Compounds, methods of making and uses thereof

Abstract

Provided herein are novel compounds, e.g., compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of making the compounds and methods of using the compounds, e.g., to modulate the activity of one or more STAT proteins, particularly STAT3 and / or STAT6, and / or to treat various diseases, such as cancer.

Description

Cross-reference to related applications

[0001] This application claims priority to international application No. PCT / CN2023 / 132264, filed November 17, 2023; international application No. PCT / CN2024 / 075744, filed February 4, 2024; and international application No. PCT / CN2024 / 089561, filed April 24, 2024, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0002] In various embodiments, this disclosure generally relates to novel compounds, compositions comprising said compounds, methods for preparing said compounds, and methods for using said compounds (e.g., for regulating the activity of one or more proteins (particularly STAT3 and / or STAT6) of the signal transducer and activator of transcription (STAT) family, and / or for treating a variety of diseases or conditions, such as cancer, immune and / or inflammatory diseases or conditions). Background Technology

[0003] Signal transducers and activators of transcription (STAT) proteins play crucial roles in biological processes. For example, aberrant activation of STAT signaling pathways is associated with cancer, autoimmune diseases, and other human diseases (Miklossy et al., Nat Rev Drug Discov., 12:611-629, 2013). The STAT protein family consists of seven members: STAT1, STAT2, STAT3, STAT4, STAT5, STAT5B, and STAT6. Structurally, they share five domains: an N-terminal domain, a coil-coil domain, a DNA-binding domain, an SH2 domain, and a C-terminal transactivation domain. STAT3 and STAT6 are members of the STAT transcription factor family, directly transmitting signals from extracellular signal transduction receptors to the nucleus (J. Bromberg et al., Oncogene, 19, 2468-2473, 2000). Therefore, there is a need for selective and potent STAT3 and / or STAT6 modulators for the treatment of cancer, immune and / or inflammatory diseases or conditions. Summary of the Invention

[0004] This disclosure is based in part on the applicant's discovery of compounds that can act as regulators of STAT3 and / or STAT6. In various embodiments, this disclosure provides novel compounds, pharmaceutical compositions, methods of preparation and use thereof. The compounds and compositions herein can be used to treat a variety of conditions that respond to regulation of STAT3 and / or STAT6, such as cancer or immune and / or inflammatory diseases or conditions as described herein.

[0005] In various embodiments, this disclosure provides compounds of formula I, II, III or X, or pharmaceutically acceptable salts thereof:

[0006] The variables are defined herein. In some embodiments, compounds of formula I or II may have a sub-formula according to formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A as defined herein. In some embodiments, compounds of formula X may have a sub-formula according to formula X-1, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-11, X-12, X-13, X-14, X-2a, X-3a, X-4a, X-5a, X-6a, X-7a, X-8a, X-9a, X-10a, X-11a, X-12a, X-13a, or X-14a as defined herein.

[0007] In some embodiments, this disclosure provides compounds selected from those shown in Table A or pharmaceutically acceptable salts thereof.

[0008] Certain embodiments of this disclosure relate to a pharmaceutical composition comprising one or more compounds of this disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-1-A, or I-2-A), formula II (e.g., formula II-1 or II-1-A), formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein can be formulated for various routes of administration, such as oral administration, parenteral administration, or inhalation.

[0009] Some embodiments relate to a method of treating a condition that responds to regulation of STAT3 and / or STAT6 (e.g., any of those described herein). In some embodiments, the method includes administering to a subject in need a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula I (e.g., formula I-1, I-2, I-1-A, or I-2-A), formula II (e.g., formula II-1 or II-1-A), formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[0010] In some embodiments, a method for treating cancer is provided. In some embodiments, the method includes administering to a subject in need a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula I (e.g., formula I-1, I-2, I-1-A, or I-2-A), formula II (e.g., formula II-1 or II-1-A), formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of the pharmaceutical composition described herein.

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

[0012] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments, for example, in methods of treating cancer, combination therapy includes treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy.

[0013] It should be understood that the foregoing description of the invention and the following detailed description are merely exemplary and illustrative, and do not limit the invention herein. Detailed Implementation

[0014] In a broader sense, this disclosure provides compounds and compositions that can be used to regulate (e.g., inhibit) the activity of STAT proteins (particularly STAT3 and / or STAT6) and / or to treat or prevent the various diseases or conditions described herein (e.g., cancer or immune or inflammatory diseases as described herein).

[0015] compound In some embodiments, this disclosure provides compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof:

[0016] in: X 1 For CR 11 R 12 , X 2 For CR 21 R 22 NR 23 , O, S, S(O)2 or S(O)(NH); X 3 For CR 31 R 32 NR 33 , O, S, S(O)2 or S(O)(NH); X 4 Empty, CR 41 R 42 or CR 41 R 42 -CH2-; X 5 C is arbitrarily replaced 3-6 Alkyl group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl or optionally substituted 5-10 heteroaryl groups; R 11 R 12 R 21 R 22 R 31 R 32 R 41 and R 42 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R bEach time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; or R 11 and R 12 R 21 and R 22 R 31 and R 32 and R 41 and R 42 One of them, together with the C atoms in between, forms an optional C atom that can be substituted. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 11 R 12 R 21 R 22 R 31 R 32 R 41 and R 42 The others in the list are, independently, as defined herein; or R 11 and R 21 and R 21 and R 31 One of them, together with the C and C atoms in between, forms an optional C atom that can be substituted. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 11 R 12 R 21 R 22 R 31 R 32 R 41 and R 42 The others in the list are defined independently each time they appear, as defined in this document; R 23 and R 33 Each time it appears, it is independently selected from hydrogen, R c (C) 1-4 (alkylene)-R c C(O)-R c C(O)NH-R c 、C(O)NH-(C 1-4 (alkylene)-R c C(O)NR c R dS(O)R c S(O)2R c and S(O)2-(C 1-4 (alkylene)-R c , where R c and R d Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups; Y 1 For N, CH or CR 2 ; Y 2 For N, CH or CR 2 ; Z represents NH, O, or S; W is ,in W 1 For O, C(O), or optionally halogenated, C 1-4 Alkyl or C 1-4 The methylene group substituted by a haloalkyl group is preferably O, CH2, CH(CH3), CHF, CF2 or C(O); W 2 For NH-R wa -C(O)OR wb , OR wc ; W 3 OR wd ; R wa These are residues of α- or β-natural or non-natural amino acids; R wb Hydrogen, with optional substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl or optionally substituted (C 0-1 (alkylene)-phenyl; preferably, optionally substituted C 1-4 Alkyl or optionally substituted (C 0-1 (alkylene)-phenyl; It is a 4-6 membered heterocyclic group; R 5 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group or optionally substituted C 3-6 cycloalkyl; t can be 0, 1, 2, 3, or 4; R wc and R wd Each time it appears, it is independently selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C 1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-R e and -C 1-4 Alkylene-OC(O)NR e R f Wherein C 1-4 Each of the alkylene groups is independently and optionally substituted by one or more (e.g., one, two, or three) substituents independently selected from the following: optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl and optionally substituted (C 0-1(alkylene)-phenyl, wherein R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups; R 1 Hydrogen, with optional substituted C 1-4 Alkyl groups, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group or optionally substituted C 3-6 cycloalkyl; R 2 and R 3 Each time it appears, it is independently selected from halogen, OH, NH2, CN, C(O)NH2, R g (C) 1-4 (alkylene)-R g C(O)-R g C(O)OR g OC(O)-R g C(O)NH-R g ,NHC(O)-R g S(O)R g S(O)2R g and S(O)2-(C 1-4 (alkylene)-R g , where R g Selected from the C that is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups; m can be 0, 1, 2, or 3; n is 0, 1, 2, or 3; R 4 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group and optionally substituted C 3-6 cycloalkyl; p is 0, 1, 2, 3 or 4; q is 1 or 2; L 1 The substituted 4-10 member monocyclic or bicyclic heterocyclic ring, or the substituted 5-10 member monocyclic or bicyclic heteroaryl ring, are either empty or can be substituted. L 2 The options are: empty, O, NH, C(O), C(O)O, S, S(O), SO2, C(O)NH, and any C that is substituted. 1-4 Alkylene, optionally substituted OC 1-4 Alkylene, optionally substituted NH-C 1-4 Alkylene, optionally substituted N(C) 1-6 Alkyl) or optionally substituted N(C) 1-6 alkyl)-C 1-4 Alkylene; L 3 The ring is hydrogen or optionally substituted 3-14 membered rings, wherein the 3-14 membered rings are selected from monocyclic nonaromatic rings, monocyclic aromatic rings and polycyclic structures, wherein each ring in the polycyclic structure is independently aromatic or nonaromatic, and wherein the 3-14 membered rings optionally contain 1-4 cyclic heteroatoms independently selected from O, N and S.

[0017] It will be apparent to those skilled in the art that, in certain circumstances, compounds of formula I, II, III, or X (including any of the applicable formulas as described herein) may be present in mixtures of tautomers. This disclosure is not limited to any particular tautomer. Rather, this disclosure covers any and all such tautomers, whether or not explicitly drawn or mentioned.

[0018] In some embodiments, compounds of formula I, II, III, or X (including any of the applicable formulas described herein) may exist as isotopically labeled compounds (in particular, deuterated analogs), wherein one or more hydrogen atoms of the compound of formula I, II, III, or X (including any of the applicable formulas described herein) are substituted with deuterium atoms in abundance higher than their native abundance, for example, CD3 analogs when the compound has a CH3 group. Not wishing to be bound by theory, it is believed that in some cases, deuterated analogs may have a better or more desirable pharmacokinetic profile compared to their non-deuterated counterparts.

[0019] In some embodiments, the compound of formula I may be characterized by having formula I-1 or I-2:

[0020] Where X 1 X2 X 3 Y 1 Y 2 Z, W, R 1 R 2 R 3 m, n, L 1 L 2 and L 3 Defined in this article.

[0021] In some embodiments, the compound of formula I may be characterized by having formula I-1-A or I-2-A:

[0022] Where X 1 X 2 X 3 W, R 1 R 2 R 3 m, n, L 1 L 2 and L 3 Defined in this article.

[0023] In some embodiments, the compound of formula II may be characterized by having formula II-1:

[0024] Where X 5 Y 1 Y 2 Z, W, R 1 R 2 R 3 m, n, L 1 L 2 and L 3 Defined in this article.

[0025] In some embodiments, the compound of formula II may be characterized by having formula II-1-A:

[0026] Where X 5 W, R 1 R 2 R 3 m, n, L 1 L 2 and L 3 Defined in this article.

[0027] In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 1 For CR11 R 12 , where R 11 and R 12 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; or R 11 and R 12 Together with the C atoms in between, they form optional substituted C atoms. 3-6 A carbocyclic base ring or an optionally substituted 4-6 membered heterocyclic base ring. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 1 For CR 11 R 12 , where R 11 and R 12 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups substituted with F 1-4 Alkyl and C 3-4 cycloalkyl; or R 11 and R 12 Together with the C atoms in between, they form optional substituted C atoms. 3-4A carbocyclic base ring or an optionally substituted 4-5 membered heterocyclic base ring. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 1 It is -CH2-.

[0028] In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For CR 21 R 22 , where R 21 and R 22 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; or R 21 and R 22 Together with the C atoms in between, they form optional substituted C atoms. 3-6 A carbocyclic base ring or an optionally substituted 4-6 membered heterocyclic base ring. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For CR 21 R 22 , where R 21 and R 22Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups substituted with F 1-4 Alkyl, C 3-4 Cycloalkyl or 4-5 membered heterocyclic rings; or R 21 and R 22 Together with the C atoms in between, they form optional substituted C atoms. 3-4 A carbocyclic base ring or an optionally substituted 4-5 membered heterocyclic base ring. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For CR 21 R 22 , where R 21 For H and R 22 For hydrogen, OH, C 1-4 Alkyl, C 3-4 Cycloalkyl or a 4-5 membered heterocyclic ring containing one or two independent cyclic heteroatoms selected from N, O, and S; or R 21 and R 22 Together with the C atoms in between, they form C 3-4 Carbon ring-based ring. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For -CH2-. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 Selected from In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For NR 23 , where R 23 Selected from hydrogen, R c (C) 1-4 (alkylene)-R c C(O)-R c C(O)NH-R c 、C(O)NH-(C 1-4 (alkylene)-R c C(O)NR c R d S(O)R c S(O)2R c and S(O)2-(C 1-4 (alkylene)-R c , where R c and R d Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl group and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For NR 23 , where R 23 C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)-C 1-6 Alkyl group. In some preferred embodiments, X is in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A. 2 Selected from In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For NR 23 , where R 23 It is C(O)-(5-10 membered heterocyclic ring) or C(O)-(5-10 membered heteroaryl), wherein the heterocyclic ring or the heteroaryl contains one, two or three cyclic heteroatoms independently selected from N, O and S, and optionally is independently selected by one or more (e.g. one, two or three) halogens (e.g., F or Cl), OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For NR 23 , where R 23 It is C(O)-(9-membered heterocyclic ring) or C(O)-(9-membered heteroaryl), wherein the heterocyclic ring or the heteroaryl group contains one or two cyclic heteroatoms independently selected from N, O, and S, and optionally one or two independently selected from halogens (such as F or Cl), OH, C 1-4 Alkyl and OC 1-4 The alkyl group is substituted. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 for In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 for or In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 It can be O, S, S(O)2 or S(O)(NH).

[0029] In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For CR 31 R 32 , where R 31 and R 32 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; or R 31 and R 32 Together with the C atoms in between, they form optional substituted C atoms. 3-6 A carbocyclic base ring or an optionally substituted 4-6 membered heterocyclic base ring. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For CR 31 R 32 , where R 31 and R 32 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C.1-4 Alkyl groups, C groups substituted with F 1-4 Alkyl, C 3-4 Cycloalkyl and 4-5 membered heterocyclic rings; or R 31 and R 32 Together with the C atoms in between, they form optional substituted C atoms. 3-4 A carbocyclic base ring or an optionally substituted 4-5 membered heterocyclic base ring. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For CR 31 R 32 , where R 31 For H and R 32 For hydrogen, OH, C 1-4 Alkyl, C 3-4 Cycloalkyl or a 4-5 membered heterocyclic ring containing one or two independent cyclic heteroatoms selected from N, O, and S; or R 31 and R 32 Together with the C atoms in between, they form C 3-4 Carbon ring-based ring. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For -CH2-. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 Selected from In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For NR 33 , where R 33 Selected from hydrogen, R c (C) 1-4 (alkylene)-R c C(O)-R c C(O)NH-R c 、C(O)NH-(C 1-4 (alkylene)-R c C(O)NR c R d S(O)R c S(O)2R c and S(O)2-(C 1-4 (alkylene)-R c , where R c and R d Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl group and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For NR 33 , where R 33 C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)-C 1-6 Alkyl group. In some preferred embodiments, X is in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A. 3 Selected from In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For NR 33 , where R 33 It is C(O)-(5-10 membered heterocyclic ring) or C(O)-(5-10 membered heteroaryl), wherein the heterocyclic ring or the heteroaryl contains one, two or three cyclic heteroatoms independently selected from N, O and S, and optionally is independently selected by one or more (e.g. one, two or three) halogens (e.g., F or Cl), OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 For NR 33 , where R 33 It is C(O)-(9-membered heterocyclic ring) or C(O)-(9-membered heteroaryl), wherein the heterocyclic ring or the heteroaryl group contains one or two cyclic heteroatoms independently selected from N, O, and S, and optionally one or two independently selected from halogens (such as F or Cl), OH, C 1-4 Alkyl and OC 1-4 The alkyl group is substituted. In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 for In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 3 for or In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X3 It can be O, S, S(O)2 or S(O)(NH).

[0030] In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 1 For CR 11 R 12 And X 2 For CR 21 R 22 , where R 11 and R 21 Together with the C and C atoms in between, they form optional substituted C atoms. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 12 and R 22 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl group and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 1 For CR 11 R 12 And X 2 For CR 21 R 22 , where R 11and R 21 Together with the C and C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring and R 12 and R 22 Each time it appears, it is independently selected from hydrogen and C. 1-4 Alkyl group. In some preferred embodiments, X is in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A. 1 -X 2 for In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 1 -X 2 for or .

[0031] In some implementations, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For CR 21 R 22 And X 3 For CR 31 R 32 , where R 21 and R 31 Together with the C and C atoms in between, they form optional substituted C atoms. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 22 and R 32 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl group and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 For CR 21 R 22 And X 3 For CR 31 R 32 , where R 21 and R 31 Together with the C and C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring and R 22 and R 32 Each time it appears, it is independently selected from hydrogen and C. 1-4 Alkyl group. In some preferred embodiments, X is in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A. 2 -X 3 for In some preferred embodiments, in formula I or III, or in formula I-1, I-2, I-1-A or I-2-A, X 2 -X 3 for or .

[0032] In some implementations, in formula I or III, or in formula I-1 or I-2, X 4 Empty. In some implementations, in formula I or III, or in formula I-1 or I-2, X 4 For CR 41 R 42 or CR 41 R 42 -CH2-, where R 41 and R 42 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NRa R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; or R 41 and R 42 Together with the C atoms in between, they form optional substituted C atoms. 3-6 A carbocyclic base ring or an optionally substituted 4-6 membered heterocyclic base ring. In some embodiments, in formula I or III, or in formula I-1 or I-2, X 4 For CR 41 R 42 or CR 41 R 42 -CH2-, where R 41 and R 42 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups substituted with F 1-4 Alkyl and C 3-4 cycloalkyl; or R 41 and R 42 Together with the C atoms in between, they form optional substituted C atoms. 3-4 A carbocyclic base ring or an optionally substituted 4-5 membered heterocyclic base ring. In some preferred embodiments, in formula I or III, or in formula I-1 or I-2, X 4 For -CH2-. In some preferred embodiments, in formula I or III, or in formula I-1 or I-2, X 4 It is -CH2CH2-.

[0033] In some implementations, in Formula II, or in Formula II-1 or II-1-A, X 5 C is arbitrarily replaced 3-6 Alkyl group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10Aryl or optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula II, or in formula II-1 or II-1-A, X 5 C 3-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic ring, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, the heterocyclic ring, the phenyl or the heteroaryl is optionally selected by one or more independently from halogen (such as F or Cl), OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and OC 1-4 The alkyl group is substituted. In some embodiments, in formula II, or in formula II-1 or II-1-A, X 5 It is isopropyl, cyclopropyl, tert-butyl, or phenyl.

[0034] In some implementations, in formula I or II, or in formula I-1, I-2, or II-1, Y 1 For N. In some embodiments, in formula I or II, or in formula I-1, I-2, or II-1, Y 1 For CH. In some embodiments, in formula I or II, or in formula I-1, I-2 or II-1, Y 1 For CR 2 , where R 2 Defined in this article.

[0035] In some implementations, in formula I or II, or in formula I-1, I-2, or II-1, Y 2 For N. In some embodiments, in formula I or II, or in formula I-1, I-2, or II-1, Y 2 For CH. In some embodiments, in formula I or II, or in formula I-1, I-2 or II-1, Y 2 For CR 2 , where R 2 Defined in this article.

[0036] In some embodiments, Z is NH in Formula I, II, or III, or in Formula I-1, I-2, or II-1. In some embodiments, Z is O in Formula I, II, or III, or in Formula I-1, I-2, or II-1. In some embodiments, Z is S in Formula I, II, or III, or in Formula I-1, I-2, or II-1.

[0037] In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is ,in W1 For O, C(O), or optionally halogenated, C 1-4 Alkyl or C 1-4 The methylene group substituted by a haloalkyl group is preferably O, CH2, CH(CH3), CHF, CF2 or C(O); W 2 For NH-R wa -C(O)OR wb , OR wc ; W 3 OR wd ; R wa These are residues of α- or β-natural or non-natural amino acids; R wb Hydrogen, with optional substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl or optionally substituted (C 0-1 (alkylene)-phenyl; preferably, optionally substituted C 1-4 Alkyl or optionally substituted (C 0-1 (alkylene)-phenyl; It is a 4-6 membered heterocyclic group; R 5 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group and optionally substituted C 3-6 cycloalkyl; t can be 0, 1, 2, 3, or 4; R wc and R wd Each time it appears, it is independently selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-R e and -C 1-4 Alkylene-OC(O)NR e R f Wherein C 1-4 Each of the alkylene groups is independently and optionally substituted by one or more (e.g., one, two, or three) substituents independently selected from the following: optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl and optionally substituted (C 0-1 (alkylene)-phenyl, wherein R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups.

[0038] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, W 1 It is CH2, CHF, or CF2. In some embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W 1 for or In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W 1It is O or C(O). In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, W 1 For CH(CH3). In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, W 2 For NH-R wa -C(O)OR wb And W 3 OR wd , where R wa For α- or β-residues of natural or non-natural amino acids; R wb C is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl or optionally substituted (C 0-1 (alkylene)-phenyl; preferably, optionally substituted C 1-4 Alkyl or optionally substituted (C 0-1 (alkylene)-phenyl; and R wd Selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C 1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-R e and -C 1-4 Alkylene-OC(O)NR e Rf Wherein C 1-4 Each of the alkylene groups is independently and optionally substituted by one or more (e.g., one, two, or three) substituents independently selected from the following: optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl and optionally substituted (C 0-1 (alkylene)-phenyl, wherein R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, W 2 OR wc And W 3 OR wd , where R wc and R wd Each time it appears, it is independently selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C 1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-Re and -C 1-4 Alkylene-OC(O)NR e R f Wherein C 1-4 Each of the alkylene groups is independently and optionally substituted by one or more (e.g., one, two, or three) substituents independently selected from the following: optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl and optionally substituted (C 0-1 (alkylene)-phenyl, wherein R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, -P(O)(W) in the definition of W herein. 2 (W) 3 ) part (For example, )or In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from... (For example, ) In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from... In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from... In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is (For example, In some preferred embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, W is selected from... (For example, ) In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from... In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from... (For example, In some preferred embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, W is selected from: In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from: In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, W is selected from: .

[0039] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, R 1 Hydrogen, with optional substituted C 1-4 Alkyl groups, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group or optionally substituted C 3-6Cycloalkyl. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, R 1 For hydrogen, C 1-3 Alkyl groups, C groups substituted with F 1-3 Alkyl, or C 3-4 Cycloalkyl. In some preferred embodiments, R is present in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. 1 It is hydrogen.

[0040] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, R 2 Each time it appears, it is independently selected from halogen, OH, NH2, CN, C(O)NH2, R g (C) 1-4 (alkylene)-R g C(O)-R g C(O)OR g OC(O)-R g C(O)NH-R g ,NHC(O)-R g S(O)R g S(O)2R g and S(O)2-(C 1-4 (alkylene)-R g , where R g Selected from the C that is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl group and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, R 2 Each occurrence is independently F, Cl, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4Alkyl groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 Alkylthio groups (e.g., CH3S-), fluorinated C 1-4 Alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy.

[0041] In some embodiments, m is 0, 1, 2, or 3 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some embodiments, m is 0 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some embodiments, m is 1 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some embodiments, m is 2 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some implementations, m is 3 in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A.

[0042] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, R 3 Each time it appears, it is independently selected from halogen, OH, NH2, CN, C(O)NH2, R g (C) 1-4 (alkylene)-R g C(O)-R g C(O)OR g OC(O)-R g C(O)NH-R g ,NHC(O)-R g S(O)R g S(O)2R g and S(O)2-(C 1-4 (alkylene)-R g , where R g Selected from the C that is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10Aryl group and optionally substituted 5-10 heteroaryl groups. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, R 3 Each occurrence is independently F, Cl, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkyl groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 Alkylthio groups (e.g., CH3S-), fluorinated C 1-4 Alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy.

[0043] In some embodiments, n is 0, 1, 2, or 3 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some embodiments, n is 0 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some embodiments, n is 1 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some embodiments, n is 2 in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A. In some implementations, n is 3 in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A.

[0044] In some implementations, in formula I, II, or III, R 4 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group and optionally substituted C 3-6 Cycloalkyl. In some embodiments, R in formula I, II, or III 4 Each time it appears, it is independently selected from halogens (such as F and Cl), OH, NH2, CN, C. 1-2Alkyl groups, C groups substituted with F 1-2 Alkyl and C 3-4 Cycloalkyl.

[0045] In some embodiments, p is 0, 1, 2, 3, or 4 in Formula I, II, or III. In some embodiments, p is 0 in Formula I, II, or III. In some embodiments, p is 1 in Formula I, II, or III. In some embodiments, p is 2 in Formula I, II, or III. In some embodiments, p is 3 in Formula I, II, or III. In some embodiments, p is 4 in Formula I, II, or III.

[0046] In some embodiments, q is 1 or 2 in formula I, II, or III. In some embodiments, q is 1 in formula I, II, or III. In some embodiments, q is 2 in formula I, II, or III.

