Amide compounds and use thereof

Abstract

Provided in the present invention are compounds of formula I and formula II and pharmaceutically acceptable salts, solvates, optical isomers, stereoisomers, polymorphs or isotopically enriched compounds thereof, a pharmaceutical composition comprising same, and the use of the compounds in the preparation of other drugs, including TRIM21-related targeted drugs or drugs for TRIM21-mediated targeted protein degradation.

Description

Amide compounds and uses thereof

[0001] Cross-reference to related applications

[0002] This application is based on Chinese Patent Application No. 202411376874.7, filed on September 29, 2024, Chinese Patent Application No. 202411621024.9, filed on November 13, 2024, and Chinese Patent Application No. 202511013598.2, filed on July 22, 2025, and claims priority to these Chinese Patent Applications, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and specifically relates to an amide compound, a pharmaceutical composition containing the same, and application of the compound in the preparation of drugs and other drug synthesis. BACKGROUND

[0004] TRIM21 belongs to the TRIM family of E3 ligases, which are involved in the regulation of various cellular signaling pathways. Unlike general E3 ligases, TRIM21 is an E3 ligase activated by multimeric protein substrates. Therefore, developing TRIM21 small molecule ligands and creating targeted protein degradation compounds based thereon has many potential application scenarios in the field of pharmacy. SUMMARY

[0005] In a first aspect, the present application provides a compound represented by Formula (I), or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof:

[0006] wherein,

[0007] A ring is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered cycloalkyl, and a 3-10 membered heterocycle; the A ring is optionally substituted with one, two, three, or four independent R, wherein each R is independently selected from hydrogen, halogen, cyano, nitro, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, -C 0-4 alkylene-OR a , -C 0-4 alkylene-OC(=O)R a , -C 0-4 alkylene-SR a , -C 0-4 alkylene-S(=O)2R a , -C 0-4alkylene-S(=O)R a , -C 0-4 alkylene-S(=O)2R a R b , -C 0-4 alkylene-S(=O)NR a R b , -C 0-4 alkylene-C(=O)R a , -C 0-4 alkylene-C(=O)OR a , -C 0-4 alkylene-C(=O)NR a R b , -C 0-4 alkylene-NR a R b , -C 0-4 alkylene-NR a C(=O)R b , -C 0-4 alkylene-NR a S(=O)2R b , -C 0-4 alkylene-NR a S(=O)R b , -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aryl), -C 0-4 alkylene-(5-10 membered heteroaryl); wherein R a , R b are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, halogen-substituted C 2-6 alkenyl, halogen-substituted C 2-6 alkynyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aryl), -C 0-4 alkylene-(5-10 membered heteroaryl);

[0008] X1, X2, X3are each independently selected from CRc, CH or N, wherein Rc is selected from halogen, alkyl, alkoxy, or when X3is CRc, Rc, R1together with the atoms to which they are attached form a 4 to 6 membered ring;

[0009] R1is selected from -H, -S(=0)2R 1a , -P(=0)R 1a R 1b , -C(=0)R 1a , -S(=0)(=NH)R 1a , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring; provided that when R1is selected from -S(=0)2R 1a , X1, X2, X3are not simultaneously CH;

[0010] R2and R3are each independently selected from hydrogen, -OR 2a , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -C 0-4 alkylene-OR 2a , -C 0-4 alkylene-OC(=0)R 2a , -C 0-4 alkylene-SR 2a , -C 0-4 alkylene-S(=0)2R 2a , -C 0-4 alkylene-S(=0)R 2a , -C 0-4 alkylene-S(=0)2NR 2a R 2b , -C 0-4 alkylene-S(=0)NR 2a R 2b , -C 0-4 alkylene-C(=0)R 2a , -C 0-4 alkylene-C(=0)OR 2a , -C 0-4 alkylene-NR 2a R 2b , -C 0-4 alkylene-NR 2a R 2b , -C 0-4 alkylene-NR 2a C(=0)R2b 0-4 2a 2b 0-4 2a 2b 0-4 0-4 0-4 0-4 2a 2b each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, halogen-substituted C 2-6 alkenyl, halogen-substituted C 2-6 alkynyl.

[0011] In some embodiments, the A ring is selected from a 6-10 membered aromatic ring (such as phenyl, naphthyl), and the A ring is optionally substituted with two independent R, wherein each R is independently selected from halogen (e.g., F, Cl, Br, or I), substituted or unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl), -C 0-4 alkylene-OR a (e.g., -OH, -OCH3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3), wherein R a is independently selected from hydrogen, C 1-6 alkyl.

[0012] In some embodiments, the A ring is selected from phenyl substituted with one or two independent R, wherein each R is independently selected from halogen (e.g., F, Cl, Br, or I), -C 0-4 alkylene-OR a , wherein R a is independently selected from hydrogen, C 1-6 alkyl.

[0013] In some embodiments, the A ring is selected from phenyl substituted with one or two independent R, wherein each R is independently selected from halogen, -OCH3.

[0014] ​​​​​​​​​​​​In some embodiments, the A ring is selected from a 5-10 membered aromatic heterocycle (e.g., pyrrole, thiophene, imidazole, oxazole, furan, thiazole, pyran ring, etc.), and the A ring is optionally substituted with one or two independent R, wherein each R is independently selected from halogen (F, CI, Br, or I), substituted or unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl), -C 0-4 alkylene-OR a (e.g., -OH, -OCH3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3), wherein R a is independently selected from hydrogen, C 1-6 alkyl.

[0015] In some embodiments, the A ring is selected from a 3-10 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), and the A ring is optionally substituted with one or two independent R, wherein each R is independently selected from halogen (F, CI, Br, or I), substituted or unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl), -C 0-4 alkylene-OR a (e.g., -OH, -OCH3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3), wherein R a is independently selected from hydrogen, C 1-6 alkyl.

[0016] In some embodiments, the A ring is selected from a 3-10 membered heterocycle (e.g., morpholine, pyrrolidine, tetrahydrothiophene, oxetane, etc.), and the A ring is optionally substituted with one or two independent R, wherein each R is independently selected from halogen (F, CI, Br, or I), substituted or unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl), -C 0-4 alkylene-OR a (e.g., -OH, -OCH3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3), wherein R a is independently selected from hydrogen, C 1-6 alkyl.

[0017] In some embodiments, each of X1, X2, X3is independently selected from CH or N.

[0018] In some embodiments, each of X1, X2, X3is independently selected from CH.

[0019] In some embodiments, X1is N. In some embodiments, X2is N. In some embodiments, X3is N.

[0020] In some embodiments, X3is CRc, and Rc, together with R1, along with the atoms to which they are attached, form a 5-membered ring, such as a 5-membered S-containing heterocycle or a 5-membered S- and N-containing heterocycle.

[0021] In some embodiments, R2and R3are each independently selected from C 1-6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), -C 0-4 alkylene-(3-8 membered cycloalkyl) (such as -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl), -C 0-4 alkylene-(5-10 membered heterocycle) (such as -CH2-tetrahydrofuran, -CH2-tetrahydropyran, -CH2-cyclopropyl), or -C 0-4 alkylene-(5-10 membered heteroaromatic ring) (e.g., -CH2-isoxazole,

[0022] In some embodiments, R2and R3are each independently selected from C 1-6 alkyl,

[0023] In some embodiments, R2and R3are each independently selected from C 1-4 alkyl,

[0024] In some embodiments, R2and R3are each independently selected from methyl,

[0025] In some embodiments, R1is selected from -H, -S(=O)2CH3, -C(=O)CH3, -C(=O)CF3, -P(=O)CH3CH3, -S(=O)(=NH)CH3, -S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH2CH3), -N=S(=O)(CH2CH3)(CH2CH3),

[0026] In some embodiments, the compound has a structure according to Formula (Ia):

[0027] wherein R1is selected from -H, -P(=O)R1a R 1b , -C(=O)R 1a , -S(=O)(=NH)R 1b , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring.

[0028] In some embodiments, R1is selected from -H, -C(=O)CH3, -C(=O)CF3, -P(=O)CH3CH3, -S(=O)(=NH)CH3, -S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH2CH3), -N=S(=O)(CH2CH3)(CH2CH3),

[0029] In some embodiments, the compound has a structure according to Formula (IIa):

[0030] wherein each R is independently selected from: hydrogen, halogen, e.g., fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, e.g., methyl, ethyl, propyl, isopropyl; -OR a , wherein R a is independently selected from hydrogen, methyl, ethyl, propyl;

[0031] R1is selected from -H, -S(=O)(=NH)R 1a , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b , wherein R 1a and R 1b are each independently C 1-6 alkyl, e.g., methyl, ethyl, propyl, cyclopropyl, isopropyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring; R1is selected from, e.g., -C(=O)CH3, -C(=O)CF3, -P(=O)CH3CH3, -S(=O)(=NH)CH3, -S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH2CH3), and

[0032] R2and R3are each independently selected from the group consisting of C 1-6 alkyl, for example methyl, ethyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), for example

[0033] In some embodiments, the compound has the structure of Formula (Ib):

[0034] wherein R1is selected from -S(=O)2R 1a , -C(=O)R 1a , -P(=O)R 1a R 1b , -S(=O)(=NH)R 1b , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atom to which they are attached form a 4- to 6-membered ring.

[0035] In some embodiments, the compound has the structure of Formula (IIb):

[0036] wherein each R is independently selected from halogen, for example fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, for example methyl, ethyl, propyl, cyclopropyl, isopropyl; -OR a , wherein R a is independently selected from hydrogen, methyl, ethyl, cyclopropyl, isopropyl, propyl;

[0037] R1is selected from -S(=O)2R 1a , -P(=O)R 1a R 1b , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from C1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, or R 1a and R 1b together with the atom to which they are attached form a 4- to 6-membered ring; R1is selected from, for example, -S(=O)2CH3, -C(=O)CH3, -C(=O)CF3, -P(=O)CH3CH3, -S(=O)(=NH)CH3, -S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH2CH3), and

[0038] R2and R3are each independently selected from: C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), such as

[0039] In some embodiments, the compound has the structure of Formula (Ic):

[0040] wherein R1is selected from -S(=O)2R 1a , -C(=O)R 1a , -P(=O)R 1a R 1b , -S(=O)(=NH)R 1b , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atom to which they are attached form a 4- to 6-membered ring.

[0041] In some embodiments, the compound has the structure of Formula (IIc):

[0042] wherein each R is independently selected from: halogen, such as fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, such as methyl, ethyl, propyl, cyclopropyl, isopropyl; -OR a wherein R a is independently selected from hydrogen, methyl, ethyl, propyl;

[0043] R1is selected from -S(=O)2R 1a , -N=S(=O)R1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, for example methyl, ethyl, propyl, cyclopropyl, isopropyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring; R1is selected from, for example, -S(=O)2CH3, -C(=O)CH3, -C(=O)CF3, -P(=O)CH3CH3, -S(=O)(=NH)CH3, -S(=O)(CH3)(CH3), -N=S(=O)(CH3)(CH2CH3),

[0044] R2and R3are each independently selected from: C 1-6 alkyl, for example methyl, ethyl, cyclopropyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), for example

[0045] In some embodiments, the compound has the structure of Formula (Id):

[0046] wherein R1is selected from -S(=O)2R 1a , -C(=O)R 1a , -P(=O)R 1a R 1b , -S(=O)(=NH)R 1b , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b ; wherein R 1a are each independently selected from substituted or unsubstituted C 1-6 alkyl.

