Compounds targeting irak4 protein degradation and uses thereof

Abstract

The application discloses a compound for targeting IRAK4 protein degradation and application thereof. The compound is a compound shown in formula I, and formula I is T-L-E. In formula I, T is selected from groups shown in formulae T-1 and T-2; E is selected from groups shown in formulae E-1, E-2 and E-3; and L is a linking group with a length of 0-15 atoms. The compound adopts a double-target molecule structure, wherein one end of the molecule is targeted to combine with E3 ligase, and the other end of the molecule is targeted to combine with a target protein (IRAK4 protein) to be degraded. The two ends of the structure are connected through a chain (linker) to form a complete compound molecule. The molecule can reduce the IRAK4 protein level, so that the kinase catalytic function and the scaffold function of the IRAK4 protein are lost at the same time, and a new direction is provided for the treatment of IRAK4 related diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a compound that targets the degradation of IRAK4 protein and its applications. Background Technology

[0002] PROTAC (Proteolysis Targeting Chimeras) technology is an emerging chemical probe or drug discovery method that utilizes the ubiquitin-proteasome system to induce the degradation of target proteins. PROTAC technology involves bifunctional small molecules simultaneously binding to both the target protein and an E3 ligase. This allows the target protein to be recognized and ubiquitinated by the E3 ligase, subsequently being degraded by the proteasome. These drug-like molecules offer the possibility of temporarily controlling protein expression and have been widely used in research and treatment of diseases such as cancer.

[0003] IL-1 receptors (IL-1 receptors) and TLRs share a conserved intracellular domain of the Toll / IL-1R receptor (TIR), thus their downstream signaling pathways are similar. Interleukin-1 receptor-associated kinase 4 (IRAK4) is an important mediator located at the signaling junction of the interleukin (IL)-1 family receptors and Toll-like receptors (TLRs). IL-1R family members (except TLR3) can recruit the myeloid differentiation primary response 88 (MyD88) protein to the C-terminus of the TIR. Simultaneously, the death domain of MyD88 can recruit IRAKs, which together form the signaling complex Myddosome. This leads to IRAK4 autophosphorylation and activation of other IRAK kinases, activating downstream related signaling pathways (NF-κB, JNK, p38, etc.). This, in turn, promotes the secretion of inflammatory cytokines and the proliferation and differentiation of immune cells.

[0004] IRAK4 plays a crucial role in the entire signaling pathway, its activity altered through conformational changes and post-translational modifications. In the myddosome, IRAK4 is activated via trans-autophosphorylation, followed by phosphorylation of IRAK1 / 2, which in turn activates downstream signaling pathways, producing pro-inflammatory cytokines. Therefore, it may play an important role in the pathogenesis and progression of inflammatory diseases. For many years, researchers have linked IRAK4 activity to inflammation and immune conditions, including arthritis, atherosclerosis, Alzheimer's disease, gout, systemic lupus erythematosus, and psoriasis. Some studies in animal models have shown therapeutic effects on inflammatory diseases such as septic shock, SLE, cardiovascular disease, and Alzheimer's disease by mutating or inhibiting IRAK4 activity.

[0005] The innate immune response mediated by Toll-like receptors or certain interleukin receptors is a crucial mediator for the body's initial defense against foreign antigens, and its dysregulation is closely related to the occurrence and progression of cancer. Toll-like receptor (TLR) and IL-1 receptor (IL-1R) family signaling, through the adaptor protein MYD88, leads to the assembly and activation of IRAK4, initiating a signaling cascade that induces the expression of cytokines and survival factors mediated by the transcription factor NF-κB. Recently, it has been further recognized that mutations in proteins within the TLR / IL-1R pathway can lead to overactive signaling and increased NF-κB activity, thus promoting cancer.

[0006] Based on the above mechanisms, research on IRAK4 modulators for autoimmune diseases (septic shock, SLE, cardiovascular disease, Alzheimer's disease, rheumatoid arthritis) and tumors has increased in recent years. Although no modulators have yet been approved for marketing, several small molecule inhibitors have entered clinical trials. IRAK4 has become a hot target in the field of autoimmune diseases and is expected to become a new target for the treatment of autoimmune diseases in the future. This also provides both opportunities and challenges for PROTAC technology, which can efficiently degrade IRAK4 protein.

[0007] Therefore, IRAK4 kinase degraders show promise as drugs for anti-tumor treatment or for treating autoimmune diseases and require further development. Summary of the Invention

[0008] The purpose of this invention is to provide a compound that targets the degradation of IRAK4 protein and its application. This compound employs a dual-target molecular structure, wherein one end of the molecule targets and binds to E3 ligase, and the other end targets and binds to the target protein (IRAK4 protein) to be degraded. These two ends are linked by a linker to form a complete compound molecule. This molecule can reduce the level of IRAK4 protein, causing it to lose both its kinase catalytic function and scaffold function, thus providing a new direction for the treatment of IRAK4-related diseases.

[0009] This invention provides a compound, which is the compound shown in Formula I.

