Kinase inhibitors, their production method and use

Abstract

The present application provides novel compounds, e.g., compounds having the structure of Formulae III-1 to III-12, or a pharma- cologically acceptable salt thereof. The present application also provides methods of making the compounds and methods of using the compounds, e.g., to inhibit DGK in cells and / or to treat various diseases, such as cancer or viral infections.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to International Application No. PCT / CN2022 / 084377, filed March 31, 2022, and International Application No. PCT / CN2022 / 118935, filed September 15, 2022, the entire contents of which are incorporated herein by reference.

[0002] In various embodiments, the present disclosure generally relates to novel compounds, compositions containing such compounds, methods for making the same, and methods of using such compounds to inhibit DGK and / or treat multiple diseases or conditions (e.g., cancer or infection). [Background technology]

[0003] Diacylglycerol kinases (DGKs) have been shown to function as intracellular checkpoints. Inhibition of DGKs is expected to enhance T cell signaling pathways and T cell activation. (See, for example, Riese MJ et al., Journal of Biological Chemistry, (2011) 7:5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock BA et al., (2006) 11:1174-81). DGKa (DGK alpha) and DGKz (DGK zeta) are targets for cancer immunotherapy. There remains a need for compounds that can be used as inhibitors of one or both of DGKa and DGKz. Summary of the Invention

[0004] The present disclosure is based, in part, on the applicant's discovery of compounds that have inhibitory activity as one or both of DGKα and DGKz. In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions thereof, methods for their preparation, and methods of use. Generally, the compounds herein are DGK inhibitors, e.g., DGKα and / or DGKz inhibitors. The compounds and compositions herein can be used to treat various diseases or conditions, e.g., cancer or viral infections.

[0005] In some embodiments, the present disclosure provides a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula III-2 is characterized by having a structure of a subformula of formula III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b. In some embodiments, the compound of Formula III-3 is characterized by having a structure of a subformula of Formula III-3-A. In some embodiments, the compound of Formula III-4 is characterized by having a structure of a subformula of Formula III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f. In some embodiments, the compound of Formula III-8 is characterized by having a structure of a subformula of Formula III-8-A or III-8-B. In some embodiments, the present disclosure also provides a compound selected from the group consisting of the compounds set forth in Table A herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure also provides a compound selected from the group consisting of compounds 1-347 of the present application, 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 the following formulae: III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D-5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2-D-17, III-2-D-18, III-2-D I-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2 -E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. and a compound of any one of Nos. 1 to 347, a compound set forth in Table A of the present application, or a pharmaceutically acceptable salt thereof), and an optional pharmaceutically acceptable excipient. The pharmaceutical compositions according to the present application can be prepared for various routes of administration, such as oral administration, parenteral administration or inhalation.

[0007] Some embodiments relate to methods for treating diseases or conditions associated with the activity of DGKa, DGKz, or both DGKa and DGKz. 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 the following formulae: III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D ...5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2-D-17, III-2-D-18, III-2-D-19, III-2-D-20, III-2-D-21, III-2-D-22, III-2-D-23, III-2-D-24, III-2-D-25, III-2-D-26, III-2-D-27, III-2-D-28, III-2-D-29, III-2-D-30, III-2-D-31, III-2-D-32, III-2-D-33, III-2-D-34, III-2-D-35, III-2-D-36, III-2-D-3 -D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2 b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. For example, the present invention includes administering a therapeutically effective amount of a compound selected from the group consisting of compounds of formula III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., compounds of formula III-8-A or III-8-B), III-9, III-10, III-11, or III-12, compounds of formula III-10-A, III-11-B, III-12-C, III-12-D, III-12-E, III-12-F, III-12-H, III-12-I ... Diseases or conditions associated with the activity of DGKa, DGKz, or both DGKa and DGKz that are suitable for treatment by the method include diseases or conditions according to the present application.

[0008] In some embodiments, a method of treating cancer is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of the following formulae: III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D, III-2-D-5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2-D-17, III-2-D-18, III-2-D-19, III-2-D-20, III-2-D-21, III-2-D-22, III-2-D-23, III-2-D-24, III-2-D-19 ... 2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2 b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. For example, the present invention includes administering a therapeutically effective amount of a compound selected from the group consisting of compounds of formula III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., compounds of formula III-8-A or III-8-B), III-9, III-10, III-11, or III-12, compounds of formula III-10-A, III-11-B, III-12-C, III-12-D, III-12-E, III-12-F, III-12-H, III-12-I ... In various embodiments, the cancer may be colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and / or melanoma.

[0009] In some embodiments, a method for treating a viral infection is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of the following formulae: III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III- 2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2 b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. For example, the present invention includes administering a therapeutically effective amount of a compound selected from the group consisting of compounds of formula III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., compounds of formula III-8-A or III-8-B), III-9, III-10, III-11, or III-12, compounds of formula III-10-A, III-11-B, III-12-C, III-12-D, III-12-E, III-12-F, III-12-H, III-12-I ...

[0010] The 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, intrapleural, intrathecal, or parenteral.

[0011] The compounds of the present disclosure can be used as monotherapy or combination therapy. In some embodiments, the combination therapy includes treating a subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, and / or immunotherapy. In some embodiments, the combination therapy includes treating a subject with an immuno-oncology agent of the present application. In some embodiments, the combination therapy includes treating a subject with one or more additional antiviral agents.

[0012] In some embodiments, the present disclosure provides the following exemplary embodiments 1-49. Embodiment 1. A compound of formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11 or III-12, or a pharmaceutically acceptable salt thereof: TIFF2025510945000001.tif235166 formula, R 1 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, COOH, CONH2, R A , OR A , NH(R A ), N(R A )2, COOR A , CONH(R A ), CON(R A )2, SR A , SOR A , SO2R A or P(O)(R A )2 and R A may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; R 2 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, RB , OR B , NH(R B ) or N(R B )2 and R B may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl; R 3 may be substituted with hydrogen or C 1-4 alkyl, or an optionally substituted 3-7 membered ring, for example, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 4-7 membered heterocyclyl (e.g., saturated 4-7 membered heterocyclyl); J is O, CO, SO2, NR 15 or optionally substituted methylene; W is non-existent or (W 1 ) p where p is 1, 2 or 3, and W 1 Each time it is expressed, it is independently C(O), NR 15 , SO2, O or optionally substituted methylene, provided that W 1 One of the following examples is C(O), NR 15 , SO2 or O; R 15 represents each independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 alkynyl, an optionally substituted 3-6 membered ring, or a nitrogen protecting group; X is N or CR 5 and R 5 However, hydrogen, halogens, OH, NH2, NH(R C ), N(R C )2, CN, CONH2, COOH, CONH(R C ), CON(R C )2, OR C, or COOR C and R C may be substituted independently each time C represents 1-4 is alkyl; U is N or CR 6 and R 6 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, R D , OR D , NH(R D ) 、 N(R D )2, COOH, CONH2, COOR D , CONH(R D ) 、 CON(R D )2, SR D , SOR D , SO2R D , or P(O)(R D )2 and R D may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; Y is N or CR 7 and R 7 may be substituted with hydrogen, F, Cl, CN, or C 1-4 Alkyl or optionally substituted C 1-4 is heteroalkyl; Z is C(O), C(=N-OH), C(=NO-(C 1-4 alkyl), C(=N-NH2), C(=N-NH-(C 1-4 alkyl), C(=NN(C 1-4 Alkyl)(C 1-4 alkyl), SO, SO2, S(O)(=NH) or S(O)(=N-(C 1-4 alkyl); Ring C is a 5- or 6-membered ring, preferably a 5- or 6-membered heteroaryl having 2-3 ring-forming heteroatoms, for example, a 5-membered heteroaryl having 2-3 ring-forming nitrogen atoms, for example, an imidazole ring or a triazole ring, and in formula III-8, ring C and the adjacent ring share two ring-forming atoms; L 1 is an optionally substituted 4- to 12-membered ring, preferably a 4- to 12-membered heterocyclylene having one or more rings and 1 to 4 ring-forming heteroatoms each independently selected from the group consisting of O, N, or S, or —N(R E )- and R E may be replaced by C 1-4 alkyl or an optionally substituted 3-7 membered ring; L 2 However, non-existent, O, NH, -N(R E2 )-, C(O), SO2, optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, optionally substituted C 1-4 Alkynylene, optionally substituted C 1-4 heteroalkylene, or an optionally substituted 3- to 7-membered ring; R E2 may be replaced by C 1-4 alkyl or an optionally substituted 3-7 membered ring; R 30 is hydrogen, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 8-12 membered ring having two or more rings; R 9 Each time it is expressed, it can independently represent halogen, CN, OH, R N , OR N , NHR N , N(R N )2, COOR N , C.O.R. N , CONH(R N ), or CON(R N )2 and R N may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or an optionally substituted 3-7 membered ring, for example, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 7-membered heterocyclyl, or optionally substituted 5- or 6-membered heteroaryl; and n1 is 0, 1, 2 or 3, preferably n1 is 0 or 1, and R 9 Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 It is alkyl (e.g., CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3, or CH2NHC(O)OCH3. Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Y is N. Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH. Embodiment 4. A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein U is N. Embodiment 5.U is CR 6 4. The compound of any one of embodiments 1 to 3, wherein: Embodiment 6.R 6 is hydrogen, or a pharmaceutically acceptable salt thereof. Embodiment 7.R 6 But C 1-4 Alkoxy or TIFF2025510945000002.tif1778, or a pharmaceutically acceptable salt thereof. Embodiment 8. If applicable, R 1 The compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is CN. Embodiment 9. If applicable, (i) R 1 is a halogen, e.g., F or Cl; (ii) R 1 but, TIFF2025510945000003.tif1173; (iii) R 1 is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, such as an optionally substituted pyrimidyl or an optionally substituted thiazolyl, e.g., R 1 but, TIFF2025510945000004.tif1883 or TIFF2025510945000005.tif1883; or (iv) R 1 But, SR A1 and R A1 each independently represents an optionally substituted C 1-4 alkyl, e.g., R 1 The compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is SCH3. Embodiment 10. The compound of embodiment 1, characterized in that it has the structure of formula III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, or III-4-D-2, or a pharmaceutically acceptable salt thereof. TIFF2025510945000006.tif109166 Embodiment 11.R 2 The compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Embodiment 12.(i)R 3 may be replaced by C 1-4 alkyl, for example, CH3, CD3, etc.; (ii) R 3 is hydrogen; (iii) R 3 may be replaced by C 1-4 alkyl, for example, CH(CH3)2, CH2CH3, CH2CHF2, etc.; or (iv) R 3 may be replaced by C 3-6 12. The compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, which is cycloalkyl, for example, cyclopropyl, cyclobutyl, etc. Embodiment 13. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Z is C(O). Embodiment 14. Where applicable, R 9 may be substituted independently each time C represents 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl, preferably CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 A compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl (e.g., CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3 or CH2NHC(O)OCH3. Embodiment 15. A compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein, where applicable, X is N. Embodiment 16. Where applicable, X is CR 5 and R 5 The compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is CN. Embodiment 17. Where applicable, X is CR 5 , R 5 However, CONH2, COOH, CONH(R C1 ), CON(R C1 )2, or COOR C1 and R C1 Each time, independently, C 1-4 15. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, for example, methyl. Embodiment 18. Where applicable, L 1 but, TIFF2025510945000007.tif33108 or TIFF2025510945000008.tif33108 (One of the two linkers of piperidine, N or C, is L) 2 (which may be concatenated to wherein n is 0, 1, 2, 3, or 4; and (1)R 9A Each time it is expressed, it can independently represent halogen, CN, OH, R N , OR N , NHR N , N(R N )2, COOR N , C.O.R. N , CONH(R N ) or CON(R N )2 and R N may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or an optionally substituted 3-7 membered ring, for example, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 7-membered heterocyclyl, or optionally substituted 5- or 6-membered heteroaryl; or (2)R 9A two examples of may be linked to form a double bond or a 3- to 5-membered ring, and R 9A Any remaining example of (1) is defined as 18. A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. Embodiment 19.R 9A Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 The compound of embodiment 18, or a pharmaceutically acceptable salt thereof, wherein R is alkyl (e.g., CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3, or CH2NHC(O)OCH3. Embodiment 20. Where applicable, L 1 is selected from the group consisting of the following items (the lower connecting hand N or C is L 2 18. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. TIFF2025510945000009.tif76133 Embodiment 21. If applicable, L 1is selected from the group consisting of the following items (the lower connecting hand N or C is L 2 18. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. TIFF2025510945000010.tif74133 Embodiment 22. If applicable, L 1 is an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring-forming heteroatoms each independently selected from the group consisting of O, N, or S, and when substituted, the substituents may be linked to any one or more of the two or more rings, or a pharmaceutically acceptable salt thereof. Embodiment 23. Where applicable, L 1 is selected from the group consisting of the following bicyclic heterocyclylenes (wherein the lower linker N or C is L) 2 18. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. TIFF2025510945000011.tif68126 In the formula, each bicyclic heterocyclylene has 1 to 3 R 10 may be substituted with R 10 each occurrence independently represents halogen, OH, NH, oxo (where applicable), R J , OR J , CN, NH(R J ) or N(R J )2 and R J may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 alkynyl, or an optionally substituted 3- or 4-membered ring. Embodiment 24. Where applicable, L 1 is selected from the group consisting of the following bicyclic heterocyclylenes (wherein the lower linker N or C is L) 2 18. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. TIFF2025510945000012.tif69165Embodiment 25. If applicable, L 1 But -N(C 1-4 18. The compound of any of embodiments 1-17, wherein the aryl group is —N(CH 3 )—, such as —N(CH 3 )—, or a pharmaceutically acceptable salt thereof. Embodiment 26.L 2 The compound of any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein is absent. Embodiment 27.L 2 may be substituted C selected from the group consisting of the following items: 1-4 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein is alkylene. TIFF2025510945000013.tif42119In formula, R 13 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, COOH, CONH2, SO2NH2, COR K , COOR K , CONH(R K ), CON(R K )2, SO2R K , SO2NH(R K ), SO2N(R K )2, R K , OR K , NH(R K ), N(R K )2, SR K , SOR K , SO2R K or P(O)(R K )2, and R K may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl, and when substituted, optionally substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl is substituted with 1-3 substituents independently selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F, 1-4 alkyl, C optionally substituted with 1-3 F 1-4 Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl. Embodiment 28.R 13 28. The compound of embodiment 27, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Embodiment 29.R 13 is CN, OH, COOH, CONH2, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S, and when substituted, the optionally substituted phenyl or 5- or 6-membered heteroaryl is optionally substituted with halogen (preferably F or Cl), OH, CN, 1-3 F, 1-4 alkyl, C optionally substituted with 1-3 F 1-4 28. The compound of embodiment 27, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with 1-3 substituents selected from the group consisting of heteroalkyl, and a 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl. Embodiment 30.L 2The compound according to any of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein is O or C(O). Embodiment 31.L 2 optionally substituted 5- or 6-membered heteroarylene, for example, TIFF2025510945000014.tif3587, or a pharmaceutically acceptable salt thereof. Embodiment 32. Where applicable, L 1 But -N(R E )- and L 2 optionally substituted phenylene, for example, TIFF2025510945000015.tif3393 or TIFF2025510945000016.tif3393, R 30 18. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Embodiment 33. Where applicable, L 1 , L 2 and R 30 But together, TIFF2025510945000017.tif49120 or 18. The compound according to any one of embodiments 1 to 17, wherein the compound is TIFF2025510945000018.tif49120, or a pharmaceutically acceptable salt thereof. Embodiment 34.R 30 is optionally substituted phenyl, for example, 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, NH, R M , OR M , COOH, CONH2, COOR M , CONH(R M ), CON(R M )2, NHCO(R M ), N(R M )CO(R M ), SO2R M, SO2NH2, S(O)(NH)R M , S(O)(NR M )R M , SO2N(R M )2, NHSO2R M , N(R M )SO2R M , P(O)(R M )2, P(O)(OR M )2, NH(R M ), N(R M )2, SR M or SF5, R M may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 The compound of any one of embodiments 1 to 31, wherein the compound is cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, or optionally substituted 4- to 7-membered heterocyclyl, or a pharmaceutically acceptable salt thereof. Embodiment 35.R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 may be substituted independently each time C represents 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 The alkyl or 3- or 4-membered ring is independently substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F1-4 alkyl, C optionally substituted with 1-3 F 1-4 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with heteroalkyl, F and / or methyl; 35. The compound of embodiment 34, or a pharmaceutically acceptable salt thereof. Embodiment 36.R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 The compound of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, e.g., CF3. Embodiment 37.R 30 is an optionally substituted 5- or 6-membered heteroaryl, e.g., 1-3 (e.g., 1 or 2) R 22 Pyridyl substituted with (e.g., TIFF2025510945000019.tif2383 or TIFF2025510945000020.tif2463) or pyrimidyl (e.g., TIFF2025510945000021.tif2487) and R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, NH, R M , OR M , COOH, CONH2, COOR M , CONH(R M ), CON(R M )2, NHCO(R M ), N(R M )CO(R M ), SO2R M , SO2NH2, S(O)(NH)R M , S(O)(NR M )R M , SO2N(RM )2, NHSO2R M , N(R M )SO2R M , P(O)(R M )2, P(O)(OR M )2, NH(R M ), N(R M )2, SR M or SF5, R M may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 The compound of any one of embodiments 1 to 31, wherein the compound is cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, or optionally substituted 4- to 7-membered heterocyclyl, or a pharmaceutically acceptable salt thereof. Embodiment 38.R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000022.tif1878) or pyridyl (e.g., TIFF2025510945000023.tif2384 or TIFF2025510945000024.tif2384) or pyrimidyl (e.g., TIFF2025510945000025.tif2388) and R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 may be substituted independently each time C represents 1-4alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 The alkyl or 3- or 4-membered ring is independently substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with heteroalkyl, F and / or methyl; 38. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof. Embodiment 39.R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000026.tif1774) or pyridyl (e.g., TIFF2025510945000027.tif2385 or TIFF2025510945000028.tif2385) or pyrimidyl (e.g., TIFF2025510945000029.tif2389) and R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, e.g., CF3. Embodiment 40.R 30 32. The compound of any one of embodiments 1 to 31, wherein the compound has the structure S-1-A, S-1-B, S-1-C, or S-1-D, or a pharmaceutically acceptable salt thereof. TIFF2025510945000030.tif66166 formula, R 8C, which may be substituted with 1-3 F 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl, or The file is TIFF2025510945000031.tif1484. Embodiment 41.L 1 , L 2 , and R 30 But together (i.e., L 1 -L 2 -R 30 ) selected from the group consisting of: TIFF2025510945000032.tif82136 or L 1 -L 2 -R 30 but, TIFF2025510945000033.tif39124 or TIFF2025510945000034.tif39124, 18. A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. Embodiment 42.L 1 , L 2 , and R 30 are taken together from the group consisting of: TIFF2025510945000035.tif43161 or L 1 -L 2 -R 30 but, TIFF2025510945000036.tif45166 or TIFF2025510945000037.tif30144, 18. A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. Embodiment 43.L 1 , L 2 , and R 30 are taken together from the group consisting of: TIFF2025510945000038.tif139166 or L 1 -L 2 -R 30 but, TIFF2025510945000039.tif202166 or TIFF2025510945000040.tif29113, Or, L 1 , L 2 , and R 30 are taken together from the group consisting of: TIFF2025510945000041.tif41115 or TIFF2025510945000042.tif41115 or L 1 , L 2 , and R 30 are taken together from the group consisting of: TIFF2025510945000043.tif3491 or TIFF2025510945000044.tif3491 A compound according to any one of embodiments 1 to 17, or a pharmacologically acceptable salt thereof. Embodiment 44.R 30 is selected from the group consisting of: TIFF2025510945000045.tif80131 or R 30 but, TIFF2025510945000046.tif47131, Alternatively, R 30 but, TIFF2025510945000047.tif100163, Alternatively, R 30 but, TIFF2025510945000048.tif26127, A compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof. Embodiment 45. A compound selected from the group consisting of compounds 1 to 347 or any of the compounds disclosed in Table A, or a pharmaceutically acceptable salt thereof. Embodiment 46. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 45 or a pharmaceutically acceptable salt thereof, and an optional pharmaceutically acceptable excipient. Embodiment 47. A method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of any one of Embodiments 1 to 45, wherein the disease is cancer or a viral infection. Embodiment 48. The method of embodiment 47, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and melanoma. Embodiment 49. A method for inhibiting the activity of at least one diacylglycerol kinase selected from the group consisting of diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKz), comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of any of Embodiments 1-45.

[0013] It should be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. [Brief explanation of the drawings]

[0014] [Figure 1] In the MC38 homologous gene tumor model, compound 67 (cpd67) has demonstrated antitumor activity as a single agent and in combination with an anti-mouse PD-1 antibody (mPD-1). DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description Broadly, the present disclosure provides compounds and compositions that can inhibit DGKs (diacylglycerol kinases), e.g., DGKa and / or DGKz, and / or treat or prevent various diseases or conditions described herein, e.g., cancer or infectious diseases, e.g., viral infections.

[0016] compound Some embodiments of the present disclosure relate to novel compounds, which may generally be DGK inhibitors and can be used to treat various diseases or conditions, such as cancer or viral infections, as described herein.

[0017] Formulas III-1 to III-12 In some embodiments, the disclosure provides a compound of Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, or a pharmaceutically acceptable salt thereof. TIFF2025510945000049.tif236166 formula, R 1 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, COOH, CONH2, R A , OR A , NH(R A ), N(R A )2, COOR A , CONH(R A ), CON(R A )2, SR A , SOR A , SO2R A or P(O)(R A )2 and R A may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6cycloalkyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; R 2 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, R B , OR B , NH(R B ) or N(R B )2 and R B may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl; R 3 may be substituted with hydrogen or C 1-4 alkyl, or an optionally substituted 3-7 membered ring, for example, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 4-7 membered heterocyclyl (e.g., saturated 4-7 membered heterocyclyl); J is O, CO, SO2, NR 15 or optionally substituted methylene; W is absent or -(W 1 ) p -, p is 1, 2 or 3, and W 1 Each time it is expressed, it is independently C(O), NR 15 , SO2, O or optionally substituted methylene, provided that W 1 One of the following examples is C(O), NR 15 , SO2 or O; provided that when W is absent, the ring containing J is a 5-membered ring; when p is 1, the ring containing J and W is a 6-membered ring; when p is 2 or 3, the ring containing J and W is a 7- or 8-membered ring, respectively; R 15 represents each independently hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 alkynyl, an optionally substituted 3-6 membered ring, or a nitrogen protecting group; X is N or CR 5 and R 5 But hydrogen, halogen, OH, NH2, NHR C , N(R C )2, CN, CONH2, COOH, CONH(R C ), CON(R C )2, OR C , NO2 or COOR C and R C may be substituted independently each time C represents 1-4 is alkyl; U is N or CR 6 and R 6 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, R D , OR D , NH(R D ) 、 N(R D )2, COOH, CONH2, COOR D , CONH(R D ) 、 CON(R D )2, SR D , SOR D , SO2R D or P(O)(R D )2 and R D may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; Y is N or CR 7 and R 7 may be substituted with hydrogen, F, Cl, CN, or C 1-4Alkyl or optionally substituted C 1-4 is heteroalkyl; Z is C(O), C(=N-OH), C(=NO-(C 1-4 alkyl), C(=N-NH2), C(=N-NH-(C 1-4 alkyl), C(=NN(C 1-4 Alkyl)(C 1-4 alkyl), SO, SO2, S(O)(=NH) or S(O)(=N-(C 1-4 alkyl); Ring C is a 5- or 6-membered ring, preferably a 5- or 6-membered heteroaryl having 2-3 ring-forming heteroatoms, for example, a 5-membered heteroaryl having 2-3 ring-forming nitrogen atoms, for example, an imidazole ring or a triazole ring, and in formula III-8, ring C and the adjacent ring share two ring-forming atoms; L 1 is an optionally substituted 4- to 12-membered ring, preferably a 4- to 12-membered heterocyclylene having one or more rings and 1 to 4 ring-forming heteroatoms each independently selected from the group consisting of O, N, or S, or —N(R E )- and R E may be replaced by C 1-4 alkyl or an optionally substituted 3-7 membered ring; L 2 is absent or O, NH, -N(R E2 )-, C(O), SO2, optionally substituted C 1-4 Alkylene, optionally substituted C 2-4 Alkenylene, optionally substituted C 1-4 Alkynylene, optionally substituted C 1-4 heteroalkylene or an optionally substituted 3- to 7-membered ring, R E2 may be replaced by C 1-4 alkyl or an optionally substituted 3-7 membered ring; R 30 is hydrogen, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 8-12-membered ring having two or more rings; R 9Each time it appears, it independently represents halogen, CN, OH, R N , OR N , NHR N , N(R N )2, COOR N , C.O.R. N , CONH(R N ) or CON(R N )2 and R N may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl or an optionally substituted 3-7 membered ring, for example, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 7-membered heterocyclyl, or optionally substituted 5- or 6-membered heteroaryl; and n1 is 0, 1, 2 or 3.

[0018] As used herein, unless otherwise stated or otherwise clearly contradicted by the context, an "x- to y-membered ring" is understood to include any ring structure having the specified number of ring members, e.g., such a ring may be carbocyclic, heterocyclic, aryl, or heteroaryl, may have a single ring, a double ring, or two or more rings, each of which may be saturated, partially unsaturated, or aromatic, and may contain one or more ring-forming heteroatoms. Also, where applicable, such an "x- to y-membered ring" should be understood to be connected to the remainder of the molecule by one or more ring-forming atoms.

[0019] It should be noted that the terms "substituted" or "unsubstituted," when used in conjunction with a variable herein, are understood to mean that said variable is substituted or unsubstituted, without regard to the bond between the variable and the remainder of the molecule. For example, an unsubstituted phenylene is understood to mean that the other ring-forming atoms of the phenylene, other than the two ring atoms connecting the phenylene to the remainder of the molecule, are unsubstituted, while in a substituted phenylene, at least one ring-forming atom, other than the two ring atoms connecting the phenylene to the remainder of the molecule, is substituted with a substituent herein.

[0020] In some embodiments, the compounds of Formulas III-1 to III-12 may have stereoisomers. In such embodiments, the compounds of Formulas III-1 to III-12 may exist as a single enantiomer, diastereomer, atropisomer, and / or geometric isomer (if applicable) or as a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some embodiments, where applicable, the compounds of Formulas III-1 to III-12 may exist as any proportional mixture of a pair of enantiomers, including a 1:1 racemic mixture. In some embodiments, where applicable, the compounds of Formulas III-1 to III-12 may exist as an isolated or enriched single enantiomer essentially free of the other enantiomer (e.g., containing less than 20%, less than 10%, less than 5%, less than 1%, or even undetectable amounts by weight, HPLC or SFC area, or both).

[0021] In some embodiments, the present disclosure provides compounds having the structure of Formula III-1, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-2, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-3, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-4, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-5, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-6, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-7, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the present disclosure provides compounds having the structure of Formula III-8, or a pharmaceutically acceptable salt thereof, with the variables defined and preferred herein. In some embodiments, the compound of Formula III-8 is designated as having the structure of Formula III-8-A or III-8-B. TIFF2025510945000050.tif52166In the formula, variable R 1 , R 2 , U, X, Y, L1, L 2 and R 30are defined herein, for example, as described in combination with Formula III-2 in Embodiments A2-A36 below. In some embodiments, the disclosure provides compounds having the structure of Formula III-9, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the disclosure provides compounds having the structure of Formula III-10, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the disclosure provides compounds having the structure of Formula III-11, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein. In some embodiments, the disclosure provides compounds having the structure of Formula III-12, or a pharmaceutically acceptable salt thereof, with the variables as defined and preferred herein.