[0047] In some embodiments, the compound has the structure of Formula (IId):

[0048] wherein R is each independently selected from: halogen, for example fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, for example methyl, ethyl, propyl, isopropyl; -OR a , wherein R a is independently selected from hydrogen, methyl, ethyl, propyl;

[0049] R1is selected from -S(=O)2R 1a, -C(=O)R 1a ; wherein R 1a each independently is selected from C 1-6 alkyl, such as methyl, ethyl, cyclopropyl, propyl, isopropyl;

[0050] R2and R3are each independently selected from: C 1-6 alkyl, such as methyl, ethyl, propyl, cyclopropyl, isopropyl; -C 1-4 alkylene-(5-10 membered heteroaromatic ring), such as

[0051] In some embodiments, the compound is selected from the group consisting of the compounds shown below, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof:

[0052] In some embodiments, the compound is also selected from the group consisting of the compounds shown below, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof:

[0053] In a second aspect, the present application provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof:

[0054] wherein R1, R2, X1, X2, X3and A ring can be any of the definitions applicable to the first aspect of the present application;

[0055] L represents a linker group, typically a heteroatom-containing subunit, such as PEG, saturated or unsaturated alkylene, or a subunit containing aromatic, heteroaromatic, saturated or unsaturated cyclic alkylene, saturated or unsaturated heterocyclic alkylene. L structures are optionally referenced with heteroatoms and cyclic structures to modulate physicochemical properties and overall pharmacodynamics of the molecule.

[0056] P represents H, OH, or a ligand group targeting degradation of a target protein. The target protein can be a certain pathogenic protein, including but not limited to a protein causing diseases such as tumors, immunity, inflammation, central nervous system, etc.

[0057] For L and P and their binding sites, the person skilled in the art can select or design according to the specific knowledge of the relevant disease protein target.

[0058] In some embodiments, L represents a saturated or unsaturated alkylene or a PEG-based subunit, optionally a saturated or unsaturated C1-10 alkylene or a PEG subunit with a degree of polymerization of 1 to 100.

[0059] In some embodiments, L represents a C1-C10 alkylene group, such as methylene, ethylene, propylene, butylene, but not limited thereto. It should be understood that the saturated or unsaturated alkylene group can be optionally substituted, for example, OH-substituted alkylene, amino-substituted alkylene, cyano-substituted alkylene, etc., but not limited thereto.

[0060] In some embodiments, L represents a PEG formula, i.e., (-CH2CH2O-)n, wherein n is 1 to 50, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., wherein the alkylene group in the PEG can be optionally substituted, for example, OH-substituted alkylene, amino-substituted alkylene, cyano-substituted alkylene, etc., but not limited thereto.

[0061] In some embodiments, L represents a combination of the above-mentioned groups, such as C1-C10 alkylene-(-CH2CH2O-)n, or -(-CH2CH2O-)n1-W-(-CH2CH2O-)n2, wherein n1+n2=n, W represents an alkylene group, a cyclic alkylene group, a heterocyclic alkylene group, an arylene group, etc., but not limited thereto.

[0062] In a second aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound, and a pharmaceutically acceptable carrier.

[0063] In a third aspect, the present application provides use of the above-mentioned compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph or isotopically enriched compound thereof, in the preparation of a medicament, including but not limited to the use of the above-mentioned compound and derivatives, or the above-mentioned pharmaceutical composition to induce TRIM21-mediated targeted protein degradation in cells.

[0064] In a third aspect, the present application provides use of the above-mentioned compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph or isotopically enriched compound thereof, in the preparation of a medicament, including but not limited to the use of the above-mentioned compound and derivatives, or the above-mentioned pharmaceutical composition to induce TRIM21-mediated targeted protein degradation in cells.

[0065] In some embodiments, the above-mentioned medicament is used for treating or preventing a TRIM21-mediated targeted protein-related disease or disorder, including but not limited to a tumor or cancer, inflammation, immune system disease, neurodegenerative disease, etc. In some embodiments, the above-mentioned medicament is a drug for targeted protein degradation.

[0066] In a fourth aspect, the present application provides use of the above-mentioned compound, or a chemical synthesis route thereof, or a synthetic intermediate thereof, in the synthesis of a medicament.

[0067] In a fifth aspect, the present application provides a method for treating or preventing a TRIM21 -dominated or TRIM21 -mediated target protein related disease or disorder, comprising administering to a subject an effective amount of a compound and / or a pharmaceutical composition described above, thereby treating the related disease.

[0068] Further, the present application also provides a kit comprising any of the above- described compounds or pharmaceutically acceptable salts, solvates or stereoisomers, polymorphs, isotopically enriched compounds or any of the above-described compositions, which can be prepared for use in treating, inhibiting or preventing a TRIM21 -dominated target protein related disease or disorder. DETAILED DESCRIPTION

[0069] DEFINITIONS

[0070] To provide a clear and consistent understanding of the terminology used in the specification for the application, certain definitions are provided below. Furthermore, unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0071] The use of the word "a" or "an" when used in the context of the patent claims and / or specification means "one or more", but it is also intended to cover "one" and "more than one" or "at least one". Similarly, the words "another" and "yet another" when used in the context of the patent claims and / or specification mean "at least a second" or "more than one".

[0072] The words "comprise", "have", "include" and "contain" are to be construed as

[0073] The term "about" is used to indicate that a value includes the error that would be expected by instrument and method variability.

[0074] As used herein, the term "substituted" or "having substituents" means that the parent compound or moiety has at least one substituent group. The term "unsubstituted" or "having no substituents" means that the parent compound or moiety has no substituents other than the hydrogen atoms chemically necessary to satisfy the valency of the parent molecule. As described herein, "substituent" or "substituent group" means a group selected from halogen (F, CI, Br, or I), hydroxyl, thiol, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphonyl, or other organic moiety conventionally used and accepted in organic chemistry.

[0075] As used herein, the term "alkyl" refers to saturated hydrocarbons having, for example, 1 to 6 carbon atoms, including straight chain, branched chain, and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, and the like. The term alkyl includes unsubstituted alkyl groups and substituted alkyl groups. The term "Ci-C6alkyl" (where n is an integer from 1 to 6) means an alkyl group having 1 to the indicated "n" number of carbon atoms. The alkyl residue can be substituted or unsubstituted. In some embodiments, for example, the alkyl group can be substituted with a hydroxyl, halogen (F, CI, Br, or I), amino, or the like group. n The term "alkyl" (where n is an integer from 1 to 6) means an alkyl group having 1 to the indicated "n" number of carbon atoms. The alkyl residue can be substituted or unsubstituted. In some embodiments, for example, the alkyl group can be substituted with a hydroxyl, halogen (F, CI, Br, or I), amino, or the like group.

[0076] As used herein, the term "3-10 membered cycloalkyl" refers to saturated or unsaturated non-aromatic hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) systems having 3 to 10 carbon atoms (e.g., C 3-8 , C 3-6 , or C 4-8 ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl.

[0077] As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the above-described alkyl groups but containing at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl) and branched chain alkenyl groups. In certain embodiments, straight chain or branched chain alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term "C 2-6 alkenyl" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C 3-6 alkenyl" includes alkenyl groups containing 3 to 6 carbon atoms.

[0078] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the above-described alkyl groups but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl) and branched chain alkynyl groups. In certain embodiments, straight chain or branched chain alkynyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term "C

[0079] As used herein, the term "6-10 membered aromatic ring" refers to an aromatic group having "4n+2" (pi) electrons in a conjugated monocyclic or polycyclic ring system (fused or non-fused) and having 6 to 10 ring atoms, where n is an integer from 1 to 2. Aryl groups can be attached directly or through a C1-C3 alkyl group (also referred to as arylalkyl or aralkyl). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, and the like.

[0080] As used herein, the term "heteroaromatic ring" refers to an aryl group as defined above, but having 1 to 4 heteroatoms (e.g., N, O, and S) in the ring structure. As used herein, the term "heteroaromatic ring" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycle consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (e.g., 1 or 1-2 or 1-3 or 1-4 heteroatoms). Nitrogen atoms can be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). Nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N— >0 and S(O) p where p = 1 or 2).

[0081] As used herein, the term "heterocycle" refers to any ring structure (saturated or unsaturated) containing at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O, and S). Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran.

[0082] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine, encompassing "partially halogenated" and "perhalogenated," i.e., replacement of some or all of the hydrogen atoms of a group by halogen atoms.

[0083] As used herein, the term "C 0-4 alkylene" denotes the absence of the alkylene group as well as C 1-4 alkylene (e.g., methylene, ethylene, propylene, butylene, and the like).

[0084] As used herein, it is known to those skilled in the art that "alkylene," "arylene," "heteroarylene," "cycloalkylene or cycloalkanylene," "heterocycloalkylene" are divalent groups of "alkyl," "aromatic ring," "heteroaromatic ring," "cycloalkyl," "heterocycle" as described above.

[0085] In the present specification, for the sake of convenience, in some cases, the structural formula of a compound represents a certain isomer, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like. In addition, the compound represented by the general formula can exist as a crystal polymorph. It should be noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included within the scope of the present application. The term "crystal polymorph", "polymorph" or "crystal form" means a crystal structure in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, the rate of crystallization, the storage temperature, and other factors can cause one crystal form to dominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0086] A "pharmaceutically acceptable salt" of a compound means a salt of a compound that is pharmaceutically acceptable. Ideal salts (basic, acidic, or charged functional groups) of a compound can retain or improve the biological activity and properties of the parent compound as defined by the present application and are not biologically undesirable. Examples of pharmaceutically acceptable salts are mentioned by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977), including but not limited to:

[0087] (1) acid addition salts formed by the addition of an acid to a basic or positively charged functional group, in which an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonic acid; or an organic acid such as acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, t-butylacetic acid, beta-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylsulfamic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, lauryl sulfonic acid, lauryl sulfuric acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid (embonic acid), pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, and the like.

[0088] (2) when the parent compound contains an acidic proton or has been substituted by a metal ion, a base addition salt by reaction with a base, including alkali metal ions (for example lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium) or other metal ions such as aluminium, zinc, iron, etc., or complexed with an organic base such as ammonia, ethylamine, diethylamine, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, etc.

[0089] Pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared either by reaction of the compound (free acid or base) with an equal chemical equivalent of the base or acid in water or in an organic solvent or in a mixture of both. The salts can be prepared in situ during the final isolation or purification of the compounds of the application by reacting the purified compound in its free acid or base form with the desired corresponding base or acid and isolating the salt thus formed. The term "pharmaceutically acceptable salts" also includes zwitterionic compounds, which contain both cationic and anionic groups by covalent bonds, which are known as "inner salts". It is understood that all acid, base and other ionic and non-ionic forms of the compounds of the present application are encompassed within the scope of the present application. For example, if a compound of the present application is an acid, then a salt form of the compound is also

[0090] The term "isotopically enriched compound" as used herein refers to a compound in which one or more specific isotopes are increased. Typically, in an isotopically enriched compound or derivative, a specific isotope element is enriched or increased at a specific position of the compound. However, it is understood that a compound can have two or more isotope elements enriched or increased, including different isotopes of the same element and respective isotopes of different elements. Further, an isotopically enriched compound can be in a mixed form of isotopic enrichment, i.e., containing multiple specific isotopes or elements or both. Typically, employable isotopes include 1 H, D, T, 18 O, 17 O, 15 N and 13 C, etc.

[0091] "Pharmaceutically acceptable" means the drug, medicament, inert ingredient, and the like, as the term describes a drug, medicament, inert ingredient, etc., which is suitable for use with cells or tissues of humans and animals without an unusually toxic, incompatibilistic, unstable, irritating, allergic, and the like, reaction, commensurate with a reasonable benefit / risk ratio. It generally refers to compounds or compositions approved or approvable by a regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0092] "Pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, carrier, or vehicle with which a compound is administered.

[0093] "Pharmaceutical composition" means a composition comprising a compound as described herein, and at least one component, depending on the mode of administration and dosage form desired, comprising a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or vehicle, such as a preservative, filler, disintegrant, wetting agent, emulsifying agent, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant, and dispersing agent, and the like.

[0094] In some embodiments, the term "prevention" means reducing the likelihood (i.e., causing at least one clinical symptom of a disease to not develop in a patient who can be exposed to or predisposed to the disease, but has not yet experienced or demonstrated symptoms of the disease) of acquiring a disease or disorder (or susceptibility to). The term "treatment" means alleviating at least one disease or disorder. In certain embodiments, "treatment" means alleviating at least one physical parameter, which can or can not be discernible by the patient. In certain embodiments, "treatment" means inhibition of the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In certain embodiments, "treatment" means improvement in quality of life or alleviation of a side effect of the disease in a subject in need thereof. An "effective amount" means the amount of a compound administered to a subject for treatment or prevention of a disease sufficient to effect treatment or prevention of the disease. The "effective amount" will vary depending on the compound; the disease and its severity; the age, body weight, general health of the subject to be treated or prevented; and the like. As used herein, "effective amount" means the amount of a compound or composition sufficient to prevent, treat, inhibit, reduce, alleviate or eliminate one or more causes, symptoms or complications of a disease, such as cancer.