[0047] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 1 Empty. In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 The substituted 4-10 member monocyclic or bicyclic heterocyclic ring or the substituted 5-10 member monocyclic or bicyclic heteroaryl group is used. In some embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 It is a 4-7 membered monocyclic or bicyclic heterocyclic ring containing one or two cyclic heteroatoms independently selected from N, O, and S, and optionally by one or more cyclic heteroatoms independently selected from halogens (such as F and Cl), OH, CN, C. 1-2 Alkyl groups, C groups substituted with F 1-2 Alkyl, OC 1-2 Alkyl and C 2-3 The alkynyl group is substituted by a substituent. In some embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 It is a 4-, 5-, or 6-membered monocyclic heterocyclic ring (such as azirrobutyl, pyrrolidinyl, and morpholinyl) containing one or two cyclic heteroatoms independently selected from N, O, and S, and optionally by one or more (e.g., one, two, or three) independently selected from halogen, OH, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 2-4The alkynyl group is substituted by a substituent. In some embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 It is a 7-8 membered bicyclic heterocyclic base ring (such as a spirocyclic or bridged bicyclic heterocyclic base ring, for example, azepispirolyl, oxa-azepi-bicycloheptyl, and oxa-azepi-bicyclooctyl) containing one or two cyclic heteroatoms independently selected from N, O, and S, and optionally by one or more (e.g., one, two, or three) independently selected from halogen, OH, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 2-4 The alkynyl group is substituted by a substituent. In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 Selected from where * represents L 2 or L 3 The connection and Represents the connection with C(O). In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 Selected from where * represents L 2 or L 3 The connection and Represents the connection with C(O). In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 for where * represents L 2 or L 3 The connection and Represents the connection with C(O). In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 Selected from where * represents L 2 or L 3 The connection and This represents the connection with C(O).

[0048] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 2For empty, O, NH, C(O, C(O)O, S, S(O), SO2, C(O)NH, and optionally substituted C 1-4 Alkylene, optionally substituted OC 1-4 Alkylene, optionally substituted NH-C 1-4 Alkylene, optionally substituted N(C) 1-6 Alkyl) or optionally substituted N(C) 1-6 alkyl)-C 1-4 Alkylene. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 2 empty, C(O), S(O)2, C 1-2 Alkylene or C 1-2 Alkylene-O-. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 2 Empty. In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 2 For C(O). In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 2 It is a methylene group.

[0049] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 The 3-14 membered ring structure is hydrogen or optionally substituted, wherein the 3-14 membered ring structure is selected from monocyclic nonaromatic rings, monocyclic aromatic rings, and polycyclic structures, wherein each ring in the polycyclic structure is independently aromatic or nonaromatic, and wherein the 3-14 membered ring structure optionally contains 1-4 cyclic heteroatoms independently selected from O, N, and S. In some embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 It is hydrogen. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 The heterocyclic ring is a 6-membered heterocyclic ring containing one or two cyclic heteroatoms independently selected from N, O, and S, a phenyl group, or a 6-membered heteroaryl group containing one or two cyclic N atoms, wherein the heterocyclic ring, the phenyl group, or the heteroaryl group is optionally selected by one or more of the following independently: halogen (e.g., F and Cl), OH, oxo, C.1-4 Alkyl and OC 1-4 Alkyl groups are substituted. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 For optional selection by one or more independently selected halogens, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-4 cycloalkyl and C 1-4 The phenyl group substituted with an alkoxy group. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 It contains one or two ring N atoms (e.g., imidazole group) and is optionally C 1-4 5-membered heteroaryl group substituted with alkyl group. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 It contains one or two ring nitrogen atoms (e.g., pyridinyl and pyrimidinyl) and is optionally selected by one or more atoms, each independently chosen from halogens (e.g., F), oxo, C. 1-4 Alkyl (e.g., methyl), C 1-4 Haloalkyl, C 3-4 cycloalkyl, C 1-4 Alkyl groups (e.g., methoxy groups), N(C) 1-4 Alkyl)(C 1-4 The 6-membered heteroaryl group is substituted with an alkyl group (e.g., N(CH3)2) and a substituent containing one or two cyclic heteroatoms independently selected from N and O (e.g., azirrobutyl and morpholinyl). In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 It contains one or two cyclic heteroatoms (e.g., morpholino) and is optionally C 1-4 alkyl-substituted 6-membered heterocyclic groups. In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 Selected from: In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 for In some preferred embodiments, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 Selected from: .

[0050] In some implementations, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 1 for or where * represents L 2 or L 3 The connection and L represents the connection with C(O). 2 It is empty, and L 3 It is phenyl or contains one or two ring nitrogen atoms (e.g., pyridinyl and pyridone groups) and optionally is selected independently by one or more halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-4 cycloalkyl, C 1-4 Alkoxy and N(C) 1-4 Alkyl)(C 1-6 The 6-membered heteroaryl group substituted with an alkyl group. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 -L 2 -L 1 Selected from In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 for where * represents L 2 or L 3 The connection and L represents the connection with C(O). 2 It is empty, and L 3 It contains one or two ring nitrogen atoms (e.g., imidazolium, pyridinium, and pyrimidinium) and is optionally selected by one or more halogens (e.g., F, C) independently. 1-4 Alkyl (e.g., methyl), C 1-4 Haloalkyl, C 3-4 cycloalkyl, C 1-4 Alkyl groups (e.g., methoxy groups), N(C) 1-4 Alkyl)(C 1-6The 5-6 membered heteroaryl group is substituted with an alkyl group (e.g., N(CH3)2) and a substituent containing one or two cyclic heteroatoms independently selected from N and O (e.g., azirrobutyl and morpholinyl). In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 -L 2 -L 1 Selected from: In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 1 for where * represents L 2 or L 3 The connection and L represents the connection with C(O). 2 It is either empty or methylene, and L 3 It is H or phenyl. In some embodiments, in formula I, II or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1 or II-1-A, L 3 -L 2 -L 1 Selected from: In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 -L 2 -L 1 for In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 -L 2 -L 1 for In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 -L 2 -L 1 Selected from In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 -L 2 -L 1 for In some implementations, in formula I, II, or III, or in formula I-1, I-2, I-1-A, I-2-A, II-1, or II-1-A, L 3 -L 2 -L 1 for .

[0051] This disclosure also provides the following non-limiting enumerated embodiments 1-37: Implementation Scheme 1. A compound of formula X or a salt thereof, , Formula X in: G 1 and G 2A Defined in either (a) or (b) below: (a) G 1 For hydrogen or R 4 And G 2A C is arbitrarily replaced 3-6 Alkyl group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted aryl group, or optionally substituted 5-10 membered heteroaryl group; or (b) G 1 and G 2A The connection makes the equation X Some are 7-9 member monocyclic or 8-12 member bicyclic, each of which, in addition to the cyclic nitrogen atom, optionally has one cyclic heteroatom N, O, or S, wherein the cyclic sulfur atom (if present) is optionally selected from S(O), S(O)2, and S(=NG). 10 The oxidation form of (=O), where G 10 It is hydrogen or C 1-4 Alkyl group; wherein the 7-9 member monocyclic ring or the 8-12 member bicyclic ring is optionally selected by one or more (e.g., 1 or 2) independently from F, CN, G. 11 L A -G 12 C 1-4 Alkylene-L A -G 12 and C 1-4 Heteroalkyl-L A -G 12 The substituents are replaced by the substituents. Where L A Each occurrence is independently classified as O or NG. 13 C(O), C(O)O, C(O)NG 13 S(O)2 or S(O)2NG 13 , G12 It is independently hydrogen or G each time it appears. 11 , G 13 Each time it appears, it is independently hydrogen or C, optionally replaced by deuterium and / or F. 1-4 alkyl, G 11 Each time it appears, it is independently selected as one or more Gs. 14 The C that was replaced 1-4 Alkyl, optionally with one or more G 14 The C that was replaced 1-4 Heteroalkyl or optionally with one or more G 15 The replaced 3-14 member ring, Among them G 14 Each time it appears, it is independently F, OH, CN, or C optionally replaced by deuterium and / or F. 1-4 Alkoxy or optionally with one or more G 15 The 3-6 member rings that are replaced; Among them G 15 Each time it appears, it is independently of deuterium, halogen (e.g., F), oxo, OH, CN, G. 16 Or a 3-5 membered ring, wherein the 3-5 membered ring is optionally coated with F, OH or G. 16 Replaced, of which G 16 It is C independently each time it appears. 1-4 Alkyl or C 1-4 Heteroalkyl groups, optionally substituted with deuterium and / or F; G 2B C is hydrogen or optionally replaced by F and / or OH. 1-4 alkyl; G 3A and G 3B Each is independently hydrogen, and the C atoms can be optionally substituted. 1-6 Alkyl groups or optionally substituted 3-10 membered rings; or G 3A and G 3B Together with the nitrogen atoms to which they are all attached, they form bonds except for G. 3A and G 3B All connected to the cyclic nitrogen atom are optionally substituted 4-14 membered heterocyclic rings having 1-4 cyclic heteroatoms outside the ring. For example, the 4-14 membered heterocyclic rings are optionally replaced by one or more (e.g., 1, 2 or 3) independently selected from deuterium, halogen (e.g., F), oxo, OH, CN, G. 3C OG 3C and C(O)G 3C The substituents are replaced by G, where G is the substituent. 3C Each time it appears, it is independently C that is arbitrarily replaced by deuterium and / or F.1-4 Alkyl groups, C groups optionally substituted with deuterium, oxo, and / or F. 1-4 Heteroalkyl groups or optionally selected independently from one or more deuterium, halogen (e.g., F), oxo, OH, CN, C 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups on 3-14 membered rings (e.g., C14-C2 ... 3-6 cycloalkyl, 4-8 membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl), wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally substituted with deuterium and / or F; or G 3C For 3-14 member rings (e.g., C 3-6 Cycloalkyl, 4-8-membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl), optionally selected by one or more elements independently selected from deuterium, halogen (e.g., F), oxo, OH, CN, C 1-4 Alkyl, C 1-4 Substituents of heteroalkyl groups and 3-7 membered carbocyclic or heterocyclic rings, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may optionally be substituted with deuterium and / or F, and the 3-7 membered carbocyclic or heterocyclic ring may optionally be selected independently from deuterium, halogen (e.g., F), oxo, OH, CN, C. 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups; G 4A and G 4B Each can be independently hydrogen, methyl, or F; A 1 -G 5 and A 2 -G 6 Make Part of , or its phosphate derivatives (A 1 and A 2 All are O, G 5 and G 6 At least one of them is not hydrogen), and its phosphonamide ester derivative (A) 1 and A 2 One of them is O, and A 1 and A 2 Another one (linked to a P(O) group via a nitrogen atom) or its diaminophosphate derivative (A) 1 and A 2 All are connected to the P(O) group via a nitrogen atom, for example, A 1 and A 2 Each can be independently O, NH or N (A) S), where A S C 1-4 Alkyl groups, which may be optionally substituted, or A S Together with the nitrogen atom it is attached to, and G 5 or G 6 The atoms are linked (if applicable) to form 4-7 membered heterocyclic rings, which may optionally be substituted; G 5 and G 6 Each is independently hydrogen, and the C atoms can be optionally substituted. 1-20 Alkyl groups, optionally substituted C 3-20 Alkenyl group, optionally substituted C 3-20 alkynyl group, optionally substituted C 1-20 Heteroalkyl groups or optionally substituted 3-14-membered rings, R 1 Hydrogen, with optional substituted C 1-4 Alkyl groups, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group or optionally substituted C 3-6 cycloalkyl; R 2 and R 3 Each time it appears, it is independently selected from halogen, OH, CN, or optionally substituted C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted aryl and optionally substituted 5-10 membered heteroaryl; m is 0 or 1; n is 0, 1, or 2; R 4 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group and optionally substituted C 3-6 cycloalkyl; and p is 0, 1, 2, 3, or 4; and q is 1 or 2, Preferably, the salt is a pharmaceutically acceptable salt.

[0052] Implementation Scheme 2. The compound of Implementation Scheme 1 or a salt thereof, characterized in that it has a structure according to Formula X-1:

[0053] Formula X-1.

[0054] Implementation Scheme 3. The compound of Implementation Scheme 1 or 2 or a salt thereof, wherein G 2B It is hydrogen.

[0055] Implementation Scheme 4. A compound or a salt thereof from any one of Implementation Schemes 1-3, wherein R 1 It is hydrogen.

[0056] Implementation Scheme 5. A compound or a salt thereof from any one of Implementation Schemes 1-4, wherein G 1 and G 2A The connection makes the equation X Partially a 7-9 membered monocyclic base ring, which, apart from the cyclic nitrogen atom, does not contain cyclic heteroatoms, wherein the 7-9 membered monocyclic base ring is unsubstituted or substituted by one or two substituents independently selected from: F, OH, CN, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 Heteroalkyl groups and optionally one or more independently selected from deuterium, F, oxo, OH, CN, C 1-4 Alkyl and C 1-4 The 3-6 membered ring substituted by a heteroalkyl substituent, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally replaced by deuterium and / or F.

[0057] Implementation Scheme 6. The compound of Implementation Scheme 5 or a salt thereof, characterized in that it has a structure according to formula X-2, X-3, X-4 or X-5:

[0058] Formula X-2 Formula X-3

[0059] Formula X-4 Formula X-5 Among them G 20 F, OH, or C optionally replaced by deuterium and / or F 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 An alkoxy group, a 3-6 membered carbocyclic ring, or a 4-6 membered heterocyclic ring having one or two cyclic heteroatoms independently selected from O, N, and S, wherein the 3-6 membered carbocyclic ring or the 4-6 membered heterocyclic ring is optionally selected by one or more atoms each independently selected from deuterium, F, oxo, OH, CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted by a substituent, wherein the C 1-4alkyl or the C 1-4 The alkoxy group may be optionally replaced by deuterium and / or F.

[0060] Implementation Scheme 7. The compound of Implementation Scheme 6 or a salt thereof, characterized in that it has a structure according to formula X-2a, X-3a, X-4a or X-5a:

[0061] Formula X-2a Formula X-3a

[0062] Formula X-4a and Formula X-5a.

[0063] Implementation Scheme 8. A compound or a salt thereof from any one of Implementation Schemes 1-4, wherein G 1 and G 2A The connection makes the equation X Partially, it is a 7-9 member monocyclic ring, containing, in addition to the cyclic nitrogen atom, a cyclic heteroatom, wherein the cyclic heteroatom is an epoxy atom or a cyclic sulfur atom, wherein the cyclic sulfur atom is optionally in the oxidized form of S(O)2 or S(=NH)(O), wherein the 7-9 member monocyclic ring is unsubstituted or substituted by one or two substituents independently selected from: F, OH, CN, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 Heteroalkyl groups and optionally one or more independently selected from deuterium, F, oxo, OH, CN, C 1-4 Alkyl and C 1-4 The 3-6 membered ring substituted by a heteroalkyl substituent, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally replaced by deuterium and / or F.

[0064] Implementation Scheme 9. The compound of Implementation Scheme 8 or a salt thereof, characterized in that it has a structure according to formula X-6, X-7 or X-8:

[0065] Type X-6, Type X-7, Type X-8 in A 3 It is O, S(O)2 or S(=NH)(=O), and G 21 C is hydrogen, optionally replaced by deuterium and / or F. 1-4Alkyl, 3-6 membered carbocyclic ring, or 4-6 membered heterocyclic ring having one or two independent cyclic heteroatoms selected from O, N, or S, wherein the 3-6 membered carbocyclic ring or the 4-6 membered heterocyclic ring is optionally composed of one or more independently selected from deuterium, F, oxo, OH, CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted by a substituent, wherein the C 1-4 alkyl or the C 1-4 The alkoxy group may be optionally replaced by deuterium and / or F.

[0066] Implementation Scheme 10. The compound of Implementation Scheme 9 or a salt thereof, characterized in that it has a structure according to formula X-6a, X-7a or X-8a:

[0067] Formula X-6a, Formula X-7a, Formula X-8a.

[0068] Implementation Scheme 11. A compound or a salt thereof from any one of Implementation Schemes 1-4, wherein G 1 and G 2A The connection makes the equation X Partially, it is a 7-9 member monocyclic base ring, which, in addition to a cyclic nitrogen atom from an intercalary atom, contains a cyclic heteroatom, wherein the cyclic heteroatom is a cyclic nitrogen atom, and wherein the 7-9 member monocyclic base ring is unsubstituted or is independently selected from F, CN, G by one or more (e.g., 1 or 2). 11 L A -G 12 C 1-4 Alkylene-L A -G 12 and C 1-4 Heteroalkyl-L A -G 12 The substituents are replaced by G, where G is the substituent. 11 G 12 and L A As defined in Implementation Scheme 1.

[0069] Implementation Scheme 12. The compound of Implementation Scheme 11 or a salt thereof, characterized in that it has a structure according to formula X-9, X-10 or X-11:

[0070] Type X-9, Type X-10, Type X-11 Among them G 22 For hydrogen, G 11 C(O)-G 12C(O)OG 12 or C(O)N(G) 13 )-G 12 G 11 G 12 and G 13 As defined in Implementation Scheme 1, for example, G 22 C can be arbitrarily replaced by deuterium and / or F. 1-4 Alkyl, 3-6 membered carbocyclic ring, or 4-6 membered heterocyclic ring having one or two independent cyclic heteroatoms selected from O, N, and S, wherein the 3-6 membered carbocyclic ring or the 4-6 membered heterocyclic ring is optionally selected by one or more atoms each independently selected from deuterium, F, oxo, OH, CN, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted by a substituent, wherein the C 1-4 alkyl or the C 1-4 The alkoxy group may be optionally substituted with deuterium and / or F; or G 22 C(O)-(C 1-4 Alkyl) or C(O)-(5-10 heteroaryl), wherein the C 1-4 The alkyl group may optionally be substituted with deuterium and / or F; and the 5-10 heteroaryl group may optionally be selected independently from halogen, CN, OH, C. 1-4 Alkyl and C 1-4 The alkoxy group is substituted by a substituent, wherein the C 1-4 alkyl or the C 1-4 The alkoxy group may be optionally replaced by deuterium and / or F.

[0071] Implementation Scheme 13. The compound of Implementation Scheme 12 or a salt thereof, characterized in that it has a structure according to formula X-9a, X-10a or X-11a:

[0072] Formula X-9a, Formula X-10a, Formula X-11a.

[0073] Implementation Scheme 14. A compound or a salt thereof from any one of Implementation Schemes 1-4, wherein G 1 and G 2A The connection makes the equation X Partially, it is an 8-12 membered bicyclic ring, which, apart from the cyclic nitrogen atom, does not contain cyclic heteroatoms, wherein the 8-12 membered bicyclic ring is either unsubstituted or substituted by one or two substituents independently selected from: F, OH, CN, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4Heteroalkyl groups or optionally selected by one or more elements independently chosen from deuterium, F, oxo, OH, CN, C 1-4 Alkyl and C 1-4 The 3-6 membered ring substituted by a heteroalkyl substituent, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally replaced by deuterium and / or F.

[0074] Implementation Scheme 15. The compound of Implementation Scheme 14 or a salt thereof, characterized in that it has a structure according to formula X-12, X-13 or X-14:

[0075] Formula X-12, Formula X-13, Formula X-14.

[0076] Implementation Scheme 16. The compound of Implementation Scheme 15 or a salt thereof, characterized in that it has a structure according to formula X-12a, X-13a or X-14a:

[0077] Formula X-12a, Formula X-13a, Formula X-14a.

[0078] Implementation Scheme 17. A compound or a salt thereof from any one of Implementation Schemes 1-16, wherein G 4A For hydrogen and G 4B It is F.

[0079] Implementation Scheme 18. A compound or a salt thereof from any one of Implementation Schemes 1-16, wherein G 4A and G 4B All are hydrogen or all are F.

[0080] Implementation Scheme 19. A compound or a salt thereof from any one of Implementation Schemes 1-18, wherein A 1 It is O or NH, and G 5 Hydrogen or selected from: (1) C 1-6 alkyl; (2) -C 1-6 Alkylene-L B -G 5A ; (3) -C 1-6 Heteroalkyl-L B -G 5A ; (4) 3-10 membered ring; (5) –(3-10 elemental ring)-L B -G5A ; (6) -C 1-6 Alkylene – (3-10 membered ring); (7) -C 1-6 Alkylene–(3-10 membered ring)-L B -G 5A ; (8) -C 1-6 Heteroalkyl groups – (3-10 membered rings); and (9) -C 1-6 Heteroalkyl–(3-10 membered ring)-L B -G 5A ; in When it exists, L B For O, NG 5B S, C(O), C(O)O, C(O)NG 5B S(O), S(O)2, S(O)2NG 5B ,OC(O)O-, -OC(O)NG 5B -, SC(O) or -N(G) 5B )S(O)2N(G 5B )-; G 5A Each time it appears, it is independently hydrogen or C. 1-6 Alkyl, C 1-6 Heteroalkyl groups or 3-10 membered rings; G 5B Each time it appears, it is independently hydrogen or C, optionally replaced by deuterium, F, and / or OH. 1-4 alkyl; Each 3-10 membered ring is independently selected from 3-10 membered carbocyclic rings, 4-10 membered heterocyclic rings, phenyl rings, naphthyl rings, and 5-10 membered heteroaryl rings, and each is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, NH2, COOH, CONH2, CN, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 Heteroalkyl groups and 3-5-membered rings, wherein the 3-5-membered rings are optionally substituted with F, OH, or C groups optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Substituted with heteroalkyl groups; Among them (1)-(9) or G 5A The aforementioned C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkylene or C 1-6Each heteroalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, OH, NH2, COOH, CONH2, CN, and 3-5 membered rings, wherein the 3-5 membered ring is optionally substituted by F, OH, or C substituted by deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Substituted with heteroalkyl groups.

[0081] Implementation Scheme 20. A compound or a salt thereof from any one of Implementation Schemes 1-19, wherein A 1 It is O.

[0082] Implementation Scheme 21. The compound of Implementation Scheme 20 or a salt thereof, wherein G 5 The phenyl group is optionally substituted as described in Embodiment 19, for example, optionally substituted with one or more C molecules independently selected from deuterium, halogen, CN, or C molecules optionally substituted with deuterium and / or F. 1-4 Alkyl groups and C groups optionally substituted with deuterium and / or F 1-4 The alkoxy group is replaced by a substituent.

[0083] Implementation Scheme 22. A compound or a salt thereof from any one of Implementation Schemes 1-21, wherein A 2 It is O or NH, and G 6 Hydrogen or selected from: (1) C 1-6 alkyl; (2) -C 1-6 Alkylene-L C -G 6A ; (3) -C 1-6 Heteroalkyl-L C -G 6A ; (4) 3-10 membered ring; (5) –(3-10 elemental ring)-L C -G 6A ; (6) -C 1-6 Alkylene – (3-10 membered ring); (7) -C 1-6 Alkylene–(3-10 membered ring)-L C -G 6A ; (8) -C 1-6 Heteroalkyl groups – (3-10 membered rings); and (9) -C 1-6 Heteroalkyl–(3-10 membered ring)-L C -G 6A ; in When it exists, L C For O, NG 6B S, C(O), C(O)O, C(O)NG 6B S(O), S(O)2, S(O)2NG 6B ,OC(O)O-, -OC(O)N(G 6B -, SC(O) or -N(G) 6B )S(O)2N(G 6B )-; G 6A Each time it appears, it is independently hydrogen or C. 1-6 Alkyl, C 1-6 Heteroalkyl groups or 3-10 membered rings; G 6B Each time it appears, it is independently hydrogen or C, optionally replaced by deuterium, F, and / or OH. 1-4 alkyl; Each 3-10 membered ring is independently selected from 3-10 membered carbocyclic rings, 4-10 membered heterocyclic rings, phenyl rings, naphthyl rings, and 5-10 membered heteroaryl rings, and each is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, NH2, COOH, CONH2, CN, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 Heteroalkyl groups and 3-5-membered rings, wherein the 3-5-membered rings are optionally substituted with F, OH, or C groups optionally substituted with deuterium and / or F. 1-4 Alkyl groups and C groups optionally substituted with deuterium and / or F 1-4 Substituted with heteroalkyl groups; Among them (1)-(9) or G 6A The aforementioned C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkylene or C 1-6 Each heteroalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, OH, NH2, COOH, CONH2, CN, and 3-5 membered rings, wherein the 3-5 membered ring is optionally substituted by F, OH, or C substituted by deuterium and / or F. 1-4 Alkyl groups and C groups optionally substituted with deuterium and / or F 1-4 Substituted with heteroalkyl groups.

[0084] Implementation Scheme 23. A compound or a salt thereof from any one of Implementation Schemes 1-22, wherein A 1 -G 5 and A 2 -G 6 They are the same.

[0085] Implementation Scheme 24. A compound or a salt thereof from any one of Implementation Schemes 1-23, wherein A 1 -G 5 It is OH and A 2 -G 6 It is OH.

[0086] Implementation Scheme 25. A compound or a salt thereof from any one of Implementation Schemes 1-21, wherein A 2 It is NH.