[0010] TLE

[0011] Formula I

[0012] In formula I, T is selected from the groups shown in formulas T-1 and T-2 below:

[0013]

[0014] In equations T-1 and T-2, X1 is CH or N;

[0015] Y is NH, O, or S;

[0016] M is absent or is CH2, C=O, NH, O, or S;

[0017] Each of A is independently selected from at least one of 3-7 membered cycloalkyl, 4-7 membered heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged, aryl and heteroaryl; at least one of the 3-7 membered cycloalkyl, 4-7 membered heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged, aryl and heteroaryl is substituted by 0 to 4 substituted by at least one of H, halogen, hydroxyl, CN and NH2;

[0018] B is absent or independently selected from at least one of 3-7 membered cycloalkyl, 4-7 membered heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged, aryl and heteroaryl groups; at least one of the 3-7 membered cycloalkyl, 4-7 membered heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged, aryl and heteroaryl groups is substituted by 0 to 4 groups selected from at least one of halogen, -CF3, hydroxyl, amino, cyano, C1-C4 alkyl and C1-C4 alkoxy groups;

[0019] R1 is absent or is selected independently from halogens, C1-C3 alkyl groups, or CN;

[0020] R2 is hydrogen, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl, or heteroaryl; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl, or heteroaryl is optionally substituted with one or two independent groups selected from cyano, hydroxyl, halogen, C1-C3 alkyl, C3-C7 cycloalkyl, phenyl, 5-6 heteroaryl, 9-10 heteroaryl, or 4-7 heterocyclic alkyl; wherein the C3-C7 cycloalkyl, phenyl, 5-6 heteroaryl, 9-10 heteroaryl, or 4-7 heterocyclic alkyl is optionally substituted with 1-3 independent groups selected from halogen, -CF3, hydroxyl, amino, C1-C4 alkyl, and C1-C4 alkoxy.

[0021] R3 is independently selected from at least one of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, heterocyclic ring, heterospirocyclic ring, heterobridged ring, aryl, and heteroaryl; wherein each of the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclic alkyl, heterocyclic ring, heterospirocyclic ring, heterobridged ring, aryl, or heteroaryl is optionally substituted with halogen, hydroxyl, amino, C1-C8 alkoxy, cycloalkyl, heterocyclic alkyl, aryl, or heteroaryl; wherein the hydroxyl, amino, alkoxy, cycloalkyl, heterocyclic alkyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxyl, amino, or 1-4 membered alkyl.

[0022] R4 is at least one of hydrogen, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl, aromatic heteroyl and 5-10 membered heterocyclic ring;

[0023] In R4, the C1-C6 alkyl group is optionally substituted with one or two independent groups selected from cyano, hydroxy, halogen, C1-C3 alkyl, C3-C7 cycloalkyl, phenyl, 5-6 heteroaryl, 9-10 heteroaryl, and 4-7 heterocyclic alkyl; wherein the C3-C7 cycloalkyl, phenyl, 5-6 heteroaryl, 9-10 heteroaryl, and 4-7 heterocyclic alkyl groups are optionally substituted with 1-3 independent groups selected from halogen, -CF3, hydroxy, amino, C1-C4 alkyl, and C1-C4 alkoxy.

[0024] In R4, the C3-C7 cycloalkyl or 4-7 heterocyclic alkyl group is optionally substituted with 1-3 amino- or C1-C4 alkoxy groups, each independently selected from halogen, hydroxyl, amino, cyano, CF3, CF3O, C1-C4 alkyl, C1-C4 alkyl-substituted amino- or C1-C4 alkoxy groups.

[0025] In R4, the aryl or aromatic heterocyclic 5-10 membered heterocyclic ring is optionally substituted by 1-3 independent amino or alkoxy groups selected from halogen, hydroxyl, amino, cyano, CF3, CF3O, C1-C4 alkyl, C1-C4 alkyl-substituted amino, or C1-C4 alkoxy.

[0026] E is selected from the groups shown in the following formulas: E-1, E-2, and E-3.

[0027]

[0028] In equations E-1, E-2, and E-3, X2 is CH2 or C=O;

[0029] u is 0, 1, or 2;

[0030] R5 is independently selected from at least one of hydrogen, deuterium, halogen, cyano, nitro, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein in R5, the -C1-8 alkyl, -C2-8 alkenyl, -C2-8 ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted with halogen, hydroxyl, -C1-8 alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0031] L is a linking group with a length of 0 to 15 atoms; the linking group is a straight-chain alkylene group with 0 to 15 carbon atoms, wherein one or more carbon atoms are each independently selected from O, S, NH, NCH3, carbonyl, alkynyl, 4-7 member heteromonocyclic, 5-10 member heterocyclic, 6-12 member heterospirocyclic, 7-10 member heterobridged, 3-7 member monocyclic alkyl, 5-10 member fused cycloalkyl, 6-12 member spirocyclic alkyl, 7-10 member bridged cycloalkyl, 5-10 member heteroaryl, or 6-10 member aryl; wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic, or heterobridged ring is optionally further substituted by 0 to 4 substituents selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, oxygen-containing group, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxyl-substituted C1-4 alkyl, or C1-4 alkoxy.

[0032] In the above-described compounds, T is selected from at least one of the following groups:

[0033]

[0034]

[0035] In the above-described compounds, E is selected from at least one of the following groups:

[0036]

[0037] In the above-described compounds, L is selected from at least one of the following groups:

[0038]

[0039]

[0040] The L shown above is connected to T on its left and to E on its right.

[0041] Of the compounds described above, the compound represented by Formula I is any compound with the following structural formula:

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] The present invention also provides a drug in which the active ingredient is the above-mentioned compound or its stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs.

[0052] In the aforementioned drugs, the excipients of the drugs are at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants, and mediators.

[0053] The compounds described in this invention, or their stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs, are used in the preparation of medicaments for the treatment or prevention of non-Hodgkin's lymphoma or autoimmune diseases.

[0054] In the above applications, the autoimmune disease is at least one of rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, multiple sclerosis, asthma, and chronic arthritis.