[0022] It should be noted that the definitions and preferred definitions of the variables in any of the formulas III-1 to III-12 described herein also apply to the corresponding variables in any of the sub-formulas, unless specifically defined or contradicted in the sub-formula. For example, the definitions and preferred definitions of the variables in formula III-2 described herein also apply to the corresponding variables in the sub-formulas, unless specifically defined or contradicted in the sub-formula, for example, formulas III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D-5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2-D-17, III-2-D-18, III-2-D-19, III-2-D-20, III-2-D-21, III-2-D-22, III-2-D-23, III-2-D-24, III-2-D-25, III-2-D-26, III-2-D-27, III-2-D-28, III-2-D-29, III-2-D-29, III-2-D-29, III-2-D-21, III-2-D-22, III-2-D-23, III-2-D-24, III-2-D-25, III-2-D-26, III-2-D-27, III-2-D-28, III I-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, II Also applicable to I-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b. Likewise, the definitions and preferred definitions of the variables in formula III-4 described herein also apply to the corresponding substituents in subformulas herein, unless specifically defined or contradicted in the subformula, e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f.

[0023] Generally, in formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11 or III-12, Y is N.

[0024] In some embodiments, in formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, Y is CR 7 and R 7 may be substituted with hydrogen, F, Cl, CN, or C 1-4 Alkyl or optionally substituted C 1-4 For example, in some embodiments, Y is CH.

[0025] Generally, U in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11 or III-12 is CR 6 and R 6 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, R D , OR D , NH(R D ), N(R D )2, COOH, CONH2, COOR D , CONH(R D ), CON(R D )2, SR D , SOR D , SO2R D or P(O)(R D )2 and R D may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 In some preferred embodiments, R is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, or an optionally substituted 4- to 7-membered heterocyclyl. 6 is hydrogen, i.e., U is CH. In some embodiments, R 6 may be halogen, e.g., F or Cl. In some embodiments, R 6 But, ORD R may be D is as defined herein. In some embodiments, R 6 But, OR D1 R may be D1 may be replaced by C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 4- to 7-membered heterocyclyl having 1 or 2 ring-forming heteroatoms independently selected from the group consisting of O, N and S; when substituted, optionally substituted C 1-4 Alkyl, C 3-6 The cycloalkyl or 4- to 7-membered heterocyclyl may be substituted with one or more (e.g., 1-3) substituents, e.g., each substituent independently selected from halogen (e.g., F), OH, CN, C 1-4 Alkyl or C 1-4 For example, in some embodiments, R 6 But C 1-4 In some specific embodiments, R 6 but, TIFF2025510945000051.tif1668. In some specific embodiments, R 6 but, TIFF2025510945000052.tif1768. In some specific embodiments, R 6 but, It could also be TIFF2025510945000053.tif1568.

[0026] In some embodiments, U is N in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12.

[0027] For formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11 or III-12, multiple groups may be R1 For example, in some embodiments, R 1 OH, COOH, CONH2, NH2, R A , OR A , COOR A , NH(R A ), N(R A )2, CONH(R A ), CON(R A )2, SR A , SOR A , SO2R A or P(O)(R A )2, and R A is as defined herein. In some embodiments, R A may be replaced whenever C represents 1-4 It may also be alkyl.

[0028] In some preferred embodiments, in formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 1 But it is CN.

[0029] In some preferred embodiments, in R1 in formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 1 is a halogen, preferably F or Cl.

[0030] In some embodiments, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 1 But C 2-3 Alkynyl, for example TIFF2025510945000054.tif1165.

[0031] In some embodiments, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 1 is an optionally substituted 5- or 6-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of O, S, and N. For example, in some embodiments, R 1 may be optionally substituted pyrimidyl or optionally substituted thiazolyl, for example, R 1 but, TIFF2025510945000055.tif1897 or The file is TIFF2025510945000056.tif1897.

[0032] In some embodiments, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 1 But, SR A and R A is as defined herein. For example, in some embodiments, R 1 But, SR A1 R may be A1 each independently represents an optionally substituted C 1-4 alkyl, e.g., R 1 are each independently SCH3. Other suitable R 1 However, as described herein.

[0033] In some embodiments, in Formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 1 However, (i)R 1 is a halogen, e.g., F or Cl; (ii) R 1 but, TIFF2025510945000057.tif1191; (iii) R 1is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, such as an optionally substituted pyrimidyl or an optionally substituted thiazolyl, e.g., R 1 but, TIFF2025510945000058.tif1673 or TIFF2025510945000059.tif1673; or (iv) R 1 But, SR A1 and R A1 each independently represents an optionally substituted C 1-4 alkyl, e.g., R 1 is SCH3.

[0034] Generally, in formula III-1, III-2, III-3, III-4, III-6, III-7 or III-8, R 2 is hydrogen. In some embodiments, R 2 is halogen (e.g., F, Cl, or Br), CN, OH, NH2, R B , OR B , NH(R B ) or N(R B )2, and R B is as defined herein. In some embodiments, R B may be replaced by C 1-4 It may be alkyl or an optionally substituted 3-4 membered cycloalkyl.

[0035] Generally, R in formula III-1, III-3, III-4, III-6 or III-7 3 may be replaced by C 1-4 alkyl, e.g., CH, CD, etc. In some preferred embodiments, R 3 is CH3. In some preferred embodiments, R 3 is CD3. In some preferred embodiments, R 3 is CH2CH3. In some preferred embodiments, R 3is CH(CH). In some preferred embodiments, R 3 is CH2CHF2. In some embodiments, R 3 may be replaced by C 3-6 In some preferred embodiments, R 3 is cyclopropyl. In some preferred embodiments, R 3 is cyclobutyl. In some preferred embodiments, R 3 is hydrogen.

[0036] Generally, Z in formula III-1, III-3, III-4, III-5, III-6, III-7, III-9, III-11 or III-12 is C(O).

[0037] In some embodiments, Z in formula III-1, III-3, III-4, III-5, III-6, III-7, III-9, III-11, or III-12 can be S(O)2.

[0038] In some exemplary embodiments, X in formula III-1, III-2, III-5, III-6, III-7, III-8, or III-9 is N.

[0039] In some embodiments, X in formula III-1, III-2, III-5, III-8, or III-9 is CR 5 and R 5 is as defined herein. In some embodiments, X is CR 5 and R 5 In some embodiments, X is CR 5 and R 5 However, CONH2, COOH, CONH(R C1 ), CON(R C1 )2 or COOR C1 and R C1 Each time, independently, C 1-4 Alkyl, for example, methyl.

[0040] In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, R 9 Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 alkyl (e.g., CF2H), cyclopropyl or cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3 or CH2NHC(O)OCH3.

[0041] In some embodiments, in formula III-6 or III-7, J is NR 15 and R 15 is as defined herein. For example, in some embodiments, J is N(C 1-4 alkyl), for example, NCH3.

[0042] In some embodiments, in Formula III-6 or III-7, J is optionally substituted methylene. For example, in some embodiments, J is CH. In some examples, J is CF, CHCH, C(CH), CHOH, etc.

[0043] In some embodiments, in formula III-6 or III-7, J is O. In some embodiments, in formula III-6 or III-7, J is NH or NCH 3 .

[0044] In some embodiments, in formula III-6 or III-7, W is absent, so that the ring containing J is a 5-membered ring.

[0045] In some embodiments, in formula III-6 or III-7, p is 1 and W is W 1 and W 1 is as defined herein. For example, in some embodiments, W 1is C(O), SO2, CH2, CF2, CHCH3, C(CH3)2, CHOH, etc. In such embodiments, the ring comprising J and W is a six-membered ring.

[0046] In some embodiments, in formula III-6 or III-7, p is 2 and W is -W 1 -W 1 - and each W 1 are as defined herein. For example, in some embodiments, each W 1 are each independently C(O), SO, CH, CF, CHCH, C(CH), CHOH, etc. In some embodiments, two W 1 In some embodiments, one W 1 But it is O and another W 1 is CH2. In some embodiments, one W 1 is C(O), and another W 1 is O, NH, NCH3, or CH2. In such embodiments, the ring comprising J and W is a seven-membered ring.

[0047] Generally, in formula III-1, III-2, III-5, III-8 or III-9, L 1 In some embodiments, L in Formula III-1, III-2, III-5, III-8, or III-9 is an optionally substituted 4- to 12-membered heterocyclylene. 1 is an optionally substituted 4-12 membered heterocyclylene having one or more rings and 1-4 ring-forming heteroatoms, each independently being O, N, or S. In some embodiments, L in Formula III-1, III-2, III-5, III-8, or III-9 is 1 But -N(R E )-, and R E may be replaced by C 1-4 alkyl or an optionally substituted 3-7 membered ring. For example, in some embodiments, L 1 But -N(C 1-4alkyl)-, for example, -N(CH3)-.

[0048] In some embodiments, L in formula III-1, III-2, III-5, III-8, or III-9 1 is an optionally substituted 4- to 7-membered monocyclic heterocyclylene having one or two ring-forming heteroatoms, each independently O, N, or S. In some embodiments, the 4- to 7-membered monocyclic heterocyclylene is a saturated heterocyclylene having one or two ring-forming heteroatoms (e.g., one or two ring-forming nitrogen atoms), such as a piperazine or piperidine ring. The heterocyclylene is typically linked to the rest of the molecule by two ring-forming nitrogen atoms or one ring-forming nitrogen atom and one ring-forming carbon atom.

[0049] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 but, TIFF2025510945000060.tif31106 or TIFF2025510945000061.tif31106 (One of the two linkers of piperidine, N or C, is L) 2 (which may be linked to wherein n is 0, 1, 2, 3, or 4; and (1)R 9A Each time it appears, it independently represents halogen, CN, OH, R N , OR N , NHR N , N(R N )2, COOR N , C.O.R. N , CONH(R N ) or CON(R N )2 and R N may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted 3-7 membered ring, for example, optionally substituted C3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl; or (2)R 9A may be linked to form a double bond or a 3- to 5-membered ring, and R 9A The remaining examples are as defined in (1). In some embodiments, R 9A Each time, R N In some embodiments, R 9A may be substituted independently each time C represents 1-4 C alkyl, and when substituted, the substituents have 1 or 2 heteroatoms which may be independently substituted with F, OH, or fluorine. 1-4 In some embodiments, R may be selected from the group consisting of heteroalkyl or 3-4 membered rings (e.g., cyclopropyl or cyclobutyl, etc.). 9A Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 alkyl (e.g., CFH), cyclopropyl, or cyclobutyl, CHOH, CHOCH, CHOCHCH, CHNH, CHN, or CHNHC(O)OCH. Preferably, R 9A each occurrence is independently CH3, CH2CH3 or CH2CH2CH3, more preferably R 9A is CH2CH3 whenever it appears. Generally, in formula III-1, III-2, III-5, III-8, III-9, III-10, III-11 or III-12, n is 0, 1 or 2. For example, L 1 but, TIFF2025510945000062.tif31141, and any of the two linkers can be selected from the group consisting of L 2 may be linked to

[0050] In some preferred embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 may be selected from the group consisting of the following (where the lower linker N or C is L) 2 (concatenated to): TIFF2025510945000063.tif75134

[0051] In some preferred embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 may be selected from the group consisting of the following (where the lower linker N or C is L) 2 (concatenated to): TIFF2025510945000064.tif73133

[0052] In some embodiments, L in formula III-1, III-2, III-5, III-8, or III-9 1 may be an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring-forming heteroatoms, each independently being O, N, or S, and when substituted, the substituents may be attached to any one or more of the two or more rings. For example, in some embodiments, L 1 is an optionally substituted 8- to 12-membered fused, spiro, or bridged bicyclic heterocyclylene having 1-4 ring-forming heteroatoms, each independently O, N, or S, wherein each ring of the bicyclic heterocyclylene may be saturated, partially unsaturated, or aromatic, and each ring of the bicyclic heterocyclylene may have 0, 1, 2, or 3 ring-forming heteroatoms, provided that the bicyclic heterocyclylene as a whole is not completely aromatic and the total number of heteroatoms in the bicyclic heterocyclylene is 4 or less. 1may be an optionally substituted 8- to 11-membered fused bicyclic heterocyclylene having 1-3 ring-forming heteroatoms, each independently O, N, or S, wherein (1) one of the two fused rings is phenyl or a 5- or 6-membered heteroaryl, and (2) the other of the two fused rings is a 5- to 7-membered heterocycle having one or two ring-forming heteroatoms, each independently O, N, or S, and preferably the 5- to 7-membered heterocycle has at least one ring-forming nitrogen atom. 1 may be an optionally substituted 8-11 (e.g., 8, 9, or 10)-membered spiro bicyclic heterocyclylene having 1 to 4 ring heteroatoms, each independently being O, N, or S, wherein (1) one of the two spiro rings is a 5-7-membered heterocycle having one or two ring heteroatoms, each independently being O, N, or S, and preferably the 5-7-membered heterocycle has one ring nitrogen atom; and (2) the other of the two spiro rings is a 4-6-membered heterocycle having 1 to 3 ring heteroatoms, each independently being O, N, or S, and for example, one of the two spiro rings is a pyrrole ring, a piperidine ring, or a nitrogen-containing ring, and the other of the two spiro rings is azetidine, pyrrole, pyrrolidone, piperidinone, oxazoline, isoxazoline, thiazoline, isothiazolinone, etc.

[0053] For example, in some preferred embodiments, L in formula III-1, III-2, III-5, III-8, or III-9 1 may be selected from the group consisting of the following (where the lower linker N or C is L) 2 (concatenated to): TIFF2025510945000065.tif66125In the formula, in each bicyclic heterocyclylene, each of the two rings has 1 to 3 R 10 may be substituted with R 10 each occurrence independently represents halogen, OH, NH, oxo (where applicable), R J , OR J , CN, NH(R J ) or N(R J)2 and R J may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 It is an alkynyl or an optionally substituted 3-4 membered ring.

[0054] In some preferred embodiments, L in formula III-1, III-2, III-5, III-8 or III-9 1 may be selected from the group consisting of the following (where the lower linker N or C is L) 2 (concatenated to): TIFF2025510945000066.tif68166

[0055] In some embodiments, L in formula III-1, III-2, III-5, III-8, or III-9 1 But -N(C 1-4 alkyl)-, for example, -N(CH3)-.

[0056] In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 However, it may be non-existent.

[0057] In some embodiments, L in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 2 may be replaced by C 1-4 alkylene, e.g., one or more R 13 In some embodiments, R 13 Each time it appears, it independently represents a halogen (e.g., F, Cl, or Br), CN, OH, NH2, COOH, CONH2, SO2NH2, COR K , COOR K, CONH(R K ), CON(R K )2, SO2R K , SO2NH(R K ), SO2N(R K )2, R K , OR K , NH(R K ), N(R K )2, SR K , SOR K , SO2R K or P(O)(R K )2, and R K may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, N, or S, or optionally substituted 4- to 7-membered heterocyclyl.

[0058] In some embodiments, L in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 2 But unsubstituted C 1-4 It may be alkylene, for example, CH2, CH(CH3), CH(C2H5), CH(C3H7), etc.

[0059] In some embodiments, L in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 2 But unsubstituted C 1-4 alkylene, CH2, or TIFF2025510945000067.tif17166.

[0060] In some embodiments, L in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12 2 may be replaced by C 1-4 may be alkylene, TIFF2025510945000068.tif40118, In the formula, R 13 is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH2, COOH, CONH2, SO2NH2, COR K , COOR K , CONH(R K ), CON(R K )2, SO2R K , SO2NH(R K ), SO2N(R K )2, R K , OR K , NH(R K ), N(R K )2, SR K , SOR K , SO2R K or P(O)(R K )2, and R K may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl, and when substituted, optionally substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Heteroalkyl, C 3-6Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl is substituted with 1-3 substituents, and the substituents are independently halogen (preferably F or Cl), OH, CN, or optionally substituted with 1-3 F. 1-4 alkyl, C optionally substituted with 1-3 F 1-4 Heteroalkyl and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl. For example, in some embodiments, R 13 is hydrogen. In some embodiments, R 13 But C 1-4 alkyl, for example, methyl, ethyl, isopropyl, etc. In some embodiments, R 13 is methyl. In some embodiments, R 13 is isopropyl. In some embodiments, R 13 is R as defined in this application. K In some embodiments, R 13 But OH or OR K and R K is defined in the present application, for example, C 1-4 In some embodiments, R 13 is CN, OH, COOH, CONH2, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S, and when substituted, the optionally substituted phenyl or 5- or 6-membered heteroaryl is substituted with 1-3 substituents, and the substituents are independently selected from halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4 In some embodiments, R is selected from the group consisting of heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl. 13is a 3-4 membered ring, such as cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc., which may be substituted, for example, with F and / or methyl. For example, in some embodiments, R 13 is cyclopropyl. In some embodiments, R 13 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O and S, for example, an optionally substituted phenyl or thiazolyl, which are optionally substituted with 1-3 substituents, and the substituents are independently halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F, 1-4 alkyl, C optionally substituted with 1-3 F 1-4 Heteroalkyl and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl. For example, in some embodiments, R 13 but, TIFF2025510945000069.tif2194 or TIFF2025510945000070.tif2194. In some embodiments, R 13 OH, methoxy, cyclopropyl, phenyl, TIFF2025510945000071.tif2289 or The file is TIFF2025510945000072.tif1669.

[0061] In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2may be O, and preferably, in formula III-4, L 2 But it's not O.

[0062] In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 optionally substituted phenylene, for example, It could also be TIFF2025510945000073.tif2870.

[0063] In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, L 2 optionally substituted 5- or 6-membered heteroarylene, for example, It could also be TIFF2025510945000074.tif3589.

[0064] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 But -N(R E )-, L 2 optionally substituted phenylene, for example, TIFF2025510945000075.tif3393 or TIFF2025510945000076.tif3393 and R 30 is hydrogen. For example, in some embodiments, L 1 , L 2 and R 30 But together, TIFF2025510945000077.tif51100 or The file is TIFF2025510945000078.tif51100.

[0065] In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 30 is optionally substituted phenyl, for example, 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, NH, R M , OR M , COOH, CONH2, COOR M , CONH(R M ), CON(R M )2, NHCO(R M ), N(R M )CO(R M ), SO2R M , SO2NH2, S(O)(NH)R M , S(O)(NR M )R M , SO2N(R M )2, NHSO2R M , N(R M )SO2R M , P(O)(R M )2, P(O)(OR M )2, NH(R M ), N(R M )2, SR M or SF5, R M may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 In some embodiments, R is cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, or optionally substituted 4- to 7-membered heterocyclyl. 22 One example of is halogen, such as F, Cl or Br, and R 22The remaining examples (if any) are as defined herein. In some embodiments, R 22 two or three instances of are halogen, each independently being F, Cl or Br, and R 22 The remaining examples (if any) are as defined herein. In some embodiments, R 22 One example of this is CN, and R 22 The remaining examples (if any) are as defined herein. In some embodiments, R 22 One example is R M , OR M , S.R. M , SF5 or SO2R M and R M is defined in the present application, and may be substituted with, for example, fluorine. 1-3 alkyl (e.g., CF3, CF2CH3, CHF2, etc.) or cyclopropyl, and R 22 The remaining examples (if any) are as defined herein. For example, in some embodiments, R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 may be substituted independently each time C represents 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 The alkyl or 3- or 4-membered ring is substituted with 1-3 substituents, and the substituents are independently halogen (preferably F or Cl), OH, CN, or optionally substituted with 1-3 F. 1-4 alkyl, C optionally substituted with 1-3 F 1-4Preferably, R is selected from the group consisting of 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with heteroalkyl, F and / or methyl. More preferably, R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 alkyl, for example, CF. In some embodiments, R 22 Each occurrence of each independently represents a C optionally substituted with halogen, CN, or 1 to 3 F. 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl or TIFF2025510945000079.tif1576. In some preferred embodiments, R 22 each occurrence is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl).

[0066] In some embodiments, in Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 30 is an optionally substituted 5- or 6-membered heteroaryl, e.g., 1-3 (e.g., 1 or 2) R 22 Pyridyl substituted with (e.g., TIFF2025510945000080.tif2686 or TIFF2025510945000081.tif2686) or pyrimidyl (e.g., TIFF2025510945000082.tif2491) and R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, NH, R M , OR M , COOH, CONH2, COOR M , CONH(R M ), CON(R M )2, NHCO(R M ), N(R M )CO(R M ), SO2R M , SO2NH2, S(O)(NH)R M , S(O)(NR M )R M , SO2N(R M )2, NHSO2R M , N(R M )SO2R M , P(O)(R M )2, P(O)(OR M )2, NH(R M ), N(R M )2, SR M or SF5, R M may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 In some embodiments, R is cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, or optionally substituted 4- to 7-membered heterocyclyl. 22 One example of is halogen, for example, F, Cl or Br, and R 22 The remaining examples (if any) are as defined herein. In some embodiments, R 22 two or three instances of are halogen, each independently being F, Cl or Br, and R22 The remaining examples (if any) are as defined herein. In some embodiments, R 22 One example of this is CN, and R 22 The remaining examples (if any) are as defined herein. In some embodiments, R 22 One example is R M , OR M , S.R. M , SF5 or SO2R M and R M may be substituted with, for example, fluorine, as defined herein. 1-3 alkyl (e.g., CF3, CF2CH3, CHF2, etc.) or cyclopropyl, and R 22 The remaining examples (if any) are as defined herein. For example, in some embodiments, R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000083.tif1895) or pyridyl (e.g., TIFF2025510945000084.tif2381 or TIFF2025510945000085.tif2381) or pyrimidyl (e.g., TIFF2025510945000086.tif2290) and R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 may be substituted independently each time C represents 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4The alkyl or 3- or 4-membered ring is substituted with 1-3 substituents, and the substituents are independently halogen (preferably F or Cl), OH, CN, or optionally substituted with 1-3 F. 1-4 alkyl, C optionally substituted with 1-3 F 1-4 Preferably, R is selected from the group consisting of 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with heteroalkyl, F and / or methyl. More preferably, R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000087.tif1790) or pyridyl (e.g., TIFF2025510945000088.tif2392 or TIFF2025510945000089.tif2392) or pyrimidyl (e.g., TIFF2025510945000090.tif2389) and R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 alkyl, for example, CF. In some embodiments, R 22 Each occurrence of each independently represents a C optionally substituted with halogen, CN, or 1 to 3 F. 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl or TIFF2025510945000091.tif1478. In some preferred embodiments, R 22each occurrence is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl).

[0067] In some embodiments, in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, or III-12, R 30 may have the structure of formula S-1, S-2, S-3 or S-4 below. TIFF2025510945000092.tif55166In the formula, ring B is L 2 Connected to Ring B is a 5- to 7-membered ring containing 0, 1, or 2 ring-forming heteroatoms, and 1 to 3 R G may be substituted with R G Each occurrence of represents independently a halogen, OH, oxo, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 is alkoxy; In the formula S-1, S-2, S-3 or S-4, phenyl, pyridyl or pyrimidyl is selected from the group consisting of q R 8 may be substituted with examples of: q is an integer of 0 to 3 within the range of acceptable valence, preferably 1 or 2; R 8 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, NH, R H , OR H , NH(R H ), N(R H )2, SR H , SF5, or an optionally substituted 5- to 8-membered carbocyclic ring having two or more rings, and R H may be substituted independently each time C represents 1-4 Alkyl, optionally substituted C2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl; When substituted, the optionally substituted C 1-4 Alkyl, C 1-4 Alkoxy, 5-8 membered carbocyclic ring, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 The cycloalkyl or 4- to 7-membered heterocyclyl may be substituted with one or more (e.g., 1-3) substituents, e.g., each substituent independently selected from halogen (e.g., F), OH, CN, C 1-4 Alkyl or C 1-4 In the representation of the S-1, S-2, S-3 or S-4 structural formula, R 8 It is understood that (if present) is attached to the phenyl, pyridyl, or pyrimidyl moiety in the structure, i.e., is not in Ring B, and if Ring B is substituted, 1-3 R as defined herein G It should be understood that the group is replaced by

[0068] In some embodiments, in S-1, S-2, S-3, or S-4, ring B does not contain a heterocyclic ring atom. In some embodiments, in S-1, S-2, S-3, or S-4, ring B contains one heterocyclic ring atom, for example, O, N, or S. In some embodiments, in S-1, S-2, S-3, or S-4, ring B does not contain a heterocyclic ring atom and is unsubstituted. In some embodiments, in S-1, S-2, S-3, or S-4, ring B does not contain a heterocyclic ring atom and may be substituted with one or more substituents described herein, for example, in some embodiments, ring B contains 1-3 R G1 may be substituted with R G1 Each occurrence of each independently represents F, OH, C optionally substituted with 1 to 3 F 1-4 alkyl, or C optionally substituted with 1-3 F 1-4 It is an alkoxy.

[0069] The phenyl, pyridyl or pyrimidyl moiety of S-1, S-2, S-3 or S-4 generally has one R 8 That is, q is 1 and R 8 is as defined herein. In some embodiments, the phenyl, pyridyl, or pyrimidyl moiety of S-1, S-2, S-3, or S-4 is selected from two R 8 may be substituted with R 8 is as defined herein. In some embodiments, R 8 Each time, R H1 , OR H1 , S.R. H1 SF5 or an optionally substituted 5-8 membered carbocyclic ring having two or more rings, and R H1 C, which may be substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4 C optionally substituted with alkoxy or 1-3 substituents 3-6 Cycloalkyl, wherein the substituents are independently selected from the group consisting of F, OH, methyl, and methoxy, and when substituted, the optionally substituted 5-8 membered carbocyclic ring is substituted with 1-3 substituents, each of which is independently selected from the group consisting of halogen (e.g., F), OH, CN, C 1-4 Alkyl and C 1-4 In some embodiments, R 8 may be an optionally substituted 5-8 membered carbocyclic ring having two or more rings, e.g., a bicyclic carbocyclic ring. For example, in some embodiments, R 8 may be a 5-8 membered bicyclic carbocyclic ring, for example a bridged bicyclic carbocyclic ring, for example TIFF2025510945000093.tif1681, which may be substituted, and when substituted, the bicyclic carbocyclic ring may be substituted with one or more (e.g., 1-3) substituents, for example, each substituent independently selected from halogen (e.g., F), OH, CN, C 1-4 Alkyl or C 1-4In some embodiments, R 8 but, TIFF2025510945000094.tif1484. In some embodiments, R 8 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl or It could also be TIFF2025510945000095.tif1379.

[0070] For example, in some embodiments, R 30 may have the structure S-1-A, S-1-B, S-1-C or S-1-D. TIFF2025510945000096.tif68166 formula, R 8 C, which may be substituted with 1-3 F 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl, or The file is TIFF2025510945000097.tif1581.

[0071] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000098.tif76166

[0072] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000099.tif102166

[0073] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000100.tif100166

[0074] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000101.tif83162

[0075] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000102.tif31134

[0076] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000103.tif29159

[0077] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000104.tif29149

[0078] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000105.tif3193

[0079] In some preferred embodiments, R in Formulas III-1 to III-12 30 is not selected from the group consisting of: TIFF2025510945000106.tif3188

[0080] In some preferred embodiments, R in Formulas III-1 to III-12 30 may be selected from the group consisting of: TIFF2025510945000107.tif29139

[0081] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30 but, TIFF2025510945000108.tif2493 or It could also be TIFF2025510945000109.tif2493.

[0082] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30 but, TIFF2025510945000110.tif25100 or Not TIFF2025510945000111.tif25100.

[0083] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30 may be selected from the group consisting of: TIFF2025510945000112.tif153159

[0084] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30 may be selected from the group consisting of: TIFF2025510945000113.tif159165

[0085] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30may be selected from the group consisting of: TIFF2025510945000114.tif65166

[0086] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30 may be selected from the group consisting of: TIFF2025510945000115.tif66166

[0087] In some embodiments, in Formulae III-1 to III-12, -L 2 -R 30 but, TIFF2025510945000116.tif2797 or It could also be TIFF2025510945000117.tif2797.