[0095] A "pharmaceutical composition" is a formulation containing a compound of the disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is bulk or in unit dosage form. A unit dosage form is any of a variety of forms including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (e.g., a formulation of a disclosed compound or salt, hydrate, solvate, or isomer thereof) in a unit dose of composition is an effective amount and varies according to the particular treatment involved. One skilled in the art will recognize that it is sometimes necessary to make routine

[0096] Pharmaceutical compositions containing the compounds of the present application can be manufactured by means known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions can be formulated in

[0097] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TMThe composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, sodium chloride and the like isotonic agents. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

[0098] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from the previously sterile-filtered solution thereof.

[0099] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.

[0100] Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or acacia; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0101] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0102] Systemic administration can also be by way of transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

[0103] In therapeutic applications, dosages of the pharmaceutical compositions used in accordance with the disclosure will vary depending on the agent, the age, weight, and clinical condition of the patient, and the experience and judgment of the clinician or practitioner administering the therapy, as well as other factors.

[0104] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0105] The compounds of Formula I, Formula II provided in the present application can be effectively used for diseases or disorders related to TRIM21. TRIM21 can induce a series of tumor growth and spread (Alomari, M. Pharmaceutical Research 2021, 165, 105443) and induce the degradation of pathogenic protein tau in brain nerve cells (Mukadam, A.S. et al Science 2023, 379(6639, 1336). As a class of intracellular antibody receptors or sensors, TRIM21 is an innate immune defense line against viral invasion. For viruses that have escaped the action of neutralizing antibodies and are adsorbed by non-neutralizing antibodies to invade cells through the cell membrane, TRIM21 can play an antiviral role by binding to the Fc segment of the antibody in the virus-antibody complex, preventing viral replication and inducing cellular immunity. The dual effect of degrading viral particles and activating immune signals of TRIM21 is strictly regulated by its ubiquitination and phosphorylation. In addition, TRIM21 can also play a synergistic role with the complement system. In summary, TRIM21 ligands and their derived small molecules targeting protein degradation have broad potential applications in the treatment of tumors, neurodegenerative diseases, viral infections, immune inflammation and many other diseases. Therefore, the compounds or compositions provided in the present application can be used for the treatment of tumors, neurodegenerative diseases, viral infections, immune inflammation and many other diseases or disorders.

[0106] In some embodiments, the compounds and compositions of the application can be used in combination with one or more additional agents. The one or more additional agents can have TRIM21 modulating activity and / or they can act through a different mechanism of action. In some embodiments, such agents include radiation (e.g. local radiotherapy or systemic radiotherapy) and / or other treatment modalities of non-pharmacological nature. When combination therapy is used, the compounds of the application and the additional agents can be in the form of a single composition or of multiple compositions, and the modes of treatment can be administered simultaneously, sequentially or by some other regimen. The combination therapy can have an additive effect or a synergistic effect.

[0107] Examples

[0108] The present application will be more readily understood by reference to the following examples, which are intended to illustrate the present application and are not to be construed as limiting the scope of the application.

[0109] Unless otherwise defined, or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application.

[0110] Example 1: Preparation of Compound 1

[0111] Step 1: A mixture of compound 1-1 (200 mg, 0.587 mmol), dimethylsulfinylimine (54.64 mg, 0.587 mmol), Xantphos (33.94 mg, 0.059 mmol), Pd2(dba)3(26.86 mg, 0.029 mmol) and Cs2CO3(286.70 mg, 0.880 mmol) in dioxane (4 mL) was heated to 100 °C under nitrogen protection for 3 h. After the reaction was completed, the reaction was poured into water (30 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 1-2 (170 mg, crude) as a yellow oil, which was used directly in the next step. MS-ESI (m / z): 306.0 / 308.0 [M+H] + .

[0112] Step 2: A mixture of compound 1-2 (170 mg, 0.555 mmol), compound 1-3 (141.55 mg, 0.833 mmol), Pd(dppf)Cl2(40.63 mg, 0.056 mmol) and K2CO3(191.84 mg, 1.388 mmol) in dioxane (4 mL) and water (1 mL) was heated to 100 °C for 3 h under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove most of the organic solvent, poured into water (30 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 1-4 (195 mg, crude) as a yellow oil, which was used directly in the next reaction. MS-ESI (m / z): 352.1 [M+H] + .

[0113] Step 3: To a solution of compound 1-4 (195 mg, 0.555 mmol) in MeOH (4 mL) and H2O (2 mL) was added NaOH (66.59 mg, 1.665 mmol), the resulting mixture was heated to reflux for 1 h. After completion of the reaction, the reaction mixture was diluted with H2O (30 mL), adjusted to pH = 6 with concentrated hydrochloric acid, extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 1-5 (180 mg, crude) as a yellow-brown oil, which was used directly in the next reaction. MS-ESI (m / z): 338.1 [M+H] + .

[0114] Step 4: A solution of compound 1-5 (180 mg, 0.534 mmol), HATU (304.31 mg, 0.800 mmol) and DIEA (0.265 mL, 1.601 mmol) in DMF (1 mL) was stirred at 25 °C for 5 min, then compound 1-6 (73.72 mg, 0.534 mmol) was added to the above solution and stirred for 1 h. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 1-7 (200 mg, crude) as a yellow solid, which was used directly in the next reaction.

[0115] MS-ESI (m / z): 458.1 [M+H] + .

[0116] Step 5: To a solution of compound 1-7 (200 mg, 0.437 mmol) in DMF (4 mL) was added NaH (69.94 mg, 1.749 mmol, 60% in mineral oil) under nitrogen atmosphere at 25 °C. The resulting reaction mixture was stirred at the same temperature for 10 min. Then Mel (0.142 mL, 1.749 mmol) was added to the above suspension and the reaction was continued at the same temperature for 1 h. After completion of the reaction, H2O (1 mL) was added slowly and carefully to quench the reaction. The resulting solution was directly concentrated to dryness under reduced pressure to afford compound 1-8 (205 mg, crude) as a yellow solid, which was used directly for the next step. MS-ESI (m / z): 472.2 [M+H] + .

[0117] Step 6: To a solution of compound 1-8 (205 mg, 0.435 mmol) in dioxane (2 mL) was added concentrated HCl (1 mL) and the resulting reaction mixture was heated to 100 °C and stirred for 6 h. After completion of the reaction, the reaction mixture was adjusted to pH = 8 with saturated NaHC03and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with saturated brine (10 mL), dried over anhydrous Na2S04, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to afford compound 1 (15 mg, overall yield in six steps: 5.6%) as a yellow solid.

[0118] 1 H-NMR (400 MHz, DMSO-d6) δ 11.48 (1H, brs), 7.34-7.40 (2H, m), 7.21-7.30 (1H, m), 7.15-7.20 (1H, m), 6.97-7.09 (2H, m), 6.85-6.92 (1H, m), 6.23-6.52 (1H, m), 6.04-6.21 (1H, m), 3.78-3.85 (3H, m), 3.34-3.40 (5H, m), 3.22-3.31 (3H, m), 2.82-2.90 (3H, m).

[0119] MS-ESI (m / z): 458.1 [M+H] + .

[0120] Example 2: Preparation of compound 2

[0121] Step 1: To a solution of compound 1-6 (465 mg, 3.365 mmol) in dichloromethane (5 mL) was added triethylamine (1.871 mL, 13.462 mmol) and di-tert-butyl dicarbonate (0.773 mL, 3.365 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1) to give compound 2-1 (648 mg, yield: 80.8%) as yellow oil. MS-ESI (m / z): 239.1 [M+H] + .

[0122] Step 2: To a solution of compound 2-1 (648 mg, 2.719 mmol) in tetrahydrofuran (12 mL) was added NaH (261.06 mg, 10.878 mmol, 60% in mineral oil) in portions at 10 min intervals in an ice bath. Then iodomethane (0.331 mL, 4.079 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The mixture was purified by silica gel column chromatography (PE / EtOAc = 5 / 1) to give compound 2-2 (539 mg, yield: 78.6%) as colorless oil. MS-ESI (m / z): 253.1 [M+H] + .

[0123] Step 3: To a solution of compound 2-2 (360 mg, 1.427 mmol) in dioxane (2 mL) was added concentrated hydrochloric acid (1 mL), the resulting reaction was heated to 100 °C and stirred for 6 hours. After the reaction was completed, the reaction was directly concentrated to dryness under reduced pressure to give compound 2-3 (197 mg, crude) as a white solid.

[0124] MS-ESI (m / z): 139.2 [M+H] + .

[0125] Step 4: A mixture of compound 1-1 (400 mg, 0.587 mmol), dimethyl phosphine oxide (99.42 mg, 1.291 mmol), Xantphos (135.77 mg, 0.253 mmol), Pd2(dba)3 (107.44 mg, 0.117 mmol) and K3PO4 (540.34 mg, 2 mmol) in dioxane (8 mL) was heated to 100 °C and stirred for 8 hours under nitrogen protection. After the reaction was completed, the reaction was poured into water (60 mL) and extracted with EtOAc (20 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to pure EtOAc) to give compound 2-4 (177 mg, yield 48.05%) as yellow oil.

[0126] MS-ESI (m / z): 290.9 / 293.0 [M+H] + .

[0127] Step 5: A mixture of compound 2-4 (177 mg, 0.555 mmol), compound 1-3 (103.34 mg, 0.608 mmol), Pd(dppf)Cl2(44.49 mg, 0.061 mmol) and K2CO3(252.11 mg, 1.824 mmol) in dioxane (4 mL) and water (1 mL) was heated to 100 °C under nitrogen protection for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove most of the organic solvent, poured into water (30 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 2-5 (116 mg, crude) as a brown oil, which was used directly in the next reaction. MS-ESI (m / z): 337.1 [M+H] + .

[0128] Step 6: To a solution of compound 2-5 (116 mg, 0.555 mmol) in MeOH (4 mL) and H2O (2 mL) was added NaOH (41.39 mg, 1.035 mmol), the resulting mixture was heated to reflux with stirring for 1 h. After completion of the reaction, the reaction mixture was diluted with H2O (20 mL), adjusted to pH = 6 with concentrated hydrochloric acid, extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 2-6 (110 mg, crude) as a brown solid, which was used directly in the next reaction. MS-ESI (m / z): 323.1 [M+H]+.

[0129] Step 7: A solution of compound 2-6 (60 mg, 0.186 mmol), HATU (77.87 mg, 0.205 mmol) and DIEA (0.092 mL, 0.559 mmol) in DMF (1 mL) was stirred at 25 °C for 5 min, then compound 2-3 (73.72 mg, 0.534 mmol) was added to the above solution and stirred for 1 h. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (5 mL x 3), the combined extracts were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give compound 2 (3.96 mg, yield: 5.6%) as a white solid.

[0130] 1 H-NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 7.82-7.87 (m, 1H), 7.62-7.72 (m, 1H), 7.29-7.47 (m, 3H), 7.02-7.10 (m, 1H), 6.84-6.95 (m, 1H), 6.17-6.39 (m, 2H), 4.15-4.49 (m, 2H), 3.75-3.85 (m, 3H), 2.77-2.88 (m, 3H), 1.74 (s, 3H), 1.70 (s, 3H).

[0131] MS-ESI (m / z): 433.1 [M+H] + .

[0132] Example 3: Preparation of compound 3

[0133] Step 1: A mixture of compound 1-1 (100 mg, 0.293 mmol), compound 3-1 (39.07 mg, 0.293 mmol), Xantphos (16.97 mg, 0.029 mmol), Pd2(dba)3 (11.87 mg, 0.015 mmol) and K3PO4 (124.51 mg, 0.587 mmol) in dioxane (4 mL) was stirred at 100 °C for 8 h under nitrogen. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to give compound 3-2 (68 mg, crude) as yellow oil, which was used directly in the next step. MS-ESI (m / z): 347.90 / 350.00 [M+H] + .

