Si(C 1-6 alkyl group)3, -OSi(C 1-6 alkyl group)3-C(=S)N(C 1-6 alkyl group), C(=S)NH(C 1-6 alkyl group), C(=S)NH2, -C(=O)S(C 1-6 alkyl group), -C(=S)SC 1-6 Alkyl group, -SC(=S)SC 1-6 Alkyl group, -P(=O)(OC 1-6 alkyl group)2, -P(=O)(C 1-6 alkyl group)2, -OP(=O)(C 1-6 alkyl group)2, -OP(=O)(OC 1-6 Alkyl group)2, C 1~6 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 an aryl group, a 3- to 10-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; or two geminal R gg The substituents may be linked to form =O or =S; - is the counter ion.

[0207] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain charge neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions are halogen ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , 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.), carborate 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) - ) Exemplary multivalent counterions include CO 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, glucosate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0208] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0209] 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 means a moiety selected from the group consisting of aa and R bb as defined in this disclosure.

[0210] Where valency allows, nitrogen atoms may be substituted or unsubstituted, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )Raa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups, and 5- to 14-membered heteroaryl groups, or two R groups linked to a nitrogen atom. cc groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently contains 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd is defined as above.

[0211] In some embodiments, the substituent at the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rdedition, John Wiley & Sons, 1999. Exemplary nitrogen protecting groups include those that form carbamates, such as carboxybenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), Troc, 9-fluorenylmethoxycarbonyl (Fmoc), etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfamides, such as, for example, toluenesulfonyl, p-nitrobenzenesulfonyl, etc.; and others, such as, for example, p-methoxyphenyl.

[0212] 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, including, but not limited to, X - , R aa , R bb and R ccis as defined in the present disclosure. In some embodiments, the oxygen atom substituent on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. Exemplary oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyl groups (e.g., 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like; silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), and the like; acetals or ketals such as tetrahydropyranyl (THP); esters such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, and the like; carbonates; sulfonates such as methanesulfonates (methanesulfonate), benzylsulfonates, and toluenesulfonates (Ts), and the like.

[0213] The term "leaving group" has its usual meaning in the art of synthetic organic chemistry, e.g., an atom or group displaceable by a nucleophile. See, e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable 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, alkyl-carbonyl groups (e.g., acetoxy groups), arylcarbonyl groups, aryloxy groups, methoxy groups, N,O-dimethylhydroxyamino groups, 9-phenylpixyl, and haloformate groups.

[0214] The term "pharmacologically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0215] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds by the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a 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 a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include ketone to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0216] As used in this disclosure, the term "subject" (alternatively referred to in this disclosure as a "patient") refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0217] As used in this disclosure, the terms "treatment," "treating," and the like refer to the elimination, alleviation, or amelioration of a disease or condition and / or its associated symptoms. Although not excluded, treatment of a disease or condition need not necessarily result in the complete elimination of the disease, condition, or its associated symptoms. As used in this disclosure, the terms "treatment," "treating," and the like can include "prophylactic treatment," which refers to reducing the likelihood of disease or condition redevelopment or recurrence in a subject who does not experience disease or condition redevelopment or recurrence, but who is at risk of disease or condition redevelopment or recurrence, or who is prone to disease or condition redevelopment or recurrence. The term "treatment" and synonyms refer to the administration of a therapeutically effective amount of a compound according to the present disclosure to a subject in need of such treatment.

[0218] As used in this disclosure, the singular forms "a," "an," and "the" include plural referents unless expressly stated otherwise or unless the context clearly indicates that this is not intended.

[0219] In the present disclosure, the term "and / or" as used in phrases such as "A and / or B" 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.

[0220] Titles and subtitles are used for convenience or formal compliance only, do not limit the subject technology, and are not related to the interpretation of the subject technology description. In various embodiments, features described under one title or one subtitle of this disclosure may be combined with features described under other titles or subtitles. Furthermore, not all features under a single title or a single subtitle may be used together in the examples.

[0221] Example The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. 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.

[0222] Exemplary embodiments of the synthesis process for the products described in this disclosure are described in more detail below. Some examples discussed in this disclosure can be prepared by isolation from the corresponding racemic mixture. As will be understood by those skilled in the art, the compounds described in the Examples section immediately prior to the chiral resolution step (e.g., performed by supercritical fluid chromatography (SFC)) exist as racemates and / or stereoisomeric mixtures. It should be noted that the enantiomeric excess ("ee") reported in these examples is representative of the exemplary methods of this disclosure, but is not limiting; as will be understood by those skilled in the art, enantiomers with different ee, e.g., higher ee, can be obtained according to this disclosure.

[0223] Unless specifically stated otherwise or conflicting with the context, abbreviations used in the Examples section are understood to have their ordinary meaning in the art. TIFF2024532845000206.tif153143TIFF2024532845000207.tif216143TIFF2024532845000208.tif118166

[0224] Step 1: A solution of Br (43 g, 266 mmol) in CHCN (50 mL) was added dropwise to a solution of 3,6-dichloropyridazin-4-amine (21.8 g, 133 mmol) and NaOAc (21 g, 266 mmol) in CHCN (200 mL) at 80 °C and stirred for 1 h. The mixture was cooled and diluted with tetrahydrofuran and ethyl acetate. The organic layer was separated and washed with aqueous NaHCO, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred in methyl tert-butyl ether for 30 min, filtered, and the solid was dried to give 1-1.

[0225] Step 2: To a solution of 1-1 (20 g, 82.3 mmol) in DMF (200 mL) was added CsCO (53.6 g, 164.6 mmol) and 4-bromobut-1-ene (12.2 g, 90.5 mmol). The reaction was stirred with nitrogen gas at 65 °C for 16 h. The mixture was cooled, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane and stirred for 30 min. The mixture was filtered, and the solid was collected and dried to give 1-2. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether to petroleum ether / ethyl acetate = 2 / 1) to provide another batch of 1-2.

[0226] Step 3: To a solution of 1-2 (1 g, 3.4 mmol) in NMP (25 mL) was added CuI (1.5 g, 8 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.5 g, 8 mmol). The mixture was stirred in an oil bath preheated to 105 °C with N for 1 h. After cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether to petroleum ether / ethyl acetate = 3 / 1) to give 1-3.

[0227] Step 4: To a solution of 1-3 (460 mg, 1.6 mmol) in DMAc (15 mL) under N was added Pd(OAc) (36 mg, 0.16 mmol), P(o-toluyl) (122 mg, 0.4 mmol), and KOAc (980 mg, 10 mmol). The mixture was stirred at 80 °C for 20 min under microwave conditions. The mixture was cooled, diluted with ethyl acetate, and washed with water and saturated aqueous NaHCO (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 1-4.

[0228] Step 5: To a solution of 1-4 (80 mg, 0.32 mmol) in CHCN (4 mL) and CCl (4 mL) was added a solution of NaIO (204 mg, 0.96 mmol) in HO (4.5 mL), followed by a solution of RuCl (6.6 mg, 0.032 mmol) in HO (1.5 mL). The mixture was stirred under N at room temperature for 2.5 hours and then diluted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 3) to give 1-5.

[0229] Step 6: To a solution of 1-5 (46 mg, 0.09 mol) in THF (6 mL) at 0 °C under N was added NaBH (38 mg, 1 mmol). The reaction was stirred at room temperature for 6 h and quenched with a solution of AcOH (240 mg, 4 mmol) in THF (2 mL) and saturated aqueous NH Cl (10 mL). The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 15% to 45%) to provide 1-6.

[0230] Step 7: To a solution of 31-3 (20.0 g, 66 mmol) in dichloromethane (200 mL) at 0 °C, TEA (26.5 g, 262.4 mmol) and chloroacetyl chloride (8.2 g, 72.1 mmol) were added. The reaction mixture was stirred at room temperature for 5 h, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 1-7.

[0231] Step 8: To a solution of 1-6 (100 mg, 0.3 equiv. TFA salt, 0.36 mmol) in DMF (20 mL) at 0° C. under N2, NaH (80 mg, 60% in oil, 2 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 0.5 h. The mixture was cooled to 0° C., and a solution of 1-7 (145 mg, 0.48 mmol) in DMF (6 mL) was added. The reaction was stirred at room temperature under N2 for 16 h, after which it was cooled to 0° C., diluted with ethyl acetate, and quenched with saturated aqueous NH4Cl (30 mL). The organic layer was washed with HO and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 15% to 45%) to provide 1-8.

[0232] Step 9: To a solution of 1-8 (15 mg, 0.028 mmol) in AcOH (4 mL) was added NaOAc (23 mg, 0.28 mmol). The mixture was stirred at 100 °C for 3 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 15% to 45%) to provide 1. LCMS (ESI, m / z): [M+H] + =508.2; 1H NMR(400MHz,DMSO-d6)δ 12.34(s,1H),8.72(d,J=0.8Hz,2H),7.55(d,J=2.0Hz,1H),4.37(m,J=2.8Hz,1H),4.2 7(s,2H),3.85-3.77(m,5H),3.55-3.43(m,5H),2.18-2.15(m,1H),1.89-1.81(m,1H). 19 F NMR(376MHz,DMSO-d6)δ -55.68(3F),-59.32(3F).