[0055] The drug described in this invention is used in the preparation of drugs for the treatment or prevention of non-Hodgkin's lymphoma or autoimmune diseases.

[0056] In the above applications, the autoimmune disease is at least one of rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, multiple sclerosis, asthma, and chronic arthritis.

[0057] This invention further provides the use of the said compound or its stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs, or the said drug, in the preparation of any of the functional pharmaceutical products described in 1)-2):

[0058] 1) Drugs used to degrade or inhibit IRAK4;

[0059] 2) Treatment or prevention of IRAK4-related diseases.

[0060] In the above applications, the IRAK4-related diseases are non-Hodgkin's lymphoma or autoimmune diseases.

[0061] In the above applications, the autoimmune disease is at least one of rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, multiple sclerosis, asthma, and chronic arthritis.

[0062] This invention provides a method for treating a patient's disease or condition using the aforementioned drug, comprising the steps of administering a therapeutically effective dose of the drug as an IRAK4 modulator to the patient. In some embodiments, the disease or condition is related to IRAK4; preferably, the disease or condition is cancer or an autoimmune disease.

[0063] The present invention has the following beneficial effects:

[0064] 1. Traditional small molecule inhibitors can only inhibit the kinase activity of IRAK4, while the compounds of this invention can degrade the IRAK4 protein as a whole.

[0065] 2. Traditional small molecule inhibitors can only block the inflammatory response caused by phosphorylation of IRF5 / 7 after inhibiting kinase activity, and cannot target the protein backbone function of IRAK4 in the Myddosome complex, resulting in limited therapeutic effects. The degrading agent of this invention has excellent degradation effect on IRAK4 protein, and has been shown to simultaneously block the kinase-catalyzed IRF5 / 7 and the non-kinase-dependent NF-κB and MAPK pathways. Through the synergistic effect of multiple signaling pathways, a better therapeutic effect on IRAK4-related diseases is achieved.

[0066] 3. Compared with existing IRAK4 degrading agents, the compound of this invention, when used as a degrading agent, has a higher DC content. 50 The Dmax is significantly improved, outperforming all existing IRAK4 degraders reported in the literature; at the same time, the compounds of this invention use novel IRAK4 ligands, which not only have comparable activity to existing functional compounds, but also have better bioavailability. Attached Figure Description

[0067] Figure 1 This is a graph showing the results of measuring the degradation of IRAK4 protein by compounds from some examples in THP-1 cells. Figure 1 IRAK4 was the target protein, and GAPDH and Actin were internal controls.

[0068] Figure 2 To determine the time-dependent degradation of IRAK4 at a concentration of 100 nM in Example 35 of this invention; Figure 2 IRAK4 is the target protein, and Actin is the internal control. Detailed Implementation

[0069] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0070] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0071] In this invention, the compound of Formula I or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs or pharmaceutical compositions may be administered via any common route, provided that it can reach the intended tissue. Various routes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, dermal, oral, topical, nasal, pulmonary, and rectal, but the invention is not limited to these exemplified routes of administration. However, when administered orally, the active ingredient of the orally administered composition should be coated or formulated to prevent its degradation in the stomach. Furthermore, the compound of Formula I or the pharmaceutical composition of this invention may be administered using specific devices for delivering the active ingredient to target cells.

[0072] The term "treatment" is used to refer to achieving a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses the treatment of diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in individuals susceptible to disease but not yet diagnosed with it; (b) suppression of disease; or (c) relief of disease, such as reduction of disease-related symptoms. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or suppress the individual's disease, including but not limited to the administration of a compound or pharmaceutical composition containing Formula I or II described herein to an individual in need.

[0073] According to embodiments of the invention, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in delivering or transporting a compound usable in the invention to a patient to enable it to perform its intended function. Generally, such a construct is delivered or transported from one organ or part of the body to other organs or parts of the body. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation (including compounds usable in the invention) and without harm to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer solutions; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delay agents, and analogs compatible with the activity of compounds available in this invention, and physiologically acceptable to patients. Additional active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of compounds available in this invention.

[0074] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0075] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0076] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0077] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0078] In various parts of this specification, the substituents of the disclosed compounds are disclosed according to the type or range of groups. In particular, this invention includes every independent secondary combination of the members of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, propane, butane, pentane, and hexane.

[0079] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0080] As used in this invention, the term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 10 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. Unless otherwise specified, an alkyl group contains 1 to 8 carbon atoms.

[0081] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1 to 15 carbon atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and so on.

[0082] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "tans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-8 carbon atoms; in another embodiment, the alkenyl group comprises 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0083] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0084] The term "heteroalkyl" means an alkyl chain with one or more heteroatoms inserted into it, wherein the alkyl group and the heteroatom have the meanings as described in this invention. Unless otherwise specified, a heteroalkyl group contains 2-10 carbon atoms, and examples of such groups include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, etc.

[0085] The term "alkenyl" refers to an olefinic group obtained by removing two hydrogen atoms from a straight-chain or branched olefin. The alkenyl group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or aryloxy. Examples include, but are not limited to, vinylene (-CH=CH-), isopropenylene (-C(CH3)=CH-), 3-methoxypropene-1,1-diyl, 2-methylbutene-1,1-diyl, etc.

[0086] The term "carbocyclic" ("cycloalkyl") refers to a saturated divalent hydrocarbon ring obtained by removing two hydrogen atoms from a monocyclic ring containing 3-12 carbon atoms or a bicyclic ring containing 7-12 carbon atoms, wherein the carbocyclic or cycloalkyl has the meaning as described in this invention. Examples of such compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-eneyl, 1-cyclopent-2-eneyl, etc.