[0087] Implementation Scheme 26. The compound of Implementation Scheme 25 or a salt thereof, wherein A 2 -G 6 The characteristic lies in the corresponding compound HA 2 -G 6 For G 6 -NH2, which is an amino acid (e.g., natural proteogenic amino acids such as alanine, non-proteogenic α-amino acids, β-amino acids, etc.), its ester or its amide.

[0088] Implementation Scheme 27. A compound or a salt thereof from any of Implementation Schemes 1-16, wherein formula X or its derivative contains... Part of .

[0089] Implementation Scheme 28. A compound or salt thereof from any of Implementation Schemes 1-16, wherein formula X or its derivative contains... Part of Phosphonamide ester derivatives or salts thereof, wherein the phosphonamide ester derivative can be converted in vivo after administration of said compound or a pharmaceutically acceptable salt thereof to a human. For example, in equation X or its sub-equations Part of .

[0090] Implementation Scheme 29. A compound or a salt thereof from any one of Implementation Schemes 1-28, wherein G 3A and G 3BTogether with the nitrogen atoms to which they are all attached, they connect to form azircyclic butyl, 2,5-diazaspiro[3.4]octyl, pyrrolyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazabicyclo[3.2.0]heptyl, piperazine, spiro[indoline-3,3'-pyrrolidine]yl, 6',7'-dihydrospiro[azircyclic butane-3,5'-pyrrolo[1,2-a]imidazolyl]yl, 3,4-dihydro-2 / 7-benzo[b][ The following groups are selected: 1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine, 2,3-dihydro-1H-pyrido[2,3-b][l,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][l,4]oxazetrinyl, 1,2,3,4-tetrahydroquinoxalinyl, l-azaspiro[3.5]nonyl or 4-azaspiro[2.4]heptyl, each of which may be optionally substituted by one or more substituents independently selected from: (i) F, oxo, OH or CN, (ii) C groups optionally substituted by deuterium and / or F. 1-4 Alkyl groups, (iii) C groups optionally substituted with deuterium, oxo, and / or F. 1-4 Heteroalkyl groups, and (iv) selected from C 3-6 Cycloalkyl, 4-8-membered heterocyclic rings, phenyl, and 5- or 6-membered heteroaryl rings, optionally selected by one or more independently chosen from deuterium, halogen (e.g., F), oxo, OH, CN, C 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally replaced by deuterium and / or F.

[0091] Implementation Scheme 30. A compound or a salt thereof from any one of Implementation Schemes 1-28, wherein G 3A and G 3B Together with the nitrogen atoms to which they are all attached, they form azircyclic butyl or 4-azirspiro[2,4]heptyl groups, each of which is optionally substituted by one or more substituents independently selected from: (i) F, oxo, OH or CN, (ii) C groups optionally substituted by deuterium and / or F. 1-4 Alkyl groups, (iii) C groups optionally substituted with deuterium, oxo, and / or F. 1-4 Heteroalkyl groups, and (iv) selected from C 3-6 Cycloalkyl, 4-8-membered heterocyclic rings, phenyl, and 5- or 6-membered heteroaryl rings, optionally selected by one or more independently chosen from deuterium, halogen (e.g., F), oxo, OH, CN, C 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups, wherein the C 1-4 alkyl or the C 1-4The heteroalkyl group may be optionally replaced by deuterium and / or F.

[0092] Implementation Scheme 31. A compound or a salt thereof from any one of Implementation Schemes 1-28, wherein -NG 3A G 3B The representative has a basis The structural parts, for example or G 30 It is hydrogen, methyl, or CN; and G 31 It is a phenyl or a 5- or 6-membered heteroaryl group, each of which is optionally selected by one or more elements independently selected from deuterium, halogen, OH, CN, C. 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally substituted with deuterium and / or F, for example, -NG. 3A G 3B Representatives selected The part.

[0093] Implementation Scheme 32. The compound of Implementation Scheme 31 or a salt thereof, wherein G 30 It can be hydrogen or CN.

[0094] Implementation Scheme 33. The compound of Implementation Scheme 31 or 32 or a salt thereof, wherein G 31 It is a 6-membered heteroaryl group having one or two cyclic nitrogen atoms, such as pyridyl, pyrimidinyl, etc., which is optionally substituted as described in Embodiment 31, for example, G 31 for , or .

[0095] Implementation Scheme 34. A compound or a salt thereof from any one of Implementation Schemes 1-28, wherein -NG 3A G 3B The representative has a basis The structural part, in which G 32 It is a 5- or 6-membered heteroaryl group, each of which is optionally selected by one or more elements independently chosen from deuterium, halogen, OH, CN, C. 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may be optionally substituted with deuterium and / or F; or G 32 It is a 5- or 6-membered heteroaryl group, optionally selected by one or more elements independently chosen from deuterium, halogen (e.g., F), OH, CN, C. 1-4 Alkyl, C 1-4Substituents of heteroalkyl groups and 3-7 membered carbocyclic or heterocyclic rings, wherein the C 1-4 alkyl or the C 1-4 The heteroalkyl group may optionally be substituted with deuterium and / or F, and the 3-7 membered carbocyclic or heterocyclic ring may optionally be selected independently from deuterium, halogen (e.g., F), oxo, OH, CN, C. 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups.

[0096] Implementation Scheme 35. The compound of Implementation Scheme 34 or a salt thereof, wherein G 32 It is a 6-membered heteroaryl group having one or two cyclic nitrogen atoms, such as pyridyl, pyrimidinyl, etc., which is optionally substituted as described in Embodiment 34, for example, G 32 for .

[0097] Implementation Scheme 36. A compound or salt thereof from any of Implementation Schemes 1-35, wherein, unless otherwise stated or contrary to the context, the variables may have any of the corresponding definitions shown in Table A herein.

[0098] Implementation Scheme 37. A compound or salt thereof of any of Implementation Schemes 1-35, wherein, unless otherwise stated or contrary to the context, each variable may have any corresponding definition as defined herein with respect to Formula I or II (including its subformulas).

[0099] It should be clarified that the divalent linker in any of the implementation schemes 1-37 should be understood as capable of connecting to the rest of the molecule in either direction. For example, in L... A -G 12 In the definition, when L A It is described as S(O)2NG 13 At that time, it includes -S(O)2-N(G) 13 )-G 12 and -N(G 13 )-S(O)2-G 12 Both. Unless otherwise stated or contrary to the context, other definitions should be understood similarly.

[0100] Unless otherwise stated or contrary to context, 3-14 membered rings as used herein can be 3-14 membered carbocyclic rings, 4-14 membered heterocyclic rings, phenyl or naphthyl rings, or 5-10 membered heteroaryl rings, which can be monocyclic (typically having a ring size of 3-8) or polycyclic (including bicyclic, typically having a ring size of 5-14), and in the case of polycyclic rings, each ring is independently a carbocyclic ring, heterocyclic ring, aryl ring, or heteroaryl ring. 3-10 membered rings should be understood similarly.

[0101] Unless otherwise stated or contrary to context, the 3-6 membered ring in this document may be a 3-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaryl ring.

[0102] Unless otherwise stated or contrary to context, the 3-5 membered ring in this document may be a 3-5 membered carbocyclic ring (e.g., cyclopropyl or cyclobutyl), a 4-5 membered heterocyclic ring (e.g., oxobutyryl or azirheyryl) or a 5-membered heteroaryl ring.

[0103] Unless otherwise stated or contrary to context, C in this document refers to... 1-6 Heteroalkyl groups can be C 1-6 Alkoxy, (C 1-6 alkylene)-OH, N(C) 1-5 Alkyl)(C 1-5 Alkyl), NH(C) 1-6 alkyl), (C 1-6 (alkylene)-NH2, (C 1-6 Alkylene)-SH, SO2N(C 1-5 Alkyl)(C 1-5 Alkyl), SO2NH(C) 1-6 alkyl), (C 1-5 alkylene)-O-(C 1-5 alkyl), (C 1-5 alkylene)-O-(C 1-5 alkylene)-OH, O-(C 2-5 alkylene)-O-(C 1-4 Alkyl), O-(C) 2-5 alkylene)-O-(C 1-4 alkylene)-OH, (C 1-5 alkylene)-NH-(C 1-5 alkyl), (C 1-4 alkylene)-N(C 1-4 Alkyl)(C 1-4 Alkyl), O-(C) 2-5 alkylene)-NH-(C 1-4 Alkyl), O-(C) 2-4 alkylene)-N(C 1-3 Alkyl)(C 1-3 alkyl), (C 1-5 alkylene)-SO2-(C 1-5 Alkyl), (C 1-5 alkylene)-SO2NH-(C 1-5 Alkyl), (C 1-4 Alkylene)-SO2N(C 1-4 Alkyl)(C 1-4 Alkyl), O-(C) 1-5alkylene)-SO2-(C 1-5 Alkyl), O-(C) 1-5 alkylene)-SO2NH-(C 1-5 alkyl) or O-(C 1-4 Alkylene)-SO2N(C 1-4 Alkyl)(C 1-4 Alkyl groups, provided the total number of carbons is between 1 and 6, without regard to any optional substituents. Unless otherwise stated or contrary to context, C... 1-6 Heteroalkyl groups can be derived from (i.e., by means of C) 1-6 Heteroalkyl groups derived from the removal of any hydrogen atom from the C atom above) 1-6 A list of divalent linkers for heteroalkyl groups.

[0104] Unless otherwise stated or contrary to context, C in this document refers to... 1-4 Heteroalkyl groups can be C 1-4 Alkoxy, (C 1-4 alkylene)-OH, N(C) 1-3 Alkyl)(C 1-3 Alkyl), NH(C) 1-4 Alkyl), (C 1-4 (alkylene)-NH2, (C 1-4 Alkylene)-SH, SO2N(C 1-3 Alkyl)(C 1-3 Alkyl), SO2NH(C) 1-4 Alkyl), (C 1-3 alkylene)-O-(C 1-3 Alkyl), (C 1-3 alkylene)-O-(C 1-3 alkylene)-OH, O-(C 2-3 alkylene)-O-(C 1-2 Alkyl), O-(C) 2-3 alkylene)-O-(C 1-2 alkylene)-OH, (C 1-3 alkylene)-NH-(C 1-3 Alkyl), (C 1-3 alkylene)-N(C 1-2 Alkyl)(C 1-2 Alkyl), O-(C) 2-3 alkylene)-NH-(C 1-2 Alkyl), O-(C2 alkylene)-N(C1 alkyl)(C1 alkyl), (C 1-3 alkylene)-SO2-(C 1-3 Alkyl), (C 1-3 alkylene)-SO2NH-(C 1-3 Alkyl), (C 1-2Alkylene)-SO2N(C 1-2 Alkyl)(C 1-2 Alkyl), O-(C) 1-3 alkylene)-SO2-(C 1-3 Alkyl), O-(C) 1-3 alkylene)-SO2NH-(C 1-3 Alkyl) or O-(C2 alkylene)-SO2N(C1 alkyl)(C1 alkyl), provided that the total number of carbons is between 1 and 4, without regard to any optional substituents. Unless otherwise stated or contrary to context, C in this document refers to... 1-4 Heteroalkyl groups can be derived from the C above. 1-4 A list of divalent linkers for heteroalkyl groups.

[0105] In some embodiments, this disclosure also provides compounds selected from those shown in Table A or pharmaceutically acceptable salts thereof.

[0106] Table A: Exemplary Compounds of this Disclosure

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116] .

[0117] In some embodiments, the compounds in Table A may be present as individual stereoisomers (e.g., individual enantiomers) or as a mixture of stereoisomers (e.g., two enantiomers) in any ratio. In some embodiments, the compounds in Table A may be present in a non-zwitterionic form, in a zwitterionic form, or as a mixture of zwitterionic and non-zwitterionic forms in any ratio.

[0118] The compounds disclosed herein can be readily synthesized by those skilled in the art based on this disclosure. Synthesis of certain synthetic intermediates that can be used to synthesize the compounds disclosed herein can be found in WO2023 / 133336, WO2023 / 164,680 and WO2023 / 192,960. Example synthesis is also shown in the Examples section.

[0119] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis", 4th edition, PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents used in the reactions described herein are well-known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other reagents may be prepared by procedures described in standard reference texts, 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), as well as any available updates up to the time of this application.

[0120] Pharmaceutical Composition Some embodiments involve pharmaceutical compositions comprising one or more compounds disclosed herein.

[0121] Pharmaceutical compositions may optionally contain pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises compounds of the present disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-1-A, or I-2-A), formula II (e.g., formula II-1 or II-1-A), formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or pharmaceutically acceptable salts thereof) and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art. Suitable excipients, without limitation, include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's "The Science and Practice of Pharmacy," 21st edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in the formulation of pharmaceutical compositions and known techniques for their preparation.

[0122] The pharmaceutical composition may comprise any one or more of the compounds disclosed herein. For example, in some embodiments, the pharmaceutical composition comprises a compound of formula I (e.g., formula I-1, I-2, I-1-A, or I-2-A), formula II (e.g., formula II-1 or II-1-A), formula III, any one of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof, for example, in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compounds shown in the Examples section, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the compounds of this disclosure used in the pharmaceutical compositions herein are selected from those compounds whose IC50 value is less than 1 μmol / L (preferably less than 100 nM) when tested in STAT6 and / or STAT3 assays.

[0123] Pharmaceutical compositions may also be formulated for delivery via any known route of delivery, including but not limited to oral, parenteral, inhalation, etc.

[0124] In some embodiments, the pharmaceutical composition may be formulated for oral administration. Oral formulations may be presented in discrete units, such as capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound; in powder or granules; in solutions or suspensions in aqueous or non-aqueous liquids; or in oil-in-water or water-in-oil emulsions. Excipients used to prepare compositions for oral administration are known in the art. Suitable excipients that are not restrictive include, for example, agar, alginate, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, 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, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, and peanut oil. Oil), potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearate fumarate, sucrose, surfactants, talc, tragacanth gum, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[0125] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients used in the preparation of parenteral formulations are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, 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.

[0126] In some embodiments, the pharmaceutical composition is formulated for inhalation. Inhalable formulations may be formulated, for example, as nasal sprays, dry powders, or aerosols that can be administered via a metered-dose inhaler. Excipients used to prepare inhaled formulations are known in the art. Suitable, non-limiting excipients include, for example, lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, as well as mixtures of these substances. The spray may also contain propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0127] Pharmaceutical compositions may comprise various amounts of the compounds disclosed herein, depending on factors such as the intended use, potency, and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I (e.g., formula I-1, I-2, I-1-A, or I-2-A), formula II (e.g., formula II-1 or II-1-A)), a compound of formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of the compounds disclosed herein is an amount effective for treating diseases or conditions as described herein (such as cancer or immune and / or inflammatory diseases or conditions as described herein), which may depend on the recipient of treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound (e.g., for regulating the activity of STAT proteins (particularly STAT3 and / or STAT6), its clearance rate, and whether another drug is co-administered.

[0128] For veterinary use, the compounds disclosed herein can be administered in appropriate and acceptable formulations according to normal veterinary practice. Veterinarians can readily determine the dosing regimen and route of administration best suited for a particular animal.

[0129] In some embodiments, all necessary components for treating STAT3- and / or STAT6-mediated diseases or conditions, whether used alone or in combination with another agent or intervention conventionally used to treat such diseases, may be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for a therapeutic intervention for a disease comprising a packaged drug group including the compounds disclosed herein, buffers and other components for preparing the drug in a deliverable form, and / or a device for delivering such a drug, and / or any reagents used in combination therapies with the compounds disclosed herein, and / or instructions for treating the disease packaged with the drug. The instructions may be affixed to any tangible medium such as printed paper, or computer-readable magnetic or optical media, or instructions referencing a remote computer data source (such as a World Wide Web accessible via the Internet).

[0130] Treatment The compounds disclosed herein can be used as regulators (e.g., inhibitors) of STAT proteins, particularly STAT3 and / or STAT6. In some embodiments, the compounds disclosed herein can be used as therapeutic and / or preventive active substances for treating and / or preventing conditions (specifically, diseases or ailments) that respond to regulation of STAT3 and / or STAT6. Such diseases or ailments include any of those described herein, such as proliferative diseases (e.g., cancer), immune and / or inflammatory diseases or ailments, etc.

[0131] In some embodiments, this disclosure provides a method for modulating the activity of STAT proteins (particularly STAT3 and / or STAT6) in cells, comprising contacting cells with an effective amount of one or more compounds of this disclosure (e.g., compounds of Formula I (e.g., Formula I-1, I-2, I-1-A, or I-2-A), Formula II (e.g., Formula II-1 or II-1-A)), Formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). As used herein, the term “cell” is intended to mean a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be a portion of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “contact” means bringing together the indicated portion in an in vitro or in vivo system. For example, "contacting" a STAT protein (such as STAT3 and / or STAT6) with a compound of this disclosure includes administering a compound of this disclosure to a subject (such as a human) having a STAT protein (such as STAT3 and / or STAT6) and, for example, introducing a compound of this disclosure into a sample containing cells or a purified formulation containing a STAT protein (such as STAT3 and / or STAT6). The term "STAT3 and / or STAT6 modulator," such as STAT3 modulator or STAT6 modulator, refers to an agent capable of modulating (e.g., inhibiting) the activity of STAT3 and / or STAT6 proteins.

[0132] In some embodiments, this disclosure provides a method for modulating (e.g., inhibiting) the activity of STAT proteins (particularly STAT3 and / or STAT6), the method comprising contacting a STAT protein (such as STAT3 and / or STAT6) with an effective amount of one or more compounds of this disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-1-A or I-2-A), formula II (e.g., formula II-1 or II-1-A)), formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) to modulate the activity of the STAT protein (particularly STAT3 and / or STAT6).

[0133] In some embodiments, this disclosure provides a method of treating a condition in a subject that responds to regulation (e.g., inhibition) of STAT3 and / or STAT6, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-1-A or I-2-A), formula II (e.g., formula II-1 or II-1-A)), formula III, any of the compounds according to the listed embodiments 1-37, any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of the pharmaceutical composition described herein.

[0134] Conditions that respond to regulation (e.g., inhibition) of STAT3 and / or STAT6 include, but are not limited to, cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related conditions, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or CNS diseases. In some implementations, conditions that respond to regulation (e.g., inhibition) of STAT3 and / or STAT6 include, but are not limited to, cancer, diabetes, cardiovascular disease, viral diseases, autoimmune diseases (such as lupus and rheumatoid arthritis), autoinflammatory syndromes, atherosclerosis, psoriasis, allergic conditions, inflammatory bowel disease, inflammation, acute and chronic gout and gouty arthritis, neurological conditions, metabolic syndrome, immunodeficiency conditions (such as AIDS and HIV), destructive bone diseases, osteoarthritis, proliferative conditions, Waldenström macroglobulinemia, infectious diseases, cell death-related conditions, pathological immune conditions involving T cell activation, and CNS conditions. Proliferative disorders include, but are not limited to, benign or malignant tumors, solid tumors, fluid-filled tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer (especially colon cancer or colorectal adenoma), head and neck tumors, and epidermal hyperplasia. Phlegm, psoriasis, benign prostatic hyperplasia, tumor formation, epithelial tumors, adenomas, adenocarcinomas, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disease, MyD88 driven disease, occult relapse of indolent multiple myeloma or hematologic malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC) DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma.

[0135] In some implementations, the condition responding to regulation of STAT3 and / or STAT6 is cancer. In some implementations, the cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, melanoma of the skin, ovarian cancer, malignant peripheral nerve sheath tumor (MPNST), and pancreatic cancer. In other implementations, the cancer to be treated is selected from: glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, melanoma of the skin, ovarian cancer, malignant peripheral nerve sheath tumor (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC) (including EGFR-mutant NSCLC), urothelial carcinoma, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, and hematologic malignancies (including lymphoma, leukemia, myeloma, myeloproliferative neoplasms, and myelodysplastic syndromes). In other implementations, the cancer is selected from solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Kasman disease, uterine leiomyosarcoma, melanoma, etc.), hematologic malignancies (e.g., lymphoma, leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of CTCL include Sezary syndrome and mycosis fungoides.

[0136] In some embodiments, the compounds of this disclosure or compositions comprising said compounds may be used to treat inflammatory or obstructive airway diseases, such as those causing tissue damage, airway inflammation, bronchial hyperresponsiveness, airway remodeling, or disease progression. Inflammatory or obstructive airway diseases include asthma of any type or etiology, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection. Treatment of asthma should also be understood to include treatment, for example, of subjects younger than 4 or 5 years of age who present with wheezing symptoms and are diagnosed or can be diagnosed as “wheezing infants,” a patient category of established primary medical concern and currently commonly identified as patients with initial or early-stage asthma.

[0137] In some embodiments, the compounds of this disclosure or compositions comprising said compounds may be used to treat heterologous immune diseases, including but not limited to graft-versus-host disease, transplantation, blood transfusion, anaphylactic shock, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, dust mites, or cockroach calyxes), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0138] In some embodiments, the compounds of this disclosure or compositions comprising said compounds may be used to treat other inflammatory or obstructive airway diseases and conditions to which this invention applies, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway disease or lung disease (COPD, COAD, or COLD), including chronic bronchitis or associated dyspnea, emphysema, and exacerbations of airway hyperresponsiveness secondary to other drug treatments (particularly other inhaled drug treatments). The compounds, salts, and compositions described herein may also be used to treat bronchitis, including but not limited to acute bronchitis, peanut inhalation bronchitis, catarrhal bronchitis, grob's bronchitis, chronic bronchitis, or tuberculous bronchitis. The compounds, salts, and compositions described herein may also be used to treat pneumoconiosis of any type or etiology (an inflammatory, often occupational lung disease, frequently accompanied by airway obstruction, whether chronic or acute, and caused by repeated inhalation of dust), including, for example, aluminocytosis, carbon deposit disease, asbestos deposition disease, stone deposit disease, ostrich feather pneumoconiosis, pulmonary iron deposit disease, silicosis, smoke pneumoconiosis, and cotton pneumoconiosis.

[0139] In some embodiments, the compounds of this disclosure or compositions comprising said compounds may be used to treat inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0140] In some embodiments, the compounds of this disclosure or compositions comprising said compounds may be used to treat other diseases or conditions, such as diseases or conditions having inflammatory components, for example, diseases and conditions of the eye, such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes, including autoimmune hematologic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura); systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and Steven-Johnson syndrome. Syndrome), idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerulonephritis, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior uveitis), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyridine-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change disease, chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal diseases, aging, headaches, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, catabolism, obesity, fetal growth restriction, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, pigmentary disorders, and Paget's disease. Diseases, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reaction, anaphylactic shock, sinusitis, ocular allergies, silica-induced diseases, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease. Diseases, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura. (purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis. In some implementations, cardiovascular diseases treatable using this method include, but are not limited to: restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, post-angioplasty restenosis, post-angioplasty restenosis, post-aortocoronary shunt restenosis, stroke, transient ischemic attack, peripheral artery occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0141] In some embodiments, the compounds of this disclosure or compositions comprising said compounds may be used to treat neurodegenerative diseases, including but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0142] In some preferred embodiments, the compounds disclosed herein used in the methods herein are selected from those compounds whose IC50 value is less than 1 μmol / L (preferably less than 100 nM) when tested in STAT6 and / or STAT3 assays.

[0143] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments, for example, in cancer treatment methods, combination therapy includes treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy. In some embodiments, the compounds disclosed herein may also be administered simultaneously or sequentially with other pharmaceutically active compounds to a subject in need. In some embodiments, for example, in cancer treatment methods, combination therapy includes treating the subject with one or more other therapies such as chemotherapeutic agents or other anticancer agents.

[0144] Combination therapy may also include further administration of the therapeutic agent as described above in combination with other bioactive ingredients and / or non-pharmacological therapies (e.g., surgery or radiation therapy).

[0145] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, transdermal, pulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral. In some embodiments, the administration is oral.

[0146] Dosing regimens (including dosage) can vary and be adjusted depending on the recipient of treatment, 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 another drug is administered concurrently.

[0147] definition It should be understood that all parts and their combinations maintain the appropriate valence.

[0148] It should also be understood that the specific implementation of the variable parts in this document may be the same as or different from another specific implementation having the same identifier.

[0149] Atoms or groups suitable for the variables herein are selected independently. The non-limiting use of groups (if applicable) in compounds of Formula I, II, III, or X or their sub-formulas includes any corresponding group, alone or in any combination, as shown in the examples or in the specific compounds described in Table A herein. Furthermore, it should be understood that the definitions of variables in Formula I, II, III, or X may have the same definitions as those defined in sub-formulas of Formula I, II, III, or X, respectively. Similarly, unless otherwise stated or contrary to the context, the definitions of sub-formulas of Formula I, II, III, or X may have the same definitions as those defined with respect to Formula I, II, III, or X or another sub-formula of Formula I, II, III, or X. The definitions of variables can be combined. Taking Formula I, II, or III as an example, X in Formula I, II, or III or its sub-formulas... 1 X 2 X 3 X 4 X 5 Y 1 Y 2 Z, W, R 1 R 2 R 3 R 4 R 5 , m, n, p, q, t, L 1 L 2 and L 3 Any definition of X in equation I, II, or III or its applicable sub-equations can be related to X. 1 X 2 X 3 X 4 X 5 Y 1 Y 2 Z, W, R 1 R 2 R 3 R 4 R 5 , m, n, p, q, t, L 1 L 2 and L 3 Any other combination of definitions in the present invention. Such combinations are contemplated and are within the scope of the invention.