[0233] Step 10: Racemic compound 1 was separated by SFC (column: DAICEL CHIRALCEL® OZ, MeOH (+0.1% 7.0 M ammonia in MeOH) / CO2 = 60 / 40) to give 2 (peak 1) and 3 (peak 2), respectively. SFC analysis of 2: >99% ee; retention time: 4.39 min; column: DAICEL CHIRALCEL® OZ, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. SFC analysis of 3: >99% ee; retention time: 4.79 min; column: DAICEL CHIRALCEL® OZ, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. TIFF2024532845000209.tif62158

[0234] Step 1: To a stirred solution of 1-8 (55 mg, 0.11 mmol) in DMF (1 mL) at room temperature under N was added NaH (60%, 6 mg, 0.15 mmol). The mixture was stirred at room temperature for 1 h, then MeI (22 mg, 0.16 mmol) was added dropwise and stirred overnight. The reaction was quenched with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (ethyl acetate) to give 4-1.

[0235] Step 2: In N, 4-1 (45 mg), CHCOOH (90 mg, 1.50 mmol), and CHCOONa (90 mg, 1.10 mmol) were mixed in DMAc (2 mL). The reaction mixture was stirred at 110 °C for 60 h, cooled, quenched with HO, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to give 4-2.

[0236] Step 3: Purification of 4-2 by SFC (column: Chiral-IG, MeOH / CO2 = 30 / 70) provided 4 (peak 1, 4.2 mg) and 5 (peak 2, 5.3 mg), respectively. SFC analysis of 4: >99% ee; retention time: 10.86 min; column: Chiral-IG, MeOH in CO2, 40%; pressure: 100 bar; flow rate: 2.0 mL / min. LCMS (ESI, m / z): [M+H] += 522.0; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.60 (s, 2H), 4.86 (s, 2H), 3.99-3.89 (m, 4H), 3.66-3.54 (m, 5H), 3.41-3.40 (m, 1H), 3.16-3.14 (m, 3H), 2.38-2.34 (m, 1H), 2.04-2.01 (m, 1H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -56.47 (3F), -62.65 (3F). SFC analysis of 5: 99.3% ee; retention time: 12.58 min; column: Chiral-IG, MeOH in CO2, 40%; pressure: 100 bar; flow rate: 2.0 mL / min. LCMS (ESI, m / z): [M+H] += 522.0; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.60 (s, 2H), 4.86 (s, 2H), 4.00-3.90 (m, 4H), 3.66-3.56 (m, 5H), 3.41-3.40 (m, 1H), 3.16-3.15 (m, 3H), 2.38-2.35 (m, 1H), 2.04-2.01 (m, 1H). 19F NMR (376 MHz, methanol-d4, ppm): δ -56.47 (3F), -62.65 (3F). TIFF2024532845000210.tif74164

[0237] Step 1: To a solution of 31-3 (5 g, 16.4 mmol) in dichloromethane (50 mL) at 0 °C, TEA (6.6 g, 65.6 mmol) and acrylic anhydride (2.5 g, 19.7 mmol) were added. The mixture was stirred at room temperature for 5 h, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 6-1.

[0238] Step 2: A mixture of 1-6 (200 mg, 0.79 mmol), 6-1 (1.3 g, 4.72 mmol), and CsCO (1.5 g, 4.72 mmol) in dioxane (10 mL) was stirred at 60 °C overnight, after which it was cooled and water (20 mL) was added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to give 6-2.

[0239] Step 3: A mixture of 6-2 (55 mg, 0.1 mmol), AcOH (61 mg, 1.0 mmol), and AcONa (84 mg, 1.0 mmol) in DMAc (6 mL) was stirred at 95 °C for 48 h, after which it was cooled and water (10 mL) was added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give 6-3.

[0240] Step 4: Purification of 6-3 by SFC (column: Chiral-IG, EtOH / CO2 = 40 / 60) provided 6 (peak 1, 5 mg) and 7 (peak 2, 7 mg), respectively. SFC analysis of 6: 99.32% ee; retention time: 7.19 min; column: Chiral-IG, EtOH / CO2 = 40 / 60; pressure: 100 bar; flow rate: 2.0 mL / min. LCMS (ESI, m / z): [M+H] += 522.0; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.59 (s, 2H), 4.39 (t, J = 2.4 Hz, 1H), 3.95-3.84 (m, 6H), 3.70-3.64 (m, 4H), 3.47-3.34 (m, 2H), 2.76-2.67 (m, 2H), 2.28-2.24 (m, 1H), 1.90-1.89 (m, 1H). SFC analysis of 7: 98.62% ee; retention time: 9.16 min; column: Chiral-IG, EtOH / CO2 = 40 / 60; pressure: 100 bar; flow rate: 2.0 mL / min. LCMS (ESI, m / z): [M+H] += 522.0; 1 H NMR (400MHz, methanol-d4, ppm):δ 8.59(s,2H),4.39(t,J=2.8Hz,1H),3.95-3.85(m,6H),3.70-3.64(m,4H),3.47-3.34(m,2H),2.76-2.67(m,2H),2.28- 2.24(m,1H),1.90-1.89(m,1H). TIFF2024532845000211.tif70166

[0241] Step 1: To a solution of 10-8 (800 mg, 1.50 mmol) in acetonitrile (20 mL) was added CsF (455 mg, 3.00 mmol). The reaction was stirred at 60 °C for 6 h. The mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 3) to give 8-1.

[0242] Step 2: To a solution of 8-1 (440 mg, 1.17 mmol) in THF (20 mL) at 0 °C, 60% wt. NaH (16 mg, 0.4 mmol, 60% wt.) was added in portions. After stirring the reaction mixture at 0 °C for 20 min, 1-7 (432 mg, 1.40 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether to ethyl acetate) followed by chiral pre-SFC (column: REGIS(S,S)WHELK-O1, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 50 / 50) to give 8-2 (peak 1, 200 mg) and 8-3 (peak 2, 150 mg).

[0243] Step 3: A mixture of 8-2 (50 mg, 0.077 mmol) in 4 N HCl / dioxane (5 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC (0.05% TFA in acetonitrile and water: 5% to 65%) to give 0.40 equiv. of 8 as the TFA salt. SFC analysis: 95.96% ee; retention time: 2.86 min; column: REGIS(S,S)WHELK-O1, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =519.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 13.17(s,1H),8.72(s,2H)4.51-4.50(m,2H),4.50-4.48(m,3H),3.86-3.73(m,4H),3.60-3.45(m,4H),2.30-2.28(m,2H). 19 F NMR (376MHz, DMSO-d6, ppm): δ -59.32 (3F).

[0244] Step 4: A mixture of 8-3 (50 mg, 0.077 mmol) in 4N HCl / dioxane (3 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC (0.05% TFA in acetonitrile and water: 5% to 65%) to give 9 as a 1 equiv. TFA salt. SFC analysis: 98.98% ee; retention time: 2.33 min; column: REGIS(S,S)WHELK-O1, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =521.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 13.17(s,1H),8.72(s,2H)4.50-4.49(m,2H),4.40-4.30(m,3H),3.82-3.75(m,4H),3.46-3.44(m,4H),2.29-2.17(m,2H). 19 F NMR (376MHz, DMSO-d6, ppm): δ -59.330 (3F). TIFF2024532845000212.tif120157

[0245] Step 1: To a solution of 10-1 (15 g, 90.9 mmol) in DMF (200 mL) at 0 °C, NaH (5.5 g, 138 mmol, 60 wt%) was added in portions and stirred for 30 min, followed by the dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (24 mL, 135 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with HO, and extracted with ethyl acetate. The combined organic layer was washed with HO, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 10-2.

[0246] Step 2: To a solution of but-3-en-1-ol (6.35 g, 88 mmol) in THF (150 mL) was added NaH (3.52 g, 88 mmol, 60 wt%) in portions at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 10-2 (13 g, 44 mmol) was added. The mixture was stirred at room temperature for 1 h, quenched with HO, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 10-3.

[0247] Step 3: To a solution of 10-3 (11 g, 33.3 mmol) in DMF (200 mL) was added Pd(OAc) (2.3 g, 10 mmol), Xantphos (7.79 g, 13.3 mmol), and TEA (18.5 mL, 132 mmol). The mixture was stirred under N at 105 °C for 16 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 10-4.

[0248] Step 4: To a solution of 10-4 (5.4 g, 18.3 mmol) in a mixture of THF (100 mL) and HO (100 mL) was added potassium osmate dihydrate (dioxoosmium bis(olate) dihydrate) (67.6 mg, 0.18 mmol) and sodium periodate (15.7 g, 73.4 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with HO and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 2) to give 10-5.

[0249] Step 5: To a solution of 10-5 (4.15 g, 14 mmol) in MeOH (100 mL) at 0 °C was added NaBH (0.8 g, 21 mmol) in several portions. The reaction mixture was stirred at room temperature for 1 h, then quenched with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 10-6, which was used directly in the next step without purification.

[0250] Step 6: To a solution of 10-6 (4 g, 13.4 mmol) in DMF (100 mL) was added imidazole (2.7 g, 40.2 mmol) and triisopropylchloridesilane (6 mL, 28.1 mmol). The reaction mixture was stirred at 60 °C for 16 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 2) to give 10-7.

[0251] Step 7: To a solution of 10-7 (2 g, 4.4 mmol) and KOAc (648 mg, 6.6 mmol) in AcOH (30 mL) was added dropwise Br (0.35 mL, 6.8 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h, quenched with HO (40 mL) and saturated aqueous NaSO (5 mL), 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 chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 10-8.

[0252] Step 8: To a solution of 10-8 (1.0 g, 1.874 mmol) in DMF (20 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.08 g, 5.62 mmol) and CuI (357 mg, 1.9 mmol). The reaction mixture was stirred under N2 at 110 °C for 3 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 10-9, which was used directly in the next step without purification.

[0253] Step 9: To a solution of 10-9 (460 mg, 0.88 mmol) in acetonitrile (15 mL) was added cesium fluoride (267 mg, 1.76 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 10-10.