[0134] Step 2: A mixture of compound 3-2 (68 mg, 0.196 mmol), compound 1-3 (33.38 mg, 0.196 mmol), Pd(dppf)Cl2(14.37 mg, 0.020 mmol) and K2CO3(81.43 mg, 0.589 mmol) in dioxane (4 mL) and water (1 mL) was heated to 100 °C for 3 h under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove most of the organic solvent, poured into water (20 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 3-3 (70 mg, crude) as a brown oil, which was used directly in the next reaction. MS-ESI (m / z): 392.10 [M+H] + .

[0135] Step 3: To a solution of compound 3-3 (70 mg, 0.179 mmol) in MeOH (4 mL) and H2O (2 mL) was added NaOH (21.46 mg, 0.536 mmol), the resulting mixture was heated to reflux for 1 h. After completion of the reaction, the reaction mixture was diluted with H2O (10 mL), adjusted to pH = 6 with concentrated hydrochloric acid, extracted with EtOAc (5 mL x 2), the combined extracts were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 3-4 (65 mg, crude) as a brown oil, which was used directly in the next reaction. MS-ESI (m / z): 378.00 [M+H] + .

[0136] Step 4: A solution of compound 3-4 (65 mg, 0.172 mmol), HATU (130.97 mg, 0.344 mmol) and DIEA (0.085 mL, 0.517 mmol) in DMF (1 mL) was stirred at 25 °C for 5 min, then compound 1-6 (28.55 mg, 0.207 mmol) was added to the above solution and stirred for 1 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 3-5 (100 mg, crude) as a brown oil, which was used directly in the next reaction.

[0137] MS-ESI (m / z): 498.10 [M+H] + .

[0138] Step 5: To a solution of compound 3-5 (100 mg, 0.201 mmol) in THF (4 mL) was added NaH (24.12 mg, 0.603 mmol, 60% in mineral oil) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 10 min. Then Mel (0.049 mL, 0.603 mmol) was added to the above mixture and the resulting mixture was stirred at 50 °C for 1 h. After completion of the reaction, H2O (1 mL) was added slowly and carefully to quench the reaction. The resulting solution was directly concentrated to dryness under reduced pressure to afford compound 3-6 (100 mg, crude) as a brown solid, which was used directly in the next step. MS-ESI (m / z): 512.10 [M+H] + .

[0139] Step 6: To a solution of compound 3-6 (100 mg, 0.435 mmol) in dioxane (2 mL) was added concentrated HCl (1 mL) and the resulting mixture was heated to 100 °C for 6 h. After completion of the reaction, the reaction mixture was adjusted to pH = 8 with saturated aqueous NaHC03solution and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with saturated brine (10 mL), dried over anhydrous Na2S04, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to afford compound 3 (7.51 mg, six steps overall yield: 5.1%) as a white solid.

[0140] 1 H-NMR (400 MHz, DMSO-d6) d 11.45 (br s, 1H), 7.29-7.40 (m, 2H), 7.19-7.34 (m, 1H), 7.15 (t, J = 6.8 Hz, 1H), 6.94-7.06 (m, 2H), 6.81-6.88 (m, 1H), 6.25-6.51 (m, 1H), 6.07-6.17 (m, 1H), 4.04-4.96 (m, 2H), 3.78 (s, 3H), 3.44-3.64 (m, 2H), 3.23-3.29 (m, 2H), 2.89 (s, 3H), 1.71-2.05 (m, 4H), 1.46-1.67 (m, 2H).

[0141] MS-ESI (m / z): 498.20 [M+H] + .

[0142] Example 4: Preparation of compound 4

[0143] Step 1: A mixture of compound 1-1 (150 mg, 0.440 mmol), compound 4-1 (52.43 mg, 0.440 mmol), Xantphos (25.46 mg, 0.044 mmol), Pd2(dba)3(20.14 mg, 0.022 mmol) and Cs2CO3(93.39 mg, 0.440 mmol) in dioxane (2 mL) was heated to 110 °C under nitrogen protection for 18 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by preparative thin-layer chromatography (PE / EtOAc = 1 / 1) to give compound 4-2 (110 mg, yield: 75.2%) as a yellow solid.

[0144] MS-ESI (m / z): 332.0 / 334.0 [M+H] + .

[0145] Step 2: A mixture of compound 4-2 (110 mg, 0.331 mmol), compound 1-3 (56.27 mg, 0.331 mmol), Pd(dppf)Cl2(27.04 mg, 0.033 mmol) and K2CO3(137.28 mg, 0.993 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to 110 °C under nitrogen protection for 2 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 4-3 (71 mg, yield: 56.8%) as a white solid.

[0146] MS-ESI (m / z): 378.1 / 380.1 [M+H] + .

[0147] Step 3: To a solution of compound 4-3 (71 mg, 0.188 mmol) in MeOH (1 mL) and THF (1 mL) was added a solution of LiOH (23.68 mg, 0.564 mmol) in H2O (0.5 mL), and the resulting mixture was heated to reflux with stirring for 20 min. After completion of the reaction, the reaction mixture was adjusted to pH = 7-8 with concentrated hydrochloric acid and concentrated to dryness to give compound 4-4 (68 mg, crude) as a white solid, which was used directly in the next reaction.

[0148] MS-ESI (m / z): 364.1 [M+H] + .

[0149] Step 4: To a solution of compound 4-4 (68 mg, 0.187 mmol), HATU (85.38 mg, 0.225 mmol) and DIEA (0.093 mL, 0.561 mmol) in DMF (2 mL) was added compound 1-6 (25.85 mg, 0.187 mmol) and the stirring was continued for 1 h. After the reaction was completed, the reaction was poured into water (30 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to give compound 4-5 (90 mg, yield: 99.4%) as yellow oil.

[0150] MS-ESI (m / z): 484.1 [M+H] + .

[0151] Step 5: To a solution of compound 4-5 (90 mg, 0.186 mmol) in DMF (4 mL) was added NaH (13.40 mg, 0.558 mmol) under ice-bath cooling, the resulting reaction was stirred at this temperature for 10 min. Then Mel (0.045 mL, 0.558 mmol) was added and the reaction was carried out at 40 °C for 6 h. After the reaction was completed, H2O (0.5 mL) was added slowly and carefully to quench the reaction and the pH was adjusted to 7-8 with dilute hydrochloric acid. The resulting solution was directly concentrated to dryness under reduced pressure to give compound 4-6 (92 mg, crude) as brown solid, which was used directly in the next step. MS-ESI (m / z): 498.1 [M+H] + .

[0152] Step 6: Compound 4-6 (92 mg, 0.185 mmol) was added to hydrochloric acid dioxane (4 M, 2 mL) and the resulting reaction was heated to 80 °C and stirred for 8 h. After the reaction was completed, the reaction was concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM / MeOH = 20 / 1) to give the crude product, which was further separated by reverse phase chromatography to give compound 4 (3.13 mg, total yield over six steps: 1.5%) as yellow solid.

[0153] 1H-NMR (400 MHz, MeOD) δ 7.30-7.40 (m, 1H), 7.25-7.30 (m, 1H), 7.17-7.24 (m, 1H), 7.08-7.16 (m, 1H), 6.94-7.05 (m, 1H), 6.72-6.80 (m, 1H), 6.63-6.71 (m, 1H), 6.57-6.63 (m, 1H), 6.21-6.36 (m, 1H), 4.04-4.72 (m, 2H), 3.68-3.74 (m, 3H), 3.34-3.59 (m, 2H), 3.02-3.17 (m, 2H), 2.86-2.98 (m, 3H), 2.06-2.24 (m, 4H).

[0154] MS-ESI (m / z): 484.1 [M+H] + .

[0155] Example 5: Preparation of compound 5

[0156] Step 1: To a solution of compound 5-1 (4.0 g, 16 mmol) in THF (80 mL) was added sodium thiomethoxide (1.11 g, 16 mmol) at 0 °C and continued to stir at 0 °C for 1 h, then warmed to 25 °C and stirred for 20 h. After the reaction was completed, the reaction was poured into water (80 mL) and extracted with DCM (30 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1) to give compound 5-2 (1.32 g, yield: 23%) as a white solid.

[0157] 1 H-NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 4.00 (s, 3H), 2.46 (s, 3H).

[0158] MS-ESI (m / z): 262.0 / 264.0 [M+H] + .

[0159] Step 2: To a solution of compound 5-2 (1.1 g, 4.2 mmol) in DCM (10 mL) was added m-CPBA (1.45 g, 8.4 mmol, 85% purity) portionwise at 0 °C, after the addition was completed, the reaction was warmed to 25 °C and stirred for 18 h. After the reaction was completed, the reaction was diluted with water (100 mL), the resulting mixture was extracted with DCM (30 mL x 3), the combined extracts were washed with saturated Na2S2O4 aqueous solution (20 mL), then the organic phase was washed with saturated brine (10 mL), finally dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (PE / DCM = 5 / 1 to 1 / 1) to give compound 5-3 (630 mg, yield 73%) as a white solid.

[0160] 1 H-NMR (400 MHz, CDC13) δ 8.90 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 4.04 (s, 3H), 3.40 (s, 3H).

[0161] MS-ESI (m / z): 294.0 [M+H] + .

[0162] Step 3: A solution of compound 5-3 (30 mg, 0.102 mmol), compound 1-6 (19.07 mg, 0.112 mmol), Pd(dppf)Cl2(7.46 mg, 0.010 mmol) and K2CO3(42.29 mg, 0.306 mmol) in dioxane (3 mL) and water (1 mL) was stirred at 100 °C under nitrogen protection for 3 h. After the reaction was completed, most of the organic solvent was removed by concentration under reduced pressure, and the residue was diluted with water (6 mL), adjusted to pH = 6 with concentrated hydrochloric acid, and the precipitated solid was filtered and washed with water (1 mL x 3), and finally dried under reduced pressure to give compound 5-4 (31 mg, yield: 93.4%) as a white solid.

[0163] MS-ESI (m / z): 326.0 [M+H] + .

[0164] Step 4: A solution of compound 5-4 (20.0 mg, 0.061 mmol), compound 2-3 (7.63 mg, 0.061 mmol), HATU (28.05 mg, 0.074 mmol), DIEA (0.030 mL, 0.184 mmol) in DMF (1 mL) was stirred at 25 °C for half an hour. After the reaction was completed, the reaction was concentrated under reduced pressure to dryness. The residue was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give compound 5 (15 mg, yield: 54.8%) as a yellow solid.

[0165] 1 H-NMR (400 MHz, MeOD) δ 8.78-8.95 (m, 1H), 8.40-8.50 (m, 1H), 7.25-7.50 (m, 2H), 6.80-6.90 (m, 1H), 6.70-7.78 (m, 1H), 6.40-6.60 (m, 2H), 4.10-4.60 (m, 2H), 3.68-3.78 (m, 3H), 3.23-3.28 (m, 3H), 2.75-3.00 (m, 3H).

[0166] MS-ESI (m / z): 446.1 [M+H] + .

[0167] Example 6: Preparation of compound 6

[0168] Step 1: A mixture of compound 1-1 (70 mg, 0.205 mmol), compound 6-1 (21.59 mg, 0.205 mmol), Xantphos (11.88 mg, 0.021 mmol), Pd2(dba)3 (9.40 mg, 0.010 mmol) and Cs2CO3 (43.58 mg, 0.205 mmol) in dioxane (1 mL) was stirred at 110 °C for 18 h under nitrogen. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by preparative thin-layer chromatography (PE / EtOAc = 1 / 1) to give compound 6-2 (47 mg, yield: 71.9%) as a yellow solid.

[0169] MS-ESI (m / z): 319.2 / 321.2 [M+H] + .

[0170] Step 2: A mixture of compound 6-2 (47 mg, 0.148 mmol), compound 1-3 (25.10 mg, 0.148 mmol), Pd(dppf)Cl2 (10.81 mg, 0.015 mmol) and K2CO3 (61.24 mg, 0.443 mmol) in dioxane (2 mL) and water (0.4 mL) was stirred at 110 °C for 2 h under nitrogen. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 6-3 (41 mg, yield: 76.3%) as a white solid.