[0087] The term "subheterocyclic group" refers to a monocyclic, bicyclic, or tricyclic system in which one or more atoms on the ring are independently selected from heteroatoms and may be fully saturated or contain one or more degrees of unsaturation, but not belonging to the aromatic class, having two connection points attached to the rest of the molecule, wherein the heterocyclic group has the meaning as described in this invention. Examples of such groups include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, aziridine-1,3-diyl, pyrrolidine-1,3-diyl, etc.

[0088] The term "alkoxy" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1 to 10 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0089] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0090] The terms “haloalkyl”, “haloalkenyl”, or “haloalkoxy” refer to alkyl, alkenyl, or alkoxy groups that are replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc.

[0091] The terms "hydroxyalkyl" and "hydroxy-substituted alkyl" indicate that an alkyl group is replaced by one or more hydroxyl groups, wherein the alkyl group has the meaning described herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, etc.

[0092] The term "carbocyclic" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. Carbocyclic groups include spirobicyclic and fused carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and so on.

[0093] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0094] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein, referring to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide compound. Examples of heterocyclic groups include, but are not limited to: ethylene oxide, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaalkyl, thiaalkyl, homopiperazine, homopiperidinyl, oxacycloheptyl, thioheptanyl, oxacycloheptyl, oxacyclobutyl... 2-diazine Base, sulfur nitrogen The heterocyclic group may contain, but is not limited to, indololinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxonyl, and 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of heterocyclic groups in which the -CH2- group is substituted with -C(O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, and pyrimidinidone. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may optionally be substituted with one or more of the substituents described in this invention.

[0095] In one embodiment, the heterocyclic group is a heterocyclic group consisting of 4-7 atoms, referring to a saturated or partially unsaturated monocycle containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the heterocyclic group consisting of 4-7 atoms can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide compound. Examples of heterocyclic groups consisting of 4-7 atoms include, but are not limited to: azirobutyl, oxacyclobutyl, thioherobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaalkyl, thiaalkyl, homopiperazine, homopiperidinyl, oxacycloheptyl, thioheptanyl, oxacycloheptyl, oxacycloheptyl, oxacycloheptyl 2-diazine Base, sulfur nitrogen Examples of heterocyclic groups in which the -CH2- group is substituted with -C(O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, and pyrimidinidone. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholino. The heterocyclic group consisting of 4-7 atoms may optionally be substituted by one or more substituents described in this invention.

[0096] In another embodiment, the heterocyclic group is a four-atom heterocyclic group, referring to a saturated or partially unsaturated monocycle containing four ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the four-atom heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide compound. Examples of four-atom heterocyclic groups include, but are not limited to: azirobutyl, oxobutyl, and thiobutyl. The four-atom heterocyclic group can optionally be substituted by one or more substituents described in this invention.

[0097] In another embodiment, the heterocyclic group is a 5-atom heterocyclic group, referring to a saturated or partially unsaturated monocycle containing 5 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the 5-atom heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, and dithiocyclopentyl. Examples of heterocyclic groups where the -CH2- group is substituted with -C(O)- include, but are not limited to, 2-oxopyrrolidinyl and oxo-1,3-thiazolyl. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane. The aforementioned five-atom heterocyclic group may optionally be substituted with one or more substituents described in this invention.

[0098] In another embodiment, the heterocyclic group is a 6-atom heterocyclic group, referring to a saturated or partially unsaturated monocycle containing 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the 6-atom heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of 6-atom heterocyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, and thiaranyl. Examples of -CH2- groups in the heterocyclic group being replaced by -C(O)- include, but are not limited to, 2-piperidinone, 3,5-dioxadipinyl, and pyrimidinidone. Examples of oxidation of the sulfur atom in the heterocyclic group include, but are not limited to, 1,1-dioxothiomorpholino. The six-atom heterocyclic group may optionally be substituted with one or more substituents described in this invention.

[0099] In another embodiment, the heterocyclic group is a heterocyclic group consisting of 7-12 atoms, referring to a saturated or partially unsaturated spirobicyclic or fused bicyclic ring containing 7-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the heterocyclic group consisting of 7-12 atoms can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide compound. Examples of heterocyclic groups consisting of 7-12 atoms include, but are not limited to: indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxonyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. The heterocyclic group consisting of 7-12 atoms can optionally be substituted by one or more substituents described in this invention.

[0100] The terms “fused bicyclic,” “fused ring,” “fused bicyclic group,” and “fused ring group” are used interchangeably here to refer to a monovalent or polyvalent saturated or partially unsaturated bridged ring system, wherein the bridged ring system is a non-aromatic bicyclic system. Such a system may contain independent or conjugated unsaturated systems, but its core structure does not contain an aromatic ring or heterocyclic ring (however, aromatic groups may act as substituents thereon).

[0101] The terms “spirocyclic,” “spirocyclic,” “spirobicyclic,” or “spirobicyclic” are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated ring system, wherein one ring originates from a specific ring carbon atom on the other ring. For example, as described below, a saturated bridged ring system (rings B and B') is referred to as a “fused bicyclic,” while rings A and B, which share a carbon atom in two saturated ring systems, are referred to as a “spirocyclic” or “spirobicyclic.” Each ring in a fused bicyclic or spirobicyclic group can be a carbocyclic or heterocyclic group, and each ring may optionally be substituted by one or more substituents described in this invention.

[0102]

[0103] The term "heterocyclic alkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms.