[0254] Step 10: To a solution of 10-10 (100 mg, 0.27 mmol) and 1-7 (101 mg, 0.33 mmol) in THF (10 mL) was added NaH (33 mg, 0.825 mmol, 60% dispersion in mineral oil) in portions at 0 °C. The mixture was stirred at room temperature for 2 h, then quenched with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether to ethyl acetate) to give 10-11.

[0255] Step 11: 10-11 (115 mg, 0.18 mmol) was dissolved in HCl in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was purified by preparative HPLC (0.05% TFA in acetonitrile and water: 5% to 42%) to provide 10-12. Compound 10-12 (85 mg) was purified by SFC (column: DAICEL CHIRALCEL® OZ, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 60 / 40) to give 10 (15.5 mg) and 11 (18 mg), respectively. SFC analysis of 10: 96% ee; retention time: 3.98 min; column: DAICEL CHIRALCEL® 0Z, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =509.2; 1H NMR(400MHz,DMSO-d6)δ 13.24(s,1H),8.72(s,2H),4.55-4.38(m,3H),4.36(s,2H),3.99-3.62(m,4H),3.58-3.38(m,4H),2.35-2.12(m,2H). SFC analysis of 11: 99.36%ee; retention time: 4.63 min; column: DAICEL CHIRALCEL® OZ, MeOH (0.1% DEA) in CO2 solution, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS(ESI,m / z):[M+H] + =509.2; 1 H NMR(400MHz,DMSO-d6)δ 13.25(s,1H),8.72(s,2H),4.56-4.39(m,3H),4.41(s,2H),3.92-3.72(m,4H),3.60-3.37(m,4H),2.32-2.12(m,2H). TIFF2024532845000213.tif65166

[0256] Step 1: A mixture of 8-2 (60 mg, 0.094 mmol), CuI (9 mg, 0.047 mmol), ethynyltriisopropylsilane (52 mg, 0.28 mmol), and Pd(PPh3)4 (109 mg, 0.094 mmol) in DIPEA (1 mL) was purged with nitrogen gas for 1 minute and then stirred at 90 °C for 1 hour under microwave conditions. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (dichloromethane / ethyl acetate = 1 / 1) to give 12-1.

[0257] Step 2: To a solution of 12-1 (60 mg, 0.080 mmol) in dichloromethane (2 mL) was added TFA (137 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was basified with aqueous NaHCO (1 M) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (dichloromethane / ethyl acetate = 1 / 1) to give 12-2.

[0258] Step 3: To a solution of 12-2 (40 mg, 0.064 mmol) in acetonitrile (5 mL) was added CsF (78 mg, 0.52 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 5% to 65%) to give 0.76 equivalents of 12 as the TFA salt. LCMS(ESI,m / z):[M+H]+=464.8;1H NMR(400MHz,DMSO-d6,ppm):δ 13.04(s,1H),8.72(s,2H),4.60(s,1H),4.45-4.42(m,2H),4.36-4.34(m,3H) ,3.85-3.82(m,4H),3.73-3.51(m,4H),2.40-2.27(m,1H),2.15-2.14(m,1H). 19 F NMR (376MHz, DMSO-d6, ppm): δ -59.32 (3F). TIFF2024532845000214.tif90166

[0259] Step 1: To a solution of 13-1 (9.5 g, 56 mmol) in AcOH (100 mL) at 0 °C, acrylic acid (8.09 g, 112 mmol) and H2SO4 (55 mg, 0.56 mmol, 30 μL) were added. The resulting solution was stirred at 100 °C for 16 h. It was then cooled and concentrated. The pH of the residue was adjusted to 6 and extracted with dichloromethane. The organic layer was concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 13-2.

[0260] Step 2: P2O5 (14.71 g, 104 mmol) was added to methanesulfonic acid (100 mL) under N2. The solution was stirred at 80 °C for 1 h, then the mixture was cooled, and then 13-2 (5 g, 20.7 mmol) was added. The reaction mixture was stirred at 55 °C for 16 h. After cooling to 0 °C, 1 M NaOH was added to adjust the pH to 6, and the solution was extracted with dichloromethane. The combined organic layers were concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 13-3.

[0261] Step 3: To a solution of 13-3 (1.2 g, 5.38 mmol) in DMF (60 mL) was added KCO (3.71 g, 26.88 mmol) and MeI (7.64 g, 53.8 mmol) under N. The solution was stirred at 55 °C for 16 h. After cooling to room temperature, H2O was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 13-4.

[0262] Step 4: A solution of 13-4 (600 mg, 2.53 mmol) in THF (10 mL) was purged with N three times, cooled to −70° C., and treated with LiHMDS (1.27 g, 7.59 mmol). The mixture was stirred at −70° C. for 1 h, after which TBSOTf (1.34 g, 5.06 mmol) was slowly added. The reaction mixture was stirred at −70° C. for 30 min, quenched with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 13-5, which was used directly in the next step without further purification.

[0263] Step 5: To a solution of 13-5 (800 mg, 2.28 mmol) in dichloromethane (10 mL) was added mCPBA (786 mg, 4.55 mmol), and the mixture was stirred at room temperature overnight. Water was added, and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 13-6.

[0264] Step 6: To a solution of 13-6 (370 mg, 1.01 mmol) in MeOH (10 mL) was added N2H4 (32.26 mg, 1.01 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 13-7.

[0265] Step 7: A solution of 13-7 (300 mg, 0.86 mmol) in DMF (10 mL) was cooled to 0 °C and then treated with NaH (41 mg, 1.72 mmol). The mixture was stirred at room temperature for 1 h. Then, SEMCl (172 mg, 1.03 mmol) was added. After stirring at room temperature for 1 h, water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous NaSO, filtered, and concentrated. The mixture was concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 13-8.

[0266] Step 8: To a solution of 13-8 (280 mg, 0.58 mmol) in THF (10 mL) was added TBAF (16 mg, 0.58 mmol), and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 13-9.

[0267] Step 9: A solution of 13-9 (80 mg, 0.22 mmol) in DMF (5 mL) was cooled to 0 °C and treated with NaH (11 mg, 0.44 mmol). The mixture was stirred at room temperature for 30 min, and then 1-7 (68 mg, 0.22 mmol) was added. After stirring at room temperature for 16 h, the reaction was quenched by adding water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 30 / 1) to give 13-10.

[0268] Step 10: To a solution of 13-10 (50 mg, 0.078 mmol) in dichloromethane (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h and concentrated. The crude product was dissolved in 3 mL of THF. Aqueous ammonia was added to adjust the mixture to pH = 8. The mixture was stirred at room temperature for 1 h and concentrated. The residue was purified by preparative HPLC (0.1% FA in acetonitrile and water, 5% to 95%) and SFC (column: REGIS(S,S)WHELK-O1, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 50 / 50) to give 13 (peak 1, 9 mg) and 14 (peak 2, 4 mg). SFC analysis of 13: 99.70% ee; retention time: 1.92 min; column: REGIS(S,S)WHELK-O1, MeOH (0.1% DEA) in CO2, 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LC-MS: (ES, m / z): [M+H] += 508.3; 1H NMR (400 MHz, methanol-d4): δ 8.58 (d, J = 0.6 Hz, 2H), 7.13 (dd, J = 8.9, 2.3 Hz, 1H), 6.80 (dd, J = 12.1, 2.3 Hz, 1H), 4.53 (t, J = 2.6 Hz, 1H), 4.40 (dd, J = 32.5, 14.2 Hz, 2H), 3.90-3.80 (m, 5H), 3.69-3.43 (m, 5H), 3.10 (s, 3H). SFC analysis of 14: 97.24% ee; retention time: 2.29 min; column: REGIS(S,S)WHELK-O1, 40% CO in MeOH (0.1% DEA); pressure: 100 bar; flow rate: 1.5 mL / min. LC-MS: (ES, m / z): [M+H] += 508.3; 1 H NMR (400MHz, methanol-d4):δ 8.58(s,2H),7.14(dd,J=8.8,2.3Hz,1H),6.80(dd,J=12.1,2.3Hz,1H),4.53(t,J=2.6Hz,1H),4. 40(dd,J=32.5,14.2Hz,2H),3.90-3.79(m,5H),3.59(ddd,J=51.4,23.4,2.1Hz,5H),3.10(s,3H). TIFF2024532845000215.tif87166

[0269] Step 1: At 0 °C, a solution of 15-1 (25 g, 0.15 mol) in ethyl ether (470 mL) was added dropwise to a solution of tert-butyloxycarbonyl hydrazide (20 g, 0.15 mol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give a mixture of 15-2 and 15-3, which was used directly in the next step without further purification.

[0270] Step 2: A solution of a mixture of 15-2 and 15-3 (crude, 0.15 mol) in 1.25 M HCl / MeOH solution (340 mL, 0.43 mol) was stirred at 50° C. for 3 h. After concentration, water (150 mL) was added to the residue, and the resulting slurry was filtered. The filter cake was dried in vacuo to give 15-4.

[0271] Step 3: A solution of 15-4 (5 g, 27.78 mmol) in phosphoryl chloride (50 mL) was stirred under microwave conditions at 120° C. for 1.5 h. The solvent was evaporated under reduced pressure, and the crude material was purified by silica gel chromatography (petroleum ether / methyl tert-butyl ether=3 / 1) to give 15-5.

[0272] Step 4: To a solution of concentrated HSO (426 mg, 4.30 mmol) in water (27 mL) was added 15-5 (1.85 g, 8.52 mmol), AgNO (290 mg, 1.70 mmol), and HOAc (565 mg, 9.42 mmol) under nitrogen gas. The reaction mixture was heated to 55 °C, and a solution of (NH)SO (2.91 g, 12.76 mmol) in water (9 mL) was added dropwise within 1 h. The resulting mixture was stirred at 55 °C for 1 h. The mixture was cooled, neutralized with dilute aqueous ammonia to pH = 7, and extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give 15-6.