[0088] In some embodiments, in formula III-1 to III-12, -L 2 -R 30 but, TIFF2025510945000118.tif26103 or Not TIFF2025510945000119.tif26103.

[0089] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 , L 2 and R 30 (i.e., L 1 -L 2 -R 30 ), taken together, may be selected from the group consisting of: TIFF2025510945000120.tif83145

[0090] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 , L 2 and R 30may, together, be selected from the group consisting of: TIFF2025510945000121.tif71166 or TIFF2025510945000122.tif3078

[0091] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 , L 2 and R 30 may, together, be selected from the group consisting of: TIFF2025510945000123.tif105166 or TIFF2025510945000124.tif3290

[0092] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 -L 2 -R 30 is selected from the group consisting of: TIFF2025510945000125.tif199166 or TIFF2025510945000126.tif3188

[0093] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 , L 2 and R 30 may, together, be selected from the group consisting of: TIFF2025510945000127.tif46108 or TIFF2025510945000128.tif46108

[0094] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 , L 2 and R 30 may, together, be selected from the group consisting of: TIFF2025510945000129.tif3399 or TIFF2025510945000130.tif3399

[0095] In some embodiments, in formula III-1, III-2, III-5, III-8, or III-9, L 1 , L 2 and R 30 may, together, be selected from the group consisting of: TIFF2025510945000131.tif3996 or TIFF2025510945000132.tif3996

[0096] In some embodiments, the present disclosure provides exemplary embodiments A1-A38 listed below. Embodiments A1 to A38 Embodiment A1. A compound of Formula III-2, or a pharmaceutically acceptable salt thereof, TIFF2025510945000133.tif5454 where variables X, Y, U, R1, R 2 , L 1 , L 2 and R 30 as defined herein. Embodiment A2. The compound of embodiment A1, characterized in that it has the structure of formula III-2-A, or a pharmaceutically acceptable salt thereof: TIFF2025510945000134.tif5154Embodiment A3. The compound of embodiment A1, characterized in that it has the structure of formula III-2-B, or a pharmaceutically acceptable salt thereof: TIFF2025510945000135.tif5056 Embodiment A4.(i)R 1 is CN; (ii) R 1 is halogen, e.g., F or Cl; (iii) R 1 but, TIFF2025510945000136.tif1074; (iv) R 1is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, such as an optionally substituted pyrimidyl or an optionally substituted thiazolyl, such as R 1 but, TIFF2025510945000137.tif1780 or TIFF2025510945000138.tif1780; or (v) R 1 But, SR A1 and R A1 each independently represents an optionally substituted C 1-4 alkyl, e.g., R 1 The compound according to any one of embodiments A1 to A3, or a pharmaceutically acceptable salt thereof, wherein is SCH3. Embodiment A5.L 1 is selected from the group consisting of the following items (the lower connecting hand N or C is L 2 (concatenated to): TIFF2025510945000139.tif73132A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof. Embodiment A6.L 1 is selected from the group consisting of the following items (the lower connecting hand N or C is L 2 (concatenated to): TIFF2025510945000140.tif77140 A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof. Embodiment A7. A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, having the structure of formula III-2-C: TIFF2025510945000141.tif5665 where n is 0, 1, 2 or 3, and R 9A as defined herein. Embodiment A8. A compound according to embodiment A7, or a pharmaceutically acceptable salt thereof, having the structure of formula III-2-C-1, III-2-C-2, III-2-C-3, or III-2-C-4, TIFF2025510945000142.tif126135In the formula, two R in formula III-2-C-3 9A are selected independently. Embodiment A9.R 9A Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 A compound according to embodiment A7 or A8, which is alkyl (eg, CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3, or CH2NHC(O)OCH3. Embodiment A10. A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, having the structure of formula III-2-D, TIFF2025510945000143.tif5662 where n is 0, 1, 2 or 3, and R 9A as defined herein. Embodiment A11. A compound according to embodiment A10, or a pharmaceutically acceptable salt thereof, having the structure of formula III-2-D-1, III-2-D-2, III-2-D-3 or III-2-D-4, TIFF2025510945000144.tif127136 In the formula, two R in formula III-2-D-3 9A are selected independently. Embodiment A12.R 9A Each time it is represented, it independently represents CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 A compound according to embodiment A10 or A11, or a pharmaceutically acceptable salt thereof, wherein R is alkyl (eg, CF2H), cyclopropyl, cyclobutyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2NH2, CH2N3 or CH2NHC(O)OCH3. Embodiment A13. A compound according to any one of embodiments A1 to A12, or a pharmaceutically acceptable salt thereof, having the structure of formula III-2-E-1, III-2-E-2, or III-2-E-3, TIFF2025510945000145.tif96161, R 13 as defined herein. Embodiment A14. A compound according to any one of embodiments A1 to A12, or a pharmaceutically acceptable salt thereof, having a structure of formula III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, or III-2-E-3b, TIFF2025510945000146.tif140161In formula, R 13 as defined herein. Embodiment A15. A compound according to embodiment A13, or a pharmaceutically acceptable salt thereof, having a structure of formula III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a, or III-2-F-3b, TIFF2025510945000147.tif123161In formula, R 9A Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3 alkyl (e.g., CFH), cyclopropyl, cyclobutyl, CHOH, CHOCH, CHOCHCH, CHNH, CHN, or CHNHC(O)OCH, preferably R 9A each occurrence is independently CH3, CH2CH3 or CH2CH2CH3, more preferably R 9A However, each time it is expressed, it is CH2CH3. Embodiment A16.R 13 But hydrogen, C 1-4alkyl (e.g., methyl, isopropyl, etc.), CN, OH, COOH, CONH2, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S, and when substituted, the optionally substituted phenyl or 5- or 6-membered heteroaryl is substituted with 1-3 substituents, and the substituents are independently selected from halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F; 1-4 alkyl, C optionally substituted with 1-3 F 1-4 heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, more preferably R 13 A compound according to any of embodiments A13-A15, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Embodiment A17.L 2 A compound according to any of Embodiments A1 to A12, or a pharmaceutically acceptable salt thereof, wherein is absent, O or C(O). Embodiment A18.R 30 optionally substituted phenyl or 5- or 6-membered heteroaryl (e.g., oxadiazolyl (e.g., TIFF2025510945000148.tif1777), pyridyl (e.g., TIFF2025510945000149.tif2380 or TIFF2025510945000150.tif2380) or pyrimidyl (e.g., TIFF2025510945000151.tif2278), e.g., when substituted, phenyl or 5- or 6-membered heteroaryl may be substituted with 1-3 (e.g., 1 or 2) R 22 may be substituted with R 22 represents a halogen (e.g., F, Cl, or Br), CN, C optionally substituted with 1-3 F 1-4Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl or The compound of any of embodiments A1 to A17, wherein the compound is TIFF2025510945000152.tif1572, or a pharmaceutically acceptable salt thereof. Embodiment A19.R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 may be substituted independently each time C represents 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 The alkyl or 3- or 4-membered ring is independently substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4 Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R 22 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl). Embodiment A20.R 30 but 1-3 (e.g., 1 or 2) R 22is phenyl substituted with R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 The compound according to any one of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, eg, CF3. Embodiment A21.R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000153.tif1772) or pyridyl (e.g., TIFF2025510945000154.tif2683 or TIFF2025510945000155.tif2683) or pyrimidyl (e.g., TIFF2025510945000156.tif2473) and R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 may be substituted independently each time C represents 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 The alkyl or 3- or 4-membered ring is independently substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4Heteroalkyl, 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R 22 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl). Embodiment A22.R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000157.tif1772) or pyridyl (e.g., TIFF2025510945000158.tif2586 or TIFF2025510945000159.tif2586) or pyrimidyl (e.g., TIFF2025510945000160.tif2389) and R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 The compound according to any one of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, eg, CF3. Embodiment A23.R 30 The compound of any one of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein: TIFF2025510945000161.tif70118 formula, R 8 C, which may be substituted with 1-3 F 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl, or TIFF2025510945000162.tif1582. Embodiment A24.R 30 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000163.tif80128 Embodiment A25.R 30 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000164.tif52136 Embodiment A26.R 30 A compound according to any one of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000165.tif94157 Embodiment A27.R 30 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000166.tif32130 Embodiment A28.R 30 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000167.tif27150 Embodiment A29.R 30 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000168.tif30153 Embodiment A30.R 30 A compound according to any of embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000169.tif35101 Embodiment A31.L 1 -L 2 -R 30A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000170.tif132160 or TIFF2025510945000171.tif4271 Embodiment A32.L 1 -L 2 -R 30 A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000172.tif82166 or TIFF2025510945000173.tif3772 Embodiment A33.L 1 -L 2 -R 30 A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000174.tif160164TIFF2025510945000175.tif146166 or TIFF2025510945000176.tif3073 Embodiment A34.L 1 -L 2 -R 30 is selected from the group consisting of: TIFF2025510945000177.tif46109 or TIFF2025510945000178.tif46109 or L 1 -L 2 -R 30 is selected from the group consisting of: TIFF2025510945000179.tif32107 or TIFF2025510945000180.tif32107 or L 1 -L 2 -R 30 is selected from the group consisting of: TIFF2025510945000181.tif37103 or TIFF2025510945000182.tif37103 A compound according to any one of embodiments A1 to A4, or a pharmaceutically acceptable salt thereof. Embodiment A35.L 2 -R 30 A compound according to any of embodiments A1 to A12, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000183.tif136147 Embodiment A36.L 2 -R 30 A compound according to any of embodiments A1 to A12, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000184.tif149157Embodiment A37. Ring C is an imidazole or triazole ring and the variables X, Y, U, R 1 , R 2 , L 1 , L 2 and R 30 is as defined herein, including any of the definitions for formula III-2 shown in embodiments A2-A36, or a pharmaceutically acceptable salt thereof. Embodiment A38. A compound according to embodiment A37, or a pharmaceutically acceptable salt thereof, characterized in that it has the structural formula III-8-A or III-8-B, TIFF2025510945000185.tif62142 where variables X, Y, U, R 1 , R 2 , L 1 , L 2 and R 30 is as defined herein, including any of the definitions for formula III-2 shown in embodiments A2-A36.

[0097] In some embodiments, the present disclosure provides exemplary embodiments B1-B45 listed below. Embodiments B1 to B45 Embodiment B1. A compound of Formula III-3, or a pharmaceutically acceptable salt thereof, TIFF2025510945000186.tif6160 where variables Y, U, Z, R 1 , R 2 , R 3 , R 9 , n1, L 2 and R 30 as defined herein. Embodiment B2. A compound according to embodiment B1, having the structure of formula III-3-A, or a pharmaceutically acceptable salt thereof: TIFF2025510945000187.tif5657Embodiment B3. A compound of formula III-4, or a pharmaceutically acceptable salt thereof, TIFF2025510945000188.tif5746 where variables Y, U, Z, R 1 , R 2 , R 3 , R 9 , n1, L 2 and R 30 as defined herein. Embodiment B4. A compound according to embodiment B3, having the structure of formula III-4-A, or a pharmaceutically acceptable salt thereof: TIFF2025510945000189.tif5651Embodiment B5. The compound of embodiment B3, having the structure of formula III-4-B, or a pharmaceutically acceptable salt thereof: TIFF2025510945000190.tif5651Embodiment B6. A compound according to embodiment B5, having the structure of formula III-4-C or III-4-D, or a pharmaceutically acceptable salt thereof: TIFF2025510945000191.tif62153Embodiment B7. A compound according to embodiment B6, having a structure of formula III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1 or III-4-D-2, or a pharmaceutically acceptable salt thereof: TIFF2025510945000192.tif169144 Embodiment B8.(i)R 3 may be replaced by C 1-4alkyl, such as CH3, CD3, ethyl, isopropyl, CH2CHF2, or R 3 is an optionally substituted 3-4 membered ring, such as cyclopropyl or cyclobutyl, and when substituted, C 1-4 The alkyl or 3-4 membered ring is generally substituted with 1-3 substituents which are each independently deuterium, F or methyl, preferably R 3 is methyl or CD3; (ii) R 3 The compound according to any one of embodiments B1 to B7, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Embodiment B9.(i)R 1 is CN; (ii) R 1 is a halogen, e.g., F or Cl; (iii) R 1 but, TIFF2025510945000193.tif1263; (iv) R 1 is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, such as an optionally substituted pyrimidyl or an optionally substituted thiazolyl, such as R 1 but, TIFF2025510945000194.tif1772 or TIFF2025510945000195.tif1772; or (v) R 1 But, SR A1 and R A1 each independently represents an optionally substituted C 1-4 alkyl, e.g., R 1 The compound according to any one of embodiments B1 to B8, or a pharmaceutically acceptable salt thereof, wherein is SCH3. Embodiment B10.R 9 Each time it is represented, it is independently CH3, CH2CH3, CH2CH2CH3, fluorine-substituted C 1-3alkyl (e.g., CFH), cyclopropyl, cyclobutyl, CHOH, CHOCH, CHOCHCH, CHNH, CHN, or CHNHC(O)OCH, preferably R 9 each occurrence is independently CH3, CH2CH3 or CH2CH2CH3, more preferably R 9 The compound according to any one of embodiments B1 to B9, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently CH2CH3. Embodiment B11.L 2 may be replaced by C 1-4 The compound according to any one of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, which is alkylene. Embodiment B12.L 2 A compound according to any one of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000196.tif41120, R 13 as defined herein. Embodiment B13. A compound according to any one of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, having a structure of formula III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f, TIFF2025510945000197.tif121162, R 13 as defined herein. Embodiment B14. A compound according to any one of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, having the structure of formula III-4-C-4a: TIFF2025510945000198.tif5574, R 13 as defined herein. Embodiment B15. Essentially stereoisomerically pure, e.g., having an enantiomeric excess ("ee") of 80% or more, e.g., 90% ee, 95% ee, 98% ee, 99% ee or more, and essentially free of the stereoisomer corresponding to Formula III-4-C-4b; TIFF2025510945000199.tif5278 A compound according to embodiment B14, or a pharmaceutically acceptable salt thereof, having less than 5%, for example less than 2%, less than 1%, less than 0.5% or less than 0.1%, of the stereoisomer corresponding to formula III-4-C-4b, e.g., as measured by HPLC or SFC area % and / or weight. Embodiment B16. A compound according to any one of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, having the structure of formula III-4-C-4c, TIFF2025510945000200.tif5469 in formula, R 13 as defined herein. Embodiment B17. Essentially stereoisomerically pure, e.g., having an enantiomeric excess ("ee") of 80% or more, e.g., 90% ee, 95% ee, 98% ee, 99% ee or more, and essentially free of the stereoisomer corresponding to Formula III-4-C-4b; TIFF2025510945000201.tif5069A compound according to embodiment B16, or a pharmaceutically acceptable salt thereof, having less than 5%, for example less than 2%, less than 1%, less than 0.5% or less than 0.1%, of the stereoisomer corresponding to formula III-4-C-4d, e.g., as measured by HPLC or SFC area % and / or weight. Embodiment B18. A compound according to any one of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, having the structure of formula III-4-C-4e, TIFF2025510945000202.tif5272 formula, R 13 as defined herein. Embodiment B19. Essentially stereoisomerically pure, e.g., having an enantiomeric excess ("ee") of 80% or more, e.g., 90% ee, 95% ee, 98% ee, 99% ee or more, and essentially free of the stereoisomer corresponding to Formula III-4-C-4b; TIFF2025510945000203.tif5067A compound according to embodiment B19, or a pharmaceutically acceptable salt thereof, having less than 5%, for example less than 2%, less than 1%, less than 0.5% or less than 0.1%, of the stereoisomer corresponding to formula III-4-C-4f, e.g., as measured by HPLC or SFC area % and / or weight. Embodiment B20.R 13 is hydrogen, CN, OH, COOH, CONH2, methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S, and when substituted, the optionally substituted phenyl or 5- or 6-membered heteroaryl is substituted with 1-3 substituents, and the substituents are independently selected from halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F; 1-4 alkyl, C optionally substituted with 1-3 F 1-4 heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, more preferably R 13 The compound according to any one of embodiments B12 to B19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Embodiment B21.R 13 may be one or more independently F, OH, or C 1-4 C optionally substituted with a substituent selected from the group consisting of alkoxy 1-4 alkyl, e.g., R 13 The compound according to any of embodiments B12 to B19, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, isopropyl, CH2OH, CHOMe, or the like. Embodiment B22.R 13is phenyl optionally substituted with 1-3 substituents, and the substituents are independently halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4 heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, e.g., R 13 but, The compound of any of embodiments B12 to B19, which is TIFF2025510945000204.tif1499, or a pharmaceutically acceptable salt thereof. Embodiment B23.R 13 is a 5- or 6-membered heteroaryl optionally substituted with 1-3 substituents, for example: TIFF2025510945000205.tif2286 or TIFF2025510945000206.tif2286, wherein the substituents are independently halogen (preferably F or Cl), OH, CN, C optionally substituted with 1 to 3 F. 1-4 alkyl, C optionally substituted with 1-3 F 1-4 heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, e.g., R 13 but, TIFF2025510945000207.tif21102 or The compound of any of embodiments B12 to B19, or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF2025510945000208.tif21102. Embodiment B24.L 2 A compound according to any of embodiments B1 to B10, or a pharmaceutically acceptable salt thereof, wherein is absent or is O or C(O). Embodiment B25.R 30 optionally substituted phenyl or 5- or 6-membered heteroaryl (e.g., oxadiazolyl (e.g., TIFF2025510945000209.tif1986), pyridyl (e.g., TIFF2025510945000210.tif2288 or TIFF2025510945000211.tif2264) or pyrimidyl (e.g., TIFF2025510945000212.tif2378), e.g., when substituted, phenyl or 5- or 6-membered heteroaryl may be substituted with 1-3 (e.g., 1 or 2) R 22 may be substituted with R 22 represents a halogen (e.g., F, Cl, or Br), CN, C optionally substituted with 1-3 F 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl or The compound of any one of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF2025510945000213.tif1675. Embodiment B26.R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1 or SF5, R M1 represents each independently and may be replaced by C 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 Alkyl or 1-3 of the 3- or 4-membered rings are independently substituted with a substituent selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4alkyl, C optionally substituted with 1-3 F 1-4 Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R 22 A compound according to any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl). Embodiment B27.R 30 but 1-3 (e.g., 1 or 2) R 22 is phenyl substituted with R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4 The compound according to any one of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, eg, CF3. Embodiment B28.R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000214.tif1872) or pyridyl (e.g., TIFF2025510945000215.tif2383 or TIFF2025510945000216.tif2383) or pyrimidyl (e.g., TIFF2025510945000217.tif2376) and R 22 each occurrence independently represents a halogen (e.g., F, Cl, or Br), CN, OH, R M1 , OR M1 , SO2R M1 , P(O)(R M1 )2, SR M1or SF5, R M1 may be substituted independently each time C represents 1-4 alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C 1-4 Alkyl or 1-3 of the 3- or 4-membered rings are independently substituted with a substituent selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F 1-4 alkyl, C optionally substituted with 1-3 F 1-4 Heteroalkyl, 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R 22 A compound according to any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein each occurrence of is independently F, Cl, Br, CF3, OCF3, SCF3, SF5, OMe, CN, methyl, CHF2, CF2CH3, cyclopropyl, CH3SO2, and OCH2-(cyclopropyl). Embodiment B29.R 30 However, if valency is allowed, 1-3 (e.g., 1 or 2) R 22 5-membered heteroaryl substituted with (e.g., TIFF2025510945000218.tif1767) or pyridyl (e.g., TIFF2025510945000219.tif2587 or TIFF2025510945000220.tif2587) or pyrimidyl (e.g., TIFF2025510945000221.tif2486) and R 22 Each time it is expressed, it is independently F, Cl, CN, R M2 , OR M2 , S.R. M2 or SF5, R M2 Each occurrence of C may be independently substituted with 1 to 3 F. 1-4The compound according to any one of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, eg, CF3. Embodiment B30.R 30 The compound of any one of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein: TIFF2025510945000222.tif68121In formula, R 8 C, which may be substituted with 1-3 F 1-4 Alkyl (e.g., CH3, CF3, etc.), C optionally substituted with 1-3 F 1-4 Alkoxy (e.g., OCH3, OCF3, etc.), SCF3, SF5, cyclopropyl, cyclobutyl, or The file is TIFF2025510945000223.tif1481. Embodiment B31.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000224.tif74119 Embodiment B32.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000225.tif46130 Embodiment B33.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000226.tif93155 Embodiment B34.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000227.tif31132 Embodiment B35.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000228.tif29150 Embodiment B36.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000229.tif32162 Embodiment B37.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000230.tif3388 Embodiment B38.L 2 -R 30 The compound of any of embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000231.tif2487 or TIFF2025510945000232.tif2487 Embodiment B39.L 2 -R 30 The compound of any of embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000233.tif2293 or TIFF2025510945000234.tif2293 Embodiment B40.L 2 -R 30 The compound of any of embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000235.tif139149 Embodiment B41.L 2 -R 30 The compound of any of embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000236.tif154162 Embodiment B42.R 30 The compound of any of embodiments B1 to B24, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000237.tif29140 Embodiment B43.L 2 -R 30 The compound of any of embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000238.tif68165 Embodiment B44.L 2 -R 30 The compound of any of embodiments B1-B10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: TIFF2025510945000239.tif66164Embodiment B45. -JW- represents -CH2-O-CH2, -O-CH2-CH2-, -N(CH3)-C(O)-, -NH-C(O)-, -N(CH3)-CH2 or -NH-CH2 (from left to right, i.e., J is the first group from the left, e.g., CH2, O, NH or NCH3), and the variables Z, Y, U, R 1 , R 2 , R 3 , n1, R 9 , L 2 and R 30 is as defined herein, including any of the definitions for Formula III-3 or III-4 as set forth in embodiments B1 to B44, or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the present disclosure also provides a compound selected from the group consisting of Compound Nos. 1-347, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the present disclosure further provides a compound selected from the group consisting of the compounds set forth in Table A below, or a pharmaceutically acceptable salt thereof. TIFF2025510945000240.tif214166TIFF2025510945000241.tif222166TIFF2025510945000242.tif222166TIFF20255109450 00243.tif221166TIFF2025510945000244.tif223166TIFF2025510945000245.tif216166TIFF2025510945000246.tif220166 TIFF2025510945000247.tif220166TIFF2025510945000248.tif219166TIFF2025510945000249.tif221166TIFF20255109450 00250.tif217166TIFF2025510945000251.tif219166TIFF2025510945000252.tif220166TIFF2025510945000253.tif217166

[0100] Exemplary syntheses and properties of the above compounds are shown in the Examples section. The compounds can be prepared in racemic form with respect to one or more chiral centers, which, according to the present disclosure, can be separated into two enantiomers, including the original enantiomer, or can be prepared by chiral synthesis.

[0101] In some embodiments, to the extent applicable, the classes of compounds in the present disclosure also exclude any of the compounds specifically made and disclosed prior to the present disclosure. In other words, the classes of compounds in the present disclosure can optionally have negative limitations that exclude one or more applicable compounds selected from any of the compounds specifically made prior to the present disclosure.

[0102] In some embodiments, the class of compounds of the present disclosure includes any of the compounds set forth in claims 1-63, embodiments 1-49, embodiments A1-A38, and embodiments B1-B45 as originally filed.

[0103] The compounds of the present disclosure can be readily synthesized by one of ordinary skill in the art in light of the present disclosure, and exemplary syntheses are also provided in the Examples section.

[0104] 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.

[0105] Pharmaceutical Composition Some embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0106] The pharmaceutical composition may optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b , III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. and a pharmaceutically acceptable excipient; and a compound selected from the group consisting of compounds of Nos. 1 to 347, ... Pharmaceutically acceptable excipients are well known in the art. Non-limiting examples of suitable excipients include, for example, encapsulants 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, Remington's The Science and Practice of Pharmacy, 21, which discloses the prior art of each excipient and its preparation for preparing pharmaceutical compositions, discloses the use of various excipients.st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005, which is incorporated herein by reference).

[0107] The 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 Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D-5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2-D-17, III -2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, I II-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III- any compound selected from the group consisting of compounds of Nos. 1 to 347, compounds of Table A of the present application, or a pharmaceutically acceptable salt thereof. In any embodiment according to the present application, the pharmaceutical composition can include a therapeutically effective amount of any compound selected from the group consisting of compounds 1 to 347, or a pharmaceutically acceptable salt thereof. In any embodiment according to the present application, the pharmaceutical composition can include a therapeutically effective amount of a compound selected from the group consisting of the compounds set forth in Table A of the present application, or a pharmaceutically acceptable salt thereof.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] Pharmaceutical compositions can contain varying amounts of the compounds of the present disclosure, depending on various factors such as the intended use, potency, and selectivity of the compound. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of a compound of the present disclosure (e.g., Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D-5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2-D-17, III-2-D-18, III-2-D-19, III-2-D-20, III-2-D-21, III-2-D-22, III-2-D-23, III-2-D-24, III-2-D-25, III-2-D-26, III-2-D-27, III-2-D-28, III-2-D-29, III-2-D-30, III-2-D-31, III-2-D-32, III-2-D-33, III-2-D-34, III-2-D-35, III-2-D-36, III-2-D-37, III-2-D-38, III-2-D-39, III-2-D-41, III-2-D-19, III-2-D-19, III-2-D-19, III-2 II-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b , III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III and III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of the compounds of Nos. 1 to 347, any compound selected from the group consisting of the compounds set forth in Table A of the present application, or a pharmaceutically acceptable salt thereof). 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 potency (e.g., inhibition of DGKa and / or DGKz), its clearance rate, and whether it is used in combination with other drugs.

[0113] 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.

[0114] In some embodiments, all components necessary for the treatment of DGKa and / or DGKz-associated diseases 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 diseases. Specifically, in some embodiments, the present invention provides kits for therapeutic intervention of diseases, comprising a packaged group of drugs, including a compound of the present disclosure, buffers and other ingredients for preparing the drug in a usable format, and / or devices for delivering such drug, and / or any agent for co-treatment with a compound of the present disclosure (e.g., any of the immuno-oncology agents described herein, including protein antagonists that inhibit T cell activation, protein agonists that stimulate T cell activation, etc., as described herein, particularly one or more antibodies selected from the group consisting of anti-PD-1, anti-PD-L1, anti-CTLA-4, and combinations thereof), and / or instructions for treating the disease in the drug package. These instructions may be fixed on any tangible medium such as a paper sheet, or on a computer-readable magnetic or optical medium, or on instructions referencing a remote computer data source (e.g., a World Wide Web page accessible via the Internet).

[0115] Treatment method The compounds of the present disclosure are used as therapeutically active agents to treat and / or prevent diseases or conditions associated with the activity of DGKa, DGKz, or both DGKa and DGKz (e.g., targeted DGK inhibition in T cells), including viral and other infections (e.g., skin infections, gastrointestinal infections, urinary tract infections, genitourinary tract infections, systemic infections) and proliferative disorders (e.g., cancer).

[0116] In some embodiments, the present disclosure provides a method for inhibiting diacylglycerol kinase α and / or ζ (DGKa / z) activity in a cell, comprising combining the cell with a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-E, III-2-F, III-2-G, III-2-H, III-2-I, III-2-I-F ... II-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, II I-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F- 3a or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4 -C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4 The present invention provides a method for producing a medicament for the treatment of ...For example, the "contacting" of DGKa and DGKz enzymes with a compound of the present disclosure includes administering a compound of the present disclosure to a subject (e.g., a human) having DGKa and DGKz, as well as introducing a compound of the present disclosure into a sample of a cell preparation or purified preparation containing the DGKa and DGKz enzymes. The term "DGK inhibitor" (e.g., a DGKa and / or DGKz inhibitor) refers to a preparation that can inhibit the activity of diacylglycerol kinase α and / or diacylglycerol kinase ζ (DGKa and / or DGKz), e.g., activity that leads to T cell stimulation in T cells.