[0150] symbol When shown perpendicular to (or otherwise intersecting) the bond, it indicates the connection point between the shown portion and the rest of the molecule. It should be noted that for divalent (or multivalent) structures, one or more directly linked groups or appropriate variables shown in the formula may be indicated by the symbol. In divalent (or multivalent) structures, the direction of attachment is indicated. When neither attachment point of a divalent structure shows a directly attached group or variable, unless otherwise stated or clearly contrary to the context, it should be assumed that attachment to the rest of the molecule is permitted in either direction. The structure "XAGB" is used to indicate this, for example, if G is defined as... That is, if no directly connected groups or variables are shown, the structure "XAGB" can be or On the other hand, if G is defined as , , , or Therefore, the structure "XAGB" should be understood as .

[0151] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined according to... Handbook of Chemistry and Physics The CAS version of the periodic table is identified on the inside back cover of the 75th edition, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following literature: Thomas Sorrell, Organic Chemistry University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry , 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations VCHPublishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3rd edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0152] The compounds disclosed herein may contain one or more asymmetric centers and / or axial chirality, and therefore may exist in a variety of isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, transisomers, or geometric isomers, or may be in the form of mixtures of stereoisomers (including racemic mixtures and mixtures rich 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) or supercritical fluid chromatography (SFC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may 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); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (Edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also covers the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers (including racemic mixtures). In the specific stereochemistry plotted, it should be understood that, for that particular chiral center or axial chirality, the compound is primarily present as the stereoisomer plotted, such that, based on HPLC or SFC area or both, the amount of other stereoisomers is less than 20 wt%, less than 10 wt%, less than 5 wt%, less than 1 wt%, or the amount of other stereoisomers is undetectable. For example, in some embodiments, for that particular chiral center or axial chirality plotted, the compound may be primarily present as the stereoisomer plotted, having an enantiomeric excess (“ee”) greater than 50%, such as 80% ee or higher, 90% ee or higher, 95% ee or higher, 98% ee or higher, 99% ee or higher. Those skilled in the art can determine the presence and / or amount of stereoisomers based on this disclosure, including by using chiral HPLC or SFC.

[0153] When listing a range of values, the intention is to cover every value within that range and its subranges. For example, "C 1–6 The intention is to cover C1, C2, C3, C4, C5, C6, and C 1–6 C 1–5 C 1–4C 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 .

[0154] As used herein, the terms “compound of this disclosure” or “compound of the invention” mean any compound described herein according to formulas I, II, III, X or their derivatives, any compound shown in Table A and any compound described or prepared in the Examples section, its isotopically labeled compounds (such as deuterated analogs in which one or more hydrogen atoms are substituted with deuterium atoms in abundance greater than their native abundance), its possible stereoisomers (including diastereomers, enantiomers and racemic mixtures), its geometric isomers, its transisomers, its tautomers, its zwitterionic forms, its conformational isomers, and / or its pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts, or base addition salts such as Na salts). Hydrates and solvates of the compounds of this disclosure are considered compositions of this disclosure, wherein the compounds are associated with water or a solvent, respectively.

[0155] The compounds disclosed herein may exist in the form of isotopic labeling or isotopic enrichment, containing one or more atoms having an atomic mass or mass number different from the most abundant atomic mass or mass number found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, those... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0156] As used herein, the term "amino acid residue" refers to the portion of an amino acid remaining after the amino and carboxyl groups have been removed, which are available to form a peptide bond with a reactive group (e.g., an amino group or a carboxylic acid group) in another compound. For example, the residue of an α-amino acid having the general formula NH2CR'RC(O)OH can be structurally represented as -CR'R-; and the residue of a β-amino acid having the general formula NH2CR'RCH2-C(O)OH can be structurally represented as -CR'RCH2-. It should be further noted that, where applicable, the CR'R end of the β-amino acid residue will be attached to a nitrogen atom as described herein, while the CH2 end will be attached to a carbonyl group. In some embodiments, in the aforementioned general formula of the α-amino acid or β-amino acid, R' is H or C. 1-6 Alkyl and R is H or optionally substituted with 1 to 3 groups selected from the following 1-6 Alkyl groups: halogens, (C 1-3 alkoxy groups), OH, NH2, -NH (C 1-4 alkyl), -N(C) 1-4 Alkyl)2, SH, S(C 1-4 Alkyl), imino, COOH, -COO(C 1-4 Alkyl), -CO(C) 1-4 Alkyl), -CONH(C) 1-4 alkyl)phenyl, phenyl and 5- to 10-membered heteroaryl, wherein the C 1-6 The alkyl group may optionally be interrupted by a sulfur or nitrogen atom, and the phenyl group may optionally be interrupted by one to three atoms selected from OH, cyano, (C 1-4 Alkyl) and halogen (C) 1-4 R is substituted with an alkyl group; or R forms a 4- to 6-membered heterocyclic group together with a nitrogen atom from an α- or β-amino acid residue. For naturally occurring α-amino acids (i.e., amino acids that exist in nature), R' is H and R is selected from hydrogen, methyl, isopropyl, -CH2CH(CH3)2, -(CH2)2SCH3, -CH(CH3)(CH2CH3), CH2OH, -CH(OH)(CH3), CH2SH, -CH2C(O)NH2, -(CH2)2C(O)NH2, benzyl, p-hydroxybenzyl, -CH2(indolyl), -(CH2)4NH2, -(CH2)3NHC(=NH2)NH2, -CH2(imidazolyl), -(CH2)COOH and -(CH2)2COOH; or R forms a pyrrolidinyl ring together with a nitrogen atom from an α- or β-amino acid residue.

[0157] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a connected p-orbital system with delocalized electrons, and this system may contain lone pairs of electrons.

[0158] As used herein, the term "alkyl" on its own or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, the alkyl group may contain one to twelve carbon atoms (i.e., C64 ... 1-12 Alkyl group or a specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight-chain C1 alkyl group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-10 Alkyl group. In another embodiment, the alkyl group is a straight-chain C. 1-6 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C. 1-4 Alkyl groups. For example, C as used herein. 1-4 Alkyl groups are selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl groups. The substituted C- group is optional. 1-4 Alkyl groups refer to C14 groups that are optionally substituted with one or more permissible substituents as defined herein. 1-4 Alkyl groups. As used herein, the term "alkylene" on its own or as part of another group refers to a divalent group derived from an alkyl group. For example, non-limiting straight-chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0159] As used herein, the term "alkenyl" on its own or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, such as one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2-6 Alkenyl group. In another embodiment, the alkenyl group is C. 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0160] As used herein, the term "alkynyl" itself, or as part of another group, refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, such as one to three, carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-6 An alkynyl group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Exemplary non-limiting alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentyynyl, and hexynyl.

[0161] As used herein, the term "alkoxy" on its own or as part of another group refers to the formula OR a1 The group, wherein R a1 It is an alkyl group. As used herein, the term "cycloalkoxy" itself or as part of another group refers to the formula OR. a1 The group, wherein R a1 It is a cycloalkyl group.

[0162] As used herein, the term "haloalkyl" itself, or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In a preferred embodiment, the haloalkyl is an alkyl group substituted with one or more fluorine atoms, alternatively referred to herein as a fluorine-substituted alkyl, such as an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C10. 1-4 Haloalkyl group. In one embodiment, the haloalkyl group is a fluorine-substituted C18. 1-4 Alkyl groups.

[0163] As used herein, the term "heteroalkyl" on its own or in combination with another term, unless otherwise specified, refers to a stable straight-chain or branched alkyl group having, for example, 2 to 14 carbons, such as 2 to 10 carbons, in the chain, wherein one or more carbons have been replaced with heteroatoms selected from S, O, P, and N, and wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized. Heteroatoms S, O, P, and N may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. When heteroalkyl is described as substituted, a substituent may replace one or more carbon atoms and / or hydrogen atoms attached to the heteroalkyl group. In some embodiments, the heteroalkyl is C 1-4 Heteroalkyl, as defined herein, refers to a heteroalkyl group having 1-4 carbon atoms. C 1-4 Examples of 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, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3, and C1 heteroalkyl groups such as -CH2-OH, -CH2-NH2, -O-CH3. Preferably, C... 1-4 Heteroalkyl (or C) 1-4Heteroalkyl groups contain one or two heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. Similarly, the term "heteroalkyl" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and –O-CH2-CH2-NH-CH2-. For heteroalkyl groups, the heteroatom can also occupy one or both of the chain ends. For example (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. The term "heteroalkyl" is followed by a description of a specific heteroalkyl group such as -NR'R. '' In this context, it should be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups such as -NR'R. '' wait.

[0164] When used alone or as part of another group, “carbocyclic group” or “carbocyclic” refers to a non-aromatic ring system having 3 to 14 ring carbon atoms (“C…”). 3–14 A carbocyclic group is a group consisting of a carbocyclic group and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. The carbocyclic group can be monocyclic (“monocyclic carbocyclic”) or contain a fused, bridged, or spirocyclic ring system, such as a bicyclic system (“bicyclic carbocyclic”), and can be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclopentenyl, and cyclohexenyl.

[0165] In some embodiments, "carbocyclic group" is a saturated carbocyclic group having 3 to 14 ring carbon atoms ("C..."). 3–14 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3–10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3–8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5–6cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5–10 cycloalkyl).

[0166] When used alone or as part of another group, "heterocyclic group" or "heterocyclic" refers to a group having a 3- to 14-membered nonaromatic ring system with a ring carbon atom and one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic ring systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A heterocyclic bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic ring or the heterocyclic ring; or a ring system in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system.

[0167] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclopropane, oxacyclopropane, and thiocyclopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclobutane, oxacyclobutane, and thiocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiaranyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolidinone, etc. Exemplary 6-membered heterocyclic groups fused with aryl rings (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0168] When used alone or as part of another group, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) ("C 6–14 The aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”; for example, phenyl). 10 Aryl group; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14”). 14"Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system.

[0169] When used alone or as part of another group, "aralkyl" refers to an alkyl group that is substituted by one or more aryl groups, preferably by one aryl group. Examples of aralkyl groups include benzyl, phenethyl, etc. When aralkyl is described as optionally substituted, the alkyl or aryl portion of the aralkyl group may be optionally substituted.

[0170] When used alone or as part of another group, "heteroaryl" refers to a 5-14 membered monocyclic or bicyclic group having a cyclic carbon atom provided in the aromatic ring system and 1-4 cyclic heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) in a 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the cyclic array). In heteroaryl groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom if the valence allows. A heteroaryl bicyclic ring system can contain one or more heteroatoms in one or two rings. "Heteroaryl" includes a ring system in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on an aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have the connection point on either ring, i.e., on a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). "Heteroaryl" also includes those ring systems containing an oxo group and sharing 4n+2 π electrons in its cyclic array, such as pyranone rings. For the avoidance of ambiguity, the term "heteroaryl" as used herein also includes those heteroaryl rings in which nitrogen is oxidized, such as pyridyl N-oxide, and those heteroaryl rings in which one or more ring carbon atoms are present as C(O) in a tautomeric form, such as pyridone groups.

[0171] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. 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, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0172] When used alone or as part of another group, "heteroaryl" refers to an alkyl group that is substituted by one or more heteroaryl groups, preferably by one heteroaryl group. When a heteroaryl group is described as optionally substituted, the alkyl or heteroaryl portion of the heteroaryl group may be optionally substituted.

[0173] Unless otherwise stated or contrary to context, “heteroatom” as used herein generally refers to nitrogen, oxygen, sulfur, boron, phosphorus or silicon, more preferably nitrogen, oxygen or sulfur.

[0174] As used herein, unless otherwise stated or to the contrary, the term "ring structure," "cyclic structure," or simply "ring," such as "3-10 membered ring structure," "3-12 membered ring structure," or "5- or 6-membered ring," having a specified number of ring members, shall be understood to encompass any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having the specified number of ring members, which may be (1) monocyclic or polycyclic (where chemically feasible), such as monocyclic or bicyclic base rings (including fused, spirocyclic, and bridged bicyclic base rings, and two of which are monocyclic). (1) Ring systems in which the base rings are connected by single or double bonds; (2) Aromatic, partially unsaturated or fully saturated; and in the case of polycyclic structures, each ring may independently be aromatic, partially unsaturated or fully saturated; and (3) Free of heteroatoms (i.e., all ring members are carbon atoms) or containing 1-4 heteroatoms (i.e., ring members consist of carbon atoms and 1-4 heteroatoms); in the case of polycyclic structures, each ring may independently be free of cyclic heteroatoms or have 1-4 cyclic heteroatoms (e.g., O, N, S, etc.). When a ring is described as containing cyclic sulfur or nitrogen atoms, the sulfur or nitrogen atoms may optionally be oxidized. One or more cyclic carbon atoms in a ring structure may be present as C (=O). A fully saturated ring is one in which neither the cyclic carbon nor the nitrogen (if present) atoms form double or triple bonds with any other atom. A ring structure may optionally be substituted by one or more substituents described herein. Substituents in the ring structures described herein may also have cyclic structures, and in some cases, two substituents in a ring structure may be described as being connected to form a cyclic structure.

[0175] As is generally understood in the art, for clarity, when a structure can be characterized in multiple ways, a structure can be said to be a suitable definition of a variable as long as one such representation falls within the scope of the variable's definition herein. For example, when a monovalent variable is defined as an arbitrarily substituted 6-membered ring, the variable also encompasses (a) among other structures. or The structure of (a) can be considered as a 6-membered monocyclic or bicyclic ring substituted with a phenyl group; and (b) The structure can be viewed as a 6-membered ring, where two substituents are linked to form a cyclopropyl ring; however, this variable will not cover... This is because the connecting loop is not a 6-membered ring under any structural characterization. To further explain, when the variable is instead defined as an arbitrarily replaced single-ring 6-membered ring, then the variable does not cover... But covering The structure. And if the variable is defined as a 6-membered ring arbitrarily substituted with a halogen, then the variable can cover structures such as... Each of them can be considered as a 6-membered ring that is either unsubstituted or substituted by one or two fluorine atoms.

[0176] As is commonly understood in the art, alkylene, alkenylene, ynylene, heteroalkylene, carbocyclic, heterocyclic, arylene, and heteroarylene refer to the corresponding divalent groups of alkyl, alkenyl, ynylene, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, respectively.

[0177] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the corresponding unsubstituted or substituted group. Generally, the term "substituted," whether or not preceded by the term "optionally," refers to a substituent in which at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, for example, a substituent that, upon substitution, produces a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituents at each position can be the same or different. Typically, when substituted, the optionally substituted group herein can be replaced by one, two, three, four, or five substituents. If applicable, the substituents may be carbon substituents, nitrogen substituents, oxygen substituents or sulfur substituents.

[0178] Unless explicitly stated to the contrary, combinations of substituents and / or variables are permitted only if such combinations are chemically permissible and produce stable compounds. A “stable” compound is one that can be prepared and isolated, and whose structure and properties remain substantially unchanged or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0179] In some embodiments, the "optionally substituted" alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic groups herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents or even 5 substituents, said substituents being independently selected from F, Cl, -OH, protected hydroxyl, oxo (if applicable), NH2, protected amino, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl ((C) 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6The alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, 3-7 heterocyclic group containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, or independently selected from Br, -NH2, and -CN, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 substituents or even 4 or 5 substituents, wherein the substituents are independently selected from F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl groups (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4 The alkoxy group, or independently selected from Cl, Br, -NH2, and -CN. In some embodiments, the "optionally substituted" aryl or heteroaryl group herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents, or even 5 substituents, independently selected from F, Cl, -OH, -CN, NH2, protected amino groups, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl ((C) 1-4 Alkyl), –S(=O)(C 1-4 Alkyl), –SO2(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, or 3- to 7-membered heterocyclic groups containing 1 or 2 cyclic heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 substituents or even 4 or 5 substituents, wherein the substituents are independently selected from F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy and fluorine-substituted C 1-4 Alkyl groups, or independently selected from Cl, Br, -NH2 and -CN.

[0180] Exemplary carbon substituents include, but are not limited to, halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, and –OR. aa –ON(R) bb )2、–N(R bb )2、–N(Rbb )3 + X – 、–N(OR cc )R bb 、–SH、–SR aa 、–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)R aa , –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, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl and 5–14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; wherein X To counteract ions; Or, the two hydrogen atoms on the carbon atom are replaced by 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 ; R in each case aa Selected independently from C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R aa Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by groups; R in each case bb Independently selected from 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)(R aa 2. P(=O)(OR cc )2、–P(=O)(N(R cc )2)2、C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R bb Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; wherein X To counteract ions; R in each case cc Independently selected from hydrogen and C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R cc Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by groups; R in each case dd Independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee –ON(R) ff )2、–N(R ff )2、–N(R ff )3 + X – –N(OR) ee )R ff –SH, –SR ee –SSR ee –C(=O)R ee –CO2H, –CO2R ee –OC(=O)R ee –OCO2R ee –C(=O)N(R) ff )2、–OC(=O)N(R ff )2、–NRff C(=O)R ee –NR ff CO2R ee –NR ff C(=O)N(R ff )2、–C(=NR ff OR ee –OC(=NR) ff )R ee –OC(=NR) ff OR ee –C(=NR) ff )N(R ff )2、–OC(=NR ff )N(R ff )2、–NR ff C(=NR ff )N(R ff )2、–NR ff SO2R ee –SO2N(R) ff )2、–SO2R ee –SO2OR ee –OSO2R ee –S(=O)R ee 、–Si(R ee )3、–OSi(R ee 3. –C(=S)N(R) ff )2、–C(=O)SR ee –C(=S)SR ee –SC(=S)SR ee –P(=O)(OR) ee )2、–P(=O)(R ee )2、–OP(=O)(R ee )2、–OP(=O)(OR ee 2. C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 Aryl, 5–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Substituted by a group, or two geminal R groups dd Substituents can be linked to form =O or =S; where X To counteract ions; R in each case ee Selected independently from C1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbon cyclo group, C 6–10 Aryl, 3–10-membered heterocyclic and 3–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Substituted by groups; R in each case ff Independently selected from hydrogen and C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 aryl and 5–10 heteroaryl, or two R ff Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg The group is replaced; and R in each case gg Independently halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)3 + X – –NH(C 1–6 Alkyl)2 + X – –NH2(C 1–6 alkyl) + X – –NH3 + X – –N(OC) 1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C 1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl, –SS(C 1–6 Alkyl), –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)( C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC(=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups), –OC(NH)NH2, –NHC(NH)N(C 1–6 Alkyl)2, –NHC(=NH)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –SO2NH2, –SO2C 1–6 Alkyl, –SO2OC 1–6 Alkyl, –OSO2C 1–6 Alkyl, –SOC 1–6 Alkyl, –Si(C) 1–6 Alkyl)3、–OSi(C 1–6 Alkyl)3、–C(=S)N(C 1–6 Alkyl)2、C(=S)NH(C 1–6 Alkyl), C(=S)NH2, –C(=O)S(C 1–6 Alkyl), –C(=S)SC 1–6 Alkyl, –SC(=S)SC 1–6 Alkyl group, –P(=O)(OC) 1–6 Alkyl)2、–P(=O)(C 1–6 Alkyl)2、–OP(=O)(C 1–6 Alkyl)2、–OP(=O)(OC 1–6 Alkyl)2, C 1–6 Alkyl, C 1–6 Haloalkyl, C2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbon cyclo group, C 6–10 aryl, 3–10 heterocyclic, 5–10 heteroaryl; or two geminal Rs gg Substituents can be linked to form =O or =S; where X – To counteract ions. Regarding the term "–N(C)", 1–6 Alkyl)2", –N(OC) 1–6 Alkyl)(C 1–6 Alkyl) or –N(C) 1–6 Alkyl)3 + X – Regarding "C", two or three groups "C" 1–6 "alkyl" can be the same C 1–6 Alkyl or different C 1–6 Alkyl. This also applies to similar terms such as "–N(C)". 1–4 Alkyl)2", –N(C) 1–2 Alkyl)2", –C(C) 1–6 Alkyl)2–, –C(C 1–6 Alkyl)3", –P(=O)(C 1–6 Alkyl)2”, –P(=O)(OC) 1–6 Alkyl)2", –Si(C) 1–6 Alkyl)3” etc.

[0181] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., comprising one form of negative charge). Anionic counterions can also be polyvalent (i.e., comprising more than one form of negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., Fi). – Cl – ,Br – I – NO3 – ClO4 – OH – H2PO4 – HSO4 – Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic-5-sulfonate, ethane-1-sulfonic-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, 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 counterions that can be multivalent include CO3. 2 HPO4 2 PO4 3 B4O7 2 SO4 2 S2O3 2 Carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipic acid, pimelic acid, succinate, azelaic acid, sebacic acid, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0182] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0183] "Acyl" refers to a group selected from –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 The part where R aa and R bb As defined in this article.

[0184] When the valence allows, the nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, –OH, and –OR. aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –C(=NR) 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, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl groups, or two R groups attached to a nitrogen atom cc Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd The group is replaced, and R is therein. aa R bb R cc和 R dd As defined above.

[0185] In some embodiments, the substituents present on the nitrogen atom are nitrogen-protecting groups (also known as amino-protecting groups). Nitrogen-protecting groups include, but are not limited to, –OH and –OR. aa –N(R) cc )2、–C(=O)R aa –C(=O)N(R) cc )2、–CO2Raa –SO2R aa –C(=NR) cc )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 C 1–10 Alkyl, aromatic-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl and 5–14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl group is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. dd The group is replaced, and R is therein. aa R bb R cc and R dd As defined herein, nitrogen protecting groups are well known in the art and include... Protective Groups in Organic Synthesis Those described in detail in TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999 (which is incorporated herein by reference).

[0186] Exemplary oxygen substituents include, but are not limited to, –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, where X R aa R bb and R cc As defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include... Protective Groups in Organic Synthesis Those described in detail in TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999 (which are incorporated herein by reference). Exemplary oxygen protecting groups include, but are not limited to: alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl (such as 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.; silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc.; acetals or ketals, such as tetrahydropyranyl (THP); esters, such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc.; carbonates; sulfonates, such as methanesulfonate (methanesulfonate), benzylsulfonate, and toluenesulfonate (Ts), etc.

[0187] The term "leaving group" has its general meaning in the field of synthetic organic chemistry; for example, it can refer to an atom or group that can be replaced by a nucleophile. See, for example, Smith. March Advanced Organic Chemistry 6th edition (501-502). Examples of suitable leaving groups include, but are not limited to, halogens (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O -Dimethylhydroxyamino, 9-phenyloxanthyl (pixyl) and halocarboxylate.

[0188] The term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0189] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one form migration of hydrogen atoms and at least one change in valence (e.g., single bond to double bond, triple bond to single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone to enol, amide to imide, lactam to lactimide, enamine to imide, and enamine to (different enamines) tautomerization.

[0190] As used herein, the term “subject” (or, alternatively, “patient”) refers to an animal, preferably a mammal, and most preferably a human, as a subject of treatment, observation, or experimentation.

[0191] As used herein, the term "treatment" means the elimination, reduction, or improvement of a disease or condition, and / or its associated symptoms. While not excluding the possibility that treatment of a disease or condition does not require the complete elimination of the disease, condition, or its associated symptoms, the term "treatment" as used herein may include "preventive treatment," which refers to reducing the likelihood of developing or relapsing into a previously controlled disease or condition in a subject who does not have such a disease or condition but is at risk or susceptible to developing or relapsing into it. The term "treatment" and its synonyms encompass the administration of a therapeutically effective amount of the compounds described herein to a subject who requires such treatment.

[0192] As used herein, the terms “administration”, “application”, or other variations thereof, refer to the provision of the compound or a prodrug of the compound to an individual in need of treatment.

[0193] As used herein, the singular forms “a”, “an”, and “the” include plural references unless explicitly stated or clearly evident from the context that this is not intended.

[0194] As used herein, the term "one or more species" means one or more species. For example, in some embodiments, the term "one or more species" means one or two species. In some embodiments, the term "one or more species" means one, two, or three species. In some embodiments, the term "one or more species" means one, two, three, or four species. In some embodiments, the term "one or more species" means one, two, three, four, or five species.

[0195] As used herein, unless otherwise stated or contrary to context, when describing one or more variables or one or more substituents followed by a list of options, these variables or substituents are each independently selected from the list of options, even if the word "independently" does not appear in the expression. For example, in the description of "one or more substituents selected from A, B, and C" or "one or more substituents selected from A, B, or C," in each case, with or without the word "independently" preceding "selected from," it should be understood that each of the possible one or more substituents is independently A, B, or C, unless otherwise stated or contrary to context. Other similar expressions should be understood similarly.