[0273] Step 5: A mixture of 15-6 (770 mg, 3.41 mmol), tert-butyl 3-hydroxybenzoate (794 mg, 4.09 mmol), and K2CO3 (940 mg, 6.81 mmol) in DMF (7 mL) was stirred at 40 °C for 3 h. After quenching with saturated aqueous NH4Cl (100 mL), the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 5% to 95%) to give a mixture of 15-7 and 15-8, which was used directly in the next step without further purification.

[0274] Step 6: A mixture of 15-7 and 15-8 (988 mg, 2.55 mmol) and NaOAc (418 mg, 5.10 mmol) in HOAc (10 mL) was stirred at 120 °C for 4 h. The mixture was cooled, diluted with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a mixture of 15-9 and 15-10, which was used directly in the next step without further purification.

[0275] Step 7: A mixture of 15-9 and 15-10 (crude, 2.54 mmol) in TFA (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse-phase HPLC (acetonitrile, 0.05% TFA in water, 5% to 95%) to give a mixture of 15-11 and 15-12, which was used directly in the next step without further purification.

[0276] Step 8: To a mixture of 15-11 and 15-12 (730 mg, 2.17 mmol), 31-3 (582 mg, 2.17 mmol), and DIPEA (840 mg, 6.51 mmol) in DMF (14 mL) was added HATU (618 mg, 1.63 mmol) in portions at 0 °C under nitrogen gas. The resulting mixture was stirred at this temperature for 1.5 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile, 0.05% TFA in water, 5% to 95%) and SFC (column: DAICEL CHIRALCEL® OZ, MeOH (+0.1% 7.0 M ammonia in MeOH) / CO2) to provide 15 (51.5 mg) and 17 (221.4 mg). 15, LCMS (ESI, m / z): [M + H] + =529.2. 1H NMR(400MHz, CDCl3, ppm):δ 11.28(s,1H),8.50(s,2H),7.49(t,J=7.9Hz,1H),7.33(d,J=7.6Hz,1H),7.26-7.24 (m,1H),7.23-7.19(m,1H),4.10-3.75(m,6H),3.70-3.45(m,2H),2.53-2.50(m,3H). 17, LCMS(ESI,m / z):[M+H] + =529.2. 1 H NMR(400MHz, CDCl3, ppm):δ 8.50(s,2H),7.46(t,J=7.9Hz,1H),7.31(d,J=7.6Hz,1H),7.27-7.26(m,1H),7 .25-7.21(m,1H),4.05-3.70(m,6H),3.65-3.40(m,2H),2.45(d,J=3.2Hz,3H). TIFF2024532845000216.tif69166

[0277] Step 1: To a suspension of 19-1 (10.0 g, 65.7 mmol) in DMF (100 mL) were added BnBr (23.6 g, 138.0 mmol) and K2CO3 (36.3 g, 262.8 mmol). The resulting mixture was stirred at room temperature overnight, filtered, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was dissolved in MeOH (50 mL) and water (50 mL), and NaOH (8.1 g, 203.7 mmol, 3.1 equiv.) was added, followed by stirring at room temperature for 3 h. The mixture was concentrated to remove MeOH. The aqueous layer was adjusted to pH 2-3 with 3 N HCl and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 19-2, which was used directly in the next step without further purification.

[0278] Step 2: To a solution of 19-2 (1.0 g, 4.1 mmol) and 31-3 (1.6 g, 5.4 mmol) in DMF (10 mL) was added HOBT (670 mg, 5.0 mmol), EDCI (950 mg, 5.0 mmol), and TEA (1.5 g, 14.9 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give 19-3.

[0279] Step 3: To a solution of 19-3 (1.5 g, 3.3 mmol) in EtOH (30 mL) was added Pd / C (150 mg, 10% w / w). The mixture was stirred under H atmosphere at room temperature for 4 h, filtered through a pad of diatomaceous earth, and washed with ethyl acetate. The filtrate was concentrated to give 19-4, which was used directly in the next step without further purification.

[0280] Step 4: To a mixture of 19-4 (194 mg, 0.53 mmol) and 42-5 (100 mg, 0.44 mmol) in dioxane (5 mL) under N was added Pd(dba) (81 mg, 0.09 mmol), MetBuXphos (52 mg, 0.18 mmol), and CsCO (288 mg, 0.88 mmol). The mixture was stirred at 95 °C for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 19-5.

[0281] Step 5: To a solution of 19-5 (60 mg, 0.11 mmol) in MeCN (3 mL) was added TMSI (43 mg, 0.22 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile, aqueous solution containing 0.1% FA, 40% to 65%) to give 19. LCMS (ESI, m / z): [M+H] += 543.0; 1 H NMR (400MHz, methanol-d4, ppm):δ 8.60(s,2H),7.43(d,J=7.2Hz,1H),7.30-7.28(m,2H),4.02-3.97(m,4H ),3.83-3.81(m,2H),3.60-3.57(m,2H),2.57-2.55(m,3H),2.27(s,3H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -60.66 (3F), -62.67 (3F). TIFF2024532845000217.tif71163

[0282] Step 1: To a solution of 42-5 (290 mg, 1.28 mmol) and methyl 5-hydroxynicotinate (235 mg, 1.54 mmol) in dioxane (3 mL) was added Pd(dba) (117 mg, 0.13 mmol), Met-BuXPhos (123 mg, 0.26 mmol), and CsCO (834 mg, 2.56 mmol). The resulting mixture was degassed with nitrogen gas for 10 minutes and then stirred at 90 °C for 3.5 hours. The mixture was cooled and concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 20-1.

[0283] Step 2: To a solution of 20-1 (200 mg, 0.58 mmol) in methanol (3 mL) and water (3 mL) was added LiOH (73 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 5 hours, acidified with 1N HCl to pH = 6, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether to ethyl acetate) to give 20-2.

[0284] Step 3: To a solution of 20-2 (110 mg, 0.33 mmol) in DMF (3 mL) were added DIPEA (0.17 mL, 1.00 mmol), HATU (140 mg, 0.37 mmol), and 31-3 (99 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for an additional 30 min. The mixture was purified by reverse-phase HPLC (acetonitrile and 0.05% TFA in water, 5% to 95%) to give 20-3.

[0285] Step 4: To a solution of 20-3 (80 mg, 0.15 mmol) in acetonitrile (10 mL) was added TMSI (88 mg, 0.44 mmol). The reaction mixture was stirred at 70 °C for 1.5 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile, 0.05% TFA in water: 5% to 52%) to give 0.52 equivalents of 20 as the TFA salt. LCMS (ESI, m / z): [M+H] + =530.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 12.76(s,1H),8.72(s,2H),8.62(d,J=2.8Hz,1H),8.54(d,J=2.4Hz,1H),7.88(t,J=2.0 Hz,1H),3.92-3.89(m,4H),3.74-3.65(m,2H),3.50-3.42(m,2H),2.41(t,J=2.8Hz,3H). 19 F NMR (376MHz, DMSO-d6, ppm): δ -58.49, -59.34. TIFF2024532845000218.tif54166

[0286] Step 1: Compound 27-1 was prepared from compound 75-2 according to the process for synthesizing compound 36-3 in Example 14.

[0287] Step 2: To a solution of 3-hydroxybenzoic acid (300 mg, 2.17 mmol) and 27-2 (409 mg, 2.17 mmol) in dichloromethane (10 mL), DIEA (281 mg, 2.17 mmol, 378 μL) was added, followed by HATU (819 mg, 2.17 mmol). The mixture was stirred at room temperature for 2 hours. Water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 27-3.

[0288] Step 3: To a solution of 27-3 (270 mg, 0.88 mmol) and 27-1 (300 mg, 0.88 mmol) in toluene (10 mL) was added RockPhos (4.10 mg, 0.88 mmol), Pd(dba) (8.0 mg, 0.88 mmol), and KPO (186 mg, 0.88 mmol). The mixture was purged with N three times and then stirred at 100 °C overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 27-4.

[0289] Step 4: To a solution of 27-4 (40 mg, 0.065 mmol) in dichloromethane (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. The crude product was dissolved in THF (1 mL) and ammonia (1 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated. The crude product was purified by preparative HPLC (acetonitrile, aqueous solution containing 0.1% FA, 5% to 95%) to give 27. LCMS: (ESI, m / z): [M+H]+= 485.1. 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.42(d,J=1.9Hz,1H),7.76(dd,J=9.1,2.3Hz,1H),7.54(t,J=8.0Hz,1H), 7.41-7.27(m,3H),6.88(d,J=9.1Hz,1H),3.96-3.52(m,8H),2.52(s,3H). TIFF2024532845000219.tif72166

[0290] Step 1: To a solution of 28-1 (700 mg, 3.74 mmol) in DMF (10 mL) was added NaH (60% in oil, 180 mg, 7.48 mmol, 60%) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then a solution of 28-2 (682 mg, 3.74 mmol) in 1 mL of DMF was added. The mixture was stirred at room temperature for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over Na SO , filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 28-3.

[0291] Step 2: A solution of 28-3 (300 mg, 0.9 mol) in dichloromethane / TFA (6 mL, 2 / 1) was stirred at room temperature for 1 h. The mixture was concentrated to give 28-4, which was used directly in the next step without further purification.

[0292] Step 3: To a solution of 28-4 (150 mg, 0.64 mmol) and 28-5 (107 mg, 0.77 mmol) in dichloromethane (5 mL) was added DIEA (416 mg, 3.22 mmol, 560.20 μL) and HATU (364 mg, 0.97 mmol). The mixture was stirred at room temperature for 1 h, quenched with HO, and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) to provide 28-6.