[0117] In some embodiments, the present disclosure provides a method of treating a disease associated with activity or expression (including aberrant activity and / or overexpression) of DGKa and / or DGKz in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III- 2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, I II-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2 b, III-2-F-3a or III-2-F-3b), III-3 (e.g. III-3-A), III-4 (e.g. III-4-A, III-4-B, III-4-C, III-4-D, III-4-C- 1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, The present invention provides a method for treating a disease comprising administering a compound selected from the group consisting of compounds of Nos. III-4-C-4e or III-4-C-4f, III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of Nos. 1 to 347, and any compound set forth in Table A herein, or a pharmaceutically acceptable salt thereof. Examples of diseases include any disease, condition, or symptom associated directly or indirectly with the expression or activity (e.g., overexpression or abnormal activity) of DGKa and / or DGKz enzymes. DGKa and / or DGKz-associated diseases include any disease, condition, or symptom that can be prevented, ameliorated, or cured by modulating DGKa and / or DGKz enzyme activity. DGKa and / or DGKz-associated diseases include cancer and viral infections, such as HIV infection, hepatitis B, and hepatitis C.Examples of cancer include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia and / or melanoma.

[0118] In some embodiments, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E- 2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, I II-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f), III-5 , III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of compounds 1-347, any compound selected from the group consisting of compounds set forth in Table A herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and / or melanoma. Types of cancer treatable by the compounds of the present disclosure include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer, and bone cancer.Examples of such cancer types include neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), Hodgkin's lymphoma, non-small cell lung cancer, and ovarian cancer. Including Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia-lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0119] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-D-5, III-2-D-6, III-2-D-7, III-2-D-8, III-2-D-9, III-2-D-10, III-2-D-11, III-2-D-12, III-2-D-13, III-2-D-14, III-2-D-15, III-2-D-16, III-2 -3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2- E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f), III- The present invention provides methods for treating a rheumatoid arthritis (rheumatoid arthritis) comprising administering a therapeutically effective amount of a compound selected from the group consisting of compounds of formulas III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of formulas 1-347, or any compound set forth in Table A herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Treatable viral infections include, but are not limited to, diseases caused by the following viruses: hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV). In some embodiments, parasitic infections (e.g., malaria) can also be treated by the above methods.

[0120] In some embodiments, the present disclosure provides a method of treating a disease or condition, e.g., cancer associated with DGKa and / or DGKz, in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E, III-2-F, III-2-G, III-2-H, III-2-I, III-2-I-L ... -1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b , III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b), III-3 (e.g. III-3-A) , III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, III-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e, or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11, or III-12, any of the compounds of Nos. 1 to 347, any compound selected from the group consisting of the compounds set forth in Table A herein, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer comprises colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and / or melanoma. Other types of cancer suitable for treatment by the method include those described herein.

[0121] The compounds of the present disclosure are used as monotherapy or combination therapy. In some embodiments, combination therapy includes treating a subject with targeted therapeutic agents, chemotherapeutic agents, therapeutic antibodies, radiation therapy, cell therapy, and / or immunotherapy. In some embodiments, the compounds of the present disclosure can also be co-administered to a subject in need thereof with additional pharmaceutically active compounds, either simultaneously or sequentially in any order. In some embodiments, combination therapy includes treating a subject with one or more additional therapies, for example, antiviral agents, chemotherapeutic or other anti-cancer agents, immune enhancers, immune inhibitors, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors.

[0122] In some embodiments, the compounds of the present disclosure may be administered simultaneously or sequentially with an immuno-oncology agent. Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biologics, or small molecule agents. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including costimulatory) receptor, or (ii) an antagonist of an inhibitory (including costimulatory) signal on T cells, either of which amplifies antigen-specific T cell responses (commonly referred to as immune checkpoint modulators). Some stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the homologous TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTbR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a / TNFb, TNFR2, TNFa, LTbR, and lymphotoxin a. Includes 1b2, FAS, FASL, RELT, DR6, TROY, and NGFR.T cell responses can be stimulated by a combination of the compounds disclosed herein with one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, and Galectin-9; (9), CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H. Other formulations that can be used in combination with the compounds of the present disclosure to treat cancer include antagonists that suppress receptors on NK cells and agonists that activate receptors on NK cells. For example, the compounds of the present disclosure can be used in combination with KIR antagonists, such as lirilumab. Other agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as the CSF-1R antagonist antibody, RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).In some embodiments, compounds of the present disclosure can be used in combination with one or more of the following: agonists that bind positive costimulatory receptors; blockers that attenuate signals from inhibitory receptors; antagonists and one or more agents that increase the frequency of anti-tumor T cells systemically; agents that can overcome unique immune inhibitory pathways in the tumor microenvironment (e.g., by blocking the engagement of inhibitory receptors such as PD-L1 / PD-1 interactions, or by depleting or inhibiting Tregs (e.g., by depletion with anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo anti-CD25 beads), or by inhibiting metabolic enzymes such as IDO, or by reversing / preventing T cell hypersensitivity or failure), and agents that cause innate immune activation and / or inflammation at the tumor site. In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In some embodiments, the immuno-oncology agent is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). The immuno-oncology agent can also include pidilizumab (CT-011), which has suspected specificity for binding to PD-1. Another approach to targeting the PD-1 receptor is a recombinant protein fused to the extracellular domain of PD-L2 (B7-DC) and the Fc portion of IgG1, also known as AMP-224. In some embodiments, the immuno-oncology agent is a PD-L1 antagonist, e.g., comprises an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).In some embodiments, the immuno-oncology agent is a LAG-3 antagonist, e.g., an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273). In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist, e.g., an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433). In some embodiments, the immuno-oncology agent is a GITR agonist, e.g., an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683). In some embodiments, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, BMS-986205, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237). In some embodiments, the immuno-oncology agent is an OX40 agonist, e.g., an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, e.g., an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879). In some embodiments, the immuno-oncology agent is a CD40 agonist, for example, an agonistic CD40 antibody. In other embodiments, the immuno-oncology agent is a CD40 antagonist, for example, an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. In some embodiments, the immuno-oncology agent is a CD27 agonist, for example, an agonistic CD27 antibody.Suitable CD27 antibodies include, for example, varlilumab. In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO11 / 109400).

[0123] Combination therapy also includes the further combination of the above therapeutic agents with other biologically active ingredients and / or non-drug therapies (eg, surgery or radiation therapy).

[0124] Suitable antiviral formulations contemplated for use in combination with the compounds of the present disclosure can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs. Suitable NRTIs include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir, BCH-I0652, emitricitabine [(-)-FTC], β-L-FD4 (also known as β-L-D4C, TIFF2025510945000254.tif9131), DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. Exemplary suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nerfunavir (AG-1343), amprenavir (141W94), lasinavir, DMP-450, BMS-2322623, ABT-378, and AG-1549. Other antiviral drugs include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0125] Other combination therapies, e.g., other immuno-oncology drugs, further include drugs suitable for combination with DGK inhibitors described in any of the following disclosed patent applications: WO2019005883; WO2020006016; WO2020006018; WO2021041588; WO2021105115; WO2021105116 ;WO2021105117;WO2021127554;WO2021130638;WO2021132422;WO2021133748;WO2021133749;WO2021133750;WO2021133751;WO2021133752;WO2021214019;or WO2021214020.

[0126] 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.

[0127] Dosage regimens, including dosage, can be varied and 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 another drug.

[0128] definition It should be understood that all moieties and combinations thereof maintain the appropriate chemical value.

[0129] 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.

[0130] The present disclosure includes all combinations of aspects and / or embodiments of the present disclosure. It should be understood that any embodiment of the present disclosure can be combined with other embodiments to describe additional embodiments. It should also be understood that each individual element of an embodiment is intended to be combined with any other element of any embodiment to describe another embodiment.

[0131] The atoms or groups suitable for the variables herein are independently selected. The definitions of the variables may be combined. For example, in Formula III-4, R 1 , R 2 , R 3 , R 9 , R 30 , U, Y, Z, n1 and L 2 Any of the definitions of R in Formula III-4 1 , R 2 , R 3 , R 9 , R 30 , U, Y, Z, n1 and L 2and n is 0 or 1. Such combinations are contemplated and within the scope of the present disclosure. Non-limiting useful groups for the variables in the compounds of formulas III-1 through III-12, or subformulas thereof, include any of the respective groups individually or in any combination, as shown in the examples of this application or in the specific compounds described in Table A.

[0132] For the sake of clarity, as is well understood in the art, when a general formula in this application is said to be a subformula of a broader general formula, it should be understood that, for a variable defined in conjunction with the broader general formula, such variable in the subformula may have the same definition as any of those defined in the broader general formula, and, unless the context clearly indicates otherwise, a preferred definition of such variable in the subformula may also include the same preferred definition as any of those set forth for the broader general formula. Similarly, for a variable defined in conjunction with a subformula, such variable in the broader general formula or in a different subformula of the broader general formula may have the same definition as any of the variables defined in the subformula, unless the context clearly indicates otherwise.

[0133] Notation When a bond is perpendicular to (or crosses) a given bond, it indicates the site of attachment of the indicated moiety to the rest of the molecule. Note that for bivalent (or multivalent) structures, one or more directly bonded groups or appropriate variables shown in the general formula may be denoted in the bivalent (or multivalent) structure to indicate the direction of the bond. TIFF2025510945000256.tif799. When no directly attached groups or variables are shown at the two linking arms of a bivalent structure, it indicates that either orientation of the link to the rest of the molecule is acceptable unless otherwise specified or clearly contradicted by the context. For example, the definition of G is "XAGB" TIFF2025510945000257.tif1662, i.e., where no directly attached groups or variables are shown, the structure of "XAGB" is TIFF2025510945000258.tif20100 or TIFF2025510945000259.tif20100; whereas the definition of G is TIFF2025510945000260.tif21137 or If TIFF2025510945000261.tif2074, the structure of "XAGB" is It should be understood as TIFF2025510945000262.tif2086.

[0134] 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 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0135] 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 should be understood that the compound exists primarily as the depicted stereoisomer, with less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts 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%, greater than 95%, greater than 98%, greater than 99% or with no detectable other enantiomers. In accordance with the present disclosure, one of ordinary skill in the art can determine the presence and / or amount of stereoisomers by methods including determination by chiral HPLC or SFC. When the stereochemistry of a chiral center is not depicted, it should be understood that the structure or fragment thereof is intended to include all possible stereoisomers of that particular chiral center.

[0136] 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.

[0137] As used herein, the term "compound of the present disclosure" or "compound of the present invention" refers to a compound of formula III-1, III-2 (e.g., III-2-A, III-2-B, III-2-C, III-2-C-1, III-2-C-2, III-2-C-3, III-2-C-4, III-2-D, III-2-D-1, III-2-D-2, III-2-D-3, III-2-D-4, III-2-E-1, III-2-E-2, III-2-E-3, III-2-E-1a, III-2-E-2a, III-2-E-3a, III-2-E-1b, III-2-E-2b, III-2-E-3b, III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3 a or III-2-F-3b), III-3 (e.g., III-3-A), III-4 (e.g., III-4-A, III-4-B, III-4-C, III-4-D, III-4-C-1, III-4-C-2, III-4-C-3, II any of the compounds according to I-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f), III-5, III-6, III-7, III-8 (e.g., III-8-A or III-8-B), III-9, III-10, III-11 or III-12, any of the compounds according to I-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f, ... any of the compounds according to I-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f, any of the compounds according to I-4-C-4, III-4-D-1, III-4-D-2, III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C "Compounds 1-347" refers to any compound selected from the group consisting of: isotopically labeled compounds thereof (e.g., deuterium analogs in which one hydrogen atom is replaced with a deuterium atom, where the abundance of the deuterium atom is higher than its natural abundance); possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures); geometric isomers; atropisomers; tautomers; conformers; and / or pharmaceutically 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, Compounds 1-347 or Compounds 1-347 refer to compounds described herein in which the integers 1, 2, 3, ..., 347 are represented, for example, by 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 number) followed by "-" and an additional number, such as 1-1, 1-2, etc. (see Examples for details). Such synthetic starting material or intermediate labels should not be confused with compounds labeled only with the integer, excluding the "-" and additional number. Hydrates and solvates of compounds of the present disclosure are considered compositions of the present disclosure in which the compound is combined with water or solvent, respectively. In some embodiments, compounds of the present disclosure may be any of the compounds described in claims 1-63 as filed. In some embodiments, compounds of the present disclosure may be any of the compounds defined in embodiments 1-49 of the present disclosure. In some embodiments, compounds of the present disclosure may be any of the compounds defined in any of embodiments A1-A38 and B1-B45.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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 2~4 Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl groups.

[0142] 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.

[0143] 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 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 R a1 is a cycloalkyl group as defined herein.

[0144] 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 C 1~4 It is a haloalkyl group.

[0145] 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 rest of the molecule. For example, C 1-4 Heteroalkyl 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''.

[0146] 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, the point of attachment being 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.

[0147] 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.

[0148] 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 skilled 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, where 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, where the point of attachment is at the heterocycle, and in which case the number of ring members still refers to the number of ring members in the heterocyclic ring system.

[0149] 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.

[0150] 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" further includes ring systems comprising an aryl ring, as defined above, fused to one or more carbocyclic or heterocyclic groups, where the radical or point of attachment is on the aryl ring, and in this case the number of carbon atoms still represents the number of carbon atoms in the aromatic ring system.

[0151] An "aralkyl group," 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.

[0152] A "heteroaryl group," when used alone or as part of another group, is a group ("5-10-membered heteroaryl group") having a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared in a ring array) with ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms (each heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur) provided in the aromatic ring system. Where applicable, heteroaryl groups having a different ring size from the 5- to 10-membered heteroaryl group are designated by the different ring size designation. One of ordinary skill in the art would recognize such heteroaryl groups having a different ring size as also having a 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared in a ring array) with ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms (each heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur), each heteroatom 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 at a carbon or nitrogen atom, where valency allows. Heteroaryl bicyclic ring systems contain one or more heteroatoms in one or both rings. "Heteroaryl group" includes ring systems comprising a heteroaryl ring, as defined above, fused with one or more carbocyclic or heterocyclic groups, where 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. "Heteroaryl group" also includes ring systems comprising a heteroaryl ring, as defined above, fused with one or more aryl groups, where the point of attachment is at the aryl or heteroaryl ring, and in this case, the number of ring members represents the number of ring members in the fused (aryl group / heteroaryl group) ring system. In dicycloheteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbozolyl, etc.), the point of attachment may be in either ring, i.e., in a heteroatom ring (e.g., 2-indolyl) or in a ring without a heteroatom (e.g., 5-indolyl).

[0153] 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.

[0154] A "heteroaralkyl group," 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.

[0155] 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.

[0156] "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. Typically, the term "substituted," despite the preceding 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 whose 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.

[0157] 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).

[0158] 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 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 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, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted with 1, 2, or 3 substituents, and the substituents are independently selected from F, —OH, oxo (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:

[0159] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SRaa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)Raa ,-P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl 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 each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X 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, and 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)SR cc , -P(=O)(Raa )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, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X 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, and 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 )R ff , -SH, -SR ee , -SSRee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2,-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)(OR) ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. C 1~6 Arukaraki, C 1~6 Haruka Raki, C 2-6 アルケニbase, C 2-6 アルキニbased, C 3~10 Carbon ring group, 3~10 member complex ring group, C 6~10and aryl groups, and 5- to 10-membered heteroaryl groups, each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently selected from the group consisting of 0, 1, 2, 3, 4, or 5 R gg or two gem R dd The substituents may be linked to form =O or =S; X - 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 an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which 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, and 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, -OC 1-6 Alkyl group, -ON(C 1-6 alkyl group)2, -N(C 1-6alkyl 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 1-6 alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl group), -NHC(=NH)NH, -NHSO(C 1-6 alkyl group), -SO2N(C 1-6alkyl 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; X - is the counter ion.

[0160] 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.

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

[0162] An "acyl group" is -C(=O)R aa , -CHO, -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2, -C(=O)SR aa , or -C(=S)SR aa and R aa and R bb as defined in this disclosure.

[0163] Nitrogen atoms may be substituted or unsubstituted, where valency allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc)2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl 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, and each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group and R aa , R bb , R cc and R dd is defined as above.

[0164] 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.

[0165] Exemplary oxygen atom substituents are -R aa , -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3+X - , -P(OR cc )2, -P(OR cc )3+X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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 does 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] Exemplary embodiments carried out according to the synthesis steps of 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 immediately before the chiral resolution step (e.g., performed by supercritical fluid chromatography (SFC)) in the Examples section exist as racemates and / or stereoisomeric mixtures. It should be noted that the enantiomeric excess ("ee") and / or non-enantiomeric excess ("de") reported in these examples are representative of exemplary methods of this disclosure and are not limiting; as will be understood by those skilled in the art, enantiomers and / or diastereomers with different ee and / or de, e.g., higher ee and / or de, can be obtained according to this disclosure. Generally, when a pair of diastereoisomers (different at only one chiral center) is separated from the corresponding diastereomeric mixture, the "de" value is reported herein. In this case, the "de" value refers to the enrichment of one of the diastereomers.

[0176] Unless specifically stated otherwise or conflicting with the context, abbreviations used in the Examples section should be understood to have their ordinary meaning in the art. Listed below are some abbreviations used in the Examples section of this disclosure: TIFF2025510945000263.tif76166TIFF2025510945000264.tif249166TIFF2025510945000265.tif232166TIFF2025510945000266.tif111166

[0177] Step 1: To a solution of 1-1 (2.5 g, 10.4 mmol) in dioxane (20 mL) was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (3.0 g, 12.45 mmol), CsCO (6.76 g, 20.75 mmol), and RuPhos Pd G (867.6 mg, 1.4 mmol). The resulting mixture was degassed with N for 10 min and then stirred at 120 °C for 4 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-2.

[0178] Step 2: To a solution of 1-2 (2.8 g, 7 mmol) in dioxane (20 mL) was added HCl (4.3 mL, 43 mmol). The reaction mixture was stirred at room temperature for 5 h. The pH was adjusted to 6 by adding saturated NaHCO3. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 1-3.

[0179] Step 3: To a solution of 1-4 (24 g, 144.4 mmol) in acetonitrile (250 mL) at room temperature, NBS (28.3 g, 158.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to extract the mixture. The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 1-5.

[0180] Step 4: At room temperature, HATU (1.39 g, 3.7 mmol) and triethylamine (45.2 mL, 325.4 mmol) were added to a solution of 2-cyanoacetic acid (16.6 g, 195.2 mmol) in DMF (400 mL). The mixture was stirred at room temperature for 15 minutes. Then, 1-5 (31.9 g, 130.2 mmol) was added. The mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture. The solid was collected by filtration to give 1-6.

[0181] Step 5: To a solution of 1-6 (21.5 g, 68.9 mmol) in THF (300 mL) at room temperature was added KHMDS (1 M in THF, 89.6 mL, 89.6 mmol). The mixture was stirred at room temperature for 12 h, and HCl (1 N) was added until the pH reached 4. The solid was collected by filtration to give 1-7.

[0182] Step 6: To a solution of 1-7 (15.8 g, 59.4 mmol) in DMF (200 mL) at 0 °C, NaH (9.5 g, 60%, 237.6 mmol) was added in portions. The mixture was stirred at 0 °C for 30 min. CHCl (14.8 mL, 237.6 mmol) was added. The reaction was stirred at room temperature for 12 h and then quenched with water. The pH of the reaction mixture was adjusted to 3 with HCl (1 N). The solid was collected by filtration to give 1-8.

[0183] Step 7: To a solution of 1-8 (17.3 g, 61.8 mmol), triethylamine (25.8 mL, 185.3 mmol), and DMAP (0.8 g, 6.2 mmol) in dichloromethane (200 mL) was added TfO (34.9 g, 123.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then quenched with water and extracted with dichloromethane. The combined organic layer was dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 1-9.

[0184] Step 8: To a mixture of 1-9 (300 mg, 0.73 mmol) and 1-3 (327.9 mg, 1.1 mmol) in acetonitrile (10 mL) was added DIPEA (0.36 mL, 2.18 mmol). The mixture was stirred at 85 °C for 2 h. The reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 1-10.

[0185] Step 9: To a solution of 1-10 (210 mg, 0.37 mmol) in NMP (8 mL) was added Zn(CN) (87.7 mg, 0.75 mmol), Zn (4.9 mg, 0.075 mmol), Pd(dba) (34.2 mg, 0.037 mmol), and dppf (12.6 mg, 0.022 mmol) under N. The reaction mixture was stirred at 80 °C for 1 h. The reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / water: 5-95%) to give 1. LCMS (ESI, m / z): [M+H] + = 509.4; 1 H NMR (400 MHz, DMSO-d 6,ppm):δ 8.25(d,J = 8.8 Hz,1H),8.14(d,J = 8.8 Hz,1H),7.12(d,J = 8.4 Hz,2H),6.58(d,J = 9.2 Hz,2H),3.90-3.85(m,4H),3.52(s,3H),3.38-3.34(m,2H),3.25(s,2H),1.99(t,J = 6.8 Hz,2H),1.86-1.80(m,4H). TIFF2025510945000267.tif80166

[0186] Step 1: To a solution of 2-1 (19 g, 106.7 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (21.5 g, 106.7 mmol), and PPh3 (30.8 g, 117.3 mmol) in THF (85 mL) was added DEAD (18.6 mL, 117.3 mmol) at 0 °C and N2. The mixture was stirred at 20 °C and N2 for 16 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 2-2.

[0187] Step 2: To a solution of 2-2 (22.1 g, 61.2 mmol) in dichloromethane (20 mL) was added a solution of HCl in dioxane (4 M, 61.2 mL, 244.8 mmol) at 20° C. The mixture was stirred at 20° C. for 16 h. The mixture was concentrated under reduced pressure to give 2-3.

[0188] Step 3: To a mixture of 1-9 (600 mg, 1.46 mmol) and 2-3 (456.4 mg, 1.75 mmol) in acetonitrile (10 mL) at room temperature was added DIPEA (564.4 mg, 4.37 mmol). The mixture was stirred at 85 °C for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-4.

[0189] Step 4: To a toluene solution (15 mL) of 2-4 (300 mg, 0.57 mmol) and acetaldehyde oxime (609.5 mg, 10.3 mmol) was added Rh(PPh)Cl (53.0 mg, 0.057 mmol) at room temperature. The mixture was then heated at 110 °C for 12 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-5.

[0190] Step 5: To a mixture of 2-5 (250 mg, 0.46 mmol), Zn (6.0 mg, 0.09 mmol), and Zn(CN) (108.5 mg, 0.92 mmol) in NMP (4 mL) at room temperature, Pd(dba) (42.3 mg, 0.046 mmol) and dppf (12.8 mg, 0.023 mmol) were added. The mixture was then stirred at 90 °C for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / 0.05% TFA in water: 5%-80%) to give 2, which was 0.2 equiv of the TFA salt. LCMS (ESI, m / z): [M+H] + = 488.4; 1 H NMR (400 MHz, DMSO-d 6, ppm):δ 8.17(d,J = 8.8 Hz,1H),8.08(d,J = 8.9 Hz,1H),7.65(s,1H),7.50(s,1H),7.27(d,J = 8.6 Hz,2H),7.13-7.08(m,2H),4.73-4.65(m,1H),3.63(s,2H),3.55(s,3H),3.34-3.29(m,2H),2.13-2.10(m,2H),1.86-1.83(m,2H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-57.25(3F),-74.58(0.6F,TFA). TIFF2025510945000268.tif56166

[0191] Step 1: 3-1 (10 g, 81.2 mmol) and piperidine-4-carboxylic acid (10.5 g, 81.2 mmol) were added to PPA (53.4 g, 81.2 mmol), and the mixture was stirred at 180 °C for 2 h. The reaction mixture was cooled to 90 °C, and then water was added to quench the reaction. The pH of the mixture was adjusted to 12 with 50% KOH. The mixture was extracted with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated to give 3-2.

[0192] Step 2: Compound 3-3 was prepared from compound 3-2 according to the synthesis process for compound 1-10 in Example 1.

[0193] Step 3: Compound 3 was prepared from compound 3-3 according to the synthesis of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + = 425.2; 1 H NMR(400 MHz,DMSO-d6,ppm)δ 8.27-8.24(m,1H),8.16-8.13(m,1H),7.54-7.56(m,1H),7.51(s,1H),7.17-7.15(m,1H),4.28-4.24(m,2H),3.67(t,J = 11.2 Hz,2H),3.53(s,3H),3.50-3.46(m,1H),2.40(s,3H),2.30-2.28(m,2H),2.16-2.08(m,2H). TIFF2025510945000269.tif85166

[0194] Step 1: To a solution of 4-1 (2.5 g, 10.37 mmol) in dioxane (20 mL) was added CsCO (6.8 g, 20.75 mmol), Pd(dba) (0.9 g, 1.04 mmol), BINAP (1.3 g, 2.08 mmol), and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (2.64 g, 12.45 mmol). The resulting mixture was degassed for 10 min and then stirred at 120 °C for 4 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 4-2.

[0195] Step 2: To a solution of 4-2 (2.9 g, 7.8 mmol) in dichloromethane (20 mL) was added TFA (5 mL, 805.6 mmol). The reaction mixture was then stirred at 25 °C for 3 h. The pH was adjusted to 6 with aqueous NaHCO3, and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to give 4-3.

[0196] Step 3: Compound 4-4 was prepared from compound 4-3 according to the synthesis process for compound 1-10 in Example 1.

[0197] Step 4: Compound 4 was prepared from compound 4-4 according to the synthesis of compound 1 in Example 1, and was a TFA salt of 0.33 equivalents. LCMS (ESI, m / z): [M+H] + = 481.2; 1 H NMR(400 MHz,DMSO-d6,ppm)δ 8.24-8.22(m,1H),8.08-8.05(m,1H),7.16-7.13(m,2H),6.49-6.47(m,2H),4.40(s,2H),4.24(t,J = 6.7 Hz,2H),3.87-3.81(m,4H),3.49(s,3H),2.24(t,J = 6.9 Hz,2H). 19 F NMR(376 MHz,DMSO-d6,ppm)δ-57.34(3F),-73.62(1F,TFA). TIFF2025510945000270.tif75166

[0198] Step 1: To a solution of 5-1 (46 g, 250.6 mmol) in concentrated hydrochloric acid (170 mL) and EtOH (510 mL) at 40 °C, Fe powder (42.0 g, 751.8 mmol) was added in several portions. The mixture was then stirred at 80 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The pH of the mixture was adjusted to 8 with ammonia. The mixture was then filtered, and the filtrate was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give 5-2.

[0199] Step 2: To a solution of 5-2 (36 g, crude) in THF (400 mL) at 0 °C, pyridine (56.6 mL, 703.3 mmol), DMAP (2.9 g, 23.4 mmol), and TFAA (73.9 g, 351.6 mmol) were slowly added. The mixture was then stirred at room temperature for 0.5 h. The mixture was concentrated. Water was added to the residue. The mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 5-3.

[0200] Step 3: To a solution of 5-3 (47 g, 188.3 mmol) in DMF (450 mL) at room temperature, K2CO3 (78.1 g, 565 mmol) and CHCl (35.2 mL, 565 mmol) were added. The mixture was stirred at room temperature for 12 h and then quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 5-4.

[0201] Step 4: To a mixture of 5-4 (49.0 g, 175.4 mmol) and K2CO3 (72.7 g, 526.3 mmol) in DMSO (500 mL) was slowly added HO (30%, 59.7 g, 526.3 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 5-5.

[0202] Step 5: To a solution of 5-5 (27 g, 87.3 mmol) in DMF (300 mL) at 0 °C, NaH (60%, 7.0 g, 174.6 mmol) was added in portions. The mixture was stirred at 0 °C for 1 h, and CDI (21.2 g, 130.9 mmol) was added to the reaction mixture. The mixture was then stirred at 70 °C for 2 h. The solid was collected by filtration and washed with ethyl acetate and methanol to give 5-6.