[0196] As used herein in expressions such as “A and / or B”, the term “and / or” is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, as used in expressions such as “A, B, and / or C”, the term “and / or” is intended to cover 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); and C (alone).

[0197] Titles and subtitles are used for convenience and / or formal compliance only, and do not limit the subject matter technology, nor are they related to the interpretation of the subject matter technology description. In various embodiments, features described under one title or subtitle of the subject matter disclosure may be combined with features described under other titles or subtitles. Furthermore, all features under a single title or subtitle are not necessarily used together in all embodiments.

[0198] Example Various starting materials, intermediates, and compounds in the preferred embodiments can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Characterization of these compounds can be performed using conventional methods, such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of the steps for synthesizing the products described herein are described in more detail below.

[0199] Exemplary embodiments of the steps for synthesizing the products described herein are described in more detail below. Some of the embodiments discussed herein can be prepared by separating the respective racemic mixtures. As will be understood by those skilled in the art, the compounds described in the Example Section immediately preceding the chiral separation step (e.g., by supercritical fluid chromatography (SFC)) are in the form of racemic and / or stereoisomer mixtures. It should be understood that the enantiomer excess (“ee”) and / or diastereomer excess (“de”) reported for these embodiments are merely representative of the procedures from the examples herein and not limiting; those skilled in the art will understand that such enantiomers and / or diastereomers with different ee and / or de, such as higher ee and / or de, can be obtained according to this disclosure. Generally, a “de” value is reported herein when a pair of diastereomers (different by only one chiral center) are separated from a respective diastereomer mixture. In such cases, the “de” value indicates the enrichment of one of the diastereomers. Additionally, in some cases, particularly concerning the α-carbon of the P(=O) group in the examples herein, the absolute stereochemistry drawn may be based on SFC retention times or arbitrarily specified. It should be understood that this document explicitly covers both stereoisomers. Where the specified stereochemistry in the chemical structure in the Examples section is later found to be incorrect, that chemical structure is intended to point to the correct stereochemistry.

[0200] The abbreviations used in the Embodiments section are to be understood to have their ordinary meaning in the art, unless otherwise expressly stated or obviously contrary to the context. Some abbreviations used in the Embodiments section of this document are shown below.

[0201]

[0202] Example 1. Synthesis of Compound 1

[0203] Step 1: At 0°C, acetylenyltrimethylsilane (16.25 g, 165 mmol) was added to a solution of magnesium chloride (79 mL, 158 mmol, 2 M, in THF) in 40 mL of THF, and the mixture was stirred at 0°C for 1 hour under N2. Then, a solution of (5S)-5-(methoxycarbonyl)-2-oxotetrahydropyrrole-1-carboxylic acid (2-methylpropyl-2-yl) ester (35 g, 144 mmol) in 100 mL of THF was added dropwise under N2 at 0°C over 1 hour, and the mixture was stirred at 0°C for 1 hour under N2. The reaction mixture was then poured into a stirred mixture of 160 mL of 20% NH4Cl aqueous solution and 50 mL of iPrOAc at 0°C. The reaction was quenched with iPrOAc and water. The organic layer was separated and washed with 20% NaCl aqueous solution. The organic layer is concentrated to obtain 1-1, which is used directly in the next step.

[0204] Step 2: Add a solution of 1-1 (49 g, 144 mmol) in iPrOAc (200 mL) to a solution of NaBH(OAc)3 (39.5 g, 187 mmol) in iPrOAc (500 mL). Then, add TFA (47 mL, 617 mmol) dropwise at -10 °C under N2 for 1 hour, and stir at 10 °C under N2 for 2 hours. Pour the reaction mixture into 400 mL of 25% K2HPO4 aqueous solution at 0 °C and acidify to pH 7 with NaHCO3. Separate the reaction mixture and extract the aqueous layer twice with iPrOAc. Combine the organic layers, wash with 25% K2HPO4 aqueous solution and 20% NaCl aqueous solution, and dry with Na2SO4. Filter the organic layer and concentrate. Purify the residue by SGC (PE / EtOAc = 10 / 1) to give 1-2.

[0205] Step 3: Add TBAF (62 mL, 62.0 mmol, 1 M, in THF) to a solution of 1-2 (17 g, 52.2 mmol) in THF (68 mL) at 0 °C. Then stir the reaction mixture at 0 °C for 1 hour under N2. Concentrate the mixture. Purify the residue by SGC (PE / EtOAc = 3 / 1) to give 1-3.

[0206] Step 4: To the solution of 1-3 (7.3 g, 28.8 mmol) in EtOAc (150 mL), Lindlar catalyst (5% palladium / calcium carbonate, poisoned with lead) (365 mg, 0.17 mmol) and quinoline (7.3 mL, 61.7 mmol) were added. The mixture was then stirred at room temperature for 80 minutes under H2. The reaction mixture was filtered and concentrated. The residue was purified by SGC (PE / EtOAc = 8 / 2) to give 1-4.

[0207] Step 5: Add 4M HCl / EtOAc (20 mL) to the solution of 1-4 (5.1 g, 20.0 mmol) in EtOAc (25 mL). Then stir the reaction mixture at room temperature under N2 for 3 hours. Concentrate the reaction mixture to obtain 1-5, which is used directly in the next step.

[0208] Step 6: At 0 °C, CMPI (5.72 g, 22.4 mmol) was added to a solution of (2S)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)hex-5-enoic acid (4.67 g, 20.3 mmol), 1-5 (3.9 g, 20.4 mmol), and TEA (6.18 g, 61.0 mmol) in CH2Cl2 (100 mL), and the mixture was stirred at room temperature under N2 for 2 hours. The reaction mixture was poured into H2O at 0 °C and extracted twice with DCM. The organic layers were combined, washed with 30% NH4Cl aqueous solution and 20% NaCl aqueous solution, and dried over Na2SO4. The organic layers were filtered and concentrated. The residue was purified by SGC (PE / EtOAc = 7 / 3) to give 1-6.

[0209] Step 7: Add Grubbs second-generation catalyst (2.14 g, 2.52 mmol) to the solution of 1-6 (6.15 g, 16.8 mmol) in DCE (615 mL). The reactants were then stirred at 50 °C for 18 hours under N2. The mixture was concentrated. The residue was purified by SGC (EtOAc / PE = 2 / 3) to obtain a gray solid, which was milled with PE (50 mL) for 1.5 hours. The mixture was filtered, and the filter cake was washed with 5 mL of PE and dried to obtain 1-7.

[0210] Step 8: Add 10% Pd / C (1.2 g) to the solution of 1-7 (4.5 g, 13.3 mmol) in EtOAc (200 mL). Then stir the mixture at 25 °C for 4 hours under H2. Filter the reaction mixture and wash the filter cake with EtOAc. Concentrate the organic layer to obtain 1-8.

[0211] Step 9: Add LiOH (801 mg, 19.1 mmol) to a solution of 1-8 (1.3 g, 3.80 mmol) in THF (20 mL) and H₂O (20 mL). Stir the mixture at room temperature for 2 hours. Acidify the mixture to pH 4 with 1N HCl. Dilute the mixture with EtOAc and water. Separate the organic layer and wash with a 20% NaCl aqueous solution. Concentrate the organic layer to obtain 1-9.

[0212] Step 10: Add K₂CO₃ (678 mg, 4.90 mmol) and (bromomethyl)benzene (0.44 mL, 3.68 mmol) to a solution of 1-9 (800 mg, 2.45 mmol) in ACN (20 mL). Stir the reaction mixture at room temperature for 18 hours. Concentrate the reaction mixture. Purify the residue by SGC (EtOAc / PE = 1:1) to give 1-10.

[0213] Step 11: Add TFA (4 mL, 1.25 mmol) to the solution of 1-10 (1.0 g, 2.40 mmol) in DCM (20 mL). Stir the reaction mixture at room temperature for 1 hour. Remove the solvent under vacuum. Purify the residue by passing it through a C18 reversed-phase column (ACN / H2O (0.1% NH4OH), 5-95%) to give 1-11.

[0214] Step 12: Under N2 at -65°C, a solution of methyl pyridin-3-ylacetate (21 g, 139 mmol) was added dropwise to a solution of LDA (104 mL, 208 mmol, 2 M) in THF (420 mL). The reaction solution was stirred at -65°C for 2 hours, and then 2-bromoacetonitrile (20 g, 166 mmol) was added. After the addition was complete, the mixture was stirred at -65°C for another 1 hour. After completion, the reaction was quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by SGC (PE / EtOAc = 5 / 2) to give 1-12.

[0215] Step 13: Add EtMgBr (51.4 mL, 102.8 mmol, 2M, in THF) to a solution of 1-12 (8.5 g, 44.7 mmol) and tetraisopropoxide (15.2 g, 53.6 mmol) in THF (170 mL) at 0 °C. The reaction mixture was then stirred at 0 °C for 1 hour under N2. After completion, the reaction was quenched by adding an aqueous HCl solution (60 mL, 2N) at 0 °C. The suspension was warmed to room temperature and filtered. The filtrate was poured into ice water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by SGC (PE / EtOAc = 1 / 3) to give 1-13.

[0216] Step 14: PhSiH3 (19.3 g, 179 mmol) and RhH(CO)(PPh3)3 (2.7 g, 2.98 mmol) were added to a solution of 1-13 (5.6 g, 29.8 mmol) in dioxane (120 mL). The reaction mixture was then stirred at 100 °C for 12 hours under N2. After completion, the mixture was concentrated. The residue was milled with 1N HCl (200 mL) at 25 °C for 0.5 hours and then filtered. The filtrate was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated. The residue was purified by C18 reversed-phase column chromatography (ACN / (0.05% FA aqueous solution): 5-10%) to give 1-14.

[0217] Step 15: To a solution of 1-14 (4.9 g, 28.1 mmol) in THF (50 mL) and H₂O (6.3 mL), NaHCO₃ (5 g, 57.4 mmol) and Boc₂O (7.9 mL, 34.4 mmol) were added. The reaction mixture was then stirred at room temperature for 4 hours. The mixture was diluted with H₂O and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by SGC (PE / EtOAc = 1 / 3) to give 1-15.

[0218] Step 16: Purify 1-15 (6.5 g) by SFC (column: ChiralPak AY, 300×50mm ID, 10µm, ethanol / supercritical CO2 = 25 / 75) to obtain 1-15-P1 (1.7 g) and 1-15-P2 (1.6 g). 1-15-P1: SFC analysis: 99.82% ee; retention time: 2.476 min; column: Chiralpak AY, 150×4.6mm, 3µm, A: CO2 and B: EtOH (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 2.5 mL / min. LCMS (ESI, m / z ): [M+H] + = 275.2; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 8.58-8.50 (m, 1H), 8.48-8.40 (m,1H), 7.82-7.72 (m, 1H), 7.40-7.30 (m, 1H), 3.90-3.80 (m, 1H), 3.60-3.45 (m,1H), 3.40-3.35 (m, 1H), 2.40-2.30 (m, 1H), 2.06-1.90 (m, 1H), 1.50-1.20 (m,11H), 0.60-0.40 (m, 2H). 1-15-P2: SFC analysis: 97.18% ee; retention time: 2.674 min; column: Chiralpak AY, 150×4.6 mm, 3 µm, A is CO2 and B is EtOH (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 2.5 mL / min. LCMS (ESI, m / z ): [M+H] + = 275.2; 1 H NMR (400 MHz, DMSO- d 6, ppm):δ 8.58-8.51 (m, 1H), 8.48-8.41 (m, 1H), 7.81-7.72 (m, 1H), 7.39-7.30 (m, 1H), 3.94-3.84 (m, 1H), 3.54-3.42 (m, 1H), 3.41-3.32 (m, 1H), 2.38-2.28 (m, 1H), 2.10-1.94 (m, 1H), 1.52-1.19 (m, 11H), 0.58-0.41 (m, 2H).

[0219] Step 17: Add TFA (3 mL, 1.28 mmol) to a solution of 1-15-P1 (90 mg, 0.33 mmol) in DCM (10 mL). Stir the reaction mixture at room temperature under N2 for 1 hour. Concentrate the reaction mixture to give crude 1-16-P1, which is used directly in the next step.

[0220] Step 18: Add TFA (3 mL, 1.28 mmol) to a solution of 1-15-P2 (100 mg, 0.36 mmol) in DCM (10 mL). Stir the reaction mixture at room temperature under N2 for 1 hour. Concentrate the reaction mixture to give crude 1-16-P2.

[0221] Step 19: Pd(dppf)Cl2 (6.0 g, 8.26 mmol) and K2CO3 (34.2 g, 248 mmol) were added to a solution of 4-bromo-3-nitrobenzene-1-carboxaldehyde (19.0 g, 82.6 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (20.3 g, 90.9 mmol) in dioxane (500 mL) and H2O (50 mL). The reaction mixture was stirred at 90 °C for 3 hours under N2. The reaction mixture was concentrated. The residue was purified by SGC (EtOAc / PE = 1 / 3) to give 1-17.

[0222] Step 20: Add PPh3 (13.3 g, 50.8 mmol) to a solution of 1-17 (5 g, 20.3 mmol) in 1,2-dichlorobenzene (100 mL). Stir the reaction mixture at 150 °C for 18 hours under N2. Concentrate the reaction mixture. Purify the residue by SGC (EtOAc / PE = 1 / 2) to give 1-18.

[0223] Step 21: Add (Boc)₂O (1.43 g, 6.54 mmol), TEA (661 mg, 6.54 mmol), and DMAP (399 mg, 3.27 mmol) to a solution of 1-18 (700 mg, 3.27 mmol) in THF (10 mL) at 0 °C. Stir the mixture at 0 °C for 1 hour and then concentrate. Purify the residue by SGC (EtOAc / PE = 1 / 3) to obtain 1-19.

[0224] Step 22: Add DBU (194 mg, 1.27 mmol) and diethyl phosphonate (263 mg, 1.91 mmol) to a solution of 1-19 (400 mg, 1.27 mmol) in THF (20 mL). Stir the mixture at room temperature under N2 for 1 hour and then concentrate. Purify the residue by SGC (EtOAc / PE = 10 / 1) to give 1-20.

[0225] Step 23: Add DAST (0.37 mL, 2.76 mmol) to a solution of 1-20 (500 mg, 1.10 mmol) in DCM (30 mL) at -78 °C. Stir the reaction mixture at -78 °C for 1 hour under N2. Quench the reaction by adding dropwise NaHCO3 aqueous solution (20 mL). Separate the mixture and extract the aqueous layer twice with DCM. Combine the organic layers, wash with 20% NaCl aqueous solution, and dry with Na2SO4. Filter the organic layer and concentrate. Purify the residue by SGC (EtOAc / PE = 10 / 1) to give 1-21.

[0226] Step 24: Add 1-11 (752 mg, 2.38 mmol) to the stirred solution of 1-21 (360 mg, 0.79 mmol) in 40 mL of 2-methyl-2-butanol. Stir the mixture at 125 °C for 10 hours under microwave conditions. Remove the solvent under vacuum. Crude product 1-22 is used directly for the next step.

[0227] Step 25: At 0°C, (Boc)₂O (1.38 g, 6.33 mmol), TEA (641 mg, 0.88 mL, 6.33 mmol), and DMAP (97 mg, 0.79 mmol) were added to a solution of crude product 1-22 (515 mg, 0.79 mmol) in THF (40 mL). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated. The residue was purified by SGC (EtOAc / PE = 10 / 1) to give 1-23.

[0228] Step 26: Add 5% Pd / C (100 mg, 0.94 mmol) to the solution of 1-23 (100 mg, 0.13 mmol) in EtOAc (10 mL). Stir the mixture at room temperature under H2 for 2 hours. Filter the mixture and wash the filter cake with 5 mL of EtOAc. Concentrate the organic layer to obtain 1-24.

[0229] Step 27: DIEA (188 mg, 1.45 mmol) was added to a solution of 1-24 (80 mg, 0.12 mmol), 1-16-P1 (42 mg, 0.24 mmol), and HATU (92 mg, 0.24 mmol) in DCM (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour under N2. The mixture was diluted with DCM and water. The organic layer was separated and washed with 20% NaCl aqueous solution. The solvent was removed under vacuum. The residue was purified by passing it through a C18 reversed-phase column (ACN / H2O (0.05% NH4OH), 5-95%) to give 1-25.

[0230] Step 28: NaI (248 mg, 1.65 mmol) and TMSCl (180 mg, 0.21 mL, 1.65 mmol) were added to a solution of 1-25 (90 mg, 0.11 mmol) in acetonitrile (9 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour under N2. The reaction was quenched with 3 mL H2O (containing 0.05% TFA) at room temperature. The mixture was concentrated under vacuum at 30 °C. The residue was purified by preparative-HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–52%) to give 1. LCMS (ESI, m / z ): [M+H] + = 661.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.32 (brs, 1H), 8.60 (s, 1H),8.51-8.41 (m, 1H), 8.31-7.94 (m, 2H), 7.91-7.80 (m, 1H), 7.78-7.53 (m, 2H),7.51-7.18 (m, 3H), 6.04-5.64 (m, 1H), 5.34-5.12 (m, 1H), 4.74-4.30 (m, 3H), 3.70-3.42 (m, 2H), 2.44-2.21 (m, 2H), 2.20-1.94 (m, 5H), 1.93-1.64 (m, 7H),1.62-1.40 (m, 2H), 0.60-0.40 (m, 2H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -194.86 (1F).

[0231] Example 2. Synthesis of compounds 2 and 3

[0232] Step 1: Purify 1-21 (25.2 g) by SFC (column: ChiralPak IC, 300×50mm ID, 10µm, ethanol / supercritical CO2 = 25 / 75) to obtain 1-21-P1 (11.8 g) and 1-21-P2 (11.7 g). 1-21-P1: SFC analysis: 100% ee; retention time: 1.559 min; column: ChiralPak IC, 100×4.6mm ID, 3µm, A: CO2 and B: ethanol (0.05% DEA), 40%; pressure: 100 bar; flow rate: 2.5 mL / min. 1-21-P2: SFC analysis: 100% ee; retention time: 1.862 min; column: ChiralPak IC, 100×4.6mm ID, 3µm, A is CO2 and B is ethanol (0.05% DEA), 40%; pressure: 100 bar; flow rate: 2.5 mL / min.

[0233] Steps 2-6: Prepare compound 2 following the synthetic procedure for compound 1 in Example 1, starting from steps 1-21-P1 and 1-11. LCMS (ESI, m / z ): [M+H] + = 661.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.47 (s, 1H), 8.64 (s, 1H), 8.54-8.44 (m, 1H), 8.39-8.00 (m, 2H), 7.91-7.81 (m, 1H), 7.78-7.58 (m, 3H), 7.47-7.33 (m, 2H), 5.98-5.72 (m, 1H), 5.30-5.20 (m, 1H), 4.58-4.41 (m, 2H), 4.23-4.12 (m, 1H), 3.80-3.70 (m, 1H), 3.65-3.55 (m, 1H), 2.34-2.22 (m, 1H), 2.20-1.99 (m, 6H), 1.90-1.60 (m, 8H), 1.59-1.48 (m, 1H), 0.56-0.38 (m, 2H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -194.98 (1F).

[0234] Steps 2'-6': Compound 3 is prepared following the synthetic procedure for compound 1 in Example 1, starting from steps 1-21-P2 and 1-11. LCMS (ESI, m / z ): [M+H] + = 661.5; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.42 (brs,1H), 8.61 (s, 1H), 8.50-8.41 (m, 1H), 8.34-8.02 (m, 2H), 7.87-7.79 (m, 1H),7.78-7.50 (m, 3H), 7.45-7.30 (m, 2H), 6.00-5.80 (m, 1H), 5.32-5.16 (m, 1H), 4.58-4.42 (m, 2H), 4.22-4.10 (m, 1H), 3.82-3.70 (m, 1H), 3.68-3.54 (m, 1H),2.40-2.26 (m, 1H), 2.24-1.96 (m, 6H), 1.94-1.62 (m, 8H), 1.61-1.50 (m, 1H), 0.58-0.40 (m, 2H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -194.77 (1F).

[0235] Example 3. Synthesis of Compound 4

[0236] Step 1: DIEA (757 mg, 5.86 mmol) was added to a stirred solution of {(5S,8S,10aR)-8-(methoxycarbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazapentanoctyl-5-yl]amino}carbamate (2-methylpropyl-2-yl) ester (1.0 g, 2.93 mmol) and CbzOSu (803 mg, 3.22 mmol) in THF (20 mL). The reaction mixture was then stirred at room temperature under N2 for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by SGC (EtOAc / PE = 1 / 2) to give 4-1.

[0237] Step 2: LiOH (573 mg, 13.7 mmol) was added to a solution of 4-1 (1.3 g, 2.73 mmol) in THF (20 mL) and H2O (20 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was acidified to pH 4 with 1N HCl and diluted with EtOAc and water. The organic layer was separated, washed with 20% NaCl aqueous solution, and concentrated to obtain 4-2.

[0238] Step 3: Add 3-bromoprop-1-ene (511 mg, 4.23 mmol) to a solution of 4-2 (1.3 g, 2.82 mmol) and Cs₂CO₃ (1.84 g, 5.63 mmol) in ACN (20 mL). Stir the reaction mixture at room temperature for 5 hours. Concentrate the reaction mixture. Purify the residue by SGC (EtOAc / PE = 1 / 1) to give 4-3.

[0239] Step 4: Add TFA (3 mL, 2.19 mmol) to the solution of 4-3 (1.1 g, 2.19 mmol) in DCM (10 mL). Stir the reaction mixture at room temperature for 2 hours. Remove the solvent under vacuum. Acidify the residue with NaHCO3 to pH 7 and purify by C18 reversed-phase column (ACN / H2O (0.1% NH4OH), 5-95%) to give 4-4.

[0240] Step 5: Add 1-21-P2 (901 mg, 2.25 mmol) to a stirred solution of 4-4 (680 mg, 1.50 mmol) in 15 mL of 2-methyl-2-butanol. Then irradiate the reaction mixture with microwave at 125 °C for 10 hours. Remove the solvent under vacuum to obtain crude product 4-5, which is used directly in the next step.

[0241] Step 6: At 0°C, add (Boc)₂O (1.68 g, 7.70 mmol), TEA (779 mg, 1.1 mL, 7.70 mmol), and DMAP (188 mg, 1.54 mmol) to a solution of crude product 4-5 (1.1 g, 1.54 mmol) in THF (20 mL). Stir the reaction mixture at 0°C for 1 hour. Concentrate the reaction mixture. Purify the residue by SGC (EtOAc / PE = 8:2) to obtain 4-6.

[0242] Step 7: Add Pd(PPh3)4 (116 mg, 0.1 mmol) and tetrahydropyrrole (29 mg, 0.40 mmol) to a solution of 4-6 (420 mg, 0.50 mmol) in DCM (10 mL) at 0 °C. Stir the reaction mixture at 0 °C for 10 min under N2. Concentrate the mixture. Purify the crude product by passing it through a C18 reversed-phase column (ACN / H2O (0.05% TFA), 5-95%) to give 4-7.

[0243] Step 8: A solution of 4-7 (235 mg, 0.30 mmol), DIEA (76 mg, 0.1 mL, 0.59 mmol), and HATU (225 mg, 0.59 mmol) in DCM (5 mL) was stirred at 0 °C for 5 minutes under N2. Then, a solution of 1-16-P2 (77 mg, 0.44 mmol) and DIEA (458 mg, 3.54 mmol) in DCM (2 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with 20% NaCl aqueous solution, and concentrated. The residue was purified by C18 reversed-phase column chromatography (ACN / H2O (0.05% NH4OH), 5-95%) to give 4-8.

[0244] Step 9: Add PdCl2 (3.7 mg, 0.021 mmol), TEA (4.3 mg, 0.042 mmol), and Et3SiH (19.5 mg, 0.168 mmol) to a solution of 4-8 (40 mg, 0.042 mmol) in DCM (2 mL) at 0 °C. Stir the reaction mixture at room temperature under N2 for 1 hour. After filtration through a diatomaceous earth mat, concentrate the solvent to obtain crude product 4-9, which is used directly in the next step.

[0245] Step 10: Acetyl chloride (0.083 mL, 0.083 mmol, 1M, in DCM) was added to a solution of 4-9 (34 mg, 0.042 mmol) and TEA (12.6 mg, 0.125 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The mixture was diluted with DCM and water. The organic layer was separated and washed with 20% aqueous NaCl solution. The solvent was removed under vacuum. The residue was purified by passing it through a C18 reversed-phase column (ACN / H2O (0.05% NH4OH), 5-95%) to give 4-10.