[0293] Step 4: To a solution of 28-6 (100 mg, 0.28 mmol) and 27-1 (116 mg, 0.34 mmol) in toluene (5 mL), RockPhos (13 mg, 0.028 mmol), Pd(dba) (52 mg, 0.057 mmol), and KPO (120 mg, 0.057 mmol) were added. The mixture was stirred at 100 °C overnight. The mixture was cooled, diluted with HO, 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 chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 28-7.

[0294] Step 5: A solution of 28-7 (20 mg, 0.03 mmol) in dichloromethane / TFA (4 mL, 1 / 1) was stirred at room temperature for 1 h. The mixture was concentrated. The residue was dissolved in THF / HO (4 mL, 1 / 1) and treated with LiOH (3.6 mg, 0.015 mmol). The mixture was stirred at room temperature for 1 h. The mixture was then purified by preparative HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) to provide 28. LC-MS: (ESI, m / z): [M+H] += 530.2. 1 H NMR (400MHz, methanol-d4):δ 8.91(d,J=23.2Hz,2H),7.56-7.37(m,3H),7.32(t,J=8.1Hz,1H),6.00-5.55(m,1H),4.09-3.56(m,4H),2.64-2.46(m,3H),2.43-2.25(m,2H). TIFF2024532845000220.tif133166

[0295] Step 1: At 5-10°C under N2, CF3SO2Cl (50.5 g, 0.30 mol) was added dropwise to a suspension of Zn (600g, 117 g, 1.8 mol) in HO (200 mL) with rapid stirring. The reaction mixture was warmed to room temperature and stirred for an additional 2 h, after which it was filtered and the filter cake was washed with HO (150 mL). The combined filtrate was added dropwise to a solution of 3-chloro-6-methoxypyridazine (10.8 g, 75.0 mmol) in perfluorohexane (150 mL) at 5-10°C under N2. tert-Butyl hydroperoxide (70% aqueous solution, 48.5 g, 376.8 mmol) was then added dropwise at 5-10°C under N2. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=50 / 1) to give 31-1.

[0296] Step 2: To a solution of 2-chloro-5-(trifluoromethyl)pyrimidine in NMP (160 mL) was added tert-butyl piperazine-1-carboxylate (20.4 g, 109.6 mmol) and KCO (30.3 g, 219.2 mmol). The mixture was stirred at 80 °C for 15 h. The mixture was decanted into HO. The formed precipitate was collected by filtration, washed with water, and dried to give 31-2, which was used directly in the next step without purification.

[0297] Step 3: To a solution of 31-2 (28.4 g, 88.5 mmol) in dichloromethane (284 mL) at room temperature was added dropwise HCl in dioxane (119.8 mL, 4 M in dioxane, 479.0 mmol). The mixture was stirred at room temperature for 15 hours. The formed precipitate was collected by filtration, washed with dichloromethane, and dried in vacuo to give 31-3.

[0298] Step 4: To a solution of 31-1 (120 mg, 0.56 mmol) in ethanol (2 mL) was added methyl 2-(morpholin-2-yl)acetate hydrochloride (221 mg, 1.12 mmol) and potassium carbonate (310 mg, 2.24 mmol). The reaction mixture was stirred in a sealed tube at 100 °C for 16 h. The mixture was cooled, extracted with ethyl acetate, and washed with water. The combined organic layer was dried over sodium sulfate, filtered, and concentrated to give 31-4, which was used directly in the next step without purification.

[0299] Step 5: To a solution of 31-4 (400 mg, 1.2 mmol) in methanol / water (6 mL / 6 mL) was added lithium hydroxide monohydrate (150 mg, 3.6 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 5% to 50%) to provide 31-5.

[0300] Step 6: To a solution of 31-5 (30 mg, 0.09 mmol) in N,N-dimethylformamide (5 mL) were added 31-3 (25 mg, 0.09 mmol), N,N-diisopropylethylamine (35 mg, 0.27 mmol), and HATU (34 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 31-6.

[0301] Step 7: Compound 31-6 was purified by SFC (column: DAICEL CHIRALPAK® IC, MeOH (+0.1% 7.0 M ammonia in MeOH) / CO) to give 31-6-P1 (10 mg) and 31-6-P2 (13 mg), respectively. 31-6-P1: SFC analysis: >99% ee; retention time: 1.00 min; column: DAICEL CHIRALPAK® IC, EtOH (0.1% DEA) in CO; pressure: 100 bar; flow rate: 1.0 mL / min. 31-6-P2: SFC analysis: >99% ee; retention time: 1.53 min; column: DAICEL CHIRALPAK® IC, EtOH (0.1% DEA) in CO; pressure: 100 bar; flow rate: 1.0 mL / min.

[0302] Step 8: To a solution of 31-6-P1 (10 mg, 0.019 mmol) in acetonitrile (2 mL) was added iodotrimethylsilane (8 mg, 0.038 mmol). The mixture was stirred at 70 °C for 3 h. The mixture was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 5% to 50%) to give 0.9 equiv. of 31 as the TFA salt. LCMS (ESI, m / z): [M+H] + =522.3; 1 H NMR(400MHz,DMSO-d6)δ 12.75(s,1H),8.72(s,2H),7.92(s,1H),3.88-3.79(m,7H),3.68-3.64(m,1H),3.58-3.53(m,5H),2.79-2.66(m,2H),2.56-2.51(m,2H). 19 F NMR(376MHz,DMSO-d6)δ -59.32(3F),-65.77(3F).

[0303] Step 9: To a solution of 31-6-P2 (11 mg, 0.02 mmol) in acetonitrile (2 mL) was added iodotrimethylsilane (8 mg, 0.04 mmol). The mixture was stirred at 70 °C for 3 h. The mixture was purified by preparative HPLC (acetonitrile and 0.05% TFA in water: 5% to 50%) to give 1.8 equivalents of 32 as the TFA salt. LCMS (ESI, m / z): [M+H] + =522.3; 1 H NMR(400MHz,DMSO-d6):δ 12.76(s,1H),8.72(s,2H),7.92(s,1H),3.88-3.79(m,7H),3.68-3.64(m,1H),3.58-3.53(m,5H),2.79-2.66(m,2H),2.56-2.51(m,2H). 19 F NMR (376MHz, DMSO-d6): δ -59.32(3F), -65.77(3F). TIFF2024532845000221.tif71166

[0304] Step 1: To a solution of 6-chloropyridazin-3(2H)-one (4.0 g, 30.5 mmol) in water (50 mL) were added potassium bromide (10.9 g, 91.6 mmol), potassium acetate (4.5 g, 45.8 mmol), and bromo (14.3 g, 91.6 mmol). The mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with a solution of sodium sulfite (7.66 g, 60.7 mmol) in water (400 mL) and water (300 mL). The filter cake was dried to give 36-1, which was used directly in the next step without purification.

[0305] Step 2: To a solution of 36-1 (3.4 g, 16.3 mmol) in dimethylformamide (80 mL) was added sodium hydride (1.3 g, 32.6 mmol, 60% in oil) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (5.4 g, 32.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 36-2.

[0306] Step 3: To a solution of 36-2 (3.2 g, 9.4 mmol) in dimethylformamide (100 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (5.4 g, 28.2 mmol) and copper(I) iodate (1.8 g, 9.4 mmol). The reaction mixture was stirred with nitrogen gas at 100 °C for 2 hours. The mixture was cooled, filtered, extracted with ethyl acetate, and washed with water. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 36-3.

[0307] Step 4: To a solution of 36-3 (180 mg, 0.55 mmol) in dioxane (2 mL) were added (S)-methyl morpholine-3-carboxylate (120 mg, 0.82 mmol), cesium carbonate (360 mg, 1.1 mmol), tri(dibenzalacetone)dipalladium(0) (55 mg, 0.06 mmol), and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg, 0.1 mmol). The reaction was stirred in a sealed tube at 120° C. for 16 h. The mixture was cooled, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 36-4.

[0308] Step 5: To a solution of 36-4 (140 mg, 0.34 mmol) in methanol / water (5 mL / 5 mL) was added lithium hydroxide monohydrate (42 mg, 1 mmol). The mixture was stirred at room temperature for 1 h. The mixture was quenched with 1 M HCl to adjust the pH to 5 and extracted with dichloromethane. The combined organic layer was concentrated to give 36-5, which was used directly in the next step without purification.

[0309] Step 6: To a solution of 36-5 (120 mg, 0.28 mmol) in N,N-dimethylformamide (6 mL) were added 31-3 (76 mg, 0.28 mmol), N,N-diisopropylethylamine (110 mg, 0.85 mmol), and HATU (108 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 36-6.

[0310] Step 7: To a solution of 36-6 (60 mg, 0.12 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were concentrated. The residue was dissolved in methanol / water (1 mL / 0.5 mL) and lithium hydroxide monohydrate (15 mg, 0.36 mmol) was added. The reaction was stirred at room temperature for 1 hour. Purification by preparative HPLC (acetonitrile and 0.05% TFA in water: 5% to 50%) mixture gave 0.4 equiv. of 36 as the TFA salt. LCMS (ESI, m / z): [M+Na] + =530.2; 1H NMR(400MHz,DMSO-d6):δ 12.81(s,1H),8.74(s,2H),7.92(s,1H),4.83(s,1H),4.15-4.11(m,2H),3.97-3.81 (m,3H),3.79-3.69(m,4H),3.62-3.58(m,3H),3.42-3.38(m,1H),3.23-3.13(m,1H). 19 F NMR(376MHz,DMSO-d6)δ -59.31(3F),-65.81(3F). TIFF2024532845000222.tif112166

[0311] Step 1: A mixture of 36-2, ethynyltriisopropylsilane (2.42 g, 13.25 mmol), CuI (841 mg, 4.42 mmol), and Pd(PPh3)2Cl2 (1.24 g, 1.77 mmol) in DMF (5 mL) and TEA (50 mL) was stirred at room temperature for 16 hours. The mixture was decanted into water. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 44-1.