[0203] Step 6: To a solution of 5-6 (1.5 g, 7.09 mmol) in toluene (15 mL) at room temperature, POCl (5.27 mL, 56.71 mmol) and DIPEA (2.93 mL, 17.72 mmol) were added. The mixture was then stirred at 110 °C for 12 h. The mixture was concentrated to give 5-7, which was used directly in the next step without further purification.

[0204] Step 7: To a solution of 5-7 (crude, 1.2 g) and DIPEA (2.5 mL, 15.1 mmol) in acetonitrile (10 mL) was added 2-3 (500 mg, 1.68 mmol) at room temperature. The mixture was then stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 5-8.

[0205] Step 8: To a solution of 5-8 (98 mg, 0.22 mmol) in NMP (6 mL) at room temperature, dppf (11.9 mg, 0.022 mmol), Zn (5.6 mg, 0.088 mmol), Zn(CN) (50.6 mg, 0.43 mmol), and Pd(dba) (19.7 mg, 0.022 mmol) were added. The mixture was then stirred at 90 °C for 3 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase HPLC (acetonitrile / 0.05% TFA in water: 5%-90%) to give 5, which was a 0.4 equiv. TFA salt. LCMS (ESI, m / z): [M+H] + = 446.4; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.26(d,J = 9.2 Hz,1H),8.02(d,J = 9.2 Hz,1H),7.35-7.26(m,2H),7.18-7.06(m,2H),4.82-4.71(m,1H),3.96-3.79(m,4H),3.46(s,3H),2.20-2.05(m,2H),1.86-1.70(m,2H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-57.23(3F),-74.35(1.2F,TFA). TIFF2025510945000271.tif82166

[0206] Step 1: To a solution of 12-1 (7.4 g, 34 mmol) in DMSO (100 mL) was added 4-bromo-1H-pyrazole (5.0 g, 34 mmol), KPO (21.7 g, 102 mmol), CuO (0.2 g, 1.7 mmol), and N,N-bis(furan-2-ylmethyl)oxamide (0.4 g, 1.7 mmol). The reaction mixture was degassed with nitrogen gas three times, and then the reaction mixture was stirred at 120 °C for 14 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 12-2.

[0207] Step 2: To a solution of tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.7 g, 15.2 mmol) in dioxane (60 mL) was added 12-2 (3 g, 12.7 mmol) and K2CO3 (5.2 g, 38 mmol). The reaction mixture was degassed three times with nitrogen gas, and then Pd(dppf)Cl2 (0.9 g, 1.27 mmol) and water (20 mL) were added. The reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 12-3.

[0208] Step 3: To a solution of 12-3 (973 mg, 2.9 mmol) in dichloromethane (10 mL) was added Pd / C (10%, 97.6 mg). The reaction mixture was degassed with H2 three times. The reaction mixture was stirred at room temperature under H2 atmosphere for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 12-4.

[0209] Step 4: To a solution of 12-4 (826 mg, 2.4 mmol) in dichloromethane (5 mL) was added a solution of HCl in ethyl acetate (4 M, 5 mL, 20 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give 12-5, which was used directly in the next step without further purification.

[0210] Compound 12 was prepared from compound 12-5 according to the synthesis process of compound 5 in Example 5. LCMS (ESI, m / z): [M+H] + =426.2; 1H NMR(400 MHz,methanol-d4,ppm)δ 8.11(d,J = 8.9 Hz,1H),8.03(d,J = 8.9 Hz,1H),7.74(s,1H),7.68(s,1H),7.39-7.36(m,2H),7.33-7.30(m,2H),3.61(s,3H),3.36-3.34 (m,2H),3.32-3.29(m,2H),3.17-3.11(m,1H),2.28-2.21(m,2H),2.20(s,3H),1.94-1.81(m,2H). TIFF2025510945000272.tif128166

[0211] Step 1: To a solution of 16-1 (1.9 g, 8.36 mmol) in methanol (12 mL) at 0 °C was added NaBH (0.2 g, 10.87 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was quenched with water and concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 16-2 and 16-3.

[0212] Step 2: To a solution of 16-2 (604 mg, 2.63 mmol), 16-4 (563 mg, 3.16 mmol), and PPh3 (1.04 g, 3.95 mmol) in toluene (6 mL) was added DIAD (0.78 mL, 3.95 mmol) at 0 °C under N2. The mixture was stirred at 110 °C under N2 for 5 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 16-5.

[0213] Step 3: To a solution of 16-5 (923 mg, 2.37 mmol) in dichloromethane (5 mL) was added HCl in ethyl acetate (4 M, 2.37 mL, 9.5 mmol) at 25 °C. The mixture was stirred for 3 h at 25 °C. The mixture was concentrated to give 16-6, which was used directly in the next step without further purification.

[0214] Step 4: Compound 16-7 was prepared from compound 16-6 according to the synthesis of compound 5 in Example 5.

[0215] Step 5: Purify 16-7 (70 mg) by SFC (chromatography column: DAICELCHIR A LCEL® 0Z, methanol (+0.1% 7.0 mol / L aminomethanol solution) / supercritical CO2 = 40 / 60), 16 (31.8 mg) and 17 (7.02 mg) were obtained, respectively. 16: SFC analysis: 99.52% ee; retention time: 1.87 min; chromatography column: DAICELCHIR A LPAK® OZ, methanol (0.1% DEA) in CO2, 40%; Pressure: 1800 psi; Flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =474.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.28-8.23(m,1H),8.04-7.99(m,1H),7.33-7.29(m,2H),7.11-7.07(m,2H),4.85-4.77(m,1H), 3.47-3.43(m,4H),3.37-3.29(m,2H),2.17-2.02(m,3H),2.01-1.89(m,3H),0.87-0.79(m,3H). 19 F NMR (376 MHz, DMSO-d, ppm): δ -57.23 (3F). 17: SFC analysis: 96.6% ee; retention time: 2.14 min; chromatography column: DAICELCHIR A LPAK® OZ, methanol (0.1% DEA) in CO2, 40%; Pressure: 1800 psi; Flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + = 474.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.28-8.23(m,1H),8.04-7.99(m,1H),7.33-7.29(m,2H),7.11-7.07(m,2H),4.85-4.77(m,1H), 3.47-3.43(m,4H),3.37-3.29(m,2H),2.17-2.02(m,3H),2.01-1.89(m,3H),0.87-0.79(m,3H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-57.23(3F). TIFF2025510945000273.tif90166

[0216] Step 1: Compound 21-1 was prepared from compound 2-3 according to the synthesis process for compound 5-8 in Example 5.

[0217] Step 2: To a mixture of 21-1 (730 mg, 1.61 mmol) and (tert-butyloxy)carbohydrazide (640 mg, 4.8 mmol) in dioxane (10 mL) at room temperature, Pd(dba) (147.0 mg, 0.16 mmol), CsCO (1.57 g, 4.8 mmol), and t-BuBrettPhos (77.8 mg, 0.16 mmol) were added. The mixture was then stirred at 80 °C for 1 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 21-2.

[0218] Step 3: To a solution of 21-2 (310 mg, 0.56 mmol) in methanol (5 mL) at room temperature was added a solution of HCl in ethyl acetate (4 M, 3 mL). The mixture was then stirred at room temperature for 0.5 hours. The mixture was concentrated to give 21-3.

[0219] Step 4: To a solution of 21-3 (250 mg, crude) in methanol (6 mL) was added CH(OCH) (3 mL, 0.56 mmol) at room temperature. The mixture was then heated at 100 °C for 12 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 21. LCMS (ESI, m / z): [M+H] + =461.4; 1 H NMR(400 MHz,DMSO-d6,ppm)δ 9.49(d,J = 3.3 Hz,1H),8.26(d,J = 10.1 Hz,1H),7.77(d,J = 10.1 Hz,1H),7.33-7.26(m,2H),7.15-7.08(m,2H),4.73-4.65(m,1H),3.68-3.50(m, 5H),3.44-3.36(m,1H),3.29-3.22(m,1H),2.17-1.87(m,3H),1.78-1.65(m,1H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-57.23(3F). TIFF2025510945000274.tif125166

[0220] Step 1: 23-1 (550 mg, 2.42 mmol) was added dropwise to a solution of LDA in THF (20 mL) (2 M THF solution, 1.57 mL, 3.15 mmol) at −68 °C. After 30 min, a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonic acid methanesulfonamide (864.44 mg, 2.42 mmol) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH₄Cl and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 23-2.

[0221] Step 2: To a solution of 12-2 (1.0 g, 4.22 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.39 g, 5.48 mmol) in dioxane (20 mL) was added KOAc (0.8 g, 8.44 mmol) and Pd(dppf)Cl (0.3 g, 0.42 mmol). The mixture was stirred at 100 °C under N for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 23-3.

[0222] Step 3: To a solution of 23-2 (500 mg, 1.39 mmol) and 23-3 (395.4 mg, 1.39 mmol) in dioxane (20 mL) and water (5 mL) was added Pd(dppf)Cl (113.6 mg, 0.14 mmol) and NaCO (295 mg, 2.78 mmol). The mixture was stirred at 90 °C under N atmosphere for 16 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 23-4.

[0223] Step 4: To a solution of 23-4 (310 mg, 0.84 mmol) in methanol (10 mL) was added 10% Pd / C (179.5 mg). The mixture was degassed with H several times. Then, the mixture was stirred at 25 °C under H atmosphere (1 atmosphere) for 16 h. The mixture was filtered, and the filtrate was concentrated to give 23-5, which was used directly in the next step without further purification.

[0224] Step 5: To a solution of 23-5 (240 mg, crude) in dichloromethane (4 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give 23-6, which was used directly in the next step without further purification.

[0225] Step 6: Compound 23-7 was prepared from compound 23-6 according to the synthesis process of compound 5 in Example 5.

[0226] Step 7: Preparative SFC (chromatography column: DAICELCHIR A Purification of 23-7 (120 mg, 0.26 mmol) with LCEL® AS, methanol (+0.1% 7.0 mol / L aminomethanol solution) / supercritical CO2 = 40 / 60 gave 23 (25.05 mg), 24 (3.11 mg), and 25 (9.99 mg). 23: SFC analysis: Retention time: 1.795 min; Chromatography column: DAICELCHIR A LPAK® AS, methanol (0.1% DEA) in CO2, 40%; Pressure: 1800 psi; Flow rate: 1.5 mL / min; LCMS (ESI, m / z): [M+H] + = 454.4 , 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.13-8.06 (m, 1H), 8.06-7.98 (m, 1H), 7.76-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.39-7.33 (m, 2H), 7.33-7.25 (m, 2H), 6.12-5.00 (m, 2H), 3.72-3.35 (m, 4H), 3.00-2.48 (m, 1H), 2.35-1.69 (m, 9H), 1.16-0.94 (m, 3H). SFC analysis: 99.76% de; retention time: 2.300 min; chromatography column: DAICELCHIR A LPAK® AS, methanol (0.1% DEA) in CO2, 40%; pressure: 1800 psi; flow rate: 1.5 mL / min; LCMS (ESI, m / z): [M+H] + = 454.4 , 1H NMR (400 MHz, メタノール-d4, ppm): δ 8.16-8.05 (m, 1H), 8.05-7.96 (m, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.39-7.33 (m, 2H), 7.33-7.25 (m, 2H), 6.05-5.03 (m, 2H), 3.58 (s, 3H), 3.36 (s, 1H), 2.28-2.10 (m, 6H), 2.11-1.99 (m, 1H), 1.95-1.86 (m, 1H), 1.85-1.72 (m, 1H), 1.36-1.27 (m, 1H), 1.11-0.97 (m, 3H). 25: SFC analysis: 100% de; holding time: 2.422 min;クロマトグラフィーカラム:DAICELCHIR A LPAK (registered trademark) AS, metal in CO2 (0.1% DEA), 40%; Pressure: 1800 psi; Flow rate: 1.5 mL / min; LCMS (ESI, m / z): [M+H] + = 454.4, 1 H NMR (400 MHz, メタノール-d4, ppm): δ 8.19-8.06(m,1H),8.05-7.96(m,1H),7.75-7.70(m,1H),7.67(s,1H),7.40- 7.34(m,2H),7.34-7.27(m,2H),5.17(s,2H),3.61-3.55(m,3H),3.55-3.44( m,1H),3.00-2.81(m,1H),2.65-2.51(m,1H),2.36-2.22(m,1H),2.22-2.16( m,3H),2.14-1.98(m,1H),2.01-1.85(m,2H),1.78(s,1H),1.13-0.97(m,3H). TIFF2025510945000275.tif89166

[0227] Step 1: To a mixture of 26-1 (10 g, 46.29 mmol) and potassium trifluoro(ethylalkenyl)boronate (7.44 g, 55.55 mmol) in THF (160 mL) and water (40 mL) under N was added 1,1'-di(di-tert-butylphosphino)ferrocenedichloropalladium (3.0 g, 4.63 mmol) and KPO (24.6 g, 115.73 mmol). The mixture was then stirred at room temperature for 16 h. Water was added to quench the mixture. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 26-2.

[0228] Step 2: To a mixture of 26-2 methyl ester (7.8 g, 47.8 mmol) in AcOH (100 mL) was added PtO (2.2 g, 9.56 mmol). The mixture was degassed with H several times, and then the mixture was stirred at 80 °C under H atmosphere (1 atmosphere) for 16 h. The mixture was filtered, and the filtrate was concentrated to give 26-3, which was used directly in the next step without further purification.

[0229] Step 3: To a mixture of 26-3 (8 g, 46.72 mmol) in THF (80 mL) and water (80 mL), NaHCO (39.2 g, 467.18 mmol) and (BoC)O (21.47 mL, 93.44 mmol) were added. The mixture was then stirred at room temperature for 3 h. Water was added to quench the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous NaSO, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 26-4.

[0230] Step 4: To a mixture of 26-4 (9.6 g, 35.38 mmol) in THF (60 mL) and water (60 mL), LiOH (7.4 g, 176.89 mmol) was added. The mixture was then stirred at room temperature for 16 h. The pH of the mixture was adjusted to 4 with 1 N HCl, and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous NaSO, and concentrated to give 26-5, which was used directly in the next step without further purification.

[0231] Step 5: A mixture of 26-5 (4.55 g, crude) and PPA (100 mL) was stirred at 180 °C for 2 h. After cooling to 90 °C, the reaction was quenched with water. The filtrate pH was adjusted to about 12 with 50% aqueous potassium hydroxide solution and extracted with dichloromethane. The organic layer was dried over NaSO, filtered, and concentrated to give 26-6, which was used directly in the next step without further purification.

[0232] Step 6: Compound 26-7 was prepared from compound 26-6 according to the synthesis process of compound 5 in Example 5.

[0233] Step 7: 26-7 (150 mg, 0.35 mmol) was isolated by reverse-phase HPLC (acetonitrile / water, 5-95%) to give 26 (24.47 mg) and 27 (54.71 mg). 26: Analytical HPLC: Retention time: 1.85 min; Chromatography column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: water (0.05% TFA); Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 429.4; 1H NMR(400 MHz,DMSO-d6,ppm):δ 8.27-8.23(m,1H),8.01(d,J = 9.2 Hz,1H),7.54(d,J = 8.4 Hz,1H),7.47(s,1H),7.18-7.15(m,1H),5.77-5.44(m,1H),5.34-4.80(m,1H),3.68-3.61(m,2H),3.45 (s,3H),2.40(s,3H),2.29-2.16(m,2H),2.05-1.78(m,4H),1.00-0.89(m,3H).27: Analytical HPLC: Retention time: 1.85 min; Chromatography column: Waters ACQUITY BEH C18 2.1*50mm, 1.7µm; Mobile phase A: Water (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 429.4; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.26(d,J = 8.8 Hz,1H),8.00(d,J = 9.2 Hz,1H),7.57(d,J = 8.4 Hz,1H),7.47(s,1H),7.18-7.15(m,1H),5.37-4.81(m,2H),3.49-3.46(m,2H),3.45(s,3H),2.42(s, 3H),2.37-2.25(m,3H),2.24-2.15(m,1H),1.79-1.64(m,1H),1.53-1.45(m,1H),0.92-0.81(m,3H). TIFF2025510945000276.tif170166

[0234] Step 1: To a solution of 28-1 (4.5 g, 19.38 mmol) in THF (30 mL) at −30 °C, CHMgBr (29.07 mL, 29.07 mmol, 1 M THF solution) was added. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was isolated, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 28-2.

[0235] Step 2: To a solution of 28-2 (1 g, 3.81 mmol) in dichloromethane (10 mL) at 0 °C, DMF (0.029 mL, 0.38 mmol) and SOCl (0.42 mL, 5.72 mmol) were added. The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether) to give 28-3.

[0236] Step 3: To a solution of 28-4 (100 g, 651 mmol) in dry CHCl (1.5 mmol) was added benzaldehyde (67.5 mL, 664 mmol), KCO (90.0 g, 651 mmol), and NaSO (92.5 g, 651 mmol) with stirring. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled in an ice-water bath, and NaBH(OAc) (207.0 g, 976 mmol) was added in portions within 30 min. The mixture was then stirred at room temperature for 16 h. The solids were filtered, and the filtrate was concentrated. The residue was washed with 1 N HCl and extracted with ethyl acetate. The aqueous layer was adjusted to pH 8.0 with NaHCO. The mixture was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 28-5, which was used directly in the next step without purification.

[0237] Step 4: To a solution of (2R)-2-{[(tert-butyloxy)carbonyl]amino}butanoic acid (124 g, crude) in DMF (1 L) was added DIPEA (137 mL, 832 mmol) and HATU (253 g, 666 mmol). The reaction was stirred at 0 °C for 10 min, and then 28-5 (115 g, 555 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and evaporated to give 28-6, which was used directly in the next step without further purification.

[0238] Step 5: To a solution of 28-6 (300 g, crude) in dichloromethane (1 L), TFA (500 mL, 764 mmol) was added and the reaction was stirred at room temperature for 16 h. The solvent was removed to give 28-7, which was used directly in the next step without further purification.

[0239] Step 6: 28-7 (500 g, crude) was dissolved in methanol (1.5 L), and then the reaction mixture was heated at 70° C. for 16 h. The solvent was removed, and the residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO. The combined organic layers were dried with anhydrous NaSO, filtered, and concentrated. The residue was dissolved in prop-2-ol (500 mL) and heated at 70° C. for 1 h. The mixture was filtered, the solution was cooled to −10° C., and the solid was filtered and dried to give 28-8.

[0240] Step 7: To a solution of 28-8 (20 g, 76.82 mmol) in dry THF (500 mL) was slowly added BH3.THF (1 M, 768 mL, 768 mmol) with stirring at 0 °C. The reaction mixture was heated at 70 °C for 16 h. The reaction was quenched with methanol and 1.5 N HCl. The solvent was removed, and the residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 28-9, which was used directly in the next step without further purification.

[0241] Step 8: To a solution of 28-9 (23 g, crude) in THF (100 mL) and water (100 mL) was added NaHCO (16.6 g, 198 mmol) and (BoC)O (34.1 mL, 148.5 mmol) with stirring. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 28-10.

[0242] Step 9: To a solution of 28-10 (20 g, 60.15 mmol) in ethanol (200 mL) was added Pd / C (10%, 10 g) with stirring. The reaction mixture was stirred at room temperature under a H atmosphere for 18 hours. The reaction mixture was filtered, and the solvent was removed. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 28-11.

[0243] Step 10: To a solution of 5-7 (1.63 g, crude) and DIPEA (7 mL, 42.5 mmol) in acetonitrile (40 mL) was added 28-11 (1.37 g, 5.66 mmol) at room temperature, and the mixture was stirred at 80° C. for 1 h. The mixture was then concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 28-12.

[0244] Step 11: To a solution of 28-12 (800 mg, 1.84 mmol) in NMP (8 mL) at room temperature, dppf (207.2 mg, 0.37 mmol), zinc (120.0 mg, 1.84 mmol), Zn(CN) (431.0 mg, 3.67 mmol), and Pd(dba) (168.0 mg, 0.18 mmol) were added. The mixture was then heated at 90 °C for 12 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 28-13.

[0245] Step 12: To a solution of 28-13 (570 mg, 1.34 mmol) in dichloromethane (5 mL) at room temperature, TFA (2 mL, 1.34 mmol) was added. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated to give 28-14, which was used directly in the next step without further purification.

[0246] Step 13: A mixture of 28-14 (220 mg, 0.67 mmol), 28-3 (283.8 mg, 1.01 mmol), DIPEA (1.11 mL, 6.74 mmol), and NaI (151.5 mg, 1.01 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 24 h. The solvent was removed, and the residue was purified by reverse-phase HPLC (0.05% TFA in acetonitrile: 10% to 70%) to give 28-15.

[0247] Step 14: SFC (170 mg) (chromatography column: DAICELCHIR A Purification of 28-15 with LPAK® IG, methanol (+0.1% 7.0 mol / L aminomethanol solution) / supercritical CO2 = 40 / 60 gave 28 (28 mg) and 29 (18 mg), respectively. 28: SFC analysis: 96.44% de; retention time: 4.29 min; chromatography column: DAICELCHIR A LPAK® IB, methanol (0.1% DEA) in CO2, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + = 571.5. 1 H NMR(400 MHz,DMSO-d6,ppm)δ 8.23(d,J = 8.32 Hz,1H),7.98(d,J = 8.86 Hz,1H),7.89(d,J = 8.52 Hz,2H),7.56(d,J = 6.04 Hz,2H),5.85-5.47(m,1H),4.97-4.85(m,1H),3.71-3.62(m,1H),3.66(s,3H),3.09(d,J = 12.24 Hz,1H),2.93-2.76(m,2H),2.44-2.24(m,1H),2.22-2.06(m,1H),2.05-1.80(m, 3H),1.62-1.54(m,1H),1.53-1.39(m,1H),0.97-0.91(m,3H),0.70-0.52(m,6H); 19F NMR (376 MHz, DMSO-d, ppm): δ 87.99 (1F), 64.42 (4F) 29: SFC analysis: 97.86% de; retention time: 4.44 min; chromatography column: DAICELCHIR A LPAK® IB, methanol (0.1% DEA) in CO2, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + = 571.5. 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.27-8.19(m,1H),8.01-7.95(m,1H),7.87(d,J = 7.88 Hz,2H),7.58(d,J = 8.28 Hz,2H),6.05-5.28(m,1H),5.09-4.75(m,1H),3.64-3.50(m,2H),3.43(s,3H),3.18-3.07(m,1H) ,2.21-2.12(m,1H),2.04-1.95(m,1H),1.83-1.39(m,6H),1.00-0.91(m,3H),0.65-0.54(m,6H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ 88.00(1F),64.37(4F). TIFF2025510945000277.tif74166

[0248] Step 1: To a solution of 30-1 (5 g, 26.3 mmol) and NaOH (1.6 g, 39.5 mmol) in EtOH (30 mL) and water (15 mL) at 25 °C, hydroxylamine hydrochloride (2.2 g, 31.6 mmol) was added. The mixture was stirred at 25 °C for 16 h. Ice was added to the reaction mixture, the solid was filtered, the filter cake was washed with water, and dried to give 30-2.

[0249] Step 2: A solution of 30-2 (1.6 g, 7.8 mmol) and NCS (1.1 g, 8.6 mmol) in DMF (15 mL) was stirred at 25 °C for 16 h. The mixture was concentrated, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over NaSO, filtered, and concentrated to give 30-3.

[0250] Step 3: To a solution of 30-3 (800 mg, 3.3 mmol) and tert-butyl 3-ethylalkenylpyrrolidine-1-carboxylate (795.5 mg, 4.3 mmol) in THF (20 mL) was added triethylamine (0.93 mL, 6.7 mmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 30-4.

[0251] Step 4: To a solution of 30-4 (300 mg, 0.78 mmol) in dichloromethane (5 mL) was added HCl (4 M in ethyl acetate, 2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to give 30-5.

[0252] Step 5: Compound 30 was prepared from compound 30-5 according to the synthesis of compound 5 in Example 5. LCMS (ESI, m / z): [M+H] + = 471.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.33-8.20(m,1H),8.06-7.94(m,1H),7.88-7.76(m,2H),7.55-7.43(m,2H),4.69-4.49(m,1H),4.44- 4.19(m,1H),4.12-3.93(m,1H),3.90-3.68(m,2H),3.64-3.52(m,1H),3.46(s,3H),2.45-2.15(m,2H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-56.74(3F). TIFF2025510945000278.tif111166

[0253] Step 1: To a solution of 32-1 (15 g, 99.25 mmol) in acetonitrile (100 mL) was added CH3NH2 (200 mL, 3.56 mmol, 40% aqueous solution). The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give 32-2.

[0254] Step 2: To a solution of 32-2 (8.2 g, 50.56 mmol) in acetonitrile (150 mL) was added NCS (7.4 g, 55.61 mmol), and the reaction mixture was stirred at 60 °C for 70 min. Water was added to quench the mixture. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 32-3.

[0255] Step 3: To a solution of 32-3 (5.0 g, 25.43 mmol) in DMSO (60 mL) was added K2CO3 (5.3 g, 38.14 mmol) and H2O2 (17.3 g, 30%, 152.6 mmol). The reaction mixture was then stirred at 25 °C for 16 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to give 32-4.

[0256] Step 4: To a solution of 32-4 (5 g, 23.29 mmol) in DMF (70 mL) at 0 °C was added NaH (1.9 g, 46.59 mmol) in several portions with stirring. After stirring at 0 °C for 0.5 h, CDI (5.7 g, 34.94 mmol) was added to the mixture, and then the mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water. The organic layer was dried over Na SO , filtered, and the filtrate was concentrated to give 32-5.

[0257] Step 5: To a solution of 32-5 (1 g, 4.16 mmol) in toluene (10 mL), DIPEA (1.2 g, 9.14 mmol) and POCl (3.2 g, 20.78 mmol) were added. The mixture was stirred at 90 °C for 3 h. The reaction mixture was concentrated to give 32-6.

[0258] Step 6: A mixture of 32-6 (1.0 g, 3.86 mmol), 3-2 (1.00 g, 4.63 mmol), and DIPEA (7.5 g, 57.9 mmol) in prop-2-ol (15 mL) was stirred at 90 °C for 5 h. The mixture was cooled to room temperature. The precipitate was collected by filtration to give 32-7.

[0259] Step 7: To a solution of 32-7 (1.0 g, 2.28 mmol) in dichloromethane (10 mL) was added BBr (5.7 g, 22.8 mmol) dropwise at −78° C. N. After the addition was complete, the mixture was stirred at room temperature for 16 h. Ice water was added to the reaction mixture, which was then filtered. The precipitate was collected, washed with water, and dried to give 32-8.

[0260] Step 8: To a mixture of 32-8 (300 mg, 0.71 mmol) in DMF (10 mL), CsCO (690 mg, 2.12 mmol) and 3-bromooxolane (213.2 mg, 1.41 mmol) were added. The mixture was then stirred at 85 °C for 1 h. The solvent was removed in vacuo. The residue was purified by reverse-phase HPLC (acetonitrile / water: 5% to 42%) to give 32-9.