[0246] Step 11: Add NaI (52.3 mg, 0.35 mmol) and TMSCl (37.9 mg, 0.35 mmol) to a solution of 4-10 (15 mg, 0.017 mmol) in acetonitrile (2 mL) at room temperature. Stir the reaction mixture at room temperature under N2 for 1 hour. Quench the reaction mixture with 2 mL H2O at room temperature and then concentrate at 30 °C. Purify the residue by preparative-HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–52%) to 4. LCMS (ESI, m / z ): [M+H] + = 704.4; 1 H NMR (400MHz, DMSO- d 6, ppm): δ 12.02 (brs, 1H), 8.60 (s, 1H), 8.54-8.32 (m, 1H), 8.30-8.05 (m, 1H), 7.95-7.55 (m, 4H), 7.52-7.20 (m, 3H), 6.00-5.72 (m, 1H), 5.38-5.18 (m, 1H), 4.72-4.48 (m, 1H), 4.47-4.23 (m, 2H), 4.22-4.08 (m, 1H), 4.07-3.88 (m, 1H), 3.78-3.55 (m, 2H), 3.50-3.18 (m, 2H), 2.45-2.32 (m, 1H), 2.30-2.17 (m, 4H), 2.16-1.55 (m, 8H), 0.60-0.38 (m, 2H); 19 F NMR (376 MHz, DMSO- d 6,ppm): δ -195.12 (1F).

[0247] Example 4. Synthesis of Compound 5

[0248] Step 1: CMPI (211.47 g, 829 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (192.24 g, 754 mmol), 1-5 (144 g, 754 mmol), and TEA (228.4 g, 2262 mmol) in CH2Cl2 (1.2 L) at 0 °C, and the mixture was stirred at room temperature for 2 hours under N2. The reaction mixture was poured into H2O at 0 °C and extracted twice with DCM. The combined organic layers were washed with 30% NH4Cl aqueous solution and 20% NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated. The crude product was purified by SGC (PE / EtOAc = 7 / 3) to give 5-1.

[0249] Step 2: Add Grubbs second-generation catalyst (4.16 g, 4.90 mmol) to a solution of 5-1 (115 g, 327 mmol) in DCE (1.2 L). The mixture was then stirred at room temperature under N2 for 18 hours. The mixture was concentrated. The crude product was purified by SGC (EtOAc / PE = 2 / 3) to obtain a gray solid, which was milled with PE for 1.5 hours and then filtered. The filter cake was washed with PE and dried to obtain 5-2.

[0250] Step 3: Add 10% Pd / C (4.45 g) to the solution of 5-2 (89 g, 238 mmol) in EtOAc (1.1 L). Then stir the mixture at 25 °C for 4 hours under H2. Filter the reaction mixture and wash the filter cake with EtOAc. Concentrate the organic layer under reduced pressure to obtain 5-3.

[0251] Step 4: Add LiOH (26.5 g, 1104 mmol) to a solution of 5-3 (72 g, 221 mmol) in THF (1.0 L) and H2O (100 mL). Stir the reaction mixture at room temperature for 2 hours. Acidify the mixture to pH 5 with 1N HCl. Dilute the mixture with EtOAc and water. Separate the organic layer, wash with 20% NaCl aqueous solution, and concentrate to obtain 5-4.

[0252] Step 5: Add K₂CO₃ (67.45 mg, 489 mmol) and (bromomethyl)benzene (36.77 g, 215 mmol) to a solution of 5-4 (61 g, 196 mmol) in ACN (700 mL). Stir the reaction mixture at room temperature for 18 hours. Concentrate the reaction mixture. Purify the residue by SGC (EtOAc / PE = 1 / 3) to give 5-5.

[0253] Step 6: Add TFA (120 mL) to the solution of 5-5 (67.5 g, 167 mmol) in DCM (600 mL). Stir the reaction mixture at room temperature for 1 hour. Remove the solvent under vacuum. Purify the residue by passing it through a C18 reversed-phase column (ACN / H2O (0.1% NH4OH), 5-95%) to give 5-6.

[0254] Step 7: Add 5-6 (4.79 g, 15.8 mmol) to a stirred solution of 1-21-P2 (4.0 g, 8.8 mmol) in 15 mL of 2-methyl-2-butanol. Then irradiate the reaction mixture with microwave at 125 °C for 10 hours. Remove the solvent under vacuum to obtain crude product 5-7.

[0255] Step 8: At 0°C, add (Boc)₂O (6.06 mL, 26.4 mmol), DIEA (4.36 mL, 26.4 mmol), and DMAP (1.07 g, 8.8 mmol) to a solution of crude product 5-7 (5.6 g, 8.8 mmol) in THF (20 mL). Stir the reaction mixture at 0°C for 18 hours. Concentrate the reaction mixture. Purify the residue by SGC (EtOAc / PE = 9 / 1) to give 5-8.

[0256] Step 9: Add Lindlar catalyst (700 mg) to the stirred solution of 5-8 (700 mg, 1.0 mmol) in EtOAc (10 mL). Then stir the mixture at room temperature for 2 hours under H2. Filter the reaction mixture and wash the filter cake with EtOAc. Concentrate the organic layer to obtain 5-9.

[0257] Step 10: A solution of 5-9 (105 mg, 0.16 mmol), DIEA (0.054 mL, 0.33 mmol), and HATU (92.7 mg, 0.24 mmol) in DCM (3 mL) was stirred at 0 °C for 5 minutes under N2. Then, a solution of 1-16-P2 (42.60 mg, 0.24 mmol) and DIEA (0.323 mL, 1.95 mmol) in DCM (2 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour under N2. The mixture was diluted with DCM and water. The organic layer was separated, washed with 20% NaCl aqueous solution, and concentrated. The residue was purified by a C18 reversed-phase column (ACN / H2O (0.05% NH4OH), 5-95%) to give 5-10.

[0258] Step 11: NaI (185 mg, 1.25 mmol) and TMSCl (135 mg, 1.25 mmol) were added to a solution of 5-10 (126 mg, 0.16 mmol) in acetonitrile (6 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour under N2. The reaction mixture was quenched with 2 mL H2O at room temperature and then concentrated at 30 °C. The residue was purified by preparative-HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–52%) to give 5. LCMS (ESI, m / z ): [M+H] + = 647.4; 1 H NMR (400MHz, DMSO- d 6, ppm): δ 12.32 (brs, 1H), 8.82-8.34 (m, 3H), 8.30-8.08 (m, 1H), 7.90-7.72 (m, 2H), 7.71-7.48 (m, 2H), 7.47-7.27 (m, 2H), 6.01-5.75 (m, 1H),5.05-4.80 (m, 1H), 4.70-4.50 (m, 1H), 4.26-3.94 (m, 2H), 3.76-3.48 (m, 2H),2.30-1.92 (m, 8H), 1.89-1.65 (m, 5H), 1.62-1.48 (m, 1H), 0.58-0.36 (m, 2H); 19 FNMR (376 MHz, DMSO- d 6, ppm): δ -194.98 (1F).

[0259] Example 5. Synthesis of Compound 6

[0260] Step 1-2: Prepare compound 6-2 starting from 1-21-P1 and 1-11 according to the synthesis procedure of compound 1-23 in Example 1.

[0261] Step 3: Add 10% Pd / C (200 mg) to a stirred solution of 6-2 (150 mg, 0.20 mmol) in MeOH (20 mL). Then, stir the reaction mixture at room temperature for 8 hours under H2. Filter the reaction mixture and wash the filter cake with 5 mL of EtOAc. Concentrate the organic layer to obtain 6-3.

[0262] Steps 4-5: Compound 6 is prepared following the synthetic procedure for compound 1 in Example 1, starting from 6-3 and 1-16-P2. LCMS (ESI, m / z ): [M+H] + = 643.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.41 (s, 1H), 8.64 (s, 1H), 8.56-8.46 (m, 1H), 8.42-8.21 (m, 1H), 8.20-8.08 (m, 1H), 7.94-7.82 (m, 1H), 7.79-7.64 (m, 2H), 7.63-7.55 (m, 1H), 7.52-7.38 (m, 1H), 7.30-7.20 (m, 1H), 5.34-5.13 (m, 1H), 4.57-4.40 (m, 2H), 4.26-4.10 (m, 1H), 3.83-3.52 (m, 2H), 3.21 (d, J = 22.0 Hz, 2H), 2.42-2.28 (m, 1H), 2.27-1.96 (m, 6H), 1.94-1.62 (m, 8H), 1.60-1.50 (m, 1H), 0.60-0.41 (m, 2H).

[0263] Example 6. Synthesis of Compound 7

[0264] Step 1: Add Desmond-Martin periodide (2.6 g, 6.1 mmol) to a solution of 1-20 (1.84 g, 4.1 mmol) in DCM (30 mL). Stir the reaction mixture at 20 °C for 3 hours. Dilute the mixture with DCM and wash with saturated aqueous Na₂S₂O₃ solution, saturated aqueous NaHCO₃ solution, and brine. Concentrate the organic layer at 30 °C to obtain 7-1.

[0265] Step 2: Add DAST (2.80 mL, 21.1 mmol) to the solution of 7-1 (1.90 g, 4.2 mmol) in DCM (25 mL). Stir the reaction mixture at 20 °C for 3 hours. Quench the mixture by adding a saturated aqueous solution of NaHCO3 at 0 °C and then extract with DCM. Combine the organic layers, dry over Na2SO4, filter, and concentrate. Purify the residue by SGC (PE / EtOAc = 1 / 5) to give 7-2.

[0266] Steps 3-7: Prepare compound 7 following the synthetic procedure for compound 1 in Example 1, starting from 7-2 and 1-11. LCMS (ESI, m / z ): [M+H] + = 679.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.05 (brs, 1H),8.70-8.38 (m, 2H),8.26-7.56 (m, 4H),7.54-7.27 (m, 3H), 5.26-5.07 (m, 1H),4.89-4.45 (m, 2H), 4.24-4.10 (m, 1H), 3.84-3.72 (m, 1H), 3.68-3.55 (m, 1H), 2.40-2.34 (m, 1H), 2.24-1.98 (m, 6H), 1.91-1.52 (m, 9H), 0.57-0.39 (m, 2H).

[0267] Example 7. Synthesis of compounds 8 and 9

[0268] Step 1: tert-butyl 7-cyano-6-phenyl-4-azaspiro[2,4]heptane-4-carboxylate (365 mg) was purified by preparative SFC (column: ChiralCel OJ, 250×30mm ID, 10µm, ethanol / supercritical CO2 = 25 / 75) to obtain 8-1-P1 (66 mg) and 8-1-P2 (62 mg). 8-1-P1: SFC analysis: 100% ee; retention time: 2.056 min; column: ChiralPak AD, 150×4.6mm ID, 3µm, A: CO2 and B: methanol (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 2.5 mL / min. 8-1-P2: SFC analysis: 98.18% ee; retention time: 2.408 min; column: ChiralPak AD, 150×4.6mm ID, 3µm., A is CO2 and B is methanol (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 2.5 mL / min.

[0269] Steps 2-5: Compound 8 was prepared following the synthetic procedure for compound 11 in Example 8, starting from 8-1-P1 and 1-24. LCMS (ESI, m / z): [M+H] + = 685.4; 1H NMR (400 MHz, DMSO- d 6, ppm): δ 11.68 (brs,1H), 8.15-7.76 (m, 1H), 7.73-6.71 (m, 10H), 5.91-5.66 (m, 1H), 5.34-5.12 (m,1H), 4.85-4.24 (m, 3H), 4.02 (d, J = 8.0 Hz, 1H), 3.82-3.59 (m, 2H), 2.31-2.18(m, 2H), 2.16-1.51 (m, 12H), 0.90-0.76 (m, 1H), 0.73-0.59 (m, 1H).

[0270] Steps 2'-5': Compound 9 was prepared following the synthetic procedure for compound 11 in Example 8, starting from steps 8-1-P2 and 1-24. LCMS (ESI, m / z): [M+H] + = 685.2; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.88 (brs,1H), 8.30-7.84 (m, 1H), 7.78-6.93 (m, 10H), 5.97-5.65 (m, 1H), 5.35-5.07 (m,1H), 4.87-4.37 (m, 2H), 4.29-4.10 (m, 1H), 3.96-3.74 (m, 3H), 2.40-2.23 (m,1H), 2.22-1.94 (m, 4H), 1.92-1.64 (m, 8H), 1.62-1.47 (m, 1H), 0.91-0.75 (m,1H), 0.73-0.57 (m,1H).

[0271] Example 8. Synthesis of compounds 11 and 13

[0272]

[0273] Step 1: LDA (305 mL, 2 M, in THF) was added to a solution of 2-methoxy-4-methylpyridine (50 g, 406 mmol) in THF (500 mL) at -78 °C. The mixture was stirred at -78 °C for 1 hour. Subsequently, methyl methoxyformate (43.9 g, 487 mmol) was added and the resulting mixture was stirred at -78 °C for another 1 hour. An aqueous solution of NH4Cl was added and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by SGC (PE / EtOAc = 2 / 1) to give 11-1.

[0274] Step 2: Add LDA (268 mL, 2 M, in THF) to a solution of 11-1 (54 g, 298 mmol) in THF (750 mL) at -78 °C. Stir the mixture at -78 °C for 1 hour. Then add bromoacetonitrile (54 g, 447 mmol) and stir the mixture at -78 °C for another 1 hour. Quench the reaction with saturated NH4Cl aqueous solution and extract the mixture with EtOAc. Combine the organic layers, dry over Na2SO4, filter and concentrate. Purify the residue by SGC (PE / EtOAc = 1 / 1) to give 11-2.

[0275] Step 3: At 0 °C, a solution of EtMgBr in 2-methyltetrahydrofuran (167 mL, 3.4 M) was added to a solution of 11-2 (50 g, 227 mmol) and Ti(Oi-Pr)4 (32 g, 114 mmol) in THF (1000 mL). The mixture was stirred at 0 °C for 1 hour. The reaction was quenched with 1 M HCl aqueous solution and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by SGC (DCM / MeOH = 10 / 1) to give 11-3.

[0276] Step 4: Add PhSiH3 (111 g, 1025 mmol) to a solution of 11-3 (37.3 g, 171 mmol) and RhH(CO)(PPh3)3 (231 mg, 0.25 mmol) in dioxane (700 mL). Stir the mixture at 100 °C for 12 hours under N2. Quench the reaction with 2 M HCl aqueous solution and extract the mixture with EtOAc. Then adjust the pH of the aqueous layer to 10-12 by adding 2 M NaOH. Subsequently, extract the mixture with EtOAc. Combine the organic layers, dry over Na2SO4, filter, and concentrate to obtain 11-4.

[0277] Step 5: The solution of 11-4 (23.8 g, 116.5 mmol) in a mixture of 48% HBr / water (150 mL) and 33% HBr / AcOH (75 mL) was stirred at 100 °C for 12 hours. The mixture was concentrated. The residue was neutralized to pH 7 with 2 M NaOH. The mixture was then concentrated to give 11-5.

[0278] Step 6: Add (Boc)₂O (39.8 mL, 174 mmol) to a solution of 11-5 (22 g, 116 mmol) and TEA (32.1 mL, 231 mmol) in THF (500 mL) and H₂O (1000 mL). Stir the mixture at room temperature for 12 hours and then extract with EtOAc. Combine the organic layers, dry over Na₂SO₄, filter, and concentrate. Then purify the residue by SGC (DCM / MeOH = 8 / 1) to give 11-6.

[0279] Step 7: Preparative SFC (Column: ChiralPak AD, 300×50mm ID, 10µm, methanol (0.1% NH3) . 11-6 (22 g) was purified using H2O / supercritical CO2 (40 / 60) to yield 11-6-P1 (8.85 g) and 11-6-P2 (8.02 g). 11-6-P1: SFC analysis: 98.22% ee; retention time: 2.726 min; column: ChiralPak AD, 50 × 4.6 mm ID, 3 µm, A: CO2 and B: methanol (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 3 mL / min. 11-6-P2: SFC analysis: 99.50% ee; retention time: 3.420 min; column: ChiralPak AD, 50×4.6mm I.D., 3µm., A is CO2 and B is methanol (0.05% DEA), 5-40%; pressure: 100 bar; flow rate: 3 mL / min.

[0280] Step 8: MeI (1.07 mL, 17.2 mmol) was added to a solution of 11-6-P1 (2.0 g, 6.89 mmol) and Cs₂CO₃ (6.7 g, 20.7 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with H₂O and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. The residue was then purified by SGC (DCM / MeOH = 10 / 1) to give 11-7-P1.

[0281] Step 9: Add TFA (1 mL) to a solution of 11-7-P1 (100 mg, 0.36 mmol) in DCM (3 mL) at 20 °C. Stir the mixture at 20 °C for 3 hours and then concentrate to obtain crude 11-8-P1, which is used directly in the next step.

[0282] Steps 10-11: Starting from 11-8-P1 and 1-24, prepare compound 11 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z ): [M+H] + = 691.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.52 (brs,1H), 8.14-7.10 (m, 6H), 6.41-6.06 (m, 2H), 5.94-5.61 (m, 1H), 5.41-5.15 (m,1H), 4.73-3.95 (m, 4H), 3.73-3.45 (m, 1H), 3.17 (s, 3H), 2.29-2.10 (m, 3H), 2.09-1.83 (m, 7H), 1.77-1.52 (m, 6H), 0.56-0.37 (m, 2H).

[0283] Steps 8'-11': Compound 13 is prepared following the synthetic procedure for compound 11 in Example 8, starting from 11-6-P2. LCMS (ESI, m / z ): [M+H] + = 691.3; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.89 (brs,1H), 8.30-6.77 (m, 7H), 6.42-6.03 (m, 2H), 5.96-5.62 (m, 1H), 5.33-5.10 (m,1H), 4.85-4.33 (m, 2H), 4.16-3.94 (m, 1H), 3.75-3.55 (m, 2H), 3.31 (s, 3H), 2.39-2.23 (m, 1H), 2.22-1.38 (m, 15H), 0.57-0.35 (m, 2H).

[0284] Example 9. Synthesis of Compound 14

[0285]

[0286] Step 1-2: Starting from 1-21-P2 and 1-11, prepare compound 14-2 according to the synthesis procedure of compound 1-23 in Example 1.

[0287] Step 3: Add TMSI (176 mg, 0.88 mmol) to a solution of 14-2 (220 mg, 0.29 mmol) in DCM (3 mL) at 0 °C. Stir the reaction mixture at 0 °C for 1 hour. Concentrate the reaction mixture to obtain crude 14-3, which is used directly in the next step.

[0288] Step 4: Oxaloyl chloride (112 mg, 0.9 mmol) was added to a stirred solution of 14-3 (204 mg, 0.29 mmol) and DMF (2.1 mg, 0.03 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was then stirred at room temperature under N2 for 1 hour. The mixture was concentrated to give crude 14-4, which was used directly in the next step.

[0289] Step 5: Phenol (20 mg, 0.21 mmol) and a solution of DIEA (760 mg, 5.88 mmol) in DCM (2 mL) were added dropwise to a stirred solution of 14-4 (215 mg, 0.29 mmol) in DCM (5 mL) at 0 °C with stirring. The reaction mixture was stirred at 0 °C for 3 minutes under N2. Then, a solution of (2S)-2-aminopropionic acid propyl hydrochloride (99 mg, 0.59 mmol) and DIEA (76.0 mg, 0.59 mmol) in DCM (2 mL) was added dropwise to the stirred solution at 0 °C under N2 at room temperature for 1 hour. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with 20% NaCl aqueous solution, and concentrated. The residue was purified by SGC (EtOAc / PE = 2 / 1) to give 14-5.

[0290] Step 6: Add Lindlar catalyst (75 mg) to a stirred solution of 14-5 (25 mg, 0.028 mmol) in EtOAc (5 mL). The reaction mixture was then stirred at room temperature under H2 for 18 hours. The reaction mixture was filtered and the filter cake was washed with 10 mL of EtOAc. The organic layer was concentrated under reduced pressure to give 14-6.

[0291] Step 7: A solution of 14-6 (18 mg, 0.023 mmol), DIEA (5.9 mg, 0.045 mmol), and HATU (17.2 mg, 0.045 mmol) in DCM (3 mL) was stirred at 0 °C for 5 minutes under N2. Then, a solution of 1-16-P2 (7.90 mg, 0.045 mmol) and DIEA (35.2 mg, 0.272 mmol) in DCM (2 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with 20% NaCl aqueous solution, and concentrated. The residue was purified by C18 reversed-phase column chromatography (ACN / H2O (0.05% NH4OH), 5-95%) to give 14-7.

[0292] Step 8: The stirred solution of 14-7 (17 mg, 0.018 mmol) in 1,1,1,3,3,3-hexafluoroprop-2-ol (3 mL) was microwave-treated at 50 °C for 75 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN / H2O (0.05% NH4OH), 5-95%) to give 14. LCMS (ESI, m / z ): [M+H] + = 850.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.52 (s, 1H), 8.57-8.52 (m, 1H), 8.44-8.36 (m, 1H), 8.14-8.02 (m, 1H), 7.80-7.66 (m, 3H), 7.41-7.24 (m, 5H), 7.23-7.10 (m, 3H), 6.70-6.50 (m, 1H), 6.29-6.01 (m, 2H), 5.40-5.27 (m, 1H), 4.55-4.30 (m, 2H), 4.19-4.04 (m, 1H), 3.98-3.49 (m, 5H), 2.33-2.20 (m, 1H), 2.19-1.43 (m, 15H), 1.40-1.20 (m, 2H), 1.14-1.06 (m, 3H), 0.83-0.64 (m, 3H), 0.55-0.39 (m, 2H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -191.95 (1F), -194.48 (0.35F);31 P NMR (162 MHz, DMSO- d 6, ppm): δ 17.62 (1P), 17.33 (0.3P).

[0293] Example 10. Synthesis of Compound 15

[0294] Steps 1-6: Starting from step 6-2, prepare compound 15 according to the synthetic procedure for compound 14 in Example 9. LCMS (ESI, m / z ): [M+H] + = 850.3; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.58 (s, 1H), 8.59-8.51(m, 1H), 8.45-8.34 (m, 1H), 8.18-8.04 (m, 1H), 7.81-7.66 (m, 3H), 7.45-7.05(m, 8H), 6.82-6.47 (m, 1H), 6.34-5.97 (m, 2H), 5.47-5.20 (m, 1H), 4.57-4.28(m, 2H), 4.21-4.02 (m, 1H), 3.99-3.46 (m, 5H), 2.35-2.20 (m, 1H), 2.19-1.52(m, 14H), 1.51-1.35 (m, 2H), 1.20-1.09 (m, 1H), 0.96-0.69 (m, 6H), 0.57-0.37(m, 2H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -191.80 (1F), -194.44 (0.25F); 31 PNMR (162 MHz, DMSO- d 6, ppm): δ 17.48 (0.25P), 17.28 (1P).

[0295] Example 11. Synthesis of Compound 16

[0296] Step 1: DIEA (757 mg, 5.86 mmol) was added to a stirred solution of {[(5S,8S,10aR)-8-(methoxycarbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazapentanoctyl-5-yl]amino}carbamate (2-methylpropyl-2-yl) (1.0 g, 2.93 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (940 mg, 4.39 mmol) in a DCM (20 mL). The reaction mixture was then stirred at room temperature under N2 for 18 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by SGC (EtOAc / PE = 1 / 2) to give 16-1.

[0297] Steps 2-9: Compound 16 was prepared following the synthetic procedure for compound 5 in Example 4, starting from 16-1. LCMS (ESI, m / z ): [M+H] + = 726.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.34 (brs, 1H), 8.65-8.59 (m, 1H), 8.50-8.44 (m, 1H), 8.35-8.06 (m, 2H), 7.92-7.82 (m, 1H), 7.81-7.57 (m, 3H), 7.49-7.31 (m, 2H), 6.30-5.80 (m, 2H), 5.26-5.10 (m, 1H), 4.58-4.36 (m, 2H), 4.23-4.08 (m, 1H), 3.83-3.70 (m, 1H), 3.69-3.45 (m, 2H), 3.40-2.93 (m, 5H), 2.43-2.30 (m, 1H), 2.29-1.93 (m, 4H), 1.91-1.51 (m, 5H), 0.57-0.39 (m, 2H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -120.17 (2F), -194.95 (1F).

[0298] Example 12. Synthesis of Compound 18

[0299] Step 1: Add pyridine (0.019 mL, 0.23 mmol) and 2,2,2-trifluoroacetic acid 2,3,4,5,6-pentafluorophenyl ester (87 mg, 0.31 mmol) to a solution of 5-9 (50 mg, 0.08 mmol) in DMF (2 mL). Stir the mixture at room temperature for 1 hour. Dilute the mixture with H2O and extract with EtOAc. Combine the organic layers, wash with brine, dry over anhydrous Na2SO4, filter, and concentrate. Purify the residue by SGC (DCM / MeOH = 95 / 5) to give 18-1.

[0300] Step 2: Add TMSI (86 mg, 0.62 mmol) to a solution of 18-1 (50 mg, 0.06 mmol) in DCM (1 mL) and stir the mixture at room temperature under N2 for 18 hours. Concentrate the mixture to obtain crude 18-2, which is used directly in the next step.