[0312] Compound 44-4 was prepared from compound 44-1 according to the process for synthesizing compound 36-6 in Example 14.

[0313] Step 2: A mixture of 44-4 (160 mg, 0.2 mmol) and CsF (138 mg, 2.1 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The mixture was purified by reverse-phase HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) to give 44-5.

[0314] Step 3: 44-5 (150 mg) was purified by SFC (column: REGIS(S,S)WHELK-O1, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 50 / 50) to give 44-5-P1 (45 mg) and 44-5-P2 (65 mg), respectively. 44-5-P1: SFC analysis: 98.12% ee; retention time: 2.32 min; column: REGIS(S,S)WHELK-O1, MeOH (0.1% DEA) in CO2, 40%; pressure: 100 bar; flow rate: 1.5 mL / min. 44-5-P2: SFC analysis: 97.56% ee; retention time: 2.95 min; column: REGIS(S,S)WHELK-O1, CO2 solution in MeOH (0.1% DEA), 40%; pressure: 100 bar; flow rate: 1.5 mL / min.

[0315] Compound 44 was prepared from compound 44-5-P1 according to the synthesis of compound 36 in Example 14. LCMS (ESI, m / z): [M+H] + =478.2; 1 H NMR (400 MHz, methanol-d4): δ 8.59 (s, 2H), 7.71 (s, 1H), 4.10 (s, 1H), 4.06-3.61 (m, 13H), 2.90-2.79 (m, 2H), 2.67-2.53 (m, 2H).

[0316] Compound 45 was prepared from compound 44-5-P2 according to the synthesis of compound 36 in Example 14. LCMS (ESI, m / z): [M+H] + =478.2; 1 H NMR (400 MHz, methanol-d4): δ 8.59 (s, 2H), 7.71 (s, 1H), 4.12 (s, 1H), 4.03-3.63 (m, 13H), 2.89-2.79 (m, 2H), 2.68-2.53 (m, 2H). TIFF2024532845000223.tif65166

[0317] Step 1: To a solution of 2-aminophenol (1.1 g, 10.1 mmol) in MeOH (10 mL) was added NaHCO (1.0 g, 12.1 mmol). Then, (E)-methyl 4-bromobut-2-enoate (1.8 g, 10.1 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The mixture was filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 34-1.

[0318] Step 2: To a solution of 34-1 (1.5 g, 7.24 mmol) in MeOH (5 mL) was added KCO (100 mg, 0.72 mmol). The mixture was stirred at room temperature for 1 h. The mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile and 0.1% FA in water: 5% to 50%) to provide 34-2.

[0319] Step 3: To a solution of 34-2 (473 mg, 2.28 mmol) and 36-3 (500 mg, 1.52 mmol) in dioxane (10 mL) were added Pd(dba) (139 mg, 0.15 mmol), BINAP (190 mg, 0.30 mmol), and CsCO (546 mg, 1.67 mmol). The mixture was then stirred under N at 120 °C overnight. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) to provide 34-3.

[0320] Step 4: To a solution of 34-3 (200 mg, 0.4 mmol) in dichloromethane / TFA (3 mL / 1 mL), the mixture was stirred at room temperature for 1 hour. The mixture was concentrated. The residue was dissolved in MeOH / HO (2 mL / 2 mL). LiOH (48 mg, 2.00 mmol) was added. The mixture was stirred at room temperature for 1 hour. Purification of the mixture by reverse-phase HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) provided 34-4.

[0321] Step 5: To a solution of 34-4 (100 mg, 0.28 mmol) and 31-3 (65 mg, 0.28 mmol) in DMF (2 mL) was added DIEA (182 mg, 1.41 mmol) and HATU (159 mg, 0.42 mmol). The mixture was then stirred at room temperature for 1 h. The residue was purified by preparative HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) to provide 34-5.

[0322] Step 6: Compound 34-5 (60 mg) was purified by SFC (column: DAICEL CHIRALPAK® OJ, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 70 / 30) to give 34 (10.2 mg) and 35 (9.5 mg), respectively. 34: SFC analysis: >99% ee; retention time: 3.38 min; column: DAICEL CHIRALPAK® OJ, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =570.3; 1 H NMR (400 MHz, methanol-d4): δ 8.59 (s, 2H), 7.98 (s, 1H), 7.01-6.84 (m, 4H), 4.80-4.65 (m, 1H), 4.20-4.14 (m, 1H), 4.01-3.90 (m, 4H), 3.78-3.65 (m, 4H), 3.56-3.49 (m, 1H), 3.06-2.97 (m, 1H), 2.83-2.76 (m, 1H). 35: SFC analysis: 98.58% ee; retention time: 3.81 min; column: DAICEL CHIRALPAK® OJ, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS(ESI,m / z):[M+H] + =570.3; 1H NMR (400MHz, methanol-d4):δ 8.59(s,2H),7.96(s,1H),6.99-6.86(m,4H),4.81-4.66(m,1H),4.19-4.13(m,1H),4.03- 3.85(m,4H),3.79-3.62(m,4H),3.57-3.49(m,1H),3.05-2.98(m,1H),2.83-2.76(m,1H). TIFF2024532845000224.tif118166

[0323] Step 1: A mixture of benzaldehyde (7 g, 66 mmol) and 1-aminoprop-2-ol (5 g, 67 mmol) in EtOH (330 mL) was stirred at reflux temperature for 6 hours. After cooling to room temperature, NaBH4 (3.8 g, 100.45 mmol) was added in portions in an ice-water bath, and the resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water. The mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 42-1.

[0324] Step 2: To a solution of 42-1 (5.74 g, 34.74 mmol) and TEA (7 g, 69.18 mmol) in dichloromethane (115 mL) was added ethyl (E)-4-bromobut-2-enoate (6.2 g, 34.64 mmol). The mixture was stirred at room temperature for 16 hours. Another portion of TEA (3.5 g, 34.65 mmol) and ethyl (E)-4-bromobut-2-enoate (3.1 g, 17.32 mmol) was added, and the resulting mixture was stirred for 4 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 42-2.

[0325] Step 3: To a solution of 42-2 (2.99 g, 11.35 mmol) in toluene (60 mL) was added DBU (1.73 g, 11.36 mmol). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was cooled and concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=2 / 1) to give 42-3-P1 (less polar fraction) and 42-3-P2 (more polar fraction).

[0326] Step 4: A mixture of 42-3-P1 (2.8 g, 10.10 mmol) and 10% wet palladium on carbon (1.25 g) in EtOH (150 mL) was stirred at 1 atmosphere of H2 at room temperature for 16 hours, then filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (dichloromethane / methanol = 5 / 1) to give 42-4.

[0327] Step 5: Under N2, H2SO4 (98%, 5.0 g, 51 mmol) was added to HO (75 mL), followed by the sequential addition of 31-1 (5.0 g, 23.5 mmol), AgNO3 (800 mg, 4.7 mmol), and AcOH (5.0 g, 83.5 mmol). The mixture was heated at 55 °C, and a solution of (NH4)2SO8 (13.5 g, 59.0 mmol) in HO (30 mL) was added dropwise within 0.5 h. The resulting mixture was stirred at 55 °C for 1 h. The mixture was cooled and extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile and 0.05% TFA in water: 5% to 95%) to provide 42-5.

[0328] Step 6: To a solution of 42-5 (380 mg, 1.68 mmol) in dioxane (10 mL) were added 42-4 (673 mg, 2.52 mmol), Pd(dba) (154 mg, 0.17 mmol), BINAP (210 mg, 0.34 mmol), and CsCO (1.1 g, 3.35 mmol). The resulting mixture was stirred with N at 120 °C for 4 h. The mixture was cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile and 0.05% TFA in water: 5% to 80%) to provide 42-6.

[0329] Compound 42-9 was prepared from compound 42-6 according to the process for synthesizing compounds 31 and 32 in Example 13.

[0330] Step 7: Compound 42-9 (65 mg) was purified by SFC (column: DAICEL CHIRALPAK® OJ, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 85 / 15) to give 42 (11.9 mg) and 43 (14.7 mg), respectively. 42: SFC analysis: 98.80% ee; retention time: 2.52 min; column: DAICEL CHIRALPAK® OJ, MeOH (0.1% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =550.0; 1H NMR (400MHz, methanol-d4):δ 8.59(s,2H),4.46-4.42(m,1H),4.20-4.15(m,1H),4.00-3.85(m,4H),3.77-3.63(m,4H),3.13 -3.02(m,2H),2.93-2.88(m,3H),2.75-2.68(m,1H),2.49-2.46(m,3H),1.29(d,J=6.5Hz,3H). 43: SFC analysis: 90.92%ee; retention time: 2.60 min; column: DAICEL CHIRALPAK® OJ, MeOH (0.1% DEA) in CO2 solution, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS(ESI,m / z):[M+H] + =550.0; 1 H NMR (400MHz, methanol-d4):δ 8.59(s,2H),4.48-4.40(m,1H),4.20-4.15(m,1H),4.00-3.85(m,4H),3.78-3.62(m,4H),3.14 -3.02(m,2H),2.93-2.88(m,3H),2.75-2.68(m,1H),2.49-2.46(m,3H),1.27(d,J=6.5Hz,3H). TIFF2024532845000225.tif66166

[0331] Step 1: (S)-tert-Butyl 2-formylpyrrolidine-1-carboxylate (2.0 g, 10.0 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of LiCl (510 mg, 12.0 mmol), DIPEA (1.6 g, 12.0 mmol), and triethyl phosphinylacetate (2.7 g, 12.0 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 48-1.