[0104] The term "composed of n atoms," where n is an integer, typically describes the number of cyclic atoms in a molecule, where the number of cyclic atoms in the molecule is n. For example, piperidinyl is a heterocyclic alkyl group consisting of 6 atoms, while 1,2,3,4-tetrahydronaphthalene is a cycloalkyl group consisting of 10 atoms.

[0105] The term "unsaturated" as used in this invention means that the group contains one or more degrees of unsaturation.

[0106] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl).

[0107] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0108] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be optionally and independently substituted by one or more substituents described in this invention.

[0109] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5-7 atoms and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." The heteroaryl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the 5-10 atom heteroaryl group comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0110] Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl. 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl 1,2,3-Thiodiazolyl, 1,3,4-Thiodiazolyl, 1,2,5-Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl) (e.g., 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0111] The term "carboxyl" (or "carboxyl group"), whether used alone or in combination with other terms such as "carboxylalkyl", represents -CO2H; the term "carbonyl" (or "carbonyl group"), whether used alone or in combination with other terms such as "aminocarbonyl" or "acyloxy group", represents -(C=O)-.

[0112] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino," wherein the amino group is independently substituted by one or two alkyl groups. In some embodiments, the alkylamino group is one or two C14 groups. 1-6 The alkyl group is attached to a lower-order alkylamino group on the nitrogen atom. In other embodiments, the alkylamino group is C10. 1-3 The lower-order alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0113] The term "aromatic amino" indicates that the amino group is replaced by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the aromatic amino group may be further substituted.

[0114] The term "aminoalkyl" includes C atoms that are substituted with one or more amino groups. 1-10 Straight-chain or branched alkyl groups. In some embodiments, the aminoalkyl group is a C14 chain substituted with one or more amino groups. 1-6 Examples of “lower aminoalkyl” include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0115] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0116] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0117] As used in this invention, "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-p-gluconate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0118] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0119] Pharmaceutically usable acid addition salts can form with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactates, lacturonide, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactosates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0120] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0121] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

[0122] Pharmaceutical alkali addition salts can form with inorganic and organic bases.

[0123] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0124] Organic bases from which salts can be derived include primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Some organic amines include, for example, isopropylamine, benzathine penicillin, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0125] The pharmaceutically acceptable salts of the present invention can be synthesized using conventional chemical methods from a parent compound, a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other suitable salts can be listed, for example, in “Remington’s Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0126] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form of a solvent containing them (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0127] On the other hand, the present invention relates to intermediates for preparing compounds contained in Formula I or Formula II.

[0128] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds contained in Formula I or Formula II.

[0129] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or a combination thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0130] The Pomalidomide end derivatives (i.e., formula E-1, X2 being C=O) used in the following examples were prepared according to the method disclosed in Chemistry & Biology 22, 755-763 (2015). The Lenalidomide end derivatives (i.e., formula E-1, X2 being CH2) were prepared according to the method disclosed in J. Med. Chem (DOI:10.1021 / acs.jmedchem.6b01816). The VHL ligand (i.e., formula E-3) was prepared according to the method disclosed in ACS Chem. Biol. 2017, 12, 2570-2578.

[0131] MS measurements were performed using a Waters AQUITY UPLC™ / MS.

[0132] NMR measurements were performed using a Bruker 400MHz spectrometer. Unless otherwise specified, the NMR solvent was a mixture of deuterated chloroform and deuterated methanol in a 5:1 ratio.

[0133] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0134]

[0135] Preparation of intermediate A

[0136] In a 50 mL round-bottom flask, 4-nitropyrazole (2.0 g, 17.7 mmol), N-Boc-4-hydroxypiperidine (3.56 g, 17.7 mmol), and triphenylphosphine (6.9 g, 26.5 mmol) were added, followed by the addition of 20 mL of anhydrous THF to dissolve the precipitate. The reaction mixture was kept at 0°C with stirring, and diisopropyl azodicarbonate (4.62 g, 26.55 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by adding 30 mL of saturated sodium chloride aqueous solution. The mixture was extracted with 30 mL × 3 ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The purified intermediate A was obtained by silica gel chromatography (PE:EA = 5:1), with a yield of 91%.

[0137] Preparation of intermediate B

[0138] Pd / C (10%) was added to a methanol solution of intermediate A. The suspension was degassed under vacuum and purged three times with H2. The mixture was then stirred at room temperature for 2 hours under H2. After completion, the reaction solution was filtered, and the filtrate was concentrated under vacuum to obtain a dark red oily intermediate B in 93% yield.

[0139]

[0140] Preparation of intermediate C

[0141] 4.6 g (25.1 mmol) of 2-cyano-3-nitro-6-chloro-pyridine was added to 100 mL of anhydrous ethanol and 22.6 g (0.1 mol) of stannous chloride, and the mixture was reacted at 90 °C for 4 h. After the reaction was complete, the reaction solution was concentrated under vacuum, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate until pH 7. The organic layer was further washed with 2 M sodium hydroxide until pH 8-9. The aqueous layer was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give yellow intermediate C in 89% yield.

[0142] Preparation of intermediate D1

[0143] 3-Amino-6-chloropyridine-2-carboxamide (3 g, 17.5 mmol) was dissolved in 100 mL of 1,4-dioxane, and triphosgene (2.6 g, 8.75 mmol) was added. The mixture was reacted at 105 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of water was added and stirred for 30 min. The mixture was then filtered, and the filter cake was washed twice with EA (acetal extract), concentrated under vacuum, and dried to obtain a pale yellow product D1, with a yield of 85%.