[0261] Step 9: SFC (chromatography column: DAICELCHIR A Purification of 32-9 (100 mg) with LPAK® IC and ethanol (+0.1% 7.0 mol / L aminomethanol solution) gave 32 (14.80 mg) and 33 (15.23 mg), respectively. 32: SFC analysis: 100% ee; retention time: 9.164 min; chromatography column: DAICELCHIR ALPAK® IC, ethanol in CO (+0.1% 7.0 mol / L aminomethanol solution), 40% to 60%; pressure: 100 bar; flow rate: 1.0 mL / min; LCMS (ESI, m / z): [M+H] + = 495.4; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 7.79(s,1H),7.56(d,J = 8.0 Hz,1H),7.50(s,1H),7.20-7.16(d,J = 8.0 Hz,1H),6.91(s,1H),5.44-5.42(m,1H),4.22-4.15(m,2H),4.05-3.95(m,1H),3.95-3.78(m,3H),3.51-3.49(m,3H),3.4 9-3.38(m,2H),2.41(s,3H),2.39-2.30(m,2H),2.22-2.18(m,2H),2.09-1.94(m,3H).33: SFC analysis: 98.89%ee; Retention time: 10.858 min; Chromatography column: DAICELCHIR A LPAK® IC, ethanol in CO (+0.1% 7.0 mol / L aminomethanol solution), 40% to 60%; pressure: 100 bar; flow rate: 1.0 mL / min; LCMS (ESI, m / z): [M+H] + = 495.4; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 7.79(s,1H),7.56(d,J = 8.0 Hz,1H),7.50(s,1H),7.20-7.16(d,J = 8.0 Hz,1H),6.91(s,1H),5.44-5.41(m,1H),4.23-4.15(m,2H),4.01-3.95(m,1H),3.91-3.86(m,2H),3.83-3.78(m, 1H),3.51-3.49(m,3H),3.41-3.95(m,2H),2.41(s,3H),2.39-2.30(m,2H),2.22-2.18(m,2H),2.07-1.96(m,3H). TIFF2025510945000279.tif146166

[0262] Step 1: Compound 34-2 was prepared from compound 34-1 according to the synthesis process of compound 28-3 in Example 11.

[0263] Step 2: A mixture of 34-2 (3.2 g, 14.3 mmol), 28-9 (4.0 g, 17.2 mmol), KCO (5.9 g, 43.0 mmol), NaI (0.2 g, 1.4 mmol), and TBAI (0.5 g, 1.4 mmol) in acetonitrile (80 mL) was stirred at 90 °C for 66 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 34-3.

[0264] Step 3: To a solution of 34-3 (450 mg, 1.1 mmol) in isopropanol (10 mL) was added Pd / C (10%, 45 mg) while stirring at 25 °C. The mixture was degassed with H several times, and then the mixture was stirred at 25 °C with H for 21 h. The reaction mixture was filtered, and the filtrate was concentrated to give 34-4.

[0265] Step 4: To a mixture of 5-2 (1.0 g, 6.54 mmol) and K2CO3 (2.7 g, 19.54 mmol) in DMSO (10 mL) at 0 °C, H2O2 (2.2 g, 19.54 mmol) was slowly added. The mixture was then stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 34-5.

[0266] Step 5: To a solution of 34-5 (5.0 g, 29.2 mmol) in NMP (100 mL) under N was added Zn (0.4 g, 5.84 mmol), Zn(CN) (6.9 g, 58.4 mmol), dppf (1.0 g, 1.75 mmol), and Pd(dba) (2.7 g, 2.92 mmol). The reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 34-6.

[0267] Step 6: To a solution of 34-6 (0.5 g, 3.08 mmol) in dioxane (20 mL) under N was added triphosgene (457.5 mg, 1.54 mmol). The reaction mixture was stirred at 100 °C for 3 h. The resulting mixture was cooled to room temperature, filtered, and dried to give 34-7.

[0268] Step 7: To a solution of 34-7 (255 mg, 1.36 mmol) in toluene (10 mL) was added POCl (1.26 mL, 13.6 mmol) and DIPEA (0.67 mL, 4.06 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated to give 34-8, which was used directly in the next step without further purification.

[0269] Step 8: To a solution of 34-8 (300 mg, crude) in THF (10 mL) was added DIPEA (2.2 mL, 13.3 mmol) and 34-4 (437.8 mg, 1.33 mmol). The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 34-9.

[0270] Step 9: To a solution of 34-9 (240 mg, 0.46 mmol) in dioxane (15 mL), (tert-butyloxy)carbohydrazide (184 mg, 1.39 mmol), CsCO (453.8 mg, 1.39 mmol), tBubrettphos (22.5 mg, 0.046 mmol), and Pd(dba) (42.5 mg, 0.046 mmol) were added. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 34-10.

[0271] Step 10: To a solution of 34-10 (240 mg, 0.39 mmol) in dichloromethane (6 mL) was added TFA (3 mL). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give 34-11, which was used directly in the next step without further purification.

[0272] Step 11: A mixture of 34-11 (180 mg crude) and CH(OCH) (5 mL) was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give 34-12.

[0273] Step 12: 34-12 (90 mg) was purified by SFC (chromatography column: DAICELCHIR A Purification with LCEL® AD, EtOH (+0.1% 7.0 mol / L aminoethanol solution) / supercritical CO2 = 40 / 60 gave 34 (31.64 mg) and 35 (8.09 mg), respectively. 34: SFC analysis: 100% de; retention time: 4.35 min; chromatography column: DAICELCHIR A LPAK® AD, ethanol (0.1% DEA) in CO2, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] += 523.5. 1 H NMR (400 MHz, methanol-d4, ppm): δ 9.32(s,1H),8.77-8.75(m,1H),8.31-8.29(m,1H),7.69-7.67(m,2H),7.67- 7.55(m,2H),5.96-5.53(m,1H),3.68-3.65(m,1H),3.48-3.39(m,2H),3.12- 3.05(m,1H),2.96-2.92(m,1H),2.46(s,1H),2.23(s,1H),2.06-2.00(m,2H) ,1.73-1.65(m,1H),1.58-1.53(m,2H),1.09-1.06(m,3H),0.78-0.69(m,6H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -63.83 (3F).35: SFC analysis: 97.18% de; retention time: 4.94 min; chromatography column: DAICELCHIR A LPAK® AD, ethanol (0.1% DEA) in CO2, 5% to 40%; pressure: 1800 psi; flow rate: 1.5 mL / min. LCMS (ESI, m / z): [M+H] + = 523.5. 1 H NMR (400 MHz, methanol-d4, ppm): δ 9.32(s,1H),8.77-8.75(m,1H),8.30-8.28(m,1H),7.65-7.63(m,2H),7.60-7.58(m,2H),5.32(s,1H),3.66-3.47(m,3H),2.70- 2.66(m,1H),2.37-2.33(m,1H),2.20-2.16(m,1H),2.07-1.90(m,3H),1.70-1.56(m,3H),1.13-1.03(m,3H),0.71-0.65(m,6H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -63.82 (3F). TIFF2025510945000280.tif76166

[0274] Step 1: A mixture of LiAlH (0.30 g, 8.2 mmol) in THF (20 mL) was stirred at 0 °C under N for 0.5 h. Then, 36-1 (1 g, 4.1 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with THF, quenched with saturated NaSO (1.5 mL), and filtered. The filtrate was concentrated to give 36-2, which was used directly in the next step without further purification.

[0275] Step 2: A solution of 36-2 (700 mg, crude), 4-(trifluoromethoxy)benzoic acid (626.5 mg, 3.04 mmol), HATU (1733.5 mg, 4.56 mmol), and DIPEA (0.75 mL, 4.56 mmol) in DMF (12 mL) was stirred at 25 °C for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 36-3.

[0276] Step 3: To a solution of 36-3 (580 mg, 1.39 mmol) in dichloromethane (8 mL) was added DAST (0.28 mL, 2.08 mmol) at 0 °C. The mixture was then stirred at 20 °C for 1 h. The mixture was quenched with aqueous NaHCO and extracted with dichloromethane. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 36-4.

[0277] Step 4: To a solution of 36-4 (588 mg, 1.47 mmol) in dichloromethane (6 mL) was added a solution of HCl in ethyl acetate (4 M, 2.5 mL) at 20° C. The mixture was stirred at 20° C. for 1.5 hours. The mixture was concentrated under reduced pressure to give 36-5.

[0278] Step 5: A solution of 5-7 (250 mg, 0.87 mmol), 36-5 (208.9 mg, 0.67 mmol), and DIPEA (1.50 mL, 9.1 mmol) in acetonitrile (10 mL) was stirred at 85° C. under N2 for 3 h. The mixture was concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / water: 5%-80%) to give 37. LCMS (ESI, m / z): [M+H] + = 494.2. 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.28-8.23(m,1H),8.09-7.92(m,3H),7.55-7.42(m,2H),4.75-3.90(m,6H),3.46(s,3H),1.98-1.78(m,4H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-56.68(3F).

[0279] Step 6: A solution of 37 (100 mg, 0.20 mmol), dppf (22.5 mg, 0.040 mmol), Zn (13.2 mg, 0.20 mmol), Zn(CN) (47.6 mg, 0.41 mmol), and Pd(dba) (18.5 mg, 0.02 mmol) in NMP (8 mL) was stirred at 90 °C under N for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / water: 5%-80%) to give 36. LCMS (ESI, m / z): [M+H] + = 485.2. 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.13-7.89(m,3H),7.85-7.78(m,1H),7.54-7.43(m,2H),4.80-3.90(m,6H),3.45(s,3H),1.94-1.75(m,4H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-56.68(3F). TIFF2025510945000281.tif55166

[0280] Step 1: To a solution of 39-1 (1 g, 4.71 mmol) in NMP (10 mL) was added ZnBr (10.6 g, 47.15 mmol), Pd(dppf)Cl (0.3 g, 0.47 mmol), DIPEA (15.59 mL, 94.3 mmol), and vinylcyclopropane (3.12 g, 47.15 mmol) while stirring under N. The reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give 39-2.

[0281] Step 2: To a solution of 5-7 (583 mg, 2.53 mmol) in acetonitrile (5 mL), 39-2 (500 mg, 2.53 mmol) and DIPEA (983 mg, 7.6 mmol) were added. The reaction was stirred at room temperature under N2 for 3 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (acetonitrile / water, 5% to 50%) to give 39. LCMS (ESI, m / z): [M+H] + = 391.2; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 7.98(d,J = 8.0 Hz,1H),7.75(d,J = 8.0 Hz,1H),7.14-7.10(m,1H),6.97-6.90(m,2H),4.06-4.02(m,2H),3.50(s,3H),2.84-2.80(m,2H),1.99-1.93(m,2H),1.63-1.56(m,1H), 0.96-0.94(m,2H),0.93-0.91(m,2H).

[0282] Step 3: To a solution of 39 (140 mg, 0.36 mmol) in DMF (1.5 mL) was added Zn(CN) (420 mg, 3.58 mmol) and Pd(PPh) (206.8 mg, 0.18 mmol). The reaction mixture was then stirred at 110 °C under N for 1 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (acetonitrile / water: 5% to 50%) to give 42. LCMS (ESI, m / z): [M+H] + = 382.2; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.19(d,J = 8.0 Hz,1H),8.05(d,J = 8.0 Hz,1H),7.17-7.13(m,1H),6.96-6.94(m,2H),4.08-4.03(m,2H),3.50(s,3H),2.85-2. 82(m,2H),2.01-1.95(m,2H),1.62-1.58(m,1H),0.95-0.93(m,2H),0.92-0.91(m,2H). TIFF2025510945000282.tif65166

[0283] Step 1: To a solution of N1,N1,N2,N2-tetramethylethane-1,2-diamine (5.8 g, 56.28 mmol) in THF (80 mL) at -40°C, n-BuLi (40 mL, 64 mmol, 1.6 mol / L THF solution) was added dropwise. The reaction was stirred at -40°C for 40 min. 44-1 (7 g, 40.2 mmol) was then added to the mixture within 5 min. The mixture was stirred at -40°C for 30 min. A second portion of n-BuLi (25.328 mL, 40.525 mmol, 1.6 mol / L THF solution) was added dropwise within 5 min, and the reaction mixture was then stirred at -40°C for 2 h. The cooling bath was removed, CuBr (7.5 g, 52.26 mmol) was added to the mixture, and the reaction mixture was stirred at 25°C for an additional 1 h. The reaction was cooled to -30 °C, and a solution of 3-bromoprop-1-ene (9.73 g, 80.4 mmol) in THF (10 mL) was added dropwise within 5 minutes. The reaction mixture was then stirred at -40 °C for 2 hours. The reaction was quenched by adding methanol. The pH of the mixture was adjusted to 6 with HCl (6 M). The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 44-2.

[0284] Step 2: To a solution of 44-2 (5 g, 23.34 mmol) in THF (50 mL) was added allylmagnesium bromide (25.68 mL, 25.68 mmol), and the reaction was stirred at -40 °C for 1 h. The reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 44-3.

[0285] Step 3: To a solution of 44-3 (2.0 g, 7.8 mmol) in dichloromethane (160 mL) was added Grubbs second-generation catalyst (331 mg, 0.39 mmol). The reaction was stirred at 20 °C under N for 18 h. The reaction mixture was diluted with water. The organic layer was isolated, washed with brine, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 44-4.

[0286] Step 4: To a solution of 44-4 (1.36 g, 5.96 mmol) in EtOH (25 mL) was added 10% Pd / C (0.1 g). The suspension was degassed in vacuo and purged with H 3 times, after which the mixture was stirred at 25 °C in H for 1 h. The suspension was filtered, and the filter cake was washed with EtOH (20 mL). The combined filtrate was concentrated to give 44-5.

[0287] Step 5: To a solution of 44-5 (1 g, 4.34 mmol) in dichloromethane (25 mL) was added SOCl (0.47 mL, 6.51 mmol), and the reaction was stirred at 0 °C for 1.5 h. The reaction was quenched with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 44-6.

[0288] Step 6: To a solution of 28-14 (250 mg, 0.77 mmol) in acetonitrile (10 mL), DIPEA (0.25 mL, 1.53 mmol), NaI (344 mg, 2.3 mmol), and 44-6 (380 mg, 1.53 mmol) were added. The reaction mixture was stirred at 80 °C for 24 h. Then, another portion of 44-6 (190 mg, 0.76 mmol) was added to the reaction mixture, and the reaction was stirred at 80 °C for another 24 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 44-7.

[0289] Step 7: Purification of 44-7 (150 mg, 0.28 mmol) by reverse-phase HPLC (acetonitrile / 0.1% TFA in water: 75%) gave 44 (10.43 mg) and 45 (4.01 mg). 44: Analytical HPLC: Retention time: 1.85 min; Chromatography column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: water (0.05% TFA); Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 539.4; 1 H NMR(400 MHz, CDCl3):δ 7.89-7.77(m,1H),7.63-7.54(m,1H),7.40-7.30(m,2H),7.25-7.20(m,1H),6.16-5.54(m, 1H),5.34-5.09(m,1H),3.75-3.67(m,1H),3.64-3.34(m,5H),3.12-2.97(m,1H),2.74-2.6 3(m,1H),2.63-2.52(m,1H),2.18-2.11(m,1H),2.06-1.90(m,4H),1.87-1.75(m,2H),1.73 -1.63(m,1H),1.49-1.36(m,2H),1.31-1.25(m,1H),1.09-0.90(m,3H),0.74-0.60(m,3H). 19 F NMR (376 MHz, CDCl3, ppm): δ -62.33 (3F).45: Analytical HPLC: Retention time: 1.85 min; Chromatography column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: Water (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 539.4; 1H NMR(400 MHz, CDCl3):δ 7.89-7.77(m,1H),7.64-7.54(m,1H),7.46-7.29(m,2H),7.24-7.16(m,1H),6.03-4.80(m,2H),3.77-3.07(m,6H),2.95-2.80(m,1H), 2.78-2.53(m,2H),2.30-2.10(m,4H),2.08-1.90(m,2H),1.74-1.67(m,2H),1.41-1.29(m,3H),1.05-0.96(m,3H),0.69-0.37(m,3H). 19 F NMR(376 MHz,CDCl3,ppm):δ-62.34(3F). TIFF2025510945000283.tif63160

[0290] Step 1: To a solution of methyltriphenylphosphonium bromide (4.4 g, 12.19 mmol) in THF (25 mL) was added potassium tert-butoxide (12.19 mL, 12.19 mmol) at 20 °C. The mixture was stirred at 55 °C under N for 2 h. Then, 50-1 (1.3 g, 6.09 mmol) was added, and the mixture was stirred at 55 °C for 16 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 50-2.

[0291] Step 2: Compound 50 was prepared from 50-2 according to the synthesis of compound 30 in Example 12. LCMS (ESI, m / z): [M+H] + = 499.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.30-8.23(m,1H),8.06-7.98(m,1H),7.88-7.72(m,2H),7.53-7.42(m,2H),5.60-5.35(m,1H),5.25-4.80(m,1H),3.70- 3.60(m,1H),3.46(s,3H),3.42-3.35(m,1H),3.34-3.30(m,1H),2.24-2.10(m,1H),2.07-1.79(m,3H),1.56-1.36(m,3H). 19F NMR(376 MHz,DMSO-d6,ppm):δ-56.75(3F). TIFF2025510945000284.tif73166

[0292] Step 1: To a solution of 57-1 (45 g, 276 mmol) in EtOH (450 mL) was added thiourea (22.06 g, 290 mmol) while stirring at room temperature. The resulting mixture was stirred at 80 °C under N for 15 h. The solvent was removed under reduced pressure. The residue was diluted with water and neutralized with NaHCO to a pH of 8-9, after which dichloromethane was added to the mixture. The mixture was extracted with dichloromethane. The combined organic layer was washed with saturated NaHCO and brine, dried over anhydrous NaSO, and concentrated to give 57-2.

[0293] Step 2: To a solution of 57-2 (6 g, 19.9 mmol) and CuBr (4.3 g, 29.9 mmol) in acetonitrile (80 mL) was added t-BuONO (3.59 mL, 29.9 mmol) with stirring at 0-5 °C. The resulting mixture was stirred at room temperature for 30 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 57-3.

[0294] Step 3: Below -60 °C, n-BuLi (2.55 mL, 6.37 mmol) was added to a solution of 57-3 (1.0 g, 4.9 mmol) in THF (20 mL) while stirring under N. The resulting mixture was stirred at the same temperature for 1 h. Below -60 °C, a solution of 4-((trifluoromethyl)thio)benzaldehyde (1313.4 mg, 6.37 mmol) in THF (20 mL) was added to the above reaction mixture. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated NHCl and diluted with water. The mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 57-4.

[0295] Step 4: To a stirred solution of 57-4 (450 mg, 1.36 mmol) in dichloromethane (6 mL) at 25 °C was added SOCl (0.15 mL, 2.04 mmol). The resulting mixture was stirred at 25 °C for 15 h. The reaction mixture was concentrated to give 57-5, which was used directly in the next step without purification.

[0296] Step 5: To a solution of 57-5 (1.15 g, 2.63 mmol) and 28-14 (0.86 g, 2.63 mmol) in acetonitrile (10 mL) was added DIPEA (1.83 mL, 10.52 mmol) with stirring at 25 °C. The resulting mixture was stirred at 90 °C for 15 h. The reaction mixture was concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / 0.05% TFA in water, 0-60%) to give 57 (11.65 mg) and 58 (6.24 mg). 57: Analytical HPLC: Retention time: 1.85 min; Chromatography column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 μm; Mobile phase A: Water (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 640.2; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.09-8.03(m,1H),8.02-7.95(m,1H),7.75-7.66(m,4H),7.06(s,1H),6.19-5 .51(m,1H),5.22-5.12(m,1H),3.68-3.33(m,1H),3.56(s,3H),2.93-2.82(m,1 H),2.76-2.64(m,2H),2.46-2.31(m,1H),2.12-1.97(m,3H),1.55-1.40(m,2H ),0.98-0.84(m,6H),0.80-0.73(m,2H),0.69-0.65(m,1H),0.58-0.54(m,1H). 19F NMR (376 MHz, methanol-d4, ppm): δ -44.64 (3F).58: Analytical HPLC: Retention time: 1.85 min; Chromatography column: Waters ACQUITY BEH C18 2.1*50 mm, 1.7 um; Mobile phase A: Water (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 640.2; 1 H NMR(400 MHz, CDCl3, ppm):δ 7.86-7.81(m,1H),7.65-7.57(m,5H),6.85(s,1H),6.07-5.62(m,1H),5.68-5.56(m,1H),3.73-3.41(m,1H),3.58(s,3H),2.76- 2.55(m,2H),2.52-2.42(m,1H),2.16-1.93(m,4H),1.50-1.39(m,2H),0.93-0.90(m,2H),0.86-0.81(m,6H),0.78-0.67(m,2H). 19 F NMR(376 MHz,CDCl3,ppm):δ-42.58(3F). TIFF2025510945000285.tif104166

[0297] Step 1: Compound 59-2 was prepared from compound 59-1 according to the synthesis process of compound 30-5 in Example 12.

[0298] Step 2: To a mixture of 59-3 (4.9 g, 25.4 mmol) and methyl 2-hydroxyacetate (2.74 g, 30.4 mmol) in DMF (50 mL) was added NaH (1.22 g, 60%, 30.5 mmol) at 0 °C. The mixture was then stirred at room temperature for 1 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 59-4.

[0299] Step 3: To a solution of 59-4 (4.9 g, 19.87 mmol) in EtOH (50 mL) and HOAc (20 mL) at room temperature, Fe (5.6 g, 100 mmol) was added. The mixture was then stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to give 59-5.

[0300] Step 4: To a solution of 59-5 (2.6 g, 14.09 mmol) in THF (20 mL) at room temperature, BH THF (1 M, 65 mL, 65 mmol) was added. The mixture was then stirred at 80 °C for 2 h. The mixture was quenched with methanol and stirred at 80 °C for 30 min. The mixture was then concentrated to give 59-6, which was used directly in the next step without further purification.

[0301] Step 5: To a solution of 59-6 (1.0 g, crude) and (BoC)O (4.04 mL, 17.59 mmol) in THF (15 mL) at room temperature, DMAP (1.43 g, 11.72 mmol) and triethylamine (0.82 mL, 5.86 mmol) were added. The mixture was then stirred at 80 °C for 12 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to give 59-7.

[0302] Step 6: To a solution of 59-7 (1.5 g, 5.54 mmol) in CHCl (20 mL) at room temperature was added mCPBA (2.25 g, 11.08 mmol). The mixture was then stirred at 80 °C for 12 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 59-8.

[0303] Step 7: To a solution of 59-8 (1.2 g, 4.19 mmol) in acetonitrile (20 mL) at room temperature, TMSCN (1.25 g, 12.56 mmol) and triethylamine (1.75 mL, 12.56 mmol) were added. The mixture was then stirred at 80 °C for 12 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 59-9.

[0304] Step 8: To a solution of 59-9 (620 mg, 2.1 mmol) and KCO (870 mg, 6.29 mmol) in DMSO (10 mL) was added HO (30%, 713.0 mg, 6.29 mmol) at 0 °C. The mixture was then stirred at room temperature for 1 h. The solid was collected by filtration and washed with dichloromethane. The solid was suspended in water, and then concentrated HCl was added until the pH reached 4-5. The solid was collected by filtration to give 59-10.

[0305] Step 9: Compound 59 was prepared from 59-10 according to the synthesis of compound 5 in Example 5. LCMS (ESI, m / z): [M+H] + = 513.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 7.89(s,1H),7.84-7.76(m,2H),7.53-7.44(m,2H),5.06-4.58(m,1H),4.55-4.4 6(m,2H),4.48-4.06(m,2H),4.05-3.68(m,3H),3.35(s,2H),2.06-1.82(m,4H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-56.75(3F). TIFF2025510945000286.tif83166

[0306] Step 1: To a suspension of 64-1 (950 mg, 3.62 mmol) in CCl (20 mL) was added NBS (709.4 mg, 3.99 mmol) and AIBN (89.2 mg, 0.54 mmol). The mixture was then stirred at 85 °C for 3 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 64-2.

[0307] Step 2: To a mixture of 64-2 (500 mg, 1.17 mmol) and 28-14 (421.05 mg, 1.29 mmol) in acetonitrile (15 mL), DIPEA (0.97 mL, 5.86 mmol) and NaI (351.6 mg, 2.35 mmol) were added. The mixture was then stirred at 85 °C for 3 h. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / 0.05% TFA in water: 0-60%) to give 64-3 and 64-4.

[0308] Step 3: To a mixture of 64-3 (75 mg, 0.13 mmol) and N-[azanylidene(cyclopropyl)methyl]hydroxylamine (14.08 mg, 0.14 mmol) in DMSO (2 mL) was added DIPEA (58.3 mg, 0.15 mmol) and HATU (58.3 mg, 0.15 mmol). The mixture was stirred at room temperature for 30 min, then heated to 90 °C and stirred for 30 min. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / 0.05% TFA in water: 0-70%) to give 64, which was a 3.3 equiv. TFA salt. LCMS (ESI, m / z): [M+H] + = 651.4; 1H NMR(400 MHz,DMSO-d6,ppm):δ 8.24(d,J = 8.8 Hz,1H),8.02-7.98(m,3H),7.88-7.81(m,2H),6.00-5.37(m,2H),4.98-4.91(m,1H),3.65-3.56(m,0.5 H),3.44(s,3H),3.30-3.18(m,1H),2.90-2.82(m,0.5 H),2.2-2.57(m,1H),2.40-2.21(m,2H),2.17-2.12(m,1H),2.04-1.78(m,2H),1.63-1.39(m,2H),1.11-1.04(m,2H),0.90-0.69(m,7H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ 87.41-86.60(1F),64.20-63.80(4F),-73.59(9.9F,TFA). TIFF2025510945000287.tif176166

[0309] Step 1: NBS (28.1 g, 158 mmol) was added in portions to a solution of 67-1 (25 g, 150.4 mmol) in acetonitrile (250 mL) with stirring at 25-40° C. The reaction mixture was stirred at 25-40° C. for 2 hours. The precipitate was filtered and the filter cake was washed with acetonitrile. The filter cake was collected and dried to give 67-2.

[0310] Step 2: To a solution of 67-2 (20 g, 81.6 mmol) in THF (100 mL) was added dropwise ethyl acetoacetate (24.14 mL, 257.06 mmol) with stirring at 25 °C. The reaction mixture was stirred at 75 °C for 19 h. The reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous NaSO, and concentrated to give 67-3.

[0311] Step 3: To a solution of 67-3 (20.9 g, 72.8 mmol) and CsCO (52.2 g, 160.15 mmol) in DMF (150 mL) was added CHCl (7.7 mL, 123.7 mmol) dropwise at 5-15 °C. The reaction mixture was stirred at 25 °C for 67 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 67-4.

[0312] Step 4: A solution of KHMDS in THF (1 M, 54.6 mL, 54.6 mmol) was added to 200 mL of THF at -10 °C N2, followed by the addition of a solution of 67-4 (13.7 g, 45.5 mmol) in 400 mL of THF at -60 °C to -50 °C N2. The reaction mixture was then stirred at 20 °C for 1.5 h. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with HCl (2 N) to a pH of 3-4. The precipitate was filtered, washed with water, and dried to give 67-5.

[0313] Step 5: To a solution of 67-5 (2 g, 7.84 mmol) in AcOH (20 mL) was added HNO (1.3 mL, 31.74 mmol) with stirring at 25 °C. The reaction mixture was stirred at 80 °C for 15 h. The reaction mixture was cooled to 25 °C and diluted with water. The mixture was stirred for 10 min, and the precipitate was filtered and dried to give 67-6.

[0314] Step 6: To a solution of 67-6 (1.4 g, 4.67 mmol) in toluene (28 mL) was added DIPEA (4.06 mL, 23.33 mmol) and POCl (2.17 mL, 23.33 mmol) with stirring at 25 °C. The reaction mixture was stirred at 110 °C under N for 3 h. The reaction mixture was concentrated to give 67-7, which was used directly in the next step without further purification.

[0315] Step 7: To a solution of 67-8 (34.9 g, 292.99 mmol) in methanol (250 mL) was added triethylamine (42.76 mL, 307.63 mmol) and benzaldehyde (31.27 mL, 307.63 mmol) while stirring at 5-10 °C. The reaction mixture was stirred at the same temperature for 3 h. Then, the reaction mixture was cooled to 0 °C, and NaBH (22.2 g, 585.964 mmol) was added in several portions to the reaction mixture. The reaction mixture was stirred at 0-20 °C for 2.5 h. The reaction mixture was quenched with HCl (3N) and extracted with ethyl acetate. The organic layer was washed with HCl (3N). The aqueous layers were combined and neutralized with NaHCO powder. The aqueous layer was concentrated. The residue was dissolved in dichloromethane / methanol (10:1) and filtered. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 67-9.