[0332] Step 2: To a solution of 48-1 (1.0 g, 3.7 mmol) in MeOH (10.0 mL) was added 10% Pd / C (200 mg). The mixture was stirred in H at room temperature for 3 h. The mixture was filtered and the filtrate was concentrated to give 48-2, which was used directly in the next step without purification.

[0333] Step 3: To a solution of 48-2 (800 mg, 2.9 mmol) in methanol / water (5 mL / 2 mL) was added NaOH (580 mg, 14.5 mmol). The mixture was stirred at room temperature for 5 hours. The organic solvent was removed. The resulting aqueous solution was acidified with 1 N HCl to pH = 3 and then extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated to give 48-3, which was used directly in the next step without purification.

[0334] Step 4: EDCI (368 mg, 1.9 mmol) was added to a mixture of 48-3 (400 mg, 1.6 mmol), 31-3 (552 mg, 1.8 mmol), DIEA (620 mg, 4.8 mmol), and DMAP (39 mg, 0.3 mmol) in dichloromethane (10 mL) at room temperature. The mixture was then stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 48-4.

[0335] Step 5: A solution of 48-4 (750 mg, 1.6 mmol) in HCl ethyl acetate (5.5 mL, 2 M) was stirred at room temperature for 2 h. The mixture was concentrated. The crude product and methyl tert-butyl ether were triturated together and filtered to give 48-5.

[0336] Step 6: To a solution of 48-5 (400 mg, 1.0 mmol) and 1,4-dichlorodiazanaphthylene (438 mg, 2.2 mmol) in NMP (5 mL) was added CsCO (2.2 g, 6.6 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 48 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 48-6.

[0337] Step 7: To a solution of 48-6 (100 mg, 0.2 mmol) and NaOAc (162 mg, 2.0 mmol) in DMAc (3 mL) at room temperature, 5 drops of AcOH were added. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.1% FA in water: 5% to 95%) to provide 48. LCMS (ESI, m / z): [M+H] + =501.9; 1 H NMR (400MHz, methanol-d4):δ 8.57(d,J=0.4Hz,2H),8.34(dd,J=8.0,1.2Hz,1H),8.13(d,J=8.0Hz,1H),7.93-7.91(m,1H),7.85-7.83(m,1H),4.42-4.38(m,1H),3.93-3.90 (m,1H),3.81-3.79(m,4H),3.57-3.49(m,4H),3.28-3.27(m,1H),2.50 -2.47(m,2H),2.24-2.22(m,1H),2.02-1.99(m,2H),1.86-1.84(m,3H). 19 F NMR (376 MHz, methanol-d4) δ -62.66 (3F). TIFF2024532845000226.tif60166

[0338] Step 1: To a solution of 5-fluoroisobenzofuran-1,3-dione (1.8 g, 10.84 mmol) in 10% HCl (50 mL) was added N2H4-H2O (1.04 g, 20.8 mmol). The mixture was stirred at 100 °C for 24 hours. The mixture was cooled and filtered. The filter cake was washed with water and dried to give 49-1, which was used directly in the next step without purification.

[0339] Step 2: A mixture of 49-1 (1.8 g, 9.99 mmol) in POCl (30 mL) was stirred at 110° C. for 3 h. The mixture was cooled and decanted into ice water, then filtered and the filter cake was dried to give 49-2, which was used directly in the next step without purification.

[0340] Step 3: A solution of 49-2 (1.7 g, 7.83 mmol) in 5 M NaOH (30 mL) was stirred at room temperature overnight. The mixture was filtered. The filter cake was washed with water and dried to give a mixture of 49-3 and 49-4, which was used directly in the next step without purification.

[0341] Step 4: To a mixture of 49-3 and 49-4 (1.2 g, 6.04 mmol) in DMF (20 mL) was added NaH (60% in oil, 290 mg, 12.09 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. SEMCl (1.21 g, 7.25 mmol) was added at 0 °C. The mixture was then warmed to room temperature and stirred for 1 h. The mixture was decanted into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 49-5-P1 (less polar) and 49-5-P2 (more polar), respectively.

[0342] Compound 49-9 was prepared from compound 49-5-P1 according to the process for synthesizing compound 36 in Example 14.

[0343] Compound 49-9 (120 mg) was purified by SFC (column: DAICEL CHIRALPAK® OJ, MeOH (+0.1% 7.0 mol / L ammonia in MeOH) / CO2 = 75 / 25) to give 49 (35 mg) and 50 (29 mg), respectively. 49: SFC analysis: 98.68% ee; retention time: 3.21 min; column: DAICEL CHIRALCEL® OJ, EtOH (0.1% of DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =522.2; 1 H NMR (400MHz, methanol-d4):δ 8.59(s,2H),8.16(dd,J=8.9,5.1Hz,1H),7.97(dd,J=8.7,2.7Hz,1H),7.70(td,J=8.7,2.7Hz,1H),4.30-4.22(m,1H),4.10-3 .83(m,6H),3.82-3.59(m,4H),3.56-3.48(m,1H),3.36-3.32(m,1H),3.06-2.96(m,1H),2.88-2.74(m,2H),2.63-2.55(m,1H). 50: SFC analysis: 94.16% ee; Retention time: 3.33 min; Column: DAICEL CHIRALPAK® OJ, EtOH (0.1% DEA) in CO2 from 5% to 40%; Pressure: 100 bar; Flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =522.2; 1 H NMR (400MHz, methanol-d4):δ 8.59(s,2H),8.16(dd,J=9.0,5.1Hz,1H),7.97(dd,J=8.7,2.7Hz,1H),7.70(td,J=8.7,2.8Hz,1H),4.33-4.18(m,1H),4.11-3 .84(m,6H),3.81-3.58(m,4H),3.55-3.50(m,1H),3.35-3.32(m,1H),3.06-2.95(m,1H),2.88-2.74(m,2H),2.62-2.54(m,1H). TIFF2024532845000227.tif81164

[0344] Compound 73-1 was prepared from compound 3-hydroxybenzoic acid according to the process for synthesizing compound 31-6 in Example 13.

[0345] Step 1: To a solution of dimethyl 1H-pyrrole-2,3-dicarboxylate (1.0 g, 5.5 mmol) in DMF (10 mL) was added NaH (440 mg, 11.0 mmol, 60%) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then MeI (937 mg, 6.6 mmol) was added. The mixture was stirred at 25 °C for 3 h. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated to give 73-2, which was used directly in the next step without purification.

[0346] Step 2: To a solution of 73-2 (700 mg, 3.6 mmol) in EtOH (20 mL) at room temperature was added hydrazine hydrate (80% in water, 676 mg, 13.5 mmol). The mixture was stirred at reflux for 12 hours. The mixture was concentrated. The residue was triturated in dichloromethane / methanol (10 / 1) and filtered to give 73-3.

[0347] Step 3: A solution of 73-3 (150 mg, 0.91 mmol) in POCl (3 mL) was stirred at 80 °C for 3 h. The mixture was concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO and brine. The organic layer was dried over NaSO, filtered, and concentrated to give 73-4, which was used directly in the next step without purification.

[0348] Step 4: To a solution of 73-4 (130 mg, 0.64 mmol) in MeCN (2 mL) was added 73-1 (271 mg, 0.77 mmol) and CsCO (626 mg, 1.92 mmol) at room temperature. The mixture was stirred at 60 °C for 12 h. The mixture was cooled, decanted into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to give 73-5.

[0349] Step 5: A solution of 73-5 (100 mg, 0.19 mmol) in HCOOH (1 mL) and HO (1 mL) was stirred at 85 °C for 12 h. The mixture was cooled and adjusted to pH 5-6 with 23% aqueous NaOH. The mixture was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.1% FA in water: 30% to 53% to 100%) to provide 73. LCMS (ESI, m / z): [M+H] + =500.2; 1 H NMR (400MHz, methanol-d4, ppm):δ 8.60(s,2H),7.59-7.54(m,1H),7.42-7.40(m,2H),7.37-7.35(m,2H),6.82(d,J= 3.2Hz,1H),4.10(s,3H),4.04-3.96(m,4H),3.86-3.83(m,2H),3.61-3.58(m,2H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -62.66 (3F). TIFF2024532845000228.tif67166

[0350] Following the process for synthesizing compound 36-2 in Example 14, compound 75-2 was prepared from 6-chloro-5-methylpyridazin-3(2H)-one.

[0351] Compound 75-3 was prepared from compound 75-2 according to the process for synthesizing compound 44-1 in Example 15.

[0352] Step 1: To a solution of 75-3 (750 mg, 1.70 mmol) and 73-1 (599 mg, 1.70 mmol) in dioxane (5 mL) was added tri(dibenzalacetone)dipalladium (156 mg, 0.17 mmol), tetramethyl-di-tBuXPhos (82 mg, 0.17 mmol), and CsCO (560 mg, 1.72 mmol). The mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 75-4.

[0353] Compound 75-5 was prepared from compound 75-4 according to the process for synthesizing compound 36 in Example 14.