[0144] Preparation of intermediate D2

[0145] 2-Amino-5-iodobenzoic acid (15 g, 87.2 mmol) and urea (52.4 g, 872 mmol) were mixed thoroughly and heated to 170 °C to melt. The mixture was reacted for 3 h and then cooled to room temperature. 200 mL of water was added and the mixture was heated under reflux for 1 h. The mixture was filtered and dried to obtain a white solid D2, with a yield of 98%.

[0146] Preparation of intermediates E1 / E2

[0147] Intermediate D (5 mmol) was dispersed in 10 mL of toluene, and phosphorus oxychloride (1.7 g, 11.1 mmol) and N,N-diisopropylethylamine (1.94 mL, 11.1 mmol) were added separately. The reaction mixture was heated to reflux for 5 h. The reaction mixture was diluted with 30 mL of ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate and saturated brine, respectively. After drying with anhydrous sodium sulfate, the mixture was concentrated under vacuum and purified by silica gel chromatography (PE:EA = 50:1) to obtain intermediate E in 65% yield.

[0148] Preparation of intermediates F1 / F2

[0149] Intermediate E (4.27 mmol) was added to a mixed solution of 1-methylcyclopropylamine hydrochloride (0.48 g, 4.5 mmol), N,N-diisopropylethylamine (2.4 mL, 13.5 mmol), and dichloromethane (20 mL). The mixture was stirred at 0°C for 30 min. The reaction solution was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a pale yellow intermediate F in 94% yield.

[0150] Preparation of intermediates G1 / G2

[0151] Intermediate B (1 g, 3.9 mmol) and intermediate F (3.9 mmol) were dissolved in 20 mL of tert-butanol, and a catalytic amount of trifluoroacetic acid (20 μL) was added. The reaction was heated to reflux for 8 h with stirring. After the reaction was complete, the solvent tert-butanol was removed under reduced pressure, and 10 mL of 10% sodium bicarbonate solution was added. After stirring for 30 min, the mixture was filtered, and the filter cake was washed three times with a small amount of water and dried to obtain crude product G, with a yield of 82%.

[0152] Preparation of intermediates H1 / H2

[0153] Intermediate G (2 mmol), 5-pyrimidinephenylboronic acid (330 mg, 26 mmol), and tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) were dispersed in 10 mL of dioxane, and a solution of tripotassium phosphate (850 mg, 4 mmol) in water (2 mL) was added to the suspension. The suspension was degassed under vacuum and purged three times with argon. The mixture was then heated to 80°C and stirred for 4 h under argon atmosphere. After the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution. The organic layer was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography (DCM:MeOH = 30:1) to obtain yellow intermediate H in 55% yield.

[0154] Preparation of intermediate I1 / I2

[0155] Intermediate H (1.84 mmol) was dissolved in 1 M dioxachlor hydrochloride solution, and the reaction mixture was stirred at 25°C for 4 h. After completion, the reaction mixture was concentrated under vacuum to give target compound I as a pale yellow solid in 95% yield.

[0156]

[0157] Synthesis of intermediate J

[0158] 3-Fluorophthalic anhydride (3 g, 18.07 mmol), 3-aminopiperidine-2,6-dione hydrochloride (2.55 g, 19.88 mmol), and sodium acetate (1.92 g, 23.47 mmol) were added to acetic acid (30 mL), and the mixture was heated to 105 °C and reacted for 8 h. The acetic acid was directly evaporated to dryness using a rotary evaporator, then dissolved in a mixed solvent of dichloromethane and methanol, mixed, and purified by column chromatography (DCM:MeOH = 50:1) to obtain white intermediate J in 82% yield.

[0159] Synthesis of intermediate K, L2-L17

[0160] Taking the synthesis of intermediate L5 (n=4) as an example, 6-aminohexanoic acid (0.25 g, 1.9 mmol), 2-(2,6-dioxadiazin-3-yl)-4-fluoroisoindol-1,3-dione (0.5 g, 0.18 mmol), N,N-diisopropylethylamine (0.64 mL, 3.8 mmol), and 5 mL DMSO were added to a 5 mL round-bottom flask. The reaction mixture was stirred at 90°C for 4 h. After the reaction was complete, the mixture was cooled to room temperature and diluted with 30 mL of ethyl acetate. The organic layer was washed once with dilute hydrochloric acid, twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified using a 200-300 mesh silica gel column (DCM:MeOH = 50:1) to obtain the yellow intermediate L5 in 43% yield.

[0161] Synthesis of intermediate L1

[0162] Intermediate K (0.38 g, 1 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h, and then concentrated under vacuum to obtain a yellow solid product with a yield of 95%.

[0163]

[0164] Synthesis of target compounds 1-21 (with one end being I1 and the other end being L1-L17; or with one end being I2 and the other end being L3-5, L17)

[0165]

[0166] Example 1: Taking target compound 1 as an example, intermediate I1 (20 mg, 0.042 mmol), intermediate L1 (14.0 mg, 0.042 mmol), HATU (16 mg, 0.042 mmol), 22 μL DIPEA, and 0.5 mL LDMF were added to a 10 mL round-bottom flask, and the mixture was stirred at room temperature for 5 h. 5 mL of saturated sodium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted three times with 10 mL × 3 ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified using a 200-300 mesh silica gel column (DCM:MeOH = 20:1) to obtain the yellow solid target product 1, with a yield of 52%.