[0316] Step 8: To a solution of 67-9 (32.86 g, 157.04 mmol) and (2R)-2-{[(tert-butyloxy)carbonyl]amino}butanoic acid (31.92 g, 157.04 mmol) in DMF (350 mL) was added DIPEA (82.06 mL, 471.11 mmol) dropwise at 25 °C, and then HATU (89.6 g, 235.56 mmol) was added to the solution at 5-15 °C. The reaction mixture was stirred at 25 °C for 48 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 67-10.

[0317] Step 9: To a solution of 67-10 (28.9 g, 73.26 mmol) in methanol (280 mL) was added a solution of HCl in ethyl acetate (4 M, 50 mL) with stirring at 25-35 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to give 67-11.

[0318] Step 10: A solution of 67-11 (25.4 g, 69.14 mmol) in DIPEA (35 mL, 200.93 mmol) and methanol (300 mL) was stirred at 70 °C for 15 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give 67-12.

[0319] Step 11: To a solution of 67-12 (21 g, 80.06 mmol) in THF (100 mL) was added BH THF (1 M in THF, 22.9 mL, 22.9 mmol) while stirring under N at 0 °C. The reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was cooled to 0-10 °C and then quenched with methanol and HCl (2 N). The resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated. The residue was diluted with water (100 mL) and basified with NaHCO to pH = 8-9. The mixture was concentrated to dryness. The residue was dissolved in 10% methanol in dichloromethane, and the suspension was filtered. The filtrate was concentrated to give 67-13, which was used directly in the next step without further purification.

[0320] Step 12: To a solution of 67-13 (27.7 g, crude), DMAP (0.9 g, 7.09 mmol), and triethylamine (19.72 mL, 141.85 mmol) in dichloromethane (280 mL) was added (BoC)O (14.66 mL, 63.83 mmol) while stirring at 0-10 °C. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 67-14.

[0321] Step 13: To a solution of 67-14 (5 g, 14.95 mmol) in methanol (30 mL) was added a solution of HCl in ethyl acetate (4 M, 30 mL) with stirring at 25° C., and the reaction mixture was stirred for 15 h at 25° C. The reaction mixture was concentrated to give 67-15, which was used directly in the next step without further purification.

[0322] Step 14: A mixture of 67-15 (4.5 g, 14.61 mmol), 34-2 (8.13 g, 36.53 mmol), DIPEA (10.18 mL, 58.44 mmol), KCO (8.1 g, 58.44 mmol), and KI (4.9 g, 29.22 mmol) in CHCN (100 mL) was stirred at 90 °C for 48 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 67-16 and 67-17.

[0323] Step 15: To a solution of 67-16 (1.93 g, 4.59 mmol) in isopropanol (60 mL) was added Pd / C (5%, 450 mg) while stirring at 25 °C. The reaction mixture was degassed with H several times, and then the mixture was stirred at 60 °C for 15 h. The reaction mixture was filtered, and the filtrate was concentrated to give 67-18.

[0324] Step 16: A solution of 67-18 (1.6 g, 4.84 mmol), 67-7 (1.46 g, crude), and DIPEA (8.44 mL, 48.43 mmol) in CHCN (30 mL) was stirred at 90 °C for 15 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 67-19.

[0325] Step 17: To a solution of 67-19 (700 mg, 1.14 mmol), Zn(CN) (268.5 mg, 2.29 mmol), Zn (15.0 mg, 0.23 mmol), and DPPF (38.0 mg, 0.069 mmol) in NMP (7 mL) was added Pd(dba) (104.7 mg, 0.114 mmol) while stirring at 25 °C. The reaction mixture was degassed with N for a period of time and stirred at 90 °C for 15 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 67-20.

[0326] Step 18: To a solution of 67-20 (180 mg, 0.31 mmol) in DMF (1.8 mL) was added DBU (139.8 mg, 0.92 mmol) while stirring at 25 °C. The reaction mixture was stirred at 130 °C for 15 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) followed by reverse-phase HPLC (MeCN / 0.1% TFA aqueous solution: 0-60%) to give 67. Analytical HPLC: Retention time: 1.69 min; Chromatography column: Waters ACQUITY BEHC182.1*50 mm, 1.7 um; Mobile phase A: Water (0.05% TFA); Mobile phase B: Acetonitrile (0.05% TFA); Flow rate: 1.0 mL / min; Run time: 5 min; 95 to 5% A for 3 min, 5% A for 2 min. LCMS (ESI, m / z): [M+H] + = 512.2; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.06-7.99(m,1H),7.89-7.85(m,1H),7.68-7.62(m,2H),7.59-7.53(m,2H), 5.13-5.08(m,1H),4.41-4.35(m,1H),4.08-4.04(m,1H),3.82-3.74(m,1H),3 .71(s,3H),3.63-3.52(m,1H),3.16-3.09(m,1H),3.09-3.02(m,1H),2.74-2. 65(m,1H),2.52-2.43(m,1H),2.12-2.01(m,1H),1.81-1.59(m,3H),0.81(t,J = 7.4 Hz,3H),0.69(t,J = 7.3 Hz,3H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -63.86 (3F). TIFF2025510945000288.tif71166

[0327] Step 1: To a mixture of 72-1 methyl ester (500 mg, 2.31 mmol) in 2-methoxyethyl ether (10 mL) was added 2,2'-bipyridyl (542 mg, 3.47 mmol), AgSCF (725.4 mg, 3.47 mmol), and CuI (661 mg, 3.47 mmol). The mixture was then stirred at 130 °C under N for 24 h. Water was added to quench the mixture, and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous NaSO, and the mixture was concentrated. The residue was purified by reverse-phase HPLC (MeCN / water (0.05% TFA), 5-95%) to give 72-2.

[0328] Step 2: To a solution of 72-2 (2.2 g, 9.28 mmol) in MeOH (2 mL) was added NaBH (0.7 g, 18.55 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and saturated NH Cl solution. The mixture was isolated in vacuo, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 72-3.

[0329] Step 3: To a solution of 72-3 (1.12 g, 5.35 mmol) in DCM (15 mL) was added Dess-Martin periodinane (3.0 g, 6.96 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 72-4.

[0330] Step 4: To a solution of 72-4 (460 mg, 2.21 mmol) in THF (10 mL) was added 4-fluorophenylmagnesium bromide (0.32 mL, 0.32 mmol) at −78° C., and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and saturated NH4Cl solution. The organic layer was isolated and washed with saturated NaCl solution, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 72-5.

[0331] Step 5: To a solution of 72-5 (580 mg, 1.91 mmol) in DCM (12 mL) was added DMF (0.01 mL, 0.13 mmol) and SOCl (378 mg, 3.82 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo to give 72-6, which was used directly in the next step without further purification.

[0332] Step 6: Compounds 72 and 73 were prepared from compound 72-6 according to the synthesis of compound 28-15 in Example 11. The product was obtained by reverse-phase HPLC (MeCN / water (0.05% TFA), 0-80%). 72: 2.23 TFA salt, LCMS (ESI, m / z): [M+H] + = 598.4; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.98(s,1H),8.22(dd,J = 8.0,2.0 Hz,1H),8.14-8.01(m,2H),7.76-7.60(m,3H),7.25(t,J = 8.4 Hz,2H),6.43-5.91(m,2H),5.42-5.32(m,1H),4.10-3.99(m,1H),3.60(s ,3H),3.20-3.02(m,2H),1.91-1.59(m,5H),1.39-1.28(m,1H),0.85(t,J = 7.2 Hz,3H). 19F NMR (376 MHz, methanol-d4, ppm): δ -44.15 (3F), -77.27 (6.7F, TFA), -111.5 (1F). 73: 1.48 TFA salt LCMS (ESI, m / z): [M+H] + = 598.4; 1 H NMR (400 MHz, methanol-d4, ppm): δ 8.93(s,1H),8.21(dd,J = 8.0,2.0 Hz,1H),8.10(d,J = 8.8 Hz,1H),8.03(d,J = 8.8 Hz,1H),7.81-7.67(m,3H),7.18(t,J = 8.4 Hz,2H),6.34-5.96(m,1H),5.55-5.23(m,2H),4.10-3.85(m,1H),3.59(s,3H) ,3.28-3.15(m,1H),3.10-2.90(m,1H),1.65-1.28(m,6H),0.78-0.64(m,3H). 19 F NMR (376 MHz, methanol-d4, ppm): δ -4.24 (3F), -77.38 (4.45F, TFA), -111.5 (1F). TIFF2025510945000289.tif54166

[0333] Step 1: To a mixture of 64-3 (80 mg, 0.14 mmol) in THF (10 mL) was added CDI (44.2 mg, 0.27 mmol). After stirring at room temperature for 16 h, NaBH (5.2 mg, 0.14 mmol) was added to the mixture. The mixture was then stirred at room temperature for 20 min. Water was added to quench the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with brine and dried over anhydrous NaSO. The solvent was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 77. LCMS (ESI, m / z): [M+H] + =573.3; 1 H NMR (400 MHz, DMSO-d 6,ppm):δ 8.30-8.18(m,1H),8.01-7.91(m,1H),7.90-7.78(m,2H),7.65-7.06(m, 2H),6.12-5.57(m,0.5H),5.62-5.53(m,0.5H),5.11-4.71(m,2H),3.81- 3.64(m,5H),3.06-2.72(m,3H),2.61-2.53(m,1H),2.37-2.11(m,1H),2. 09-1.47(m,2H),1.2-1.41(m,2H),1.07-0.84(m,3H),0.79-0.56(m,3H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ 88.41(1F),64.39(4F).

[0334] Step 2: To a mixture of 77 (50 mg, 0.087 mmol) in THF (2 mL), NaH (7.0 mg, 0.17 mmol) and iodomethane (37.0 mg, 0.26 mmol) were added. The mixture was then stirred at 0 °C for 3 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with brine, then dried over anhydrous Na2SO4. The solvent was concentrated. The residue was purified by reverse-phase HPLC (MeCN / water 1 / 0 to 2 / 3) to give 78. LCMS (ESI, m / z): [M+H] + =587.3; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.31-8.17(m,1H),8.03-7.94(m,1H),7.96-7.83(m,2H),7.70-7.58(m,2H),6.09-5.78(m,0.5H),5 .53-5.26(m,0.5H),5.09-4.75(m,1H),3.98-3.80(m,1H),3.69-3.48(m,3H),3.43(s,3H),3.20(d,J = 5.2 Hz,3H),3.14-2.81(m,2H),2.37-2.16(m,1H),2.13-1.70(m,2H),1.56-1.31(m,2H),1.01-0.83(m,3H),0.77-0.55(m 3H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ 88.66(1F),64.36(4F). TIFF2025510945000290.tif83166

[0335] Step 1: To a solution of 34-8 (2.39 g, 10.62 mmol) in MeCN (50 mL) at room temperature, DIPEA (14.04 mL, 84.97 mmol) and 28-11 (2.57 g, 10.62 mmol) were added. The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 84-1.

[0336] Step 2: To a solution of 84-1 (3.66 g, 8.49 mmol) in THF (30 mL) was added N2H4.H2O (5 mL), and the mixture was stirred at 50 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 0 to 0 / 1) to give 84-2.

[0337] Step 3: 84-2 (3.6 g, 8.44 mmol) was dissolved in trimethoxymethane (30 mL), and the mixture was stirred at 100° C. under N for 16 h. The mixture was concentrated under reduced pressure to give product 84-3.

[0338] Step 4: To a solution of 84-3 (3.65 g, 8.36 mmol) in DCM (30 mL) was added TFA (10 mL) at room temperature and stirred for 5 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in DCM and washed with saturated NaHCO. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 84-4.

[0339] Step 5: To a solution of 4-(trifluoromethyl)benzoic acid (100 mg, 0.53 mmol) in DMF (5 mL), DIPEA (0.13 mL, 0.79 mmol) and HATU (240.0 mg, 0.63 mmol) were added. The mixture was stirred at 0 °C for 10 minutes, and then 84-4 (176.9 mg, 0.53 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was purified by reverse-phase HPLC (MeCN / water from 0 / 1 to 1 / 1) to give 84. LCMS (ESI, m / z): [M+H] + =509.2;. 1 H NMR(400 MHz,DMSO-d6,ppm)δ 9.55(s,1H),9.02-8.88(m,1H),8.67-8.50(m,1H),7.93-7.81(m,2H),7.74-7.59(m,2H),5.87-4.23( m,3H),3.78-3.42(m,2H),3.38-3.12(m,1H),2.03-1.54(m,4H),1.11-0.88(m,3H),0.77-0.50(m,3H). 19 F NMR(377 MHz,DMSO-d6,ppm)δ-61.21(3F). TIFF2025510945000291.tif131166

[0340] Step 1: To a solution of 91-1 (15 g, 99.25 mmol) in MeCN (100 mL) was added CH3NH2 (200 mL, 3.56 mmol, 40% aqueous solution). The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give 91-2.

[0341] Step 2: To a solution of 91-2 (8.2 g, 50.56 mmol) in MeCN (150 mL) was added NCS (7.4 g, 55.61 mmol), and the reaction mixture was stirred at 60 °C for 70 min. Water was added to quench the mixture. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 91-3.

[0342] Step 3: Compounds 91-4 and 91-5 were prepared from compound 91-3 according to the synthesis of compound 5-8 in Example 5, and the products were obtained by reverse phase HPLC (MeCN / water, 55%-65%).

[0343] Step 4: Purification of 91-4 (1.2 g) by SFC (chromatographic column: REGIS(S,S)WHELK-O1, 250 × 25 mm ID, 10 μm, A is CO₂, B is ethanol) gave 91-6 (200 mg) and 91-7 (250 mg), respectively. 91-6: SFC analysis: 100.00% ee; retention time: 5.932 min; chromatographic column: ChiralPak AD, 250 × 30 mm ID, 10 μm, A is CO₂, B is ethanol, 40%; pressure: 100 bar; flow rate: 70 mL / min. 91-7: SFC analysis: 98.76% ee; retention time: 7.760 min; chromatography column: ChiralPak AD, 250 x 30 mm ID, 10 μm, A is CO2, B is ethanol, 40%; pressure: 100 bar; flow rate: 70 mL / min.

[0344] Step 5: To a solution of 91-6 (180 mg, 0.39 mmol) in DCM (1 mL) was added BBr (3.86 mL, 3.86 mmol) dropwise at −78° C. N. After the addition was complete, the mixture was stirred at room temperature for 16 h. The mixture was quenched by adding ice water, and the precipitate was collected by filtration, washed with water, and dried to give 91-8.

[0345] Step 6: A mixture of 91-8 (160 mg, 0.35 mmol), 3-bromotetrahydrofuran (67.84 mg, 0.45 mmol), and CsCO (266.2 mg, 0.82 mmol) in DMF (5 mL) was stirred at 100 °C for 6 h. The mixture was then washed with water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated to give 91-9.

[0346] Step 7: Purification of 91-9 (110 mg) by SFC (chromatographic column: ChiralPak AD, 250 × 30 mm ID, 10 μm, A is CO₂, B is ethanol) gave 91 (26 mg) and 92 (15 mg), respectively. 91: SFC analysis: 100.00% ee; retention time: 2.519 min; chromatographic column: ChiralPak AD, 250 × 30 mm ID, 10 μm, A is CO₂, B is ethanol, 35%; pressure: 100 bar; flow rate: 80 mL / min. LCMS (ESI, m / z): [M+H]₀ = 523.4; 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.77(s,1H),7.57(d,J = 8.4 Hz,1H),7.52(s,1H),7.19(d,J = 8.4 Hz,1H),6.91(s,1H),5.45-5.40(m,1H),4.18-4.12(m,1H),3.99-3.93(m,1H),3.89-3.85(m,3H),3.82-3.71(m,2H),3.48(s,3H),3.45- 3.40(m,2H),2.38-2.32(m,2H),2.30-2.26(m,2H),2.21-2.17(m,1H),2.15-1.97(m,3H),1.58-1.52(m,1H),1.45-1.33(m,1H),0.71(t,J = 7.6 Hz, 3H).92: SFC analysis: 100.00%ee; Holding time: 2.012 min; クロマトグラフィーカラム: ChiralPak AD, 250×30mm ID, 10μm, AがCO2であり, Bがエタノールであり, 35%; pressure: 100 bar; flow rate: 80 mL / min. LCMS (ESI, m / z): [M+H]+ = 523.4; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 7.77 (s, 1H), 7.61-7.48 (m, 2H), 7.19 (d, J = 8.0 Hz,1H),6.91(s,1H),5.92-5.30(m,1H),4.20-4.15(m,1H),3.98-3.92(m,1H),3.92-3.84(m,3H),3.80-3.70(m,2H),3.55-3.45(m ,5H),2.38-2.32(m,2H),2.30-2.26(m,2H),2.21-2.15(m,1H),2.15-1.98(m,3H),1.60-1.52(m,1H),1.43-1.34(m,1H),0.71(t,J = 7.0 Hz, 3H). TIFF2025510945000292.tif54133

[0347] Step 1: To a solution of 84-4 (179.8 mg, 0.53 mmol) in DCM (2 mL) was added dropwise a solution of 1-isocyanato-4-(trifluoromethyl)benzene (100 mg, 0.53 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 95. LCMS (ESI, m / z): [M+H] + =524.2;. 1 H NMR(400 MHz,DMSO-d6,ppm)δ 9.55(s,1H),8.98-8.91(m,2H),8.63-8.55(m,1H),7.75-7.66(m,2H),7.64-7.57(m,2H),5.51-4.83(m,2 H),4.41(m,1H),4.20-4.07(m,1H),3.58(m,1H),3.33-3.13(m,1H),1.86-1.63(m,4H),0.97-0.85(m,6H). 19 F NMR(377 MHz,DMSO-d6,ppm)δ-59.99(s,3F). TIFF2025510945000293.tif140166

[0348] Step 1: Compound 98-1 was prepared from compound 28-12 according to the synthesis of compound 28-14 in Example 11.

[0349] Step 2: To a solution of 98-2 (4 g, 17.08 mmol) in DCM (100 mL) at 0 °C, triethylamine (5.18 g, 51.24 mmol), DMAP (357.2 mg, 1.71 mmol), and 4-methylbenzenesulfonic acid chloride (4.88 g, 25.62 mmol) were added. The reaction mixture was then stirred at room temperature for 4 h. The reaction was quenched with water and extracted with DCM. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 98-3.

[0350] Step 3: To a solution of 98-3 (3.8 g, 9.78 mmol) in THF (100 mL), TBAF (1 M THF solution, 14.7 mL, 14.7 mmol) and TMSCN (1.16 g, 11.74 mmol) were added. The reaction mixture was stirred at 60 °C for 1 h. Then, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 98-4.

[0351] Step 4: To a solution of 98-4 (1 g, 4.11 mmol) in acetone (20 mL), K2CO3 (1.14 g, 8.22 mmol) and H2O2 (4 mL) were added. The mixture was then stirred at 40 °C for 48 h. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 98-5.

[0352] Step 5: To a solution of 98-5 (670 mg, 2.56 mmol) in CCl (10 mL), AIBN (42 mg, 0.26 mmol) and NBS (683.44 mg, 3.84 mmol) were added. The reaction mixture was then stirred at 90 °C for 16 h. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 98-6.

[0353] Step 6: To a solution of 98-6 (200 mg, 0.59 mmol) in MeCN (4 mL) was added 98-1 (265.5 mg, 0.59 mmol), DIPEA (380 mg, 2.94 mmol), and NaI (105.8 mg, 0.71 mmol). The reaction was then stirred at 90 °C for 2 h. The solvent was removed in vacuo, and the residue was purified by reverse-phase HPLC (MeCN / HO, 5-80%) to give 98-7.

[0354] Step 7: To a solution of 98-7 (110 mg, 0.19 mmol) in THF (4 mL) was added Lawesson's reagent (74.83 mg, 0.19 mmol). The reaction mixture was then stirred at 50 °C for 30 h. The solvent was removed in vacuo, and the residue was purified by reverse-phase HPLC (MeCN / HO, 5-80%) to give 98-8.

[0355] Step 8: To a solution of 98-8 (30 mg, 0.049 mmol) in EtOH (1 mL) was added 2-bromo-1-cyclopropylethan-1-one (16 mg, 0.098 mmol). The reaction mixture was then stirred at 80 °C for 2 h. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 98-9.

[0356] Step 9: To a mixture of 98-9 (20 mg, 0.03 mmol) in DMF (1 mL), Zn(CN) (10.6 mg, 0.09 mmol) and Pd(PPh) (3.5 mg, 0.003 mmol) were added. The mixture was then stirred at 130 °C under microwave conditions for 2 h. The reaction mixture was purified by reverse-phase HPLC (MeCN / HO (0.05% TFA), 5-80%) to give 98 (5 mg) and 99 (7 ​​mg). 98: LCMS (ESI, m / z): [M+H] + = 666.4; 1H NMR(400 MHz,DMSO-d6,ppm):δ 8.23(d,J = 8.8 Hz,1H),8.01-7.88(m,3H),7.79-7.70(m,2H),7.25(s,1H),5.96-5.82(m,0.5H),5.42-5.38(m,0.5H),5.22(s,1H),4.98-4.83(m,1H),3.62-3.58(m,0.5H),3.43(s,3H),3.38-3.32(m,0.5H),2.80-2.71(m,1H),2.23-2.18(m,1H),2.05-1.88(m,3H),1.49-1.38(m,3H),0.86-0.77(m,6H),0.70-0.64(m,1H),0.62-0.45(m,3H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ 87.47(1F),64.17(4F).99:LCMS(ESI,m / z):[M+H] + = 666.4; 1 H NMR(400 MHz,DMSO-d6,ppm):δ 8.28-8.19(m,1H),8.02-7.88(m,3H),7.82-7.73(m,2H),7.30(s,1H),5.95-5.82(m,0.5H),5.43-5.38(m,0.5H),5.27(s,1H),5.01-4.85(m,1H),3.62-3.58(m,0.5H),3.49-3.42(m,3.5H),2.20-2.11(m,1H),2.08-1.84(m,4H),1.73-1.37(m,3H),0.90-0.82(m,2H),0.79-0.61(m,8H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ 87.33(1F),64.18(4F). TIFF2025510945000294.tif84166

[0357] Step 1: To a mixture of 102-1 (400 mg, 2.48 mmol) and tert-butyl 2-ethyl-4-oxopiperidine-1-carboxylate (564.3 mg, 2.48 mmol) in THF (10 mL) at room temperature, TiCl4 (235.4 mg, 1.24 mmol) was added dropwise. The mixture was stirred for an additional 30 minutes, after which sodium triacetoxyborohydride (1052.3 mg, 4.97 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 102-2.

[0358] Step 2: To a mixture of 102-2 (646 mg, 1.74 mmol) and acetaldehyde (382.1 mg, 8.68 mmol) in THF (10 mL) at room temperature, TiCl4 (164.5 mg, 0.87 mmol) was added dropwise. The mixture was stirred for an additional 30 minutes, after which sodium triacetoxyborohydride (735.2 mg, 3.47 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 102-3.

[0359] Step 3: To a solution of 102-3 (345 mg, 0.86 mmol) in DCM (5 mL), ethyl acetate / HCl (0.43 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness to give 102-4, which was used directly in the next step without further purification.

[0360] Step 4: Compound 102 was prepared from compound 102-4 according to the synthesis of compound 84-3 in Example 25. LCMS (ESI, m / z): [M+H] + = 495.3; 1H NMR(400 MHz,DMSO-d6,ppm):δ9.52(s,1H),8.95-8.93(d,J=8.8 Hz,1H),8.58-8.56(d,J=8.8 Hz,1H),7.39-7.37(d,J=8.8 Hz,2H),6.83-6.81(d,J=8.8 Hz,2H),4.75-4.69(m,2H),4.05-4.03(m,1H),3.72-3.71(m,1H),3.45 -3.34(m,2H),2.34-2.33(m,1H),2.14-1.75(m,5H),1.17-0.98(m,6H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-58.90(3F). TIFF2025510945000295.tif84166

[0361] Step 1: To a mixture of 103-1 (9.50 g, 26.79 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (7.87 g, 34.83 mmol) in dioxane (95 mL) and water (9.5 mL) at room temperature, Pd(dppf)Cl (2.0 g, 2.68 mmol) and NaCO (5.7 g, 53.59 mmol) were added. The mixture was then heated at 100 °C for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 103-2.

[0362] Step 2: To a mixture of 103-2 (12 g, 25.71 mmol) and COCl 6H O (0.6 g, 2.57 mmol) in MeOH (360 mL) and THF (180 mL) at 0 °C, NaBH (5.8 g, 154.23 mmol) was added in portions. The mixture was then stirred at room temperature for 1 h. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The combined organic layer was dried over Na SO and filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give 103-3.

[0363] Step 3: A solution of 103-3 (7.6 g, 23.12 mmol) in HCl / ethyl acetate (100 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give 103-4.

[0364] Step 4: Compound 103 was prepared from compound 103-4 according to the synthesis of compound 59 in Example 20. LCMS (ESI, m / z): [M+H] + = 511.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.07(s,1H),7.82-7.77(m,2H),7.49-7.47(m,2H),4.92-4.17(m,4H), 3.91-3.83(m,2H),3.35(s,2H),2.96-2.89(m,2H),2.02-1.90(m,6H). 19 F NMR(376 MHz,DMSO-d6,ppm):δ-56.75(3F). TIFF2025510945000296.tif82166

[0365] Step 1: A mixture of 104-1 (5.0 g, 44.59 mmol), 1-(pyridin-3-yl)prop-1-one (7.23 g, 53.51 mmol), AgNO (2.27 g, 13.38 mmol), HSO (9.75 g, 89.18 mmol), and ammonium persulfate (10.17 g, 44.59 mmol) in water (70 mL) and DCM (70 mL) was purged with N for 0.5 min, and then the mixture was stirred at 25 °C for 18 h. The mixture was quenched by adding saturated NaHCO solution, and the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, and dried over anhydrous NaSO. The solvent was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 104-2.

[0366] Step 2: To a solution of 104-2 (560 mg, 2.78 mmol) in MeOH (10 mL) was added NaBH (12.3 mg, 3.34 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was quenched by adding water, and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous NaSO, and concentrated to give 104-3.

[0367] Step 3: To a solution of 104-3 (580 mg, 2.85 mmol) in DCM (15 mL) was added DMF (21.0 mg, 0.29 mmol) and SOCl (509 mg, 4.28 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give 104-4, which was used directly in the next step without further purification.

[0368] Step 4: A mixture of 28-9 (100 mg, 0.43 mmol), 104-4 (239 mg, 1.08 mmol), DIPEA (0.29 mL, 1.72 mmol), and NaI (129 mg, 0.86 mmol) in MeCN (2 mL) was stirred for 18 h at 85° C. The mixture was filtered and concentrated, and the residue was purified by reverse-phase HPLC (0.05% aqueous NH4HCO3 / MeCN, 5-95%) to give 104-5.

[0369] Step 5: To a solution of 104-5 (80 mg, 0.19 mmol) in 1,2-dichloroethane (1 mL) was added 1-chloroethyl chloroformate (274.5 mg, 1.92 mmol), and the reaction was stirred at 110 °C for 96 h. The mixture was conc...