[0301] Step 3: At 0 °C, a solution of 3-(azacyclobutane-3-yl)-4-methoxypyridine (12.5 mg, 0.08 mmol) and DIEA (342 mg, 2.65 mmol) in DCM (2 mL) was added to a solution of 18-2 (35 mg, 0.05 mmol) and DIEA (171 mg, 1.33 mmol) in DCM (3 mL). The mixture was stirred at room temperature under N2 for 1 hour. The solvent was removed under vacuum. The residue was purified by passing it through a C18 reversed-phase column (ACN / H2O (0.05% FA), 5-95%) to give 18-2. LCMS (ESI, m / z ):[M+H] + = 637.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.82-11.39 (m, 1H), 8.50-8.29(m, 2H), 8.04-7.53 (m, 3H), 7.36-7.12 (m, 2H), 7.09-6.87 (m, 1H), 6.79-6.50(m, 1H), 5.75-5.39 (m, 1H), 5.09-4.83 (m, 1H), 4.76-4.33 (m, 2H), 4.32-3.89(m, 4H), 3.88-7.73 (m, 4H), 2.28-2.12 (m, 1H), 2.10-1.67 (m, 8H), 1.65-1.42(m, 1H).

[0302] Example 13. Synthesis of Compound 26

[0303] Steps 1-3: Starting from steps 1-24, prepare compound 26 according to the synthetic procedure for compound 18 in Example 12. LCMS (ESI, m / z ): [M+H] + = 621.2; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.37 (brs, 1H),8.70-8.42 (m, 2H), 8.41-7.98 (m, 2H), 7.97-7.79 (m, 1H), 7.78-7.18 (m, 5H),6.04-5.73 (m, 1H), 5.36-5.16 (m, 1H), 4.93-4.48 (m, 2H), 4.47-4.13 (m, 3H), 4.07-3.81 (m, 2H), 2.30-2.18 (m, 1H), 2.17-2.01 (m, 2H), 2.00-1.65 (m, 8H),1.64-1.49 (m, 1H); 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -194.72 (1F).

[0304] Example 14. Synthesis of Compound 29

[0305] Steps 1-4: Starting from steps 4-7, prepare compound 29 according to the synthetic procedure for compound 4 in Example 3. LCMS (ESI, m / z ): [M+H] + = 734.2; 1 H NMR (400 MHz, DMSO- d6, ppm): δ 11.47 (brs, 1H), 8.11-7.65 (m, 3H), 7.64-7.42 (m, 2H), 7.38-6.88 (m, 3H), 6.79-6.38 (m, 1H), 5.92-5.23 (m, 2H), 4.94-4.68 (m, 1H), 4.67-4.46 (m, 1H), 4.42-4.15 (m, 1H), 4.09-3.86 (m, 2H), 3.85-3.42 (m, 9H), 2.46 (s, 3H), 2.32-1.94 (m, 3H), 1.91-1.75(m, 2H), 1.71-1.40 (m, 1H).

[0306] Example 15. Synthesis of Compound 36

[0307] Step 1: K₂CO₃ (8.2 g, 59.1 mmol) and BnBr (6.06 g, 35.5 mmol) were added to a solution of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropane[d]pyrrolo[1,2-a]azaoctyl-3-carboxylic acid (10 g, 29.6 mmol) in ACN (150 mL). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give a crude product, which was purified by SGC (EtOAc / PE = 1:1) to give 36-1.

[0308] Step 2: Add TFA (30 mL, 2.4 mmol) to the solution of 36-1 (10.1 g, 23.6 mmol) in DCM. Stir the reaction mixture at room temperature for 1 hour. Remove the solvent under vacuum. Acidify the residue to pH 7 with NaHCO3 solution and purify by C18 reversed-phase column (ACN / H2O (0.1% NH4OH), 5%–95%) to obtain 36-2.

[0309] Step 3: Add 36-2 (542 mg, 1.7 mmol) to a solution of 1-21-P2 (500 mg, 1.1 mmol) in 10 mL of 2-methyl-2-butanol. Then irradiate the reaction mixture with microwave at 125 °C for 10 hours. Remove the solvent under vacuum to obtain crude product 36-3, which is used directly in the next step.

[0310] Step 4: To a solution of 36-3 (500 mg, 0.75 mmol) in THF (20 mL), add (Boc)₂O (0.87 mL, 3.80 mmol), TEA (0.52 mL, 3.77 mmol), and DMAP (92.2 mg, 0.75 mmol). Stir the reaction mixture at 0 °C for 1 hour, then concentrate under reduced pressure to obtain a crude product, which is purified by SGC (EtOAc / PE = 8:2) to obtain 36-4.

[0311] Step 5: Add 5% Pd / C (140 mg, 0.26 mmol) to a solution of 36-4 (140 mg, 0.18 mmol) in EtOAc (10 mL). Then stir the reaction mixture at room temperature for 6 hours under H2. Filter the reaction mixture, wash the filter cake with 20 mL EA, and concentrate the organic layer under reduced pressure to obtain 36-5.

[0312] Step 6: 2,3,4,5,6-Pentafluorophenol (32.9 mg, 0.18 mmol) was added to a solution of 36-5 (100 mg, 0.15 mmol) and EDCI (42.8 mg, 0.22 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to obtain a crude product, which was purified by SGC (EtOAc / DCM = 1:3) to obtain 36-6.

[0313] Step 7: Add TMSI (119.3 mg, 0.60 mmol) to a solution of 36-6 (25 mg, 0.03 mmol) in DCM (3 mL) at 0 °C. Stir the reaction mixture at room temperature for 16 hours and then concentrate to obtain crude product 36-7, which is used directly in the next step.

[0314] Step 8: A solution of 36-7 (18 mg, 0.03 mmol) and DIEA (13 mg, 0.1 mmol) in DCM (3 mL) was stirred at 0 °C for 10 min under N2. Then, a solution of 4-(3-(azacyclobutane-3-yl)pyridin-4-yl)morpholine (14.5 mg, 0.07 mmol) and DIEA (51.7 mg, 0.4 mmol) in DCM (3 mL) was added at 0 °C. The reaction mixture was stirred at room temperature under N2 for 0.5 h. The solvent was removed under vacuum. The residue was purified by C18 reversed-phase column (ACN / H2O (0.05% TFA), 5-95%) to give 36. LCMS (ESI, m / z ): [M+H] + = 718.6; 1H NMR (400 MHz, DMSO- d 6, ppm):δ 12.18 (brs, 1H), 8.59-7.80 (m, 4H), 7.77-7.03 (m, 5H), 5.98-5.72 (m, 1H), 5.25-5.08 (m, 1H), 4.89-4.60 (m, 1H), 4.54-4.19 (m, 4H), 4.16-3.88 (m, 2H), 3.75-3.61 (m, 4H), 3.23-2.98 (m, 4H), 2.39-1.67 (m, 8H), 1.51-1.32 (m, 1H), 0.95-0.69 (m, 2H), 0.13-0.01 (m, 1H).

[0315] Example 16. Synthesis of Compound 48

[0316] Steps 1-4: Prepare compound 48-4 by following the synthetic procedure of compound 1-25 in Example 1, starting from 1-21-P2 and 1-11.

[0317] Step 5: TMSI (100 mg, 0.71 mmol) was added to a solution of 48-4 (200 mg, 0.25 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 hours and then concentrated. The residue was purified by passing it through a C18 reversed-phase column (ACN / H2O (0.05% FA), 5-95%) to give 48-5.

[0318] Step 6: Acidify the solution of 48-5 (180 mg, 0.24 mmol) in H2O (4 mL) to pH = 8 at 0 °C using NaOH (25 mg, 0.63 mmol). Then, add dropwise a solution of AgNO3 (100 mg, 0.59 mmol) in H2O (1 mL) at 0 °C. Stir the mixture at 0 °C for 2 hours and then concentrate to obtain crude product 48-6, which is used directly in the next step.

[0319] Step 7: Add (300 mg, 1.23 mmol) of [(iodomethyl)oxy]formate (propyl-2-yl) to a solution of 48-6 (220 mg, 0.23 mmol) in toluene (5 mL). The mixture was then stirred at room temperature for 18 hours and then concentrated. The residue was purified by C18 reversed-phase column chromatography (ACN / H2O (0.05% TFA), 5-95%) to give 48-7.

[0320] Step 8: Add Yb(OTf)3 (16.7 mg, 0.03 mmol) to a stirred solution of 48-7 (26 mg, 0.03 mmol) in DCM (2 mL). The mixture was then stirred at room temperature under N2 for 18 hours and then concentrated. The residue was purified by C18 reversed-phase column chromatography (ACN / H2O (0.05% TFA), 5-95%) to give 48-7. LCMS (ESI, m / z ): [M+H] + = 893.4; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 11.80 (brs, 1H), 9.30-9.17 (m, 1H), 9.15-9.02 (m, 1H), 8.81-8.62 (m, 1H), 8.28-8.06 (m, 1H), 8.01-7.61 (m, 2H), 7.54-7.40 (m, 1H), 7.39-6.91 (m, 3H), 6.47-6.26 (m, 2H), 5.96-5.75 (m, 1H), 5.71-5.54 (m, 2H), 5.22-5.00 (m, 1H), 4.97-4.78 (m, 2H), 4.77-4.62 (m, 1H), 4.62-4.38 (m, 1H), 4.31-4.07 (m, 1H), 3.99-3.71 (m, 2H), 2.38-1.37 (m, 16H), 1.34-1.05 (m, 12H), 0.61-0.30 (m, 2H).

[0321] Example 17. Synthesis of Compound 49

[0322] Step 1: Add oxaloyl chloride (15.5 mg, 0.12 mmol) to a stirred solution of 48-5 (18.6 mg, 0.024 mmol) and DMF (0.2 mg, 0.002 mmol) in DCM (5 mL) at 0 °C. Then stir the mixture at room temperature under N2 for 1 hour. Concentrate the mixture. Crude product 49-1 is used directly in the next step.

[0323] Step 2: At room temperature with stirring, a solution of 49-1 in DCM (2 mL) was added dropwise to a solution of 2,2-dimethylthiopropionic acid (S-2-hydroxyethyl) ester (38.9 mg, 0.24 mmol), DIEA (62 mg, 0.48 mmol), and DMAP (2.9 mg, 0.024 mmol) in DCM (5 mL). The mixture was stirred at room temperature under N2 for 18 hours. The solvent was removed under vacuum. The residue was purified by passing it through a C18 reversed-phase column (ACN / H2O (0.05% ammonia), 5-95%) to give 49-2.

[0324] Step 3: Add Yb(OTf)3 (47.3 mg, 0.076 mmol) to a solution of 49-2 (8 mg, 0.008 mmol) in DCM (2 mL). Stir the mixture at room temperature under N2 for 18 hours, and then concentrate. Purify the residue by passing it through a C18 reversed-phase column (ACN / H2O (0.05% NH4HCO3), 5-95%) to give 49-2. LCMS (ESI, m / z ): [M+H] + = 949.4; 1 H NMR (400 MHz, DMSO-) d 6, ppm): δ 11.56 (brs, 1H), 8.60-8.49 (m, 1H), 8.46-8.37 (m,1H), 8.28-8.02 (m, 1H), 7.82-7.63 (m, 3H), 7.46-7.18 (m, 3H), 6.73-6.45 (m,1H), 6.42-6.20 (m, 1H), 5.43-5.20 (m, 1H), 4.57-4.28 (m, 2H), 4.22-3.85 (m,5H), 3.83-3.68 (m, 1H), 3.65-3.47 (m, 1H), 3.17-2.88 (m, 4H), 2.35-2.21 (m,1H), 2.20-1.45 (m, 15H), 1.19-1.05 (m, 18H), 0.57-0.39 (m, 2H); 19 F NMR (376MHz, DMSO- d 6, ppm): δ -194.46 (1F); 31 P NMR (162 MHz, DMSO- d 6, ppm): δ 15.51 (1P).

[0325] Example 18. Synthesis of Compound 50

[0326] Step 1: Pd(dppf)Cl2 (1.6 g, 2.2 mmol) and K2CO3 (12.0 g, 87 mmol) were added to a solution of 4-bromo-3-nitrobenzene-1-carboxaldehyde (10.0 g, 43.5 mmol) and 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborheocytane-2-yl)pyridine (13.6 g, 47.8 mmol) in dioxane (100 mL) and H2O (10 mL). The mixture was stirred at 90 °C for 3 hours under N2. The mixture was concentrated. The residue was purified by SGC (EtOAc / PE = 1:3) to give 50-1.

[0327] Step 2: PPh3 (20.9 g, 79.8 mmol) was added to a solution of 50-1 (7.0 g, 22.8 mmol) in 1,2-dichlorobenzene (70 mL). The mixture was stirred at 150 °C for 18 hours under N2 and then concentrated. The residue was purified by SGC (EtOAc / PE = 1:2) to give 50-2.

[0328] Step 3: DBU (1.1 g, 7.3 mmol) and SEM-Cl (0.7 g, 4.4 mmol) were added to a solution of 50-2 (1.0 g, 3.6 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was purified by SGC (EtOAc / PE = 1:3) to give 50-3.

[0329] Step 4: Pd-PEPPSI-iHeptCl (48.0 mg, 0.049 mmol) and K2CO3 (68.2 mg, 0.49 mmol) were added to a solution of 50-3 (100 mg, 0.25 mmol) and 1-11 (117 mg, 0.37 mmol) in dioxane (3 mL). The mixture was stirred at 100 °C for 18 hours under N2. The reactants were diluted with EtOAc and filtered. The filter cake was washed with EtOAc. The organic layers were combined and concentrated. The residue was purified by SGC (PE / EtOAc = 1 / 10) to give 50-4.

[0330] Step 5: Add DBU (23.8 mg, 0.16 mmol) and diethyl phosphonate (32.3 mg, 0.23 mmol) to a solution of 50-4 (100 mg, 0.16 mmol) in THF (5 mL). Stir the mixture at room temperature under N2 for 18 hours. Concentrate the mixture. Purify the residue by SGC (MeOH / DCM = 1:10) to obtain 50-5.

[0331] Step 6: Add DAST (103 mg, 0.64 mmol) to a solution of 50-5 (100 mg, 0.13 mmol) in DCM (5 mL) at -78 °C. Stir the mixture at -78 °C for 1 hour under N2. After allowing the reaction mixture to cool to -78 °C, add 10 mL of NaHCO3 aqueous solution dropwise. Extract the aqueous layer with DCM. Combine the organic layers, wash with 20% NaCl aqueous solution, dry over Na2SO4, filter, and concentrate. Purify the residue by SGC (MeOH / DCM = 1 / 15) to give 50-6.

[0332] Step 7: Add 5% Pd / C (30 mg, 0.28 mmol) to the solution of 50-6 (60 mg, 0.08 mmol) in EtOAc (10 mL). Stir the mixture at room temperature for 2 hours under H2. Filter the mixture and wash the filter cake with DCM. Concentrate the organic layer to obtain crude product 50-7.

[0333] Step 8: A solution of 50-7 (61.9 mg, 0.09 mmol), DIEA (23.2 mg, 0.18 mmol), and HATU (68.2 mg, 0.18 mmol) in DCM (5 mL) was stirred at 0 °C for 5 minutes under N2. Then, a solution of 1-16-P2 (23.4 mg, 0.134 mmol) and DIEA (232 mg, 1.8 mmol) in DCM (2 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour under N2. The mixture was diluted with DCM and water. The organic layer was separated and washed with a 20% aqueous NaCl solution. The solvent was removed under vacuum. The residue was purified by passing it through a C18 reversed-phase column (ACN / H2O (0.05% NH4OH), 5-95%) to give 50-8.

[0334] Step 9: Add TFA (1 mL) to a solution of 50-8 (35 mg, 0.04 mmol) in DCM (2 mL). Stir the mixture at room temperature under N2 for 2 hours. Remove the solvent under vacuum. Add the residue to ACN. Add ammonia (0.1 mL) to the mixture. Then stir the mixture at room temperature for 30 minutes. Remove the solvent under vacuum. Purify the residue by passing it through a C18 reversed-phase column (ACN / H2O (0.05% NH4OH), 5-95%) to give 50-9.

[0335] Step 10: Add NaI (83.6 mg, 0.56 mmol) and TMSCl (60.6 mg, 0.56 mmol) to a solution of 50-9 (20 mg, 0.03 mmol) in ACN (2 mL) at room temperature, and stir the mixture at room temperature under N2 for 3 hours. Quench the mixture with 2 mL of H2O. Then purify the mixture by passing it through a C18 reversed-phase column (ACN / H2O (0.05% TFA), 5-95%) to obtain 50. LCMS (ESI, m / z ): [M+H] + = 661.3; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ12.99 (brs, 1H), 8.72-8.05 (m, 3H), 8.03-6.82 (m, 6H), 6.77-6.34 (m, 1H), 6.07-5.68 (m, 1H), 5.02-4.75 (m, 1H), 4.74-4.38 (m, 2H), 4.23-4.03 (m, 1H),3.82-3.65 (m, 1H), 3.63-3.50 (m, 1H), 2.41-2.25 (m, 1H), 2.22-1.42 (m, 15H),0.57-0.40 (m, 2H).

[0336] Example 19. Synthesis of Compound 51

[0337] Step 1: K₂CO₃ (41.5 g, 300 mmol) and glycine (15.6 g, 210 mmol) were added to a stirred solution of 4-bromo-2-fluorobenzonitrile (30 g, 150 mmol) in DMF (80 mL). The reaction mixture was then stirred at 70 °C for 16 hours. H₂O (200 mL) was added dropwise to the reaction mixture. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with 20% NaCl aqueous solution, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by SGC (DCM / MeOH = 5 / 2) to give 51-1.

[0338] Step 2: Add EtONa (13.4 g, 196.8 mmol) to a solution of 51-1 (25.0 g, 98.4 mmol) in isopropanol. Then stir the mixture at 85°C for 14 hours. Filter the mixture and concentrate the filtrate to obtain 51-2.

[0339] Step 3: Add triphosgene (15.7 g, 44.2 mmol) to a solution of 51-2 (10.0 g, 39.4 mmol) in dioxane (100 mL). Stir the mixture at 110 °C for 2 hours. Filter the mixture and concentrate the filtrate to obtain 51-3.

[0340] Step 4: The solution of 51-3 (10.0 g, 35.7 mmol) in phenylphosphonic dichloride (20 mL) was stirred at 180 °C for 4 hours under N2. After cooling to room temperature, the mixture was diluted with ice-H2O (50 mL) and extracted twice with DCM. The organic layers were combined, washed with 20% NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated. The residue was purified by SGC (PE / EtOAc = 5 / 2) to give 51-4.

[0341] Step 5: Add DIEA (7.4 mL, 44.5 mmol) to the solution of 51-4 (4.7 g, 14.8 mmol) and 1-11 (4.7 g, 14.8 mmol) in ACN (80 mL). Then stir the reaction mixture at 50 °C for 16 hours. Remove the solvent under vacuum. Purify the residue by SGC (PE / EtOAc = 10 / 1) to obtain 51-5.

[0342] Step 6: To a solution of 51-5 (2.0 g, 3.35 mmol) in DMF (20 mL), add Na₂CO₃ (710 mg, 6.7 mmol), triethylsilane (1.2 g, 10.1 mmol), and Pd(dtbpf)Cl₂ (437 mg, 0.67 mmol). The mixture is then stirred at 90 °C for 24 hours under CO₂. The solvent is removed under vacuum. The residue is purified by a C18 reversed-phase column (ACN / H₂O (0.05% TFA), 5-95%) to obtain 51-6.

[0343] Step 7: Cyclopropylboronic acid (393 mg, 4.6 mmol), K₂CO₃ (759 mg, 5.5 mmol), and Pd(dtbpf)Cl₂ (236 mg, 0.36 mmol) were added to a solution of 51-6 (1.0 g, 1.8 mmol) in dioxane (10 mL). The mixture was then stirred at 100 °C for 1 hour under N₂. After cooling to room temperature, the mixture was diluted with H₂O and extracted with EtOAc. The organic layers were combined, washed with 20% NaCl aqueous solution, dried over Na₂SO₄, filtered, and concentrated. The residue was then purified by SGC (PE / EtOAc = 5 / 4) to obtain 51-7.

[0344] Step 8: To a solution of 51-7 (480 mg, 0.87 mmol) in THF (6 mL), TEA (266 mg, 2.61 mmol), (Boc)₂O (570 mg, 2.61 mmol), and DMAP (106 mg, 0.09 mmol) were added. The mixture was then stirred at room temperature under N₂ for 2 hours. After cooling to room temperature, the mixture was diluted with H₂O and extracted with EtOAc. The organic layers were combined, washed with 20% NaCl aqueous solution, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by SGC (PE / EtOAc = 5 / 2) to give 51-8.

[0345] Steps 9-13: Starting from 51-8, prepare compound 51 according to the synthetic procedure for compound 50 in Example 18. LCMS (ESI, m / z ): [M+H] + = 702.3; 1 H NMR (400 MHz, DMSO- d6, ppm): δ 11.03 (brs, 1H),8.64-8.11 (m, 2H), 8.02-6.87 (m, 5H), 6.74-6.58 (m, 1H), 5.94-5.56 (m, 1H),5.41-5.26 (m, 1H), 5.20-4.95 (m, 1H), 4.60-4.30 (m, 2H), 4.20-4.07 (m, 1H), 3.83-3.67 (m, 1H), 3.62-3.44 (m, 1H), 2.20-1.37 (m, 18H), 1.35-0.92 (m, 2H),0.54-0.37 (m, 2H).

[0346] Table 1 shows the characterization of some exemplary compounds of this disclosure.

[0347] Table 1. Characterization of some exemplary compounds of this disclosure

[0348] Bioassay Example A: In Vitro Binding Assay of STAT6 The in vitro binding assay of STAT6 was performed in a 20 µL reaction volume as follows: 5 µL of the assay compound and 5 µL of 6×His-tagged STAT6 protein (amino acids 123-658) were added to an OptiPlate-384 plate (PerkinElmer, Cat#6007299) in assay buffer (10 mM HEPES pH 7.4, 50 mM NaCl, 1 mM EDTA, 2 mM DTT, 0.05% Tween-20, 1% DMSO). After incubation at room temperature for 15 minutes, a mixture of anti-6×His-Tb (Cisbio, Cat#61HISTLA) and an IL-4RA-derived phosphorylated peptide probe (5-FAM-ApYKPFQDLI-NH2) was added. The final concentrations of STAT6 protein, anti-6×His-Tb, and IL-4RA peptide probe were 10 nM, 1 nM, and 1 µM, respectively. After incubation at room temperature for 60 minutes, TR-FRET signals were recorded at Ex320 nm / Em520 nm / Em620 nm using a Tecan Spark plate reader. The suppression percentage was calculated using the following formula: Suppression% = 100 - 100 * (RFU) 化合物 – RFU 空白 ) / (RFU 对照 – RFU 空白 RFU is the ratio of Em520 to Em620. Blank wells contain all reaction mixture components except for STAT6 protein. Control wells contain all reaction mixture components but no compound. The equation Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)) is used. 50 -X)× Hill Slope)) calculates the 50% active inhibitory concentration (IC50). 50 ).

[0349] Bioassay Example B: STAT3 In Vitro Binding Assay The in vitro STAT3 binding assay was performed in a 20 µL reaction volume as follows: 5 µL of the assay compound and 5 µL of 6×His-tagged STAT3 protein (amino acids 127-722) were added to an OptiPlate-384 plate (PerkinElmer, Cat#6007299) in assay buffer (10 mM HEPES pH 7.4, 50 mM NaCl, 1 mM EDTA, 2 mM DTT, 0.05% Tween-20, 1% DMSO). After incubation at room temperature for 15 minutes, a mixture of anti-6×His-Tb (Cisbio, Cat#61HISTLA) and an IL-6RB-derived phosphorylated peptide probe (5-FAM-GpYLPQTV-NH2) was added. The final concentrations of STAT3 protein, anti-6×His-Tb, and IL-6RB peptide probe were 10 nM, 1 nM, and 1 µM, respectively. After incubation at room temperature for 60 minutes, TR-FRET signals were recorded at Ex320 nm / Em520 nm / Em620 nm using a Tecan Spark plate reader. The suppression percentage was calculated using the following formula: Suppression% = 100 - 100 * (RFU) 化合物 – RFU 空白 ) / (RFU 对照 – RFU 空白 RFU is the ratio of Em520 to Em620. Blank wells contain all reaction mixture components except for STAT3 protein. Control wells contain all reaction mixture components but no compound. The equation Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)) is used. 50 -X) × HillSlope)) calculates the 50% activity inhibition concentration (IC50). 50 ).