[0171] MS-ESI (m / z): 364.1 / 366.1 [M+H] + .

[0172] Step 3: To a solution of compound 6-3 (41 mg, 0.113 mmol) in MeOH (1 mL) and THF (1 mL) was added a solution of LiOH (14.20 mg, 0.338 mmol) in H2O (0.5 mL), the resulting mixture was heated to reflux with stirring for 20 min. After the reaction was completed, the reaction was adjusted to pH = 7-8 with concentrated hydrochloric acid, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 6-4 (26 mg, yield: 65.9%) as a white solid. MS-ESI (m / z): 350.0 [M+H] + .

[0173] Step 4: To a solution of compound 6-4 (10.28 mg, 0.074 mmol), HATU (42.44 mg, 0.112 mmol) and DIEA (0.061 mL, 0.372 mmol) in DMF (1 mL) was added compound 2-3 (26 mg, 0.074 mmol), and the stirring was continued for 1 h. After the reaction was completed, the reaction was poured into water (30 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM / MeOH = 20 / 1) to give the crude product, which was further separated by reverse phase chromatography to give compound 6 (2.38 mg, total yield for four steps: 2.4%) as a yellow solid.

[0174] 1 H-NMR (400MHz, MeOD) δ 7.27-7.35 (m, 1H), 7.18-7.26 (m, 1H), 7.16-7.18 (m, 1H), 7.10-7.15 (m, 1H), 6.96-7.07 (m, 1H), 6.72-6.81 (m, 1H), 6.66-6.71 (m, 1H), 6.59-6.66 (m, 1H), 6.20-6.37 (m, 1H), 3.97-4.53 (m, 6H), 3.67-3.74 (m, 3H), 2.85-2.99 (m, 3H), 2.10-2.34 (m, 2H).

[0175] MS-ESI (m / z): 470.1 [M+H] + .

[0176] Example 7: Preparation of compound 7

[0177] Step 1: A mixture of compound 1-1 (100 mg, 0.293 mmol), compound 7-1 (39.07 mg, 0.293 mmol), Xantphos (16.97 mg, 0.029 mmol), Pd2(dba)3(11.87 mg, 0.015 mmol) and K3PO4(124.51 mg, 0.587 mmol) in dioxane (4 mL) was heated to 100 °C for 8 h under nitrogen protection. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 7-2 (68 mg, crude) as yellow oil, which was used directly in the next step. MS-ESI (m / z): 349.90 / 351.00 [M+H] + .

[0178] Step 2: A mixture of compound 7-2 (68 mg, 0.195 mmol), compound 1-3 (33.19 mg, 0.195 mmol), Pd(dppf)Cl2(14.29 mg, 0.020 mmol) and K2CO3(80.96 mg, 0.586 mmol) in dioxane (4 mL) and water (1 mL) was heated to 100 °C for 3 h under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated to remove most of the organic solvent, poured into water (20 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 7-3 (72 mg, crude) as brown oil, which was used directly in the next step. MS-ESI (m / z): 394.00 [M+H] + .

[0179] Step 3: To a solution of compound 7-3 (72 mg, 0.179 mmol) in MeOH (4 mL) and H2O (2 mL) was added NaOH (21.96 mg, 0.549 mmol), the resulting mixture was heated to reflux for 1 h. After completion of the reaction, the reaction mixture was diluted with H2O (10 mL), adjusted to pH = 6 with concentrated hydrochloric acid, extracted with EtOAc (5 mL x 2), the combined extracts were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 7-4 (69 mg, crude) as brown oil, which was used directly in the next step. MS-ESI (m / z): 380.00 [M+H] + .

[0180] Step 4: A solution of compound 7-4 (69 mg, 0.182 mmol), HATU (138.17 mg, 0.364 mmol) and DIEA (0.120 mL, 0.727 mmol) in DMF (1 mL) was stirred at 25 °C for 5 min, then compound 1-6 (25.13 mg, 0.182 mmol) was added to the above solution and stirred for 1 h. After completion of the reaction, the reaction was poured into water (20 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 7-5 (90 mg, crude) as a brown oil, which was used directly in the next step.

[0181] MS-ESI (m / z): 500.10 [M+H] + .

[0182] Step 5: To a solution of compound 7-5 (90 mg, 0.180 mmol) in THF (4 mL) was added NaH (43.24 mg, 1.801 mmol, 60% in mineral oil) under nitrogen at 25 °C, the resulting reaction was stirred at this temperature for 10 min. Then Mel (0.088 mL, 1.801 mmol) was added to the above suspension and stirred at 50 °C for 1 h. After completion of the reaction, H2O (1 mL) was added slowly and carefully to quench the reaction. The resulting solution was directly concentrated to dryness under reduced pressure to give compound 7-6 (90 mg, crude) as a brown solid, which was used directly in the next step. + .

[0183] Step 6: To a solution of compound 7-6 (90 mg, 0.175 mmol) in dioxane (2 mL) was added concentrated HCl (1 mL), the resulting reaction was heated to 100 °C and stirred for 6 h. After completion of the reaction, the reaction was adjusted to pH = 8 with saturated aqueous NaHCO3solution, extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give compound 7 (14.92 mg, six steps overall yield: 10.2%) as a white solid.

[0184] 1H-NMR (400 MHz, MeOD) δ 7.37-7.44 (m, 2H), 7.27-7.35 (m, 1H), 7.20-7.25 (m, 1H), 7.06-7.14 (m, 1H), 6.85-6.90 (m, 1H), 6.83-6.45 (m, 2H), 6.44-6.30 (m, 1H), 5.05-5.11 (m, 1H), 4.21-.34 (m, 1H), 3.99-4.11 (m, 4H), 3.60-3.83 (m, 3H), 3.57-3.78 (m, 2H), 3.35-3.50 (m, 2H), 2.99-3.09 (m, 3H).

[0185] MS-ESI (m / z): 500.10 [M+H] + .

[0186] Example 8: Preparation of compound 8

[0187] Step 1: Compound 2-2 (263 mg, 1.042 mmol) was added to a solution of hydrochloric acid dioxane (4 M, 3 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure to give compound 8-1 (158 mg, crude) as a white solid. MS-ESI (m / z): 153.2 [M+H] + .

[0188] Step 2: Compound 8-1 (27.07 mg, 0.178 mmol) was added to a solution of compound 1-5 (50 mg, 0.148 mmol), HATU (67.62 mg, 0.178 mmol) and DIEA (0.122 mL, 0.741 mmol) in DMF (2 mL) and stirred for 1 h. After the reaction was completed, the reaction was poured into water (30 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was separated by reverse phase chromatography to give compound 8 (30 mg, total yield for two steps: 42.5%) as a white solid.

[0189] 1H-NMR (400 MHz, DMSO-d6) δ 8.08-8.19 (m, 1H), 7.30-7.39 (m, 1H), 7.20-7.30 (m, 1H), 7.12-7.20 (m, 1H), 7.03-7.08 (m, 1H), 7.02-7.03 (m, 1H), 6.95-7.02 (m, 1H), 6.87-6.90 (m, 1H), 6.69-6.87 (m, 1H), 4.14-5.21 (m, 2H), 3.83-3.89 (m, 3H), 3.77-3.83 (m, 3H), 3.25-3.30 (m, 3H), 3.12-3.25 (m, 3H), 2.76-2.90 (m, 3H).

[0190] MS-ESI (m / z): 472.2 [M+H] + .

[0191] Example 9: Preparation of compound 9

[0192] Step 1: A mixture of compound 1-1 (150 mg, 0.440 mmol), diethyl phosphine oxide (50.86 mg, 0.484 mmol), Xantphos (50.91 mg, 0.088 mmol), Pd2(dba)3 (40.29 mg, 0.044 mmol) and K3PO4 (202.63 mg, 0.880 mmol) in dioxane (4 mL) was heated to 100 °C under nitrogen protection for 8 hours. After the reaction was completed, the reaction solution was poured into water (30 mL) and extracted with EtOAc (10 mL x 2), the combined extract was washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE / EtOAc = 10:1 to pure EtOAc) to give compound 9-1 (55 mg, yield: 39.2%) as a yellow oil.

[0193] MS-ESI (m / z): 319.00 / 321.90 [M+H] + .

[0194] Step 2: A mixture of compound 9-1 (55 mg, 0.172 mmol), compound 1-3 (32.22 mg, 0.190 mmol), Pd(dppf)Cl2(12.61 mg, 0.017 mmol) and K2CO3(71.45 mg, 0.517 mmol) in dioxane (2 mL) and water (0.5 mL) was heated to 100 °C for 3 h under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove most of the organic solvent, poured into water (10 mL) and extracted with EtOAc (5 mL x 2), the combined extracts were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 9-2 (60 mg, crude) as a brown oil, which was used directly in the next reaction. MS-ESI (m / z): 365.1 [M+H] + .

[0195] Step 3: To a solution of compound 9-2 (60 mg, 0.165 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added NaOH (19.76 mg, 0.494 mmol) and the resulting mixture was stirred at 50 °C for 1 h. After completion of the reaction, the reaction mixture was diluted with H2O (10 mL), adjusted to pH = 6 with concentrated hydrochloric acid, extracted with EtOAc (5 mL x 2), the combined extracts were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give compound 9-3 (42 mg, crude) as a brown solid, which was used directly in the next reaction. MS-ESI (m / z): 351.1 [M+H] + .

[0196] Step 4: A solution of compound 9-3 (42 mg, 0.120 mmol), HATU (68.38 mg, 0.180 mmol) and DIEA (0.059 mL, 0.360 mmol) in DMF (1 mL) was stirred at 25 °C for 5 min, then compound 2-3 (16.56 mg, 0.120 mmol) was added to the above solution and stirred for 1 h. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (5 mL x 3), the combined extracts were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give compound 9 (8.89 mg, yield: 15.6%) as a white solid.

[0197] 1H-NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 7.77-7.85 (m, 1H), 7.61-7.71 (m, 1H), 7.27-7.46 (m, 3H), 7.02-7.10 (m, 1H), 6.85-6.95 (m, 1H), 6.19-6.39 (m, 2H), 4.13-4.47 (m, 2H), 3.78-3.80 (m, 3H), 2.77-2.87 (m, 3H), 1.89-2.06 (m, 4H), 0.93-1.08 (m, 6H).

[0198] MS-ESI (m / z): 471.20 [M+H] + .

[0199] Example 10: Preparation of compound 10

[0200] Step 1: Compound 10-1 (165 mg, 0.629 mmol), compound 1-3 (117.68 mg, 0.692 mmol), Pd(dppf)Cl2(51.41 mg, 0.063 mmol) and K2CO3(260.98 mg, 1.888 mmol) were dissolved in a mixed solution of dioxane (2.5 mL) and water (2.5 mL). The solution was heated to 80 °C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated dry under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / PE = 50%-100%) to obtain compound 10-2 (166 mg, yield: 85.8%) as a white solid. MS-ESI (m / z): 308.1 [M+H] + .

[0201] Step 2: Compound 10-2 (166 mg, 0.540 mmol) and NaOH (108.02 mg, 2.701 mmol) were added to a mixture of methanol (2 mL) and water (2 mL). The reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, the pH was adjusted to 6-7 using 1M hydrochloric acid solution, and DCM (10 mL x 3) was added for extraction. The combined extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated dry under reduced pressure to obtain compound 10-3 (150 mg, crude) as a white solid, which was directly used in the next step reaction.

[0202] MS-ESI (m / z): 292.1 [M-H] + .

[0203] Step 3: Compound 10-3 (150 mg, 0.511 mmol), compound 2-3 (141.32 mg, 1.023 mmol), HATU (213.90 mg, 0.563 mmol) and DIEA (0.423 mL, 2.557 mmol) were dissolved in DMF (3 mL), the reaction solution was stirred at 25 °C for 1 h. After the reaction was completed, water (20 mL) was added to the reaction solution, extracted with EtOAc (20 mL x 3), the combined extracts were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (MeOH / DCM = 0% - 10%) to give compound 10-4 (160 mg, total yield of two steps: 71.7%) as a white solid.