Claims

1. A compound of formula III-2, or a pharma- ceutically acceptable salt thereof, In the formula, R １ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , COOH, CONH ２ , R Ａ , OR Ａ , NH(R Ａ ), N(R Ａ ) ２ , COOR Ａ , CONH(R Ａ ), CON(R Ａ ) ２ , S.R. Ａ , S.O.R. Ａ , S.O. ２ R Ａ or P(O)(R Ａ ) ２ and R Ａ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or an optionally substituted 4- to 7-membered heterocyclyl; R ２ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｂ , OR Ｂ , NH(R Ｂ ) or N(R Ｂ ) ２ and R Ｂ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, or an optionally substituted 4-7 membered heterocyclyl; X is N or CR ５ and R ５ is hydrogen, halogen, CN, CONH ２ , COOH, CONH(R Ｃ ), CON(R Ｃ ) ２ , OR Ｃ , or COOR Ｃ and R Ｃ Each time it represents, it is independently optionally substituted C １－４ is alkyl; U is N or CR ６ and R ６ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｄ , OR Ｄ , NH(R Ｄ ) 、 N (R Ｄ ) ２ , COOH, CONH ２ , COOR Ｄ , CONH(R Ｄ ) 、 CON (R Ｄ ) ２ , S.R. Ｄ , SOR Ｄ , S.O. ２ R Ｄ or P(O)(R Ｄ ) ２ and R Ｄ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or an optionally substituted 4- to 7-membered heterocyclyl; Y is N or CR ７ and R ７ is hydrogen, F, Cl, CN, optionally substituted C １－４ Alkyl or optionally substituted C １－４ is heteroalkyl; L １ is an optionally substituted 4-12 membered heterocycloalkylene having one or more rings and 1-4 ring-forming heteroatoms each independently selected from the group consisting of O, N or S, or -N(R Ｅ )-, and R Ｅ may be substituted C １－４ is an alkyl or an optionally substituted 3-7 membered ring; L ２ is absent, O, NH, -N(R Ｅ２ )-, C(O), SO ２ , optionally substituted C １－４ Alkylene, optionally substituted C ２－４ Alkenylene, optionally substituted C １－４ Alkynylene, optionally substituted C １－４ heteroalkylene, or an optionally substituted 3- to 7-membered ring; R Ｅ２ may be substituted C １－４ is an alkyl or an optionally substituted 3-7 membered ring; R ３０ is hydrogen, an optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 8-12 membered ring having two or more rings; The compound, or a pharmacologically acceptable salt thereof.

2. Y is N; 2. The compound according to claim 1, or a pharma- ceutical acceptable salt thereof.

3. U is CR ６ That is, 3. The compound according to claim 1, or a pharmacologically acceptable salt thereof.

4. R ６ is hydrogen, 4. The compound according to claim 3, or a pharmacologically acceptable salt thereof.

5. R １ But, CN.

5. The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof.

6. (i) R １ is halogen, for example F or Cl; (ii) R １ but, and (iii) R １ is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, such as an optionally substituted pyrimidyl or an optionally substituted thiazolyl, for example, R １ but, or or (iv) R １ But, S.R. Ａ１ and R Ａ１ each independently represents an optionally substituted C １－４ alkyl, for example, R １ But, SCH ３ That is, 5. The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof.

7. R ２ is hydrogen, 7. The compound according to any one of claims 1 to 6, or a pharmacologically acceptable salt thereof.

8. X is N; 8. The compound according to any one of claims 1 to 7, or a pharmacologically acceptable salt thereof.

9. L １ but, or (One of the two connecting bonds of piperidine, N or C, is L ２ (which may be linked to n is 0, 1, 2, 3 or 4, and (1) R ９Ａ Each time, R Ｎ , COOR Ｎ , C.O.R. Ｎ , CONH(R Ｎ ) or CON(R Ｎ ) ２ and R Ｎ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl; or (2) R ９Ａ may be linked to form a double bond or a 3- to 5-membered ring, and R ９Ａ Any remaining examples of the formula are as defined in (1), 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

10. R ９Ａ Each time it is expressed, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , fluorine-substituted C １－３ Alkyl (e.g., CF ２ H), cyclopropyl, cyclobutyl, CH ２ O.H., C.H. ２ OCH ３ , C.H. ２ OCH ２ CH ３ , C.H. ２ N.H. ２ , C.H. ２ N ３ or CH ２ NHC(O)OCH ３ That is, 10. The compound according to claim 9, or a pharma- ceutical acceptable salt thereof.

11. L １ However, the following (the lower link N or C is L ２ linked to 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

12. L １ However, the following (the lower link N or C is L ２ linked to 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

13. L １ is an optionally substituted 7-12 membered heterocyclylene having two or more rings and 1-4 ring-forming heteroatoms each independently selected from the group consisting of O, N or S, and when substituted, the substituents may be linked to any one or more of the two or more rings; 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

14. L １ The following bicyclic heterocyclylene (wherein the lower linker N or C is L) ２ linked to In each bicyclic heterocyclylene, each of the two rings is independently selected from 1 to 3 R １０ and R １０ Each time it is represented, it is independently a halogen, OH, NH ２ , oxo (where applicable), R Ｊ , OR Ｊ , C.N., N.H. (R Ｊ ) or N(R Ｊ ) ２ and R Ｊ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ alkynyl, or an optionally substituted 3-4 membered ring; 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

15. L １ The following bicyclic heterocyclylene (wherein the lower linker N or C is L) ２ linked to 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

16. L ２ But non-existence, 16. The compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof.

17. L ２ may be substituted C １－４ is alkylene, 16. The compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof.

18. having the structure of formula III-2-E-1, III-2-E-2 or III-2-E-3, In the formula, R １３ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , COOH, CONH ２ , S.O. ２ N.H. ２ , C.O.R. Ｋ , COOR Ｋ , CONH(R Ｋ ), CON(R Ｋ ) ２ , S.O. ２ R Ｋ , S.O. ２ NH (R Ｋ ), S.O. ２ N (R Ｋ ) ２ , R Ｋ , OR Ｋ , NH(R Ｋ ), N(R Ｋ ) ２ , S.R. Ｋ , SOR Ｋ , S.O. ２ R Ｋ or P(O)(R Ｋ ) ２ R is selected from the group consisting of Ｋ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C １－４ Heteroalkyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl, and when substituted, optionally substituted C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Heteroalkyl, C ３－６ Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl is substituted with 1-3 substituents independently selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F １－４ Alkyl, C optionally substituted with 1-3 F １－４ heteroalkyl, and 3-4 membered rings optionally substituted with F and / or methyl (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.); 16. The compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof.

19. having a structure of formula III-2-F-1a, III-2-F-1b, III-2-F-2a, III-2-F-2b, III-2-F-3a or III-2-F-3b; In the formula, R ９Ａ Each time it is expressed, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , fluorine-substituted C １－３ Alkyl (e.g., CF ２ H), cyclopropyl, cyclobutyl, CH ２ O.H., C.H. ２ OCH ３ , C.H. ２ OCH ２ CH ３ , C.H. ２ N.H. ２ , C.H. ２ N ３ or CH ２ NHC(O)OCH ３ and preferably, R ９Ａ Each time it is expressed, CH ３ , C.H. ２ CH ３ or CH ２ CH ２ CH ３ and more preferably, R ９Ａ But every time it is expressed, CH ２ CH ３ That is, 19. The compound of claim 18, or a pharma- ceutical acceptable salt thereof.

20. R １３ is hydrogen, 20. The compound according to claim 18 or 19, or a pharma- cologically acceptable salt thereof.

21. R １３ But, C １－４ Alkyl, for example, methyl, isopropyl, etc.

20. The compound according to claim 18 or 19, or a pharma- cologically acceptable salt thereof.

22. R １３ CN, OH, COOH, CONH ２ , methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S, and when substituted, the optionally substituted phenyl or 5- or 6-membered heteroaryl is substituted with 1-3 substituents, and the substituents are independently selected from halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F. １－４ Alkyl, C optionally substituted with 1-3 F １－４ Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, e.g., R １３ OH, methoxy, cyclopropyl, phenyl, or That is, 20. The compound according to claim 18 or 19, or a pharma- cologically acceptable salt thereof.

23. R ３０ is optionally substituted phenyl, e.g., 1-3 (e.g., 1 or 2) R ２２ phenyl substituted with R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｍ , OR Ｍ , COOH, CONH ２ , COOR Ｍ , CONH(R Ｍ ), CON(R Ｍ ) ２ , NHCO(R Ｍ ), N(R Ｍ ) CO(R Ｍ ), S.O. ２ R Ｍ , S.O. ２ N.H. ２ ,S(O)(NH)R Ｍ , S(O)(NR Ｍ ) R Ｍ , S.O. ２ N (R Ｍ ) ２ , N.H.S.O. ２ R Ｍ , N(R Ｍ ) S.O. ２ R Ｍ , P(O)(R Ｍ ) ２ , P(O)(OR Ｍ ) ２ , NH(R Ｍ ), N(R Ｍ ) ２ , S.R. Ｍ Or Sci-Fi ５ and R Ｍ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

24. R ３０ is 1-3 (e.g., 1 or 2) R ２２ phenyl substituted with R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, R Ｍ１ , OR Ｍ１ , S.O. ２ R Ｍ１ , P(O)(R Ｍ１ ) ２ , S.R. Ｍ１ Or Sci-Fi ５ and R Ｍ１ Each time it represents, it is independently optionally substituted C １－４ alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C １－４ The alkyl or 3-4 membered ring is independently substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F １－４ Alkyl, C optionally substituted with 1-3 F １－４ Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R ２２ Each time represents independently F, Cl, Br, CF ３ , O.C.F. ３ , SCF ３ , S.F. ５ , OMe, CN, Methyl, CHF ２ , C.F. ２ CH ３ , cyclopropyl, CH ３ SO ２ and O.C.H. ２ -(cyclopropyl), 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

25. R ３０ is 1-3 (e.g., 1 or 2) R ２２ phenyl substituted with R ２２ Each time represents independently F, Cl, CN, R Ｍ２ , OR Ｍ２ , S.R. Ｍ２ Or Sci-Fi ５ and R Ｍ２ Each occurrence of C optionally substituted by 1-3 F is independently １－４ Alkyl, e.g., CF ３ That is, 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

26. R ３０ is an optionally substituted 5- or 6-membered heteroaryl, e.g., 1-3 (e.g., 1 or 2) R ２２ Pyridyl substituted with, for example, or ) or pyrimidyl (e.g. ) and R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｍ , OR Ｍ , COOH, CONH ２ , COOR Ｍ , CONH(R Ｍ ), CON(R Ｍ ) ２ , NHCO(R Ｍ ), N(R Ｍ ) CO(R Ｍ ), S.O. ２ R Ｍ , S.O. ２ N.H. ２ , S(O)(NH)R Ｍ , S(O)(NR Ｍ ) R Ｍ , S.O. ２ N (R Ｍ ) ２ , N.H.S.O. ２ R Ｍ , N(R Ｍ ) S.O. ２ R Ｍ , P(O)(R Ｍ ) ２ , P(O)(OR Ｍ ) ２ , NH(R Ｍ ), N(R Ｍ ) ２ , S.R. Ｍ Or Sci-Fi ５ and R Ｍ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

27. R ３０ Where valency is permitted, 1-3 (e.g., 1 or 2) R ２２ 5-membered heteroaryl substituted with, for example, ) or pyridyl (e.g. or ) or pyrimidyl (e.g. ) and R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, R Ｍ１ , OR Ｍ１ , S.O. ２ R Ｍ１ , P(O)(R Ｍ１ ) ２ , S.R. Ｍ１ Or Sci-Fi ５ and R Ｍ１ Each time it represents, it is independently optionally substituted C １－４ alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C １－４ The alkyl or 3-4 membered ring is substituted with 1-3 substituents, each of which is independently selected from halogen (preferably F or Cl), OH, CN, and 1-3 F. １－４ Alkyl, C optionally substituted with 1-3 F １－４ Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R ２２ Each time represents independently F, Cl, Br, CF ３ , O.C.F. ３ , SCF ３ , S.F. ５ , OMe, CN, Methyl, CHF ２ , C.F. ２ CH ３ , cyclopropyl, CH ３ SO ２ and O.C.H. ２ -(cyclopropyl), 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

28. R ３０ Where valency is permitted, 1-3 (e.g., 1 or 2) R ２２ 5-membered heteroaryl substituted with, for example, ) or pyridyl (e.g. or ) or pyrimidyl (e.g. ) and R ２２ Each time represents independently F, Cl, CN, R Ｍ２ , OR Ｍ２ , S.R. Ｍ２ Or Sci-Fi ５ and R Ｍ２ Each occurrence of C optionally substituted by 1-3 F is independently １－４ Alkyl, e.g., CF ３ That is, 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

29. R ３０ has the structure S-1-A, S-1-B, S-1-C or S-1-D; R ８ C optionally substituted with 1-3 F １－４ Alkyl (e.g., CH ３ , C.F. ３ etc.), C optionally substituted with 1-3 F １－４ Alkoxy (e.g., OCH ３ , O.C.F. ３ etc.), SCF ３ , S.F. ５ , cyclopropyl, cyclobutyl, or That is, 23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

30. R ３０ is selected from the group consisting of:

23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

31. R ３０ is selected from the group consisting of:

23. The compound according to any one of claims 1 to 22, or a pharmacologically acceptable salt thereof.

32. L １ , L ２ and R ３０ But together (i.e., L １ -L ２ -R ３０ ) selected from the group consisting of:

9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

33. L １ , L ２ and R ３０ are taken together from the group consisting of: Or, L １ , L ２ and R ３０ But together (i.e., L １ -L ２ -R ３０ ) selected from the group consisting of: or Or, L １ , L ２ and R ３０ But together (i.e., L １ -L ２ -R ３０ ) selected from the group consisting of: or 9. The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.

34. A compound of formula III-4, or a pharma- ceutically acceptable salt thereof: In the formula, R １ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , COOH, CONH ２ , R Ａ , OR Ａ , NH(R Ａ ), N(R Ａ ) ２ , COOR Ａ , CONH(R Ａ ), CON(R Ａ ) ２ , S.R. Ａ , SOR Ａ , S.O. ２ R Ａ or P(O)(R Ａ ) ２ and R Ａ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or an optionally substituted 4- to 7-membered heterocyclyl; R ２ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｂ , OR Ｂ , NH(R Ｂ ) or N(R Ｂ ) ２ and R Ｂ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, or an optionally substituted 4-7 membered heterocyclyl; R ３ is hydrogen, optionally substituted C １－４ Alkyl, or an optionally substituted 3-7 membered ring, such as an optionally substituted C ３－６ cycloalkyl, or optionally substituted 4-7 membered heterocyclyl (e.g., saturated 4-7 membered heterocyclyl); U is N or CR ６ and R ６ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｄ , OR Ｄ , NH(R Ｄ ) 、 N (R Ｄ ) ２ , COOH, CONH ２ , COOR Ｄ , CONH(R Ｄ ) 、 CON (R Ｄ ) ２ , S.R. Ｄ , SOR Ｄ , S.O. ２ R Ｄ or P(O)(R Ｄ ) ２ and R Ｄ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or an optionally substituted 4- to 7-membered heterocyclyl; Y is N or CR ７ and R ７ is hydrogen, F, Cl, CN, optionally substituted C １－４ Alkyl or optionally substituted C １－４ is heteroalkyl; Z is C(O), C(=N-OH), C(=N-O-(C １－４ alkyl), C(=N-NH ２ ), C(=N-NH-(C １－４ alkyl), C(=N-N(C １－４ Alkyl) (C １－４ Alkyl), SO, SO ２ , S(O)(=NH) or S(O)(=N-(C １－４ alkyl); L ２ is absent, O, NH, -N(R Ｅ２ )-, C(O), SO ２ , optionally substituted C １－４ Alkylene, optionally substituted C ２－４ Alkenylene, optionally substituted C １－４ Alkynylene, optionally substituted C １－４ heteroalkylene, or an optionally substituted 3- to 7-membered ring; R Ｅ２ may be substituted C １－４ is an alkyl or an optionally substituted 3-7 membered ring; R ３０ is hydrogen, an optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 8-12 membered ring having two or more rings; R ９ Each time, R Ｎ , COOR Ｎ , C.O.R. Ｎ , CONH(R Ｎ ), or CON(R Ｎ ) ２ and R Ｎ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl; and n1 is 0, 1, 2 or 3; The compound, or a pharmacologically acceptable salt thereof.

35. Y is N; 35. The compound of claim 34, or a pharma- ceutical acceptable salt thereof.

36. U is CR ６ That is, 36. The compound according to any one of claims 34 to 35, or a pharmacologically acceptable salt thereof.

37. R ６ is hydrogen, 37. The compound of claim 36, or a pharma- ceutical acceptable salt thereof.

38. R １ But, CN.

38. The compound according to any one of claims 34 to 37, or a pharmacologically acceptable salt thereof.

39. (i) R １ is halogen, for example F or Cl; (ii) R １ but, and (iii) R １ is an optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, such as an optionally substituted pyrimidyl or an optionally substituted thiazolyl, for example, R １ but, or or (iv) R １ is SR Ａ１ and R Ａ１ each independently represents an optionally substituted C １－４ alkyl, for example, R １ But, SCH ３ That is, 38. The compound according to any one of claims 34 to 37, or a pharmacologically acceptable salt thereof.

40. R ２ is hydrogen, 40. The compound according to any one of claims 34 to 39, or a pharmacologically acceptable salt thereof.

41. Z is CO; 41. The compound according to any one of claims 34 to 40, or a pharmacologically acceptable salt thereof.

42. R ３ is hydrogen, optionally substituted C １－４ Alkyl, e.g., CH ３ , C.D. ３ , ethyl, isopropyl, CH ２ CHF ２ or an optionally substituted 3-4 membered ring, for example, cyclopropyl or cyclobutyl, preferably R ３ Methyl or CD ３ That is, 42. The compound according to any one of claims 34 to 41, or a pharmacologically acceptable salt thereof.

43. n1 is 0 or 1; 43. The compound according to any one of claims 34 to 42, or a pharmacologically acceptable salt thereof.

44. having the structure of formula III-4-C:

43. The compound according to any one of claims 34 to 42, or a pharmacologically acceptable salt thereof.

45. having the structure of formula III-4-C-4:

43. The compound according to any one of claims 34 to 42, or a pharmacologically acceptable salt thereof.

46. R ９ Each time it is expressed, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , fluorine-substituted C １－３ Alkyl (e.g., CF ２ H), cyclopropyl, cyclobutyl, CH ２ O.H., C.H. ２ OCH ３ , C.H. ２ OCH ２ CH ３ , C.H. ２ N.H. ２ , C.H. ２ N ３ or CH ２ NHC(O)OCH ３ and preferably, R ９ Each time it is expressed, CH ３ , C.H. ２ CH ３ or CH ２ CH ２ CH ３ and more preferably, R ９ Each time it is expressed, CH ２ CH ３ That is, 46. ​​The compound according to any one of claims 34 to 45, or a pharmacologically acceptable salt thereof.

47. L ２ may be substituted C １－４ is alkylene, 47. The compound according to any one of claims 34 to 46, or a pharmacologically acceptable salt thereof.

48. having the structure of formula III-4-C-4a, III-4-C-4b, III-4-C-4c, III-4-C-4d, III-4-C-4e or III-4-C-4f, In the formula, R １３ is hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , COOH, CONH ２ , S.O. ２ N.H. ２ , C.O.R. Ｋ , COOR Ｋ , CONH(R Ｋ ), CON(R Ｋ ) ２ , S.O. ２ R Ｋ , S.O. ２ NH (R Ｋ ), S.O. ２ N (R Ｋ ) ２ , R Ｋ , OR Ｋ , NH(R Ｋ ), N(R Ｋ ) ２ , S.R. Ｋ , SOR Ｋ , S.O. ２ R Ｋ or P(O)(R Ｋ ) ２ R is selected from the group consisting of Ｋ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C １－４ Heteroalkyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl, and when substituted, optionally substituted C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Heteroalkyl, C ３－６ Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl is substituted with 1-3 substituents independently selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F １－４ Alkyl, C optionally substituted with 1-3 F １－４ heteroalkyl, and 3-4 membered rings optionally substituted with F and / or methyl (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.); 47. The compound according to any one of claims 34 to 46, or a pharmacologically acceptable salt thereof.

49. R １３ is hydrogen, 49. The compound of claim 48, or a pharma- ceutical acceptable salt thereof.

50. R １３ But, C １－４ Alkyl, for example, methyl, isopropyl, etc.

49. The compound of claim 48, or a pharma- ceutical acceptable salt thereof.

51. R １３ CN, OH, COOH, CONH ２ , methoxy, ethoxy, cyclopropyl, cyclobutyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl having 1-3 ring-forming heteroatoms independently selected from the group consisting of N, O, and S, and when substituted, the optionally substituted phenyl or 5- or 6-membered heteroaryl is substituted with 1-3 substituents, and the substituents are independently selected from halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F. １－４ Alkyl, C optionally substituted with 1-3 F １－４ Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, e.g., R １３ OH, methoxy, cyclopropyl, phenyl, or That is, 49. The compound of claim 48, or a pharma- ceutical acceptable salt thereof.

52. R ３０ is optionally substituted phenyl, e.g., 1-3 (e.g., 1 or 2) R ２２ phenyl substituted with R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｍ , OR Ｍ , COOH, CONH ２ , COOR Ｍ , CONH(R Ｍ ), CON(R Ｍ ) ２ , NHCO(R Ｍ ), N(R Ｍ ) CO(R Ｍ ), S.O. ２ R Ｍ , S.O. ２ N.H. ２ ,S(O)(NH)R Ｍ , S(O)(NR Ｍ ) R Ｍ , S.O. ２ N (R Ｍ ) ２ , N.H.S.O. ２ R Ｍ , N(R Ｍ ) S.O. ２ R Ｍ , P(O)(R Ｍ ) ２ , P(O)(OR Ｍ ) ２ , NH(R Ｍ ), N(R Ｍ ) ２ , S.R. Ｍ Or Sci-Fi ５ and R Ｍ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

53. R ３０ is 1-3 (e.g., 1 or 2) R ２２ phenyl substituted with R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, R Ｍ１ , OR Ｍ１ , S.O. ２ R Ｍ１ , P(O)(R Ｍ１ ) ２ , S.R. Ｍ１ Or Sci-Fi ５ and R Ｍ１ Each time it represents, it is independently optionally substituted C １－４ alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C １－４ The alkyl or 3-4 membered ring is independently substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), OH, CN, C optionally substituted with 1-3 F １－４ Alkyl, C optionally substituted with 1-3 F １－４ Heteroalkyl, and 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R ２２ Each time represents independently F, Cl, Br, CF ３ , O.C.F. ３ , SCF ３ , S.F. ５ , OMe, CN, Methyl, CHF ２ , C.F. ２ CH ３ , cyclopropyl, CH ３ SO ２ and O.C.H. ２ -(cyclopropyl), 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

54. R ３０ is 1-3 (e.g., 1 or 2) R ２２ phenyl substituted with R ２２ Each time represents independently F, Cl, CN, R Ｍ２ , OR Ｍ２ , S.R. Ｍ２ Or Sci-Fi ５ and R Ｍ２ Each occurrence of C optionally substituted by 1-3 F is independently １－４ Alkyl, e.g., CF ３ That is, 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

55. R ３０ is an optionally substituted 5- or 6-membered heteroaryl, e.g., 1-3 (e.g., 1 or 2) R ２２ Pyridyl substituted with, for example, or ) or pyrimidyl (e.g. ) and R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, NH ２ , R Ｍ , OR Ｍ , COOH, CONH ２ , COOR Ｍ , CONH(R Ｍ ), CON(R Ｍ ) ２ , NHCO(R Ｍ ), N(R Ｍ ) CO(R Ｍ ), S.O. ２ R Ｍ , S.O. ２ N.H. ２ , S(O)(NH)R Ｍ , S(O)(NR Ｍ ) R Ｍ , S.O. ２ N (R Ｍ ) ２ , N.H.S.O. ２ R Ｍ , N(R Ｍ ) S.O. ２ R Ｍ , P(O)(R Ｍ ) ２ , P(O)(OR Ｍ ) ２ , NH(R Ｍ ), N(R Ｍ ) ２ , S.R. Ｍ Or Sci-Fi ５ and R Ｍ Each time it represents, it is independently optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ３－６ cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl having 1-4 ring-forming heteroatoms independently selected from the group consisting of O, S and N, or optionally substituted 4- to 7-membered heterocyclyl; 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

56. R ３０ Where valency is permitted, 1-3 (e.g., 1 or 2) R ２２ 5-membered heteroaryl substituted with, for example, ) or pyridyl (e.g. or ) or pyrimidyl (e.g. ) and R ２２ each occurrence independently represents halogen (e.g., F, Cl, or Br), CN, OH, R Ｍ１ , OR Ｍ１ , S.O. ２ R Ｍ１ , P(O)(R Ｍ１ ) ２ , S.R. Ｍ１ Or Sci-Fi ５ and R Ｍ１ Each time it represents, it is independently optionally substituted C １－４ alkyl or an optionally substituted 3-4 membered ring (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.), and when substituted, optionally substituted C １－４ The alkyl or 3-4 membered ring is substituted with 1-3 substituents, each of which is independently selected from halogen (preferably F or Cl), OH, CN, and 1-3 F. １－４ Alkyl, C optionally substituted with 1-3 F １－４ Heteroalkyl, 3-4 membered rings (including cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc.) optionally substituted with F and / or methyl, preferably R ２２ Each time represents independently F, Cl, Br, CF ３ , O.C.F. ３ , SCF ３ , S.F. ５ , OMe, CN, Methyl, CHF ２ , C.F. ２ CH ３ , cyclopropyl, CH ３ SO ２ and O.C.H. ２ -(cyclopropyl), 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

57. R ３０ Where valency is permitted, 1-3 (e.g., 1 or 2) R ２２ 5-membered heteroaryl substituted with, for example, ) or pyridyl (e.g. or ) or pyrimidyl (e.g. ) and R ２２ Each time represents independently F, Cl, CN, R Ｍ２ , OR Ｍ２ , S.R. Ｍ２ Or Sci-Fi ５ and R Ｍ２ Each occurrence of C optionally substituted by 1-3 F is independently １－４ Alkyl, e.g., CF ３ That is, 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

58. R ３０ has the structure S-1-A, S-1-B, S-1-C or S-1-D; R ８ C optionally substituted with 1-3 F １－４ Alkyl (e.g., CH ３ , C.F. ３ etc.), C optionally substituted with 1-3 F １－４ Alkoxy (e.g., OCH ３ , O.C.F. ３ etc.), SCF ３ , S.F. ５ , cyclopropyl, cyclobutyl, or That is, 52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

59. R ３０ is selected from the group consisting of:

52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

60. R ３０ is selected from the group consisting of:

52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

61. R ３０ is selected from the group consisting of:

52. The compound according to any one of claims 34 to 51, or a pharmacologically acceptable salt thereof.

62. A compound as defined in the present application as defined in formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11 or III-12, for example as defined in embodiments A1 to A38 and B1 to B45, or a pharma- ceutically acceptable salt thereof.

63. A compound selected from the group consisting of compounds Nos. 1 to 347 or any of the compounds disclosed in Table A, or a pharma- ceutical acceptable salt thereof.

64. 64. A pharmaceutical composition comprising a compound according to any one of claims 1 to 63 or a pharmacologically acceptable salt thereof, and an optional pharmacologically acceptable excipient.

65. 1. A method of treating a disease, comprising: administering to a subject in need thereof a therapeutically effective amount of at least one compound according to any one of claims 1 to 63 or a pharmaceutical composition according to claim 64; The disease is cancer or a viral infection; method.

66. The cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia and melanoma; 66. The method of claim 65.

67. further comprising administering to the subject an immuno-oncology agent (e.g., a protein antagonist that inhibits T cell activation and / or a protein agonist that stimulates T cell activation, e.g., as described herein); Preferably, the immuno-oncology agent is one or more antibodies selected from the group consisting of anti-PD-1, anti-PD-L1, anti-CTLA-4 and combinations thereof; 67. The method of claim 65 or 66.

68. A method for inhibiting the activity of at least one diacylglycerol kinase selected from the group consisting of diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKz), comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to any one of claims 1 to 63 or a pharmaceutical composition according to claim 64.

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