[0350] Bioassay Example C: STAT1 In Vitro Binding Assay The in vitro STAT1 binding assay was performed in a 20 µL reaction volume as follows: 5 µL of the assay compound and 5 µL of 6×His-tagged STAT1 protein (amino acids 127-716) were added to an OptiPlate-384 plate (PerkinElmer, Cat#6007299) in assay buffer (10 mM HEPES pH 7.4, 50 mM NaCl, 1 mM EDTA, 2 mM DTT, 0.05% Tween-20, 1% DMSO). After incubation at room temperature for 15 minutes, a mixture of anti-6×His-Tb (Cisbio, Cat#61HISTLA) and an INGR1-derived phosphorylated peptide probe (5-FAM-GpYDKPHVL) was added. The final concentrations of STAT1 protein, anti-6×His-Tb, and INGR1 peptide probe were 25 nM, 1 nM, and 1 µM, respectively. After incubation at room temperature for 60 minutes, TR-FRET signals were recorded at Ex320 nm / Em520 nm / Em620 nm using a Tecan Spark plate reader. The suppression percentage was calculated using the following formula: Suppression% = 100 - 100 * (RFU) 化合物 – RFU 空白 ) / (RFU 对照 – RFU 空白 RFU is the ratio of Em520 to Em620. Blank wells contain all reaction mixture components except for STAT1 protein. Control wells contain all reaction mixture components but no compound. The equation Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)) is used. 50 -X) × HillSlope)) calculates the 50% activity inhibition concentration (IC50). 50 ).

[0351] Table 2 shows the in vitro binding assays (IC50) of representative compounds for STAT6, STAT3, and STAT1. 50 ).

[0352] Table 2. In vitro binding assays (IC50) of representative compounds for STAT6, STAT3, and STAT1. 50 ) (A: <100 nM; B: 100nM - 1 μM; C: >1 μM).

[0353]

[0354] Bioassay Example D: pSTAT6 PBMC Assay Thaw cryopreserved human PBMCs and allow them to recover overnight in RPMI 1640 + 10% heat-inactivated FBS, then feed at 2 × 10⁻⁶ per well. 5 Cells were seeded in 96-well plates. Cells were treated with serially diluted compound solutions (starting at 10 μM, 4-fold serial dilutions for a total of 9 data points) for 4 hours, followed by stimulation with 100 ng / mL IL-4 (R&D, Cat#BT-004-010) for 20 minutes. Cells were fixed with Cyto-Fix buffer (BD, Cat#554655) at 4°C for 30 minutes, then centrifuged to collect the pellet and washed twice with staining buffer (PBS + 1% FBS). Cells were permeabilized with pre-chilled permeabilization buffer (BD, Cat#558050) at 4°C for 30 minutes, followed by centrifugation to collect the pellet. The cell pellet was washed twice with staining buffer and treated with 44 μL of staining buffer, 5 μL of anti-pY641-STAT6 antibody (BD, Cat#612601), and 1 μL of anti-CD3 antibody (BD, Cat#555916) at room temperature for 20 minutes. Cells were washed twice with staining buffer and pSTAT6 levels were analyzed using a BD Accuri C6 Plus flow cytometer. The percentage of inhibition was calculated using the following formula: Inhibition% = 100 - %pSTAT6 化合物 / %pSTAT6 对照 *100. The control well contains all components of the reaction mixture but no compound itself. Using the equation Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)). 50 -X) × Hill Slope)) calculates the 50% active inhibitory concentration (IC50). 50 ).

[0355] Bioassay Example E: pSTAT3 PBMC Assay Thaw cryopreserved human PBMCs and allow them to recover overnight in RPMI 1640 + 10% heat-inactivated FBS, then feed at 2 × 10⁻⁶ per well. 5Cells were seeded in 96-well plates. Cells were treated with serially diluted compound solutions (starting at 100 μM, 4-fold serial dilutions for a total of 9 data points) for 4 hours, followed by stimulation with 100 ng / mL IL-6 (MCE, Cat#HY-P7044) for 20 minutes. Cells were fixed with Cyto-Fix buffer (BD, Cat#554655) at 4°C for 30 minutes, then centrifuged to collect the pellet and washed twice with staining buffer (PBS + 1% FBS). Cells were permeabilized with pre-chilled permeabilization buffer (BD, Cat#558050) at 4°C for 30 minutes, followed by centrifugation to collect the pellet. The cell pellet was washed twice with staining buffer and treated with 39 μL of staining buffer, 10 μL of anti-pY705-STAT3 antibody (BD, Cat#612569), and 1 μL of anti-CD3 antibody (BD, Cat#555916) at room temperature for 20 minutes. Cells were washed twice with staining buffer and pSTAT3 levels were analyzed using a BD Accuri C6 Plus flow cytometer. The percentage of inhibition was calculated using the following formula: Inhibition% = 100 - %pSTAT3 化合物 / %pSTAT3 对照 *100. The control well contains all components of the reaction mixture but no compound itself. Using the equation Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)). 50 -X) × Hill Slope)) calculates the 50% active inhibitory concentration (IC50). 50 ).

[0356] Table 3 shows the pSTAT6 and pSTAT3 PBMC determinations (IC50) of representative compounds. 50 ).

[0357] Table 3. Determination of pSTAT6 and pSTAT3 PBMCs (IC50) of representative compounds 50 ) (A: <100 nM; B: 100 nM - 1μM; C: >1 μM).

[0358]

[0359] The summary and abstract section may set forth one or more, but not all, exemplary embodiments of the invention as conceived by the inventors, and therefore is not intended to limit the invention and the appended claims in any way.

[0360] The invention has been described above using functional building blocks that illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries can be defined as long as the specified functions and their relationships are properly performed.

[0361] Regarding aspects of the invention described as belonging to a genus, all individual species are considered separately as separate aspects of the invention. If an aspect of the invention is described as "comprising" a feature, the embodiment is also contemplated as "consisting of" or "substantially consisting of" that feature.

[0362] The foregoing description of the specific embodiments will fully reveal the general nature of the invention, enabling others to readily modify and / or adapt various applications of such specific embodiments by applying knowledge within the art, without excessive experimentation or departing from the general concept of the invention. Therefore, based on the teachings and guidance presented herein, such modifications and alterations are intended to be within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is for descriptive purposes and not limiting, and that the terminology or terminology of this specification will be interpreted by those skilled in the art based on the teachings and guidance.

[0363] The breadth and scope of this invention should not be limited by any of the exemplary embodiments described above.

[0364] All aspects, implementation schemes, and options described herein can be combined in any and all variations.

[0365] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in any document incorporated by reference, the meaning or definition given to that term in this document shall prevail.

Claims

1. A compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof: in: X 1 For CR 11 R 12 , X 2 For CR 21 R 22 NR 23 , O, S, S(O)2 or S(O)(NH); X 3 For CR 31 R 32 NR 33 , O, S, S(O)2 or S(O)(NH); X 4 Empty, CR 41 R 42 or CR 41 R 42 -CH2-; X 5 C is arbitrarily replaced 3-6 Alkyl group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl or optionally substituted 5-10 heteroaryl groups; R 11 R 12 R 21 R 22 R 31 R 32 R 41 and R 42 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; or R 11 and R 12 R 21 and R 22 R 31 and R 32 and R 41 and R 42 One of them, together with the C atoms in between, forms an optional C atom that can be substituted. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 11 R 12 R 21 R 22 R 31 R 32 R 41 and R 42 The others in the list are, independently, as defined herein; or R 11 and R 21 and R 21 and R 31 One of them, together with the C and C atoms in between, forms an optional C atom that can be substituted. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 11 R 12 R 21 R 22 R 31 R 32 R 41 and R 42 The others in the list are defined independently each time they appear, as defined in this document; R 23 and R 33 Each time it appears, it is independently selected from hydrogen, R c (C) 1-4 (alkylene)-R c C(O)-R c C(O)NH-R c 、C(O)NH-(C 1-4 (alkylene)-R c C(O)NR c R d S(O)R c S(O)2R c and S(O)2-(C 1-4 (alkylene)-R c , where R c and R d Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups; Y 1 For N, CH or CR 2 ; Y 2 For N, CH or CR 2 ; Z represents NH, O, or S; W is ,in W 1 For O, C(O), or optionally halogenated, C 1-4 Alkyl or C 1-4 The methylene group substituted by a haloalkyl group is preferably O, CH2, CH(CH3), CHF, CF2 or C(O); W 2 is NH-R wa -C(O)O-R wb 、 or OR wc ; W 3 is OR wd ; R wa These are residues of α- or β-natural or non-natural amino acids; R wb Hydrogen, with optional substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl or optionally substituted (C 0-1 (alkylene)-phenyl; preferably, optionally substituted C 1-4 Alkyl or optionally substituted (C 0-1 (alkylene)-phenyl; It is a 4-6 membered heterocyclic group; R 5 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group or optionally substituted C 3-6 cycloalkyl; t can be 0, 1, 2, 3, or 4; R wc and R wd Each time it appears, it is independently selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C 1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-R e and -C 1-4 Alkylene-OC(O)NR e R f Wherein C 1-4 Each of the alkylene groups is independently and optionally substituted by one or more substituents independently selected from the group consisting of: optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted (C 0-1 alkylene)-cycloalkyl, optionally substituted (C 0-1 alkylene)-heterocyclic group, optionally substituted (C 0-1 alkylene)-heteroaryl and optionally substituted (C 0-1 (alkylene)-phenyl, wherein R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups; R 1 Hydrogen, with optional substituted C 1-4 Alkyl groups, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group or optionally substituted C 3-6 cycloalkyl; R 2 and R 3 Each time it appears, it is independently selected from halogen, OH, NH2, CN, C(O)NH2, R g (C) 1-4 (alkylene)-R g C(O)-R g C(O)OR g OC(O)-R g C(O)NH-R g ,NHC(O)-R g S(O)R g S(O)2R g and S(O)2-(C 1-4 (alkylene)-R g , where R g Selected from the C that is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups; m can be 0, 1, 2, or 3; n is 0, 1, 2, or 3; R 4 Each time it appears, it is independently selected from halogens, OH, NH2, CN, and optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group and optionally substituted C 3-6 cycloalkyl; p is 0, 1, 2, 3 or 4; q is 1 or 2; L 1 The substituted 4-10 member monocyclic or bicyclic heterocyclic ring, or the substituted 5-10 member monocyclic or bicyclic heteroaryl ring, are either empty or can be substituted. L 2 The options are: empty, O, NH, C(O), C(O)O, S, S(O), SO2, C(O)NH, and any C that is substituted. 1-4 Alkylene, optionally substituted OC 1-4 Alkylene, optionally substituted NH-C 1-4 Alkylene, optionally substituted N(C) 1-6 Alkyl) or optionally substituted N(C) 1-6 alkyl)-C 1-4 Alkylene; L 3 The ring is hydrogen or optionally substituted 3-14 membered rings, wherein the 3-14 membered rings are selected from monocyclic nonaromatic rings, monocyclic aromatic rings and polycyclic structures, wherein each ring in the polycyclic structure is independently aromatic or nonaromatic, and wherein the 3-14 membered rings optionally contain 1-4 cyclic heteroatoms independently selected from O, N and S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that... Having formula I-1 or I-2: 。 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that... Having formula I-1-A or I-2-A: 。 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that... Having formula II-1: 。 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that... It has formula II-1-A: 。 6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X 1 For CR 11 R 12 , where R 11 and R 12 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups substituted with F 1-4 Alkyl and C 3-4 cycloalkyl, or R 11 and R 12 Together with the C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring or optionally substituted 4-5 membered heterocyclic ring; preferably, X 1 It is -CH2-.

7. The compound according to any one of claims 1-3 and 6, or a pharmaceutically acceptable salt thereof, wherein X 2 For CR 21 R 22 , where R 21 and R 22 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 Alkyl, C 3-4 Cycloalkyl and 4-5 membered heterocyclic rings, or R 21 and R 22 Together with the C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring or optionally substituted 4-5 membered heterocyclic ring; preferably, X 2 For CR 21 R 22 , where R 21 For H and R 22 For hydrogen, OH, C 1-4 Alkyl, C 3-4 Cycloalkyl or a 4-5 membered heterocyclic ring containing one or two independent cyclic heteroatoms selected from N, O, and S, or R 21 and R 22 Together with the C atoms in between, they form C 3-4 Carbocyclic ring; more preferably, X 2 Selected from -CH2- .

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 and 6, wherein X 2 For NR 23 , where R 23 C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)-C 1-6 Alkyl; preferably, X 2 Selected from ;or X 2 For NR 23 , where R 23 It is C(O)-(5-10 membered heterocyclic ring) or C(O)-(5-10 membered heteroaryl), wherein the heterocyclic ring or the heteroaryl group contains one, two or three cyclic heteroatoms independently selected from N, O and S, and optionally one or more independently selected from halogens (such as F or Cl), OH, C 1-6 Alkyl and OC 1-6 Alkyl substituents are used; preferably, X 2 For NR 23 , where R 23 It is C(O)-(9-membered heterocyclic ring) or C(O)-(9-membered heteroaryl), wherein the heterocyclic ring or the heteroaryl group contains one or two cyclic heteroatoms independently selected from N, O, and S, and optionally one or two independently selected from halogens (such as F or Cl), OH, C 1-4 Alkyl and OC 1-4 Alkyl substituents are used; more preferably, X 2 for , or .

9. The compound according to any one of claims 1-3 and 6, or a pharmaceutically acceptable salt thereof, wherein X 2 It can be O, S, S(O)2 or S(O)(NH).

10. The compound according to any one of claims 1-3 and 6-9, or a pharmaceutically acceptable salt thereof, wherein X 3 For CR 31 R 32 , where R 31 and R 32 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 Alkyl, C 3-4 Cycloalkyl and 4-5 membered heterocyclic rings, or R 31 and R 32 Together with the C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring or optionally substituted 4-5 membered heterocyclic ring; preferably, X 3 For CR 31 R 32 , where R 31 For H and R 32 For hydrogen, OH, C 1-4 Alkyl, C 3-4 Cycloalkyl or a 4-5 membered heterocyclic ring containing one or two independent cyclic heteroatoms selected from N, O, and S, or R 31 and R 32 Together with the C atoms in between, they form C 3-4 Carbocyclic ring; more preferably, X 3 Selected from -CH2- .

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 and 6-9, wherein X 3 For NR 33 , where R 33 C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)-C 1-6 Alkyl; preferably, X 3 Selected from ;or X 3 For NR 33 , where R 33 It is C(O)-(5-10 membered heterocyclic ring) or C(O)-(5-10 membered heteroaryl), wherein the heterocyclic ring or the heteroaryl group contains one, two or three cyclic heteroatoms independently selected from N, O and S, and optionally one or more independently selected from halogens (such as F or Cl), OH, C 1-6 Alkyl and OC 1-6 Alkyl substituents are used; preferably, X 3 For NR 33 , where R 33 It is C(O)-(9-membered heterocyclic ring) or C(O)-(9-membered heteroaryl), wherein the heterocyclic ring or the heteroaryl group contains one or two cyclic heteroatoms independently selected from N, O, and S, and optionally one or two independently selected from halogens (such as F or Cl), OH, C 1-4 Alkyl and OC 1-4 Alkyl substituents are used; more preferably, X 3 for , or .

12. The compound according to any one of claims 1-3 and 6-9, or a pharmaceutically acceptable salt thereof, wherein X 3 It can be O, S, S(O)2 or S(O)(NH).

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 and 10-12, wherein X 1 For CR 11 R 12 And X 2 For CR 21 R 22 , where R 11 and R 21 Together with the C and C atoms in between, they form optional substituted C atoms. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 12 and R 22 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; preferably, X 1 For CR 11 R 12 And X 2 For CR 21 R 22 , where R 11 and R 21 Together with the C and C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring, and R 12 and R 22 Each time it appears, it is independently selected from hydrogen and C. 1-4 Alkyl; more preferably, X 1 -X 2 for or .

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 and 6, wherein X 2 For CR 21 R 22 And X 3 For CR 31 R 32 , where R 21 and R 31 Together with the C and C atoms in between, they form optional substituted C atoms. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring, and R 22 and R 32 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups; preferably, X 2 For CR 21 R 22 And X 3 For CR 31 R 32 , where R 21 and R 31 Together with the C and C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring, and R 22 and R 32 Each time it appears, it is independently selected from hydrogen and C. 1-4 Alkyl; more preferably, X 2 -X 3 for or .

15. The compound according to any one of claims 1-2 and 6-14, or a pharmaceutically acceptable salt thereof, wherein X 4 Empty, CR 41 R 42 or CR 41 R 42 -CH2-, where R 41 and R 42 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, C(O)NH2, R a (C) 1-4 (alkylene)-R a C(O)-R a C(O)OR a OC(O)-R a C(O)NH-R a ,NHC(O)-R a C(O)NR a R b NR a C(O)-R b S(O)R a S(O)2R a and S(O)2-(C 1-4 (alkylene)-R a , where R a and R b Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 aryl and optionally substituted 5-10 heteroaryl groups, or R 41 and R 42 Together with the C atoms in between, they form optional substituted C atoms. 3-6 Carbocyclic ring or optionally substituted 4-6 membered heterocyclic ring; preferably, X 4 Empty, CR 41 R 42 or CR 41 R 42 -CH2-, where R 41 and R 42 Each time it appears, it is independently selected from hydrogen, halogens (such as F and Cl), OH, and C. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 Alkyl and C 3-4 cycloalkyl, or R 41 and R 42 Together with the C atoms in between, they form optional substituted C atoms. 3-4 Carbocyclic ring or optionally substituted 4-5 membered heterocyclic ring; more preferably, X 4 It can be empty, -CH2- or -CH2CH2-.

16. The compound according to any one of claims 1 and 4-5, or a pharmaceutically acceptable salt thereof, wherein X 5 C 3-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic ring, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, the heterocyclic ring, the phenyl or the heteroaryl is optionally selected by one or more independently from halogen (such as F or Cl), OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and OC 1-4 Alkyl substituents are used; preferably, X 5 It is isopropyl, cyclopropyl, tert-butyl, or phenyl.

17. The compound according to any one of claims 1, 2, 4 and 6-16, or a pharmaceutically acceptable salt thereof, wherein Y 1 Let N be the number of elements in the array.

18. The compound according to any one of claims 1, 2, 4 and 6-17, or a pharmaceutically acceptable salt thereof, wherein Y 2 For CH.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4 and 6-18, wherein Z is NH.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein W 1 It can be CH2, CHF, or CF2.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein W 2 For NH-R wa -C(O)OR wb And W 3 OR wd , where R wa For α- or β-residues of natural or non-natural amino acids; R wb C is arbitrarily replaced 1-4 Alkyl or optionally substituted (C 0-1 (alkylene)-phenyl; and R wd Selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C 1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-R e and -C 1-4 Alkylene-OC(O)NR e R f , where R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups.

22. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein W 2 OR wc And W 3 OR wd , where R wc and R wd Each time it appears, it is independently selected from hydrogen, R e -C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)-R e -C 1-4 Alkylene-C(O)OR e -C 1-4 Alkylene-OC(O)OR e -C 1-4 Alkylene-OC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)OC 1-4 Alkylene-OR e -C 1-4 Alkylene-SC(O)-R e -C 1-4 Alkylene-SC(O)-C 1-4 Alkylene-OR e -C 1-4 Alkylene-OC(O)NH-R e and -C 1-4 Alkylene-OC(O)NR e R f , where R e and R f Each time it appears, it is independently selected from the arbitrarily replaced C. 1-6 Alkyl groups, optionally substituted C 1-6 Alkylene-OH, optionally substituted 3-10 membered carbocyclic ring, optionally substituted 4-10 membered heterocyclic ring, optionally substituted C 6-10 Aryl groups and optionally substituted 5-10 heteroaryl groups.

23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein W is selected from... ;or W selected ;or W selected .

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-23, wherein R 1 For hydrogen, C 1-3 Alkyl groups, C groups substituted with F 1-3 Alkyl, or C 3-4 cycloalkyl; preferably, R 1 It is hydrogen.

25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R 2 Each occurrence is independently F, Cl, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkyl groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 Alkylthio groups (e.g., CH3S-), fluorinated C 1-4 Alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-25, wherein m is 0.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein R 3 Each occurrence is independently F, Cl, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkyl groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 Alkylthio groups (e.g., CH3S-), fluorinated C 1-4 Alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein n is 0.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 6-28, wherein R 4 Each time it appears, it is independently selected from halogens (such as F and Cl), OH, NH2, CN, C. 1-2 Alkyl groups, C groups substituted with F 1-2 Alkyl and C 3-4 Cycloalkyl.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 6-29, wherein p is 0.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 6-30, wherein q is 1.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-31, wherein L 1 It is a 4-7 membered monocyclic or bicyclic heterocyclic ring containing one or two cyclic heteroatoms independently selected from N, O, and S, and optionally by one or more cyclic heteroatoms independently selected from halogens (such as F and Cl), OH, CN, C. 1-2 Alkyl groups, C groups substituted with F 1-2 Alkyl, OC 1-2 Alkyl and C 2-3 The alkynyl group is substituted by a substituent; or L 1 It is a 4-, 5-, or 6-membered monocyclic heterocyclic ring (such as azirrobutyl, pyrrolidinyl, and morpholinyl) containing one or two cyclic heteroatoms independently selected from N, O, and S, and optionally by one or more (e.g., one, two, or three) independently selected from halogen, OH, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 2-4 The alkynyl group is substituted by a substituent; or L 1 It is a 7-8 membered bicyclic heterocyclic base ring (such as a spirocyclic or bridged bicyclic heterocyclic base ring, for example, azepispirolyl, oxa-azepi-bicycloheptyl, and oxa-azepi-bicyclooctyl) containing one or two cyclic heteroatoms independently selected from N, O, and S, and optionally by one or more (e.g., one, two, or three) independently selected from halogen, OH, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 2-4 The substituents of the alkynyl group are replaced; Preferably, L 1 Selected from where * represents L 2 or L 3 The connection and This represents the connection with C(O).

33. The compound according to any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein L 2 It can be empty, C(O) or methylene.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-33, wherein L 3 The heterocyclic ring is a 6-membered heterocyclic ring containing one or two cyclic heteroatoms independently selected from N, O, and S, a phenyl group, or a 6-membered heteroaryl group containing one or two cyclic N atoms, wherein the heterocyclic ring, the phenyl group, or the heteroaryl group is optionally selected by one or more of the following independently: halogen (e.g., F and Cl), OH, oxo, C. 1-4 Alkyl and OC 1-4 Substituents of alkyl groups; or L 3 It is hydrogen; or L 3 For optional selection by one or more independently selected halogens, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-4 cycloalkyl and C 1-4 The phenyl group substituted by the alkoxy group; or L 3 It contains one or two ring N atoms (e.g., imidazole group) and is optionally C 1-4 alkyl-substituted 5-heteroaryl groups; or L 3 It contains one or two ring nitrogen atoms (e.g., pyridinyl and pyrimidinyl) and is optionally selected by one or more atoms, each independently chosen from halogens (e.g., F), oxo, C. 1-4 Alkyl (e.g., methyl), C 1-4 Haloalkyl, C 3-4 cycloalkyl, C 1-4 Alkyl groups (e.g., methoxy groups), N(C) 1-4 Alkyl)(C 1-4 A 6-membered heteroaryl group substituted with an alkyl group (e.g., N(CH3)2) and a substituent containing one or two independently selected cyclic heteroatoms from N and O (e.g., azirrobutyl and morpholinyl); or L 3 It contains one or two cyclic heteroatoms (e.g., morpholino) and is optionally C 1-4 6-membered heterocyclic groups substituted with alkyl groups; Preferably, L 3 Selected from , or L 3 Selected from .

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein L 1 for or L 2 It is empty, and L 3 It is phenyl or contains one or two ring nitrogen atoms (e.g., pyridinyl and pyridone groups) and optionally is selected independently by one or more halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-4 cycloalkyl, C 1-4 Alkoxy and N(C) 1-4 Alkyl)(C 1-6 The 6-membered heteroaryl group substituted by an alkyl group; preferably, L 3 -L 2 -L 1 Selected from Preferably, L 3 -L 2 -L 1 for or .

36. The compound according to any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein L 1 for L 2 It is empty, and L 3 It contains one or two ring nitrogen atoms (e.g., imidazolium, pyridinium, and pyrimidinium) and is optionally selected by one or more halogens (e.g., F, C) independently. 1-4 Alkyl (e.g., methyl), C 1-4 Haloalkyl, C 3-4 cycloalkyl, C 1-4 Alkyl groups (e.g., methoxy groups), N(C) 1-4 Alkyl)(C 1-6 5-6-membered heteroaryl groups substituted with alkyl groups (e.g., N(CH3)2) and substituents containing one or two cyclic heteroatoms independently selected from N and O (e.g., azirrobutyl and morpholinyl); preferably, L 3 -L 2 -L 1 Selected from: More preferably, L 3 -L 2 -L 1 for .

37. The compound according to any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein L 1 for L 2 It is either empty or methylene, and L 3 It is H or phenyl; preferably, L 3 -L 2 -L 1 for More preferably, L 3 -L 2 -L 1 for .

38. A compound selected from any of the compounds shown in the Examples section or in Table A herein, or any of the compounds according to the listed embodiments 1-37, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-38.

40. A method of treating a condition that responds to regulation of STAT3 and / or STAT6, the method comprising administering to a subject in need a therapeutically effective amount of a compound according to any one of claims 1-38 or a pharmaceutical composition according to claim 39.

41. The method according to any one of claims 40, wherein the condition that responds to regulation of STAT3 and / or STAT6 is cancer.

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