[0204] MS-ESI (m / z): 414.1 [M+H] + .

[0205] Step 4: Compound 10-4 (160 mg, 0.387 mmol) was dissolved in methanol (5 mL), ammonium carbonate (55.78 mg, 0.580 mmol) and iodo-benzene diacetate (288.47 mg, 0.890 mmol) were added to the solution and stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (MeOH / DCM = 0% - 15%) to give compound 10 (150 mg, yield: 87.2%) as a white solid.

[0206] 1 H-NMR (400 MHz, DMSO-d6) d 11.52 (br s, 1H), 8.82-9.00 (m, 1H), 8.37-8.47 (m, 1H), 7.52-7.61 (m, 1H), 7.29-7.40 (m, 1H), 7.09-7.19 (m, 1H), 6.91-7.03 (m, 1H), 6.18-6.42 (m, 2H), 4.49-4.61 (m, 2H), 4.01-4.15 (m, 1H), 3.80-3.91 (m, 3H), 3.13-3.27 (m, 3H), 2.72-2.92 (m, 3H).

[0207] MS-ESI (m / z): 445.1 [M+H] + .

[0208] Example 11: Preparation of compound 11

[0209] Step 1 : To a solution of compound 11-1 (600 mg, 2.575 mmol) in N,N- dimethylacetamide (5 mL) was added sodium thiomethoxide (180.43 mg, 2.575 mmol) and the mixture was heated to 50 °C with stirring for 3 h. After completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (10 mL x 2), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2S04, filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1) to give compound 11-2 (414 mg, yield: 65.1%) as a yellow oil. MS-ESI (m / z): 228.9 / 230.9 [M-OMe] + .

[0210] Step 2: A mixture of compound 11-2 (414 mg, 1.675 mmol), compound 1-3 (284.73 mg,.675 mmol), Pd(dppf)Cl2(122.59 mg, 0.168 mmol) and K2C03(694.61 mg, 5.026 mmol) in dioxane (10 mL) and water (2 mL) was heated to 80 °C with stirring under nitrogen for 1 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1) to give compound 11-3 (260 mg, yield: 50.6%) as a yellow solid.

[0211] MS-ESI (m / z): 275.0 [M-OMe] + .

[0212] Step 3: To a solution of compound 11-3 (260 mg, 0.849 mmol) in MeOH (2 mL) and tetrahydrofuran (2 mL) was added a solution of NaOH (66.59 mg, 1.665 mmol) in H20 (0.4 mL) and the resulting mixture was heated to 65 °C with stirring for 2 h. After completion of the reaction, the reaction mixture was adjusted to pH = 7-8 with concentrated hydrochloric acid and concentrated to dryness to give compound 11-4 (248 mg, crude) as a white solid which was used directly in the next reaction. MS-ESI (m / z): 291.1 [M-H] + .

[0213] Step 4: To a solution of compound 11-4 (248 mg, 0.848 mmol), HATU (387.11 mg, 1.018 mmol) and DIEA (0.701 mL, 4.242 mmol) in DMF (3 mL) was added compound 2-3 (140.67 mg, 1.018 mmol) and stirred for 20 min. After the reaction was completed, the reaction was poured into water (30 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 11-5 (160 mg, yield: 45.7%) as a yellow solid.

[0214] MS-ESI (m / z): 413.1 [M+H] + .

[0215] Step 5: To a solution of compound 11-5 (160 mg, 0.388 mmol) in methanol (4 mL) was added ammonium carbonate (55.91 mg, 0.582 mmol) and the mixture was stirred at room temperature for 5 min. Then iodobenzenediacetic acid (289.16 mg, 0.892 mmol) was added and the reaction was continued for 30 min. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 11 (80 mg, total yield over five steps: 7.0%) as a yellow solid.

[0216] 1 H-NMR (400 MHz, DMSO-d6) d 11.46 (br s, 1H), 7.98-8.22 (m, 1H), 7.65-7.92 (m, 1H), 7.29-7.53 (m, 3H), 7.03-7.13 (m, 1H), 6.86-7.01 (m, 1H), 6.06-6.41 (m, 2H), 3.89-4.88 (m, 3H), 3.78-3.86 (m, 3H), 3.09-3.29 (m, 3H), 2.66-2.94 (m, 3H).

[0217] MS-ESI (m / z): 444.1 [M+H] + .

[0218] Example 12: Preparation of compound 12

[0219] Step 1 : To a solution of compound 11-1 (500 mg, 2.146 mmol) in DMF (3 mL) was added compound 12-1 (0.204 mL, 2.360 mmol) and potassium carbonate (385.47 mg, 2.789 mmol), the mixture was heated to 100 °C and stirred for 18 h. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (10 mL x 3), the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na2S04, filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give compound 12-2 (548 mg, yield: 83.6%) as a white oil.

[0220] MS-ESI (m / z): 328.9 / 330.9 [M+Na] + .

[0221] Step 2: A mixture of compound 12-2 (360 mg, 1.180 mmol), compound 1-3 (200.47 mg, 1.180 mmol), Pd(dppf)Cl2(86.31 mg, 0.118 mmol) and K2C03(489.06 mg, 3.539 mmol) in dioxane (10 mL) and water (2 mL) was heated to 80 °C under nitrogen protection for 1 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1) to give compound 12-3 (375 mg, yield: 99.8%) as a yellow solid.

[0222] MS-ESI (m / z): 319.0 [M+H] + .

[0223] Step 3: To a solution of compound 12-3 (379 mg, 1.190 mmol) in MeOH (5 mL) and tetrahydrofuran (5 mL) was added a solution of NaOH (238.10 mg, 5.952 mmol) in H20 (2 mL), the resulting mixture was heated to 65 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was adjusted to pH = 7-8 with concentrated hydrochloric acid and concentrated to dryness to give compound 12-4 (400 mg, crude) as a black solid, which was used directly in the next reaction. MS-ESI (m / z): 335.2 [M-H] - .

[0224] Step 4: To a solution of compound 12-4 (400 mg, 1.189 mmol) in DCE (3 mL) was added a solution of thionyl chloride (0.345 mL, 4.757 mmol) dropwise at ice bath. After the mixture was stirred at room temperature for 1 h, it was concentrated under reduced pressure to give compound 12-5 (443 mg, crude) as a black solid, which was used directly in the next step. MS-ESI (m / z): 337.1 / 339.0 [M+H-Cl] + .

[0225] Step 5: To a solution of compound 2-3 (64.85 mg, 0.469 mmol) and triethylamine (0.701 mL, 4.242 mmol) in DCM (8 mL) was added compound 12-5 (64.85 mg, 0.469 mmol) and stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give compound 12-6 (70 mg, yield: 37.6%) as a yellow solid.

[0226] MS-ESI (m / z): 475.1 [M+H] + .

[0227] Step 6: To a solution of compound 12-6 (70 mg, 0.147 mmol) in methanol (1 mL) was added ammonium carbonate (21.24 mg, 0.221 mmol) and the mixture was stirred at room temperature for 5 min. Then iodobenzenediacid (109.86 mg, 0.339 mmol) was added and the reaction was continued for 30 min. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give compound 12-7 (30 mg, yield: 43.3%) as a yellow solid. MS-ESI (m / z): 506.1 [M+H] + .

[0228] Step 7: Compound 12-7 (30 mg, 0.059 mmol) was added to a solution of 37% ammonia (30 mL) and a few drops of MeOH were added dropwise, and then stirred at 80 °C for 2 h. After being concentrated under reduced pressure, the residue was purified by reverse phase chromatography to give the crude product. The crude product was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give compound 12 (13 mg, total yield over seven steps: 6.3%) as a white solid.

[0229] 1H-NMR (400 MHz, DMSO-d6) δ 11.50 (br s, 1H), 7.69-8.16 (m, 2H), 7.40-7.59 (m, 2H), 7.28-7.38 (m, 1H), 7.04-7.13 (m, 1H), 6.83-6.98 (m, 1H), 6.14-6.47 (m, 2H), 3.77-4.21 (m, 5H), 3.35-3.66 (m, 4H), 2.75-2.93 (m, 3H), 2.10-2.38 (m, 2H).

[0230] MS-ESI (m / z): 470.1 [M+H] + .

[0231] Example 13: Preparation of compound 13

[0232] Step 1: Compound 10 (40 mg, 0.090 mmol), aqueous formaldehyde (0.007 mL, 0.099 mmol), triethylsilane (31.39 mg, 0.270 mmol) and InCl3(1.00 mg, 0.004 mmol) were dissolved in 1,2-dichloroethane (1 mL), and the reaction was stirred at 70 °C for 6 hours. After the reaction was completed, the reaction was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0% - 10%) to obtain compound 13 (3.77 mg, 9.1%) as a white solid.

[0233] 1 H-NMR (400 MHz, DMSO-d6) δ 11.50 (br s, 1H), 8.87-8.97 (m, 1H), 8.25-8.33 (m, 1H), 7.53-7.62 (m, 1H), 7.29-7.46 (m, 2H), 7.11-7.17 (m, 1H), 6.93-7.01 (m, 1H), 6.29-6.41 (m, 1H), 4.43-4.69 (m, 2H), 3.82-3.87 (m, 3H), 3.25-3.29 (m, 3H), 2.77-2.89 (m, 3H), 2.58-2.63 (m, 3H).

[0234] MS-ESI (m / z): 459.1 [M+H] + .

[0235] Example 14: Preparation of compound 14

[0236] Step 1: A solution of compound 14-1 (200 mg, 0.930 mmol), compound 1-3 (173.86 mg, 1.023 mmol), potassium carbonate (385.58 mg, 2.790 mmol), and Pd(dppf)Cl2 (68.05 mg, 0.093 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was stirred at 100 °C for 3 hours. LCMS (MS-ESI (m / z): 261.10 [M+H]) + The reaction was detected as complete. The reaction solution was diluted with MeOH (6 mL) and H₂O (4 mL), and NaOH (74.40 mg, 1.860 mmol) was added to the solution. The mixture was heated to 70 °C and stirred for 4 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 6 with 2 M dilute hydrochloric acid. The resulting solution was extracted with EtOAc (10 mL x 3), and the combined extracts were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-2 (31 mg, crude product) as a white solid, which was used directly in the next step. MS-ESI (m / z): 247.1 [M+H] + .

[0237] Step 2: A DMF solution (2 mL) containing compound 14-2 (25 mg, 0.102 mmol), compound 2-3 (15.45 mg, 0.102 mmol), HATU (57.91 mg, 0.152 mmol), and DIEA (0.050 mL, 0.305 mmol) was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain compound 14 (31 mg, crude product) as a white solid. MS-ESI (m / z): 367.1 [M+H] + .

[0238] Example 15: Preparation of Compound 15

[0239] Step 1: A solution of compound 14-1 (100 mg, 0.465 mmol), 4-fluorophenylboronic acid (65.06 mg, 0.465 mmol), potassium carbonate (192.79 mg, 1.395 mmol), and Pd(dppf)Cl2 (34.03 mg, 0.047 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 80 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE = 8%) to give compound 15-1 (80 mg, yield: 74.72%) as a white solid.

[0240] MS-ESI (m / z): 231.00 [M+H] + .

[0241] Step 2: A mixture of compound 15-1 (80 mg, 0.347 mmol) and NaOH (41.70 mg, 1.042 mmol) in water / methanol / tetrahydrofuran (3 mL, 1:1:1) was stirred at 25 °C for 1 h. After the reaction was completed, the reaction mixture was directly purified by reverse phase chromatography (C18-AQ reverse phase silica gel column, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; 5%-100% 20 min; detection wavelength 254 nm / 220 nm) to afford compound 15-2 (60 mg, yield: 79.87%) as a white solid.

[0242] MS-ESI (m / z): 215.10 [M-H] - .