[0167] The structure is confirmed as follows; LC-MS (ESI) + )m / z 755.2(M+H) + . 1 H NMR(400MHz,)δ9.46(s,2H),9.22(s,1H),8.11(d,J=9.1Hz,2H),7.91(d,J=8.7Hz,2H),7.55(t,J=7.8Hz,1H),7 .13(d,J=7.1Hz,1H),6.93(d,J=8.5Hz,1H),5.03–4.93(m,1H),4.73(d,J=13.5Hz,1H),4.41(d,J=3.0Hz,1H),4 .27–4.11(m,2H),4.04(d,J=14.0Hz,1H),3.42–3.28(m,1H),2.96(t,J=12.7Hz,1H),2.87–2.75(m,3H),2.29(d d,J=24.9,12.7Hz,2H),2.16(dt,J=8.3,4.5Hz,1H),2.12–1.92(m,2H),1.63(s,3H),1.07(s,2H),0.90(s,2H).

[0168]

[0169] Example 2: The target compound 2 was obtained from I1 and L2 using the same method as in Example 1. Purification was performed by silica gel column chromatography (DCM:MeOH = 20:1) to give the yellow target product 2 in 55% yield. LC-MS (ESI) + )m / z 770.1(M+H) + .

[0170]

[0171] Example 3: The target compound 3 was obtained from I1 and L3 using the same method as in Example 1. Purification was performed by silica gel column chromatography (DCM:MeOH = 20:1) to give the yellow target product 3 in 50% yield. LC-MS (ESI) + )m / z 784.1(M+H) + . 1 HNMR(400MHz,)δ9.42(d,J=4.2Hz,2H),9.22(d,J=2.4Hz,1H),8.12(s,1H),8.04(t,J=8.1Hz,1H),8.00–7.74(m,2H ),7.64(t,J=7.8Hz,1H),7.42(d,J=7.2Hz,1H),7.28(td,J=7.2,5.9,3.4Hz,1H),5.05–4.87(m,1H),4.73(dd,J=30. 3,12.7Hz,1H),4.40(dt,J=19.3,11.6Hz,1H),3.91–3.52(m,2H),3.39–3.13(m,3H),3.00–2.60(m,4H),2.32(dt,J =35.7,14.6Hz,2H),2.19–2.04(m,1H),2.04–1.71(m,5H),1.68–1.53(m,3H),1.14–0.95(m,2H),0.94–0.78(m,2H).

[0172]

[0173] Example 4: The target compound 4 was obtained from I1 and L4 using the same method as in Example 1. Purification was performed by silica gel column chromatography (DCM:MeOH = 20:1) to give the yellow target product 4 in 61% yield. LC-MS (ESI) + )m / z 798.2(M+H) + .

[0174]

[0175] Example 5: The target compound 5 was obtained from I1 and L5 using the same method as in Example 1. Purification was performed by silica gel column chromatography (DCM:MeOH = 20:1) to give the yellow target product 5 in 60% yield. LC-MS (ESI) + )m / z 812.1(M+H) + . 1HNMR(400MHz,)δ9.44(s,2H),9.21(s,1H),8.10(s,1H),8.05(d,J=8.8Hz,1H),7.88(d,J=8.8Hz,1H),7.79(s,1H),7.56–7.49(m, 1H),7.08(d,J=7.1Hz,1H),6.95(d,J=8.5Hz,1H),5.00–4.91(m,1H),4.73(d,J=13.6Hz,1H),4.35(s,1H),4.07(d,J=13.8Hz,1H), 3.33(d,J=7.0Hz,3H),2.82(ddt,J=18.2,14.3,5.1Hz,4H),2.46(t,J=7.5Hz,2H),2.26(dd,J=22.1,13.0Hz,2H),2.19–2.09(m,1 H),2.04–1.87(m,2H),1.73(h,J=7.0Hz,4H),1.63(s,3H),1.52(ddt,J=15.2,9.8,5.9Hz,2H),1.06(s,2H),0.89(d,J=5.6Hz,2H).

[0176]

[0177] Example 6: The target compound 6 was obtained from I1 and L6 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 6 in 73% yield. LC-MS (ESI) + )m / z 825.4(M+H) + .

[0178]

[0179] Example 7: The target compound 7 was obtained from I1 and L7 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 7 in 68% yield. LC-MS (ESI) + )m / z 840.1(M+H) + . 1HNMR(400MHz,)δ9.42(s,2H),9.22(s,1H),8.10(s,1H),8.04(d,J=8.8Hz,1H),7.88(d,J=8.9Hz,1H),7.79(s,1H),7.51(t,J=7.8Hz,1 H),7.07(d,J=7.0Hz,1H),6.93(d,J=8.6Hz,1H),5.02–4.88(m,1H),4.73(d,J=13.6Hz,1H),4.39(d,J=11.7Hz,1H),4.05(d,J=13.8Hz, 1H),3.34–3.21(m,3H),2.92–2.69(m,4H),2.42(t,J=7.7Hz,2H),2.24(dt,J=26.1,12.7Hz,2H),2.13(td,J=6.3,5.4,3.1Hz,1H),1.95 (dd,J=17.1,7.6Hz,2H),1.69(q,J=6.8Hz,4H),1.64(d,J=6.4Hz,3H),1.44(qd,J=8.7,4.5Hz,6H),1.06(s,2H),0.89(d,J=5.7Hz,2H).

[0180]

[0181] Example 8: The target compound 8 was obtained from I1 and L8 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 8 in 67% yield. LC-MS (ESI) + )m / z 854.2(M+H) + .

[0182]

[0183] Example 9: The target compound 9 was obtained from I1 and L9 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 9 in 62% yield. LC-MS (ESI) + )m / z 868.5(M+H) + .

[0184]

[0185] Example 10: Target compound 10 was obtained from I1 and L10 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 10 in 55% yield. LC-MS (ESI) +)m / z 882.5(M+H) + .