[0354] Compound 75 was prepared from compound 75-5 according to the synthesis of compound 44-5 in Example 15. LCMS (ESI, m / z): [M+H] + =485.2; 1 H NMR (400 MHz, methanol-d₄, ppm): δ 8.59 (s, 2H), 7.53 (t, J = 8.1 Hz, 1H), 7.39-7.23 (m, 3H), 4.45 (s, 1H), 4.10-3.75 (m, 6H), 3.65-3.50 (m, 2H), 2.47 (s, 3H). TIFF2024532845000229.tif34166

[0355] Following the process for synthesizing compound 31-6 in Example 13, compound 62-1 was prepared from 3-mercaptobenzoic acid.

[0356] Step 1: A mixture of 42-5 (150 mg, 0.66 mmol), 62-1 (244 mg, 0.66 mmol), Xantphos (38 mg, 0.66 mmol), DIEA (257 mg, 2 mmol), and Pd(dba) (61 mg, 0.066 mmol) in dioxane (10 mL) was stirred at 100 °C for 16 h under N. The mixture was cooled, decanted into water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 62-2.

[0357] Compound 62 was prepared from 62-2 according to the synthesis of compound 31 in Example 13. LCMS (ESI, m / z): [M+H] + =545.2; 1 H NMR (400MHz, methanol-d4, ppm): δ 8.59 (s, 2H), 7.65-7.47 (m, 4H), 4.10-3.74 (m, 6H), 3.62-3.44 (m, 2H), 2.52-2.49 (m, 3H). TIFF2024532845000230.tif53166

[0358] Following the process for synthesizing compound 36-2 in Example 14, compound 70-2 was prepared from 5,6-dichloropyridazin-3(2H)-one.

[0359] Step 1: To a solution of 70-2 (1 g, 2.67 mmol) in DMF (20 mL) were added 2-azaspiro[3.3]-heptane hydrochloride (428 mg, 3.21 mmol) and CsCO (2.61 g, 8.02 mmol). The reaction mixture was then stirred at 80 °C for 1 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 70-3.

[0360] Step 2: To a solution of 70-3 (500 mg, 1.15 mmol) in DMF (15 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (663 mg, 3.45 mmol) and CuI (219 mg, 1.15 mmol). The reaction mixture was stirred at 110 °C for 0.5 h under microwave conditions. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 70-4.

[0361] Step 3: To a solution of 70-4 (430 mg, 1.01 mmol) in DMF (8 mL) was added tert-butyl 3-hydroxybenzoate (394 mg, 2.03 mmol) and CsCO (826 mg, 2.54 mmol). The reaction mixture was then stirred at 80 °C for 8 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 70-5.

[0362] Step 4: 70-5 (100 mg, 0.17 mmol) was dissolved in a solution of HCl in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 4 h. Then the solvent was removed in vacuo. The residue was dissolved in THF (8 mL) and HO (4 mL), and then LiOH (21 mg, 0.50 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. The pH was adjusted to 5-6 by adding 1 M HCl, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over NaSO, filtered, and concentrated to give 70-6, which was used directly in the next step without purification.

[0363] Compound 70 was prepared from 70-6 and 31-3 according to the process for synthesizing compound 31-6 in Example 13. LCMS (ESI, m / z): [M+H] + =610.0; 1H NMR(400MHz,DMSO-d6,ppm):δ 11.53(s,1H),8.72(s,2H),7.50(t,J=8Hz,1H),7.40-7.20(m,3H),4.42(s,4H),3.91-3 .82(m,4H),3.72-3.65(m,2H),3.49-3.42(m,2H),2.18-2.13(m,4H),1.71-1.66(m,2H). TIFF2024532845000231.tif67156

[0364] Step 1: To a solution of 42-5 (5.0 g, 22.1 mmol) in CCl (50 mL) was added NBS (5.1 g, 28.7 mmol) and AIBN (725 mg, 4.4 mmol). The resulting mixture was stirred at reflux overnight. The mixture was cooled, diluted with water, and extracted with dichloromethane. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile with 0.05% TFA in water: 5% to 70%) to provide 71-1.

[0365] Step 2: To a solution of 71-1 (507 mg, 1.00 mmol) in MeOH (5 mL) and THF (5 mL) was added MeONa (59 mg, 1.10 mmol) at 0 °C. The mixture was then stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer w...

Claims

1. A compound of general formula I or a pharmaceutically acceptable salt thereof, where: Z is N or C, preferably N; R １ is hydrogen, CH3, ethyl, isopropyl, cyclopropyl, CN, OCH3, SCH3, CF3, F, Cl, Br, CF2H, or or R 1 is OCH 2 CF 2 H; R ２ But hydrogen, halogen, CN, OR １０ , S.R. １１ , S(O)R １２ , S(O) ２ R １３ , N.R. １４ R １５ , an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbocyclyl group, an optionally substituted phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclyl group; L １ and L ２ are independently a single bond, O, S, S(O), S(O) ２ , N.R. １６ , C(O), C(O)O, C(O)NR １６ , OC(O)NR １６ , S(O) ２ NR １６ , N.R. １７ C(O)NR １６ , N.R. １７ S (O) ２ NR １６ , an optionally substituted alkylene group, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted heteroalkylene group, an optionally substituted carbocyclylene group, an optionally substituted heterocyclylene group, an optionally substituted phenylene group, or an optionally substituted heteroarylene group, and preferably, L １ and L ２ is not a single bond at the same time, X is a single bond, C(O), G １ -C(O)-G ２ , S(O), S(O) ２ , or G １ -S(O) ２ -G ２ Among them, G １ and G ２ are each independently a single bond, O, NH, or optionally substituted C １－４ an alkylene group or an optionally substituted C １－４ a heteroalkylene group, or １ and G ２ are linked together with the atoms therebetween to form an optionally substituted 4- to 7-membered ring structure, Ring A is an optionally substituted carbocycle or heterocycle, L ３ is a single bond, O, S, S(O), S(O) ２ , N.R. １６ , optionally substituted C １－４ an alkylene group or an optionally substituted C １－４ is a heteroalkylene group, Ring B is an optionally substituted aryl or heteroaryl ring, Or, R １ and R ２ are linked together with the atoms therebetween to form an optionally substituted ring structure; Or, R ２ and L １ are linked together with the atoms therebetween to form an optionally substituted ring structure; Or, L １ and L ２ are linked together with the atoms therebetween to form an optionally substituted ring structure; Or, R １ , R ２ and L １ are linked together with the atoms therebetween to form an optionally substituted ring structure; Or, L ３ is a single bond, ring A and ring B together represent an optionally substituted cyclic structure having one ring or at least two rings, for example, a bicyclic structure; where: R １０ , R １１ , R １２ and R １３ each occurrence is independently selected from the group consisting of hydrogen, an optionally substituted alkyl group, an optionally substituted carbocyclyl group, or an optionally substituted heterocyclyl group; and R １４ , R １５ , R １６ and R １７ is independently selected from the group consisting of hydrogen, a nitrogen protecting group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group, A compound or a pharmacologically acceptable salt thereof.

2. The compound of general formula I has a structure according to general formula I-C-1-a1 or I-D-3-b, where: R G , each time it is present, independently represents halogen (preferably F, Cl, or Br); CN; a C 1-4 alkyl group optionally substituted with 1-5 (e.g., 1, 2, or 3) G C ; OH; a C 3-6 cycloalkyl group optionally substituted with 1-5 (e.g., 1, 2, or 3) G C ; a 4-6 membered heterocyclyl group having 1-3 ring-forming heteroatoms, each independently selected from the group consisting of N, O, and S, optionally substituted with 1-5 (e.g., 1, 2, or 3) G C ; NH 2 ; NH(C 1-4 alkyl group); N(C 1-4 alkyl group)(C 1-4 alkyl group); a C 1-4 alkoxy group optionally substituted with 1-5 (e.g., 1, 2, or 3) G C ; a C 3-6 cycloalkyl group optionally substituted with 1-5 (e.g., 1, 2, or 3) G C . a cycloalkoxy group; or a 4-6 membered heterocycloalkoxy group optionally substituted with 1-5 (e.g., 1, 2, or 3) G C ; h is 0, 1 or 2, and R 6 , each occurrence, is independently F, Cl, Br, CN, a C 1-4 alkyl group optionally substituted with 1-5 (e.g., 1, 2 or 3) G C , OH, cyclopropyl, cyclobutyl, a 4-6 membered heterocyclyl group having 1-3 ring heteroatoms independently selected from the group consisting of N, O and S, optionally substituted with 1-5 (e.g., 1, 2 or 3) G C , NH 2 , NH(C 1-4 alkyl group), N(C 1-4 alkyl group)(C 1-4 alkyl group), or a C 1-4 alkoxy group optionally substituted with 1-5 (e.g., 1, 2 or 3) G C ; wherein each occurrence of G C is independently F, OH, a C 1-4 alkyl group optionally substituted with 1 to 3 F, or a C 1-4 alkoxy group optionally substituted with 1 to 3 F; 2. The compound according to claim 1 or a pharmacologically acceptable salt thereof.

3. R ２ is hydrogen, CH ３ , C.F. ３ , NH ２ 、NHCH ３ 、 or and Or, R ２ but, or and Or, R ２ but, or and Or, R ２ but, or and Or, R ２ but, or and Or, R ２ is cyclopropyl, 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. L ２ But C １－４ is an alkylene group, 3. The compound according to claim 2 or a pharmacologically acceptable salt thereof.

5. Ring A is That is, 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Ring B is or and Alternatively, ring B is and Alternatively, ring B is or That is, 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of Compound Nos. 1-353 or the compounds set forth in Table A of the present application, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient.

9. 10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in a method for treating cancer in a subject in need thereof.

10. the cancer is breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, head and neck cancer (upper aerodigestive tract cancer), urinary tract cancer, or colon cancer; 10. The compound according to claim 9, or a pharmacologically acceptable salt thereof, or a pharmaceutical composition thereof.

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