[0243] Step 3: A solution of compound 15-2 (20 mg, 0.093 mmol), compound 2-3 (19.17 mg, 0.139 mmol), HATU (42.21 mg, 0.111 mmol) and DIEA (0.076 mL, 0.463 mmol) in DMF (1 mL) was stirred at 25 °C for 30 min. After the reaction was completed, the reaction mixture was directly purified by reverse phase chromatography (C18-AQ reverse phase silica gel column, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; 5%-100% 20 min; detection wavelength 254 nm / 220 nm) to afford compound 15 (18 mg, yield: 57.85%) as a white solid.

[0244] 1 H NMR (400 MHz, DMSO-d6) d 11.49 (br s, 1H), 7.67-7.80 (m, 4H), 7.42-7.61 (m, 2H), 7.25-7.38 (m, 3H), 5.89-6.35 (m, 2H), 4.26-4.57 (m, 2H), 2.94 (s, 3H).

[0245] MS-ESI (m / z): 337.10 [M+H] + .

[0246] Example 16: Preparation of compound 16

[0247] Step 1 : A solution of compound 16-1 (30 mg, 0.312 mmol), dimethylamine hydrochloride (22.13 mg, 0.328 mmol) and DIEA (0.155 mL, 0.937 mmol) in THF (0.3 mL) and MeOH (0.3 mL) was stirred at 25 °C for 3 h. Then, NaBH4(14.17 mg, 0.375 mmol) was added portionwise carefully to the above solution. After addition, the stirring was continued at this temperature for 1 h. After the reaction was completed, the reaction was directly filtered with filter membrane, and the filtrate was concentrated under reduced pressure to give compound 16-2 (35 mg, crude) as a light yellow solid, which was used directly in the next step. MS-ESI (m / z): 112.1 [M+H] + .

[0248] Step 2: A solution of compound 14-2 (33.23 mg, 0.135 mmol), compound 16-2 (15 mg, 0.135 mmol), HATU (61.58 mg, 0.162 mmol) and DIEA (0.045 mL, 0.270 mmol) in DMF (1 mL) was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was directly purified by reverse phase chromatography (C18 reverse phase silica gel column, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; 5% - 100% 20 min; detection wavelength 254 nm / 220 nm) to give compound 16 (15 mg, yield: 32.75%) as a white solid.

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (br s, 1H), 7.51 - 7.80 (m, 1H), 7.37 - 7.50 (m, 5H), 7.35 (t, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 4.0 Hz, 1H), 6.86 (td, J = 8.0, 4.0 Hz, 1H), 4.25 - 4.55 (m, 2H), 3.79 (s, 3H), 2.89 (s, 3H).

[0250] MS-ESI (m / z): 340.1 [M+H] + .

[0251] Example 17: Preparation of compound 17

[0252] Step 1: To a mixture of compound 1-5 (50 mg, 0.148 mmol) and dimethylamine hydrochloride (13.29 mg, 0.0.163 mmol) in DMF (2 mL) was added DIEA (76.62 mg, 0.593 mmol) and HATU (67.62 mg, 0.178 mmol) at 25 °C. The reaction was stirred at 25 °C for 1 h. After completion of the reaction, the reaction was directly purified by reverse phase chromatography (C18 reverse phase silica gel column, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; 5% - 100% in 20 min; detection wavelength 254 nm / 220 nm) to afford compound 17 (20.1 mg, yield: 36.92%) as a white solid.

[0253] 1 H NMR (400 MHz, DMSO-d6) d 7.32 (dd, J = 8.4, 7.0 Hz, 1H), 7.18 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.96 - 7.05 (m, 2H), 6.85 (m, 1H), 3.80 (s, 3H), 3.20 (m, 6H), 2.96 (s, 3H), 2.82 (s, 3H).

[0254] MS-ESI (m / z): 365.10 [M+H] + .

[0255] Comparative compound: Compound 57 in WO2024179572 was prepared as a comparative compound.

[0256] Test example

[0257] Test example 1. ITC experiment

[0258] Instrument: MicroCal PEAQ-ITC; Consumables: 1 ml, 200 μl and 10 μl pipettes and tips, 1.5 ml EP tubes, buffer, protein, compound; Preparation: https: / / web.expasy.org / cgi-bin / protparam / protparam Protein molecular weight and extinction coefficient were calculated at this website.

[0259] 1. PRYSPRY protein was dissolved in buffer A: 150 mM NaCl, 20 mM Hepes, pH = 8.0

[0260] 2. Compound: 20 mM stock in DMSO

[0261] 3. Compound was diluted 100 times with buffer A to get a 1% DMSO solution

[0262] 4. Buffer B for protein: 150 mM NaCl, 20 mM Hepes, pH = 8.0 + 1% DMSO replaced (change 4 times buffer) after concentration to measure the concentration.

[0263] 5. Final concentration: compound 200 μΜ, protein > 20 μΜ (not enough signal to add concentration), in buffer B.

[0264] Experimental procedure:

[0265] 1. Check the wash (more than two-thirds, DECAN90 and pure water volume ratio of 14%) and waste (less than one-third).

[0266] 2. Turn on the computer and the machine switch.

[0267] 3. The computer opens the ITC software, and waits for a while. The temperature and sample pool titration pool cleaning state can be controlled below.

[0268] 4. Cleaning:

[0269] Put the sample cleaner into the sample pool, press hard; take out the titration pool, insert the FPA tube, put it into the wash position, and press the buckle lock; select Cell clean: wash (methanol cleaning) on the software, syringe clean: wash.

[0270] After the instrument cleaning, use the desktop sample needle to suck out the residual liquid in the sample pool (hit on the paper towel, use the paper towel to wipe the syringe until it can't hit liquid, and there is no liquid film in the sample pool, about 20 times), and let the sample pool and titration pool hang for 5 minutes.

[0271] 5. Sample loading: first turn on the small light.

[0272] Sample pool: after washing the sample needle with water twice, wash it with buffer twice, and remove the bubbles. Use the sample needle to suck 300 μl of protein sample, first insert it into the bottom of the sample pool, add the sample very slowly, slowly raise it while continuing to slowly add after the small hole of the sample needle has liquid overflow, completely remove the excess liquid, and the excess volume should be about 20 μl, and the sample pool should have 280 μl.

[0273] Titration pool: take 60 μl of compound into a small tube, put it into the load position, keep the FPA inserted into the titration pool, put it into the small tube, click load on the software, and observe the titration pool after the end without bubbles. Turn off the small light.

[0274] 6. Start run: pull FPA from titration cell, slowly put titration cell into sample cell, select injection 19 method in software, input compound (syringe: 200 e-6) and protein (cell: 20 e-6) concentration, save run file, click start. Baseline height set to 10 ucals, after equilibration should be 10 plus or minus 0.5, if there is a large difference, should be reloaded; each drop interval 90 s.

[0275] 7. Data: ITC software point analyze open analysis software for analysis, open-presentation-final figure, select subtract baseline, show result, export data and image.

[0276] 8. Experimental results:

[0277] Test example 2. BLI experiment

[0278] Instrument: molecular interaction instrument BLI-R8; consumables: 1 ml, 200 μl and 10 μl pipette and gun head, 1.5 ml EP tube, buffer, protein, compound, SSA sensor;

[0279] Preparation: https: / / web.expasy.org / cgi-bin / protparam / protparam Calculate the molecular weight and light absorption coefficient of the protein at this website.

[0280] 1. PRYSPRY protein is dissolved in buffer C: PBS + 0.02% Tween-20, pH = 6.95

[0281] 2. Compound: 20 mM stock solution in DMSO

[0282] 3. Compound is diluted 100 times with buffer C to obtain a 1% DMSO solution.

[0283] 4. Protein is concentrated after replacing (changing 4 times of buffer) with buffer D: PBS + 0.02% Tween-20 + 1% DMSO, pH = 6.95. Measure the concentration.

[0284] 5. Final concentration: compound 200 μM, protein, in buffer D

[0285] Experimental procedure:

[0286] 1. Use the biotinylation kit to biotinylate the protein. Room temperature reaction for 1 h, use desalting column to elute the biotinylated protein. Measure the protein concentration.

[0287] 2. Turn on instrument (switch at bottom right corner), then computer. Open software Octet BLI discovery.

[0288] 3. Take 2N+2 (N is the number of compounds to be tested, minimum N=1, use 4 sensors) sensors, put them in empty box, put pre-wet plate under them, add 200ul protein buffer under each sensor. Pre-wet for 10 minutes.

[0289] 4. Solidify protein:

[0290] Wait for system self-check, after ready, select kinetics, blank experiment

[0291] 1) plate definition

[0292] Select buffer for first column, add buffer, select load for second column, add protein (select from top to bottom, number is compound number +1)

[0293] 2) assay definition

[0294] add baseline & loading & baseline

[0295] Change time: baseline1 (buffer well): 60s, loading (protein well): 600s, baseline2 (buffer well): 120s

[0296] Select sensor type: SSA

[0297] 3) sensor assignment

[0298] Check √ replace sensor

[0299] Delete the previous empty column, the next column is the default sensor position (same row as step 1), change sensor type to SSA

[0300] PS: select the left column of sensors for load, the right column of sensors is the control without protein.

[0301] 4) review experiment

[0302] Check if there is an error, click → simulate run

[0303] 5) run experiment

[0304] Select save data folder, rename, delete delay time and temperature control

[0305] 5. Small molecule affinity assay:

[0306] After loading, rebuild experiment method:

[0307] Kinetics, blank experiment

[0308] 1) plate definition

[0309] Select buffer in the first column, add buffer, select load in the second column, add protein (select from top to bottom, the number is the number of compounds +1)

[0310] 2) assay definition

[0311] Add association & dissociation

[0312] Change time: baseline (buffer well): 60s, association (protein well): 90s, dissociation (buffer well): 90s

[0313] Select sensor type: SSA

[0314] 3) sensor assignment

[0315] Check √ replace sensor

[0316] Delete the empty column in front, and the next column is the default sensor position (same row as step 1), change sensor type to SSA

[0317] PS: Select the left column of sensor to load

[0318] 4) review experiment

[0319] Check for errors, click → simulate run

[0320] 5) run experiment

[0321] Select save data folder, rename, delete delay time and temperature control

[0322] Single concentration experiment only 200uM compound. Multiple concentration experiment: samples from low to high concentration (concentration input in advance)

[0323] 6. Result analysis:

[0324] Open Octet Analysis Studio 13.0 software

[0325] 1, open file

[0326] 2, double subtraction reference sensor and reference sample in processed data.

[0327] Data correction: select average of baseline step, check √ savitzky-Golay filtering

[0328] 3, kinetic analysis

[0329] Select association and dissociation, type: global (multiple concentration experiment selects global, single concentration experiment selects single), Rmax: sensor. The last one selects response.

[0330] The curve fit displayed on the right can delete the concentration point without signal.

[0331] The graph settings above can cancel the baseline. Click the last group graph options to add sample ID, KD, and left check steady-state.

[0332] 7. Look at the analysis results:

[0333] 1, signal height less than 0.01, do not consider the compound has binding.

[0334] 2, if it is a negative signal, if the absolute value of the signal of the empty sensor is greater than that of the protein sensor, do not consider the compound to have binding.

[0335] 3, multiple concentration experiment with steady-state fitting KD.

[0336] Note: 1. Small molecules are designed by double subtraction method. The meaning of double subtraction method is that the last row only has protein without small molecules (reference well) and the second column only has sensor without protein (reference sensor).

[0337] 3. Add 200 μΐ of buffer or sample to all wells, protein concentration is generally 50 μg / ml, can be higher.

[0338] 4. The loading time can be extended (originally 600 s) to ensure the binding height > 4 nm.

[0339] 5. The left is the sensor and pre-wet plate, the right is the sample plate.

[0340] Test Example 3. Fluorescence polarization experiment

[0341] 1. Protein-probe titration: After the probe is prepared to the optimal concentration based on the probe-protein binding affinity, the protein is diluted at a gradient of 1:2 under the condition of constant probe concentration, and incubated in a black round-bottom 96-well plate with 50 μL of reaction system at room temperature for 20 minutes. Finally, the FP signal (using the specific excitation wavelength λex and emission wavelength λem of the probe) is measured using an enzyme marker.

[0342] 2. Protein concentration optimization: The protein concentration required to produce 50-80% of the maximum FP signal in subsequent competition experiments is determined by fitting the data (using GraphPad software).

[0343] 3. Compound competition experiment: A gradient dilution of test compounds with a concentration range from 100 μM to 0.1 μM is prepared using a fixed concentration of probe and the optimized concentration of protein in the previous step, and incubated in a 96-well plate with 50 μL of reaction system at room temperature for 20 minutes. Then the FP signal is measured.

[0344] 4. Data analysis: The EC50 value of the compound is calculated by fitting the competition experiment data (using GraphPad software).

[0345] Test Example 4. Microsomal stability

[0346] Experimental method: Add 30 μL of a mixture of the test compound and liver microsomes to a 96-well plate, and prepare two samples in parallel. After pre-incubation at 37°C for 10 min, add 15 μL of NADPH solution (6 mM) at the time point, and the final concentration of the test compound is 1 μM, the concentration of liver microsomes is 0.5 mg / mL, and the final concentration of NADPH is 2 mM. Incubate for 0, 15, 30, and 60 min, respectively. After incubation, add 150 mL of acetonitrile (containing an internal standard) to the mixed system. Centrifuge the acetonitrile-diluted sample at 4000 rpm for 5 min, and take 150 μL of supernatant to LC-MS / MS for analysis. The half-life (T 1 / 2 ) and corresponding CL int(liver)Values such as parameters. The speed of metabolism of the compound of the present application in different species of liver microsomes is analyzed.

[0347] Test Example 5. In vivo pharmacokinetic properties

[0348] Purpose of experiment: to determine the pharmacokinetic properties of the compound in balb / c mice.

[0349] Experimental materials: balb / c mice (male)

[0350] Experimental method:

[0351] 1. Use 6 male mice, weigh before administration, calculate the amount of administration according to the body weight, then divide the mice into two groups. One group of 3 mice is administered intravenously, and the other group of 3 mice is administered orally.

[0352] 2. Collect plasma samples at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Each sample is about 0.05 mL, anticoagulated with sodium heparin, and placed on wet ice after collection.

[0353] 3. After the blood sample is collected, it is placed on ice and centrifuged to separate the plasma within 1 hour. The plasma sample is stored in a -80°C refrigerator when stored before analysis.

[0354] 4. The collected samples are analyzed by LC-MS / MS and data are collected. The analysis data collected are used to calculate relevant pharmacokinetic parameters such as peak concentration (Cmax), clearance (Cl), half-life (T1 / 2), area under the curve (AUC), bioavailability (Bioavailability), etc. using Phoenix WinNonlin 8.2.0 software.

[0355] The pharmacokinetic properties of the compound of the present application in mice are analyzed by the above data.

[0356] Although the present application is described in detail with reference to the embodiments thereof, these embodiments are provided for illustration purposes only and are not intended to limit the present application. Other embodiments that can be derived from the principles of the present application are within the scope of the claims of the present application.

[0357] The contents of all documents and literature listed herein are incorporated by reference in their entirety.

Claims

1. A compound represented by Formula (I): ###0001### (I) or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof. ​ wherein, A ring is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocyclic ring, a 3-10 membered cycloalkyl ring, a 3-10 membered heterocyclic ring; said A ring is optionally substituted with one, two, three, or four independent R, wherein each R is independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -C 0-4 alkylene-OR a , -C 0-4 alkylene-OC(=O)R a , -C 0-4 alkylene-SR a , -C 0-4 alkylene-S(=O)2R a , -C 0-4 alkylene-S(=O)R a , -C 0-4 alkylene-S(=O)2NR a R b , -C 0-4 alkylene-S(=O)NR a R b , -C 0-4 alkylene-C(=O)R a , -C 0-4 alkylene-C(=O)OR a , -C 0-4 alkylene-C(=O)NR a R b , -C 0-4 alkylene-NR a R b , -C 0-4 alkylene-NR a C(=O)R b , -C 0-4 alkylene-NR a S(=O)2R b , -C 0-4 alkylene-NR a S(=O)R b , -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered heteroaromatic ring); wherein each R a , R b is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, halogen-substituted C 2-6 alkenyl, halogen-substituted C 2-6 alkynyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aryl), -C 0-4 alkylene-(5-10 membered heteroaryl); X1, X2, X3are each independently selected from CH or N; R1is selected from -H, -S(=0)2R 1a , -P(=0)R 1a R 1b , -C(=0)R 1a , -S(=0)(=NH)R 1a , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring; provided that when R1is selected from -S(=0)2R 1a , X1, X2, X3are not simultaneously CH; R2and R3are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -C 0-4 alkylene-OR 2a , -C 0-4 alkylene-OC(=O)R 2a , -C 0-4 alkylene-SR 2a , -C 0-4 alkylene-S(=O)2R 2a , -C 0-4 alkylene-S(=O)R 2a , -C 0-4 alkylene-S(=O)2NR 2a R 2b , -C 0-4 alkylene-S(=O)NR 2a R 2b , -C 0-4 alkylene-C(=O)R 2a , -C 0-4 alkylene-C(=O)OR 2a , -C 0-4 alkylene-C(=O)NR 2a R 2b , -C 0-4 alkylene-NR 2a R 2b , -C 0-4 alkylene-NR 2a C(=O)R 2b , -C 0-4 alkylene-NR 2a S(=O)2R 2b , -C 0-4 alkylene-NR 2a S(=O)R 2b , -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aryl), -C 0-4 alkylene-(5-10 membered heteroaryl), wherein R 2a , R 2b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, halogen-substituted C 2-6 alkenyl, halogen-substituted C 2-6 alkynyl.

2. The compound of claim 1, wherein, The A ring is selected from a 6-10 membered aromatic ring and the A ring is optionally substituted with two independent R groups, where each R group is independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, -C 0-4 alkylene-OR a or -SR a where R a is independently selected from hydrogen, C 1-6 alkyl.

3. The compound of claim 1 or 2, wherein, R2and R3are each independently selected from C 1-6 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aryl), or -C 0-4 alkylene-(5-10 membered heteroaryl); especially -C 0-4 alkylene-(5-10 membered heteroaryl).

4. The compound according to any one of claims 1 to 3, wherein, The compounds have a structure represented by Formula (Ia): wherein R1is selected from -H, -P(=O)R 1a R 1b , -C(=O)R 1a , -S(=O)(=NH)R 1b , -S(=O)(=NR 1a )R 1b , -N=S(=O)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring.

5. The compound of claim 4, wherein, The compound has a structure represented by Formula (IIa): wherein each R is independently selected from the group consisting of: hydrogen, halogen, such as fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl; -OR a wherein R a is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl; R1is selected from -H, -S(=0)(=NH)R 1a , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b wherein R 1a and R 1b are each independently C 1-6 1-6 alkyl, for example methyl, ethyl, propyl, cyclopropyl, isopropyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring; and R2and R3are each independently selected from the group consisting of: C 1-6 alkyl, such as methyl, ethyl, cyclopropyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), such as or or 6. The compound according to any one of claims 1 to 3, wherein, The compounds have a structure according to Formula (Ib): wherein R1is selected from -H, -S(=0)2R 1a , -C(=0)R 1a , -P(=0)R 1a R 1b , -S(=0)(=NH)R 1b , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring.

7. The compound of claim 6, wherein, The compound has a structure represented by formula (IIb): wherein each R is independently selected from the group consisting of: hydrogen, halogen, such as fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, such as methyl, ethyl, propyl, cyclopropyl, isopropyl; -OR a wherein R a is independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, propyl; R1is selected from -H, -S(=0)2R 1a , -P(=0)R 1a R 1b , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from C 1-6 1-6 alkyl, for example methyl, ethyl, propyl, isopropyl, or R 1a and R 1b together with the atom to which they are attached form a 4- to 6-membered ring; and R2and R3are each independently selected from the group consisting of: C 1-6 alkyl, such as methyl, ethyl, cyclopropyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), such as or or 8. The compound according to any one of claims 1 to 3, wherein, The compound has a structure shown in Formula (Ic): wherein R1is selected from -H, -S(=0)2R 1a , -C(=0)R 1a , -P(=0)R 1a R 1b , -S(=0)(=NH)R 1b , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from substituted or unsubstituted C 1-6 alkyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring.

9. The compound of claim 8, wherein, The compound has a structure represented by Formula (IIc): wherein each R is independently selected from the group consisting of: hydrogen, halogen, such as fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, such as methyl, ethyl, propyl, cyclopropyl, isopropyl; -OR a wherein R a is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; R1is selected from -H, -S(=0)2R 1a , -N=S(=0)R 1a R 1b ; wherein R 1a and R 1b are each independently selected from C 1-6 1-6 alkyl, for example methyl, ethyl, propyl, cyclopropyl, isopropyl, or R 1a and R 1b together with the atoms to which they are attached form a 4- to 6-membered ring; R2and R3are each independently selected from the group consisting of: C 1-6 alkyl, such as methyl, ethyl, cyclopropyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), such as or or 10. The compound according to any one of claims 1 to 3, wherein, The compounds have a structure according to Formula (Id): wherein R1is selected from -H, -S(=0)2R 1a , -C(=0)R 1a , -P(=0)R 1a R 1b , -S(=0)(=NH)R 1b , -S(=0)(=NR 1a )R 1b , -N=S(=0)R 1a R 1b ; wherein each R 1a is independently selected from substituted or unsubstituted C 1-6 alkyl.

11. The compound of claim 10, wherein, The compound has a structure shown in Formula (IId): wherein each R is independently selected from the group consisting of: hydrogen, halogen, such as fluorine, chlorine, bromine, and iodine; C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl; -OR a wherein R a is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; R1is selected from -H, -S(=0)2R 1a , -C(=0)R 1a ; wherein R 1a each is independently selected from C 1-6 alkyl, for example methyl, ethyl, cyclopropyl, propyl, isopropyl; R2and R3are each independently selected from the group consisting of: C 1-6 alkyl, such as methyl, ethyl, cyclopropyl, propyl, isopropyl; -C 1-4 alkylene-(5- to 10-membered heteroaromatic ring), such as or or 12. The compound according to any one of claims 1 to 11, wherein, The compound is selected from the compounds shown below, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof:

13. The compound according to any one of claims 1 to 11, wherein, The compound is selected from the compounds shown below, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof:

14. A compound represented by Formula (II): ###0002### (II) or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph, or isotopically enriched compound thereof. wherein R1, R2, X1, X2, X3and A ring are defined according to any one of claims 1 to 11; L represents a linking group, optionally, L is selected from a nitrogen-oxygen or other heteroatom-containing subunit, such as PEG, saturated or unsaturated alkylene, or containing aromatic, heteroaromatic, saturated or unsaturated cyclic alkylene, saturated or unsaturated heterocyclic alkylene; P represents H, OH, NH2or a ligand group targeting degradation of a target protein.

15. The compound of claim 14, wherein, L represents a saturated or unsaturated alkylene or a PEG-based subunit, optionally a saturated or unsaturated C1-10 alkylene or a PEG subunit with a degree of polymerization of 1 to 10.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, optical isomer, stereoisomer, polymorph or isotopically enriched compound thereof, and a pharmaceutically acceptable carrier.

17. Use of a compound according to any one of claims 1 to 15, or an optical isomer, stereoisomer, polymorph or isotopically enriched compound thereof, or a pharmaceutical composition of claim 16, in the manufacture of a medicament, including but not limited to inducing TRIM21 -dominated targeted protein degradation in cells by applying a compound and derivatives according to any one of claims 1 to 15, or a pharmaceutical composition of claim 16.

18. Use of a compound according to any one of claims 1 to 15, or an optical isomer, stereoisomer, polymorph or isotopically enriched compound thereof, or a pharmaceutical composition of claim 16, in the manufacture of a medicament, including but not limited to preventing or treating a TRIM21 -related or multimeric protein-related disease by applying a compound and derivatives according to any one of claims 1 to 15, or a pharmaceutical composition of claim 16.

19. Use of a compound according to any one of claims 1 to 15, or a chemical synthetic route method thereof, or all synthetic intermediates thereof, in the synthesis of other drugs.

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