[0186]

[0187] Example 11: The target compound 11 was obtained from I1 and L11 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 11 in 83% yield. LC-MS (ESI) + )m / z 894.4(M+H) + . 1 H NMR(400MHz,)δ9.43(s,2H),9.22(s,1H),8.12(s,1H),8.05(d,J=8.7Hz,1H),7.88(s,1H),7.79(s,1H),7.51(t,J=7.8Hz,1H ),7.07(d,J=7.1Hz,1H),6.92(d,J=8.5Hz,1H),4.99–4.90(m,1H),4.73(d,J=13.7Hz,1H),4.39(d,J=16.0Hz,1H),4.06(d,J= 13.5Hz,1H),3.29(q,J=9.0,7.6Hz,3H),2.81(td,J=18.8,18.2,8.0Hz,4H),2.41(t,J=7.7Hz,2H),2.26(dd,J=23.1,11.9Hz ,2H),2.14(s,1H),1.96(s,2H),1.74–1.59(m,6H),1.33(d,J=12.2Hz,11H),1.27(s,4H),1.07(s,2H),0.89(d,J=5.4Hz,2H).

[0188]

[0189] Example 12: The target compound 12 was obtained from I1 and L12 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 12 in 80% yield. LC-MS (ESI) + )m / z 810.3(M+H) + .

[0190]

[0191] Example 13: The target compound 13 was obtained from I1 and L13 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 13 in 78% yield. LC-MS (ESI)+ )m / z 810.3(M+H) + . 1 H NMR(400MHz,)δ9.37(s,2H),9.12(s,1H),7.98(d,J=8.9Hz,1H),7.80(s,1H),7.67(s,1H),7.49–7.43(m,1H),7.01(d,J=7. 1Hz,1H),6.96(d,J=8.6Hz,1H),4.92–4.82(m,1H),4.65(d,J=13.4Hz,1H),4.33–4.25(m,1H),3.97(d,J=14.2Hz,1H),3.34 (t,J=6.9Hz,2H),3.30(s,2H),3.19(t,J=12.9Hz,1H),3.08(q,J=7.3Hz,1H),2.71(t,J=16.7Hz,4H),2.46(t,J=7.0Hz,2H) ,2.16(t,J=13.1Hz,2H),2.04(d,J=7.8Hz,1H),1.95(p,J=7.0Hz,2H),1.86(s,2H),1.53(s,3H),0.97(s,2H),0.78(s,2H).

[0192]

[0193] Example 14: Target compound 14 was obtained from I1 and L14 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 14 in 73% yield. LC-MS (ESI) + )m / z 796.3(M+H) + .

[0194]

[0195] Example 15: Target compound 15 was obtained from I1 and L15 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 15 in 66% yield. LC-MS (ESI) + )m / z 832.3(M+H) + .

[0196]

[0197] Example 16: The target compound 16 was obtained from I1 and L16 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 16 in 69% yield. LC-MS (ESI) + )m / z 824.3(M+H) + .

[0198]

[0199] Example 17: Target compound 17 was obtained from I1 and L17 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 17 in 53% yield. LC-MS (ESI) + )m / z 838.3(M+H) + .

[0200]

[0201] Example 18: Target compound 18 was obtained from I2 and L3 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 18 in 57% yield. LC-MS (ESI) + )m / z 783.3(M+H) + .

[0202]

[0203] Example 19: Target compound 19 was obtained from I2 and L4 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 19 in 68% yield. LC-MS (ESI) + )m / z 797.3(M+H) + .

[0204]

[0205] Example 20: The target compound 20 was obtained from I2 and L5 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 20 in 62% yield. LC-MS (ESI) + )m / z 811.3(M+H) + .

[0206]

[0207] Example 21: Target compound 21 was obtained from I2 and L17 using the same method as in Example 1. Purification by silica gel column chromatography (DCM:MeOH = 20:1) yielded the yellow target product 21 in 73% yield. LC-MS (ESI) + )m / z 837.3(M+H) + .

[0208]

[0209] Example 22: The method was the same as in Example 1, yielding the yellow target product 22 in 63% yield. LC-MS (ESI) + )m / z 770.3(M+H) + . 1 H NMR(400MHz,)δ9.43(d,J=1.8Hz,2H),9.22(s,1H),8.03(d,J=8.8Hz,1H),7.92(t,J=8.3Hz,3H),7.64(dd,J=8. 4,5.0Hz,1H),7.02(d,J=2.2Hz,1H),6.84(dd,J=8.4,2.2Hz,1H),4.98(d,J=9.1Hz,1H),4.75(d,J=13.4Hz,1H) ,4.36(t,J=11.6Hz,1H),4.06–3.96(m,1H),3.62(dd,J=11.5,6.3Hz,2H),3.25(t,J=13.2Hz,1H),2.80(dd,J=1 8.7,8.9Hz,5H),2.67(s,1H),2.29–2.09(m,3H),1.85(s,2H),1.58(d,J=3.8Hz,3H),1.03(s,2H),0.83(s,2H).

[0210]

[0211] Example 23: Following the same method as in Example 1, yellow target product 23 was obtained in a yield of 66%. LC-MS (ESI) + )m / z 784.3(M+H) + . 1H NMR(400MHz,)δ9.43(d,J=2.3Hz,2H),9.22(s,1H),8.21–7.76(m,4H),7.60(d,J=8.3Hz,1H),6.99(s,1H),6.81(d d,J=8.5,2.1Hz,1H),4.97(dd,J=11.3,5.7Hz,1H),4.75(d,J=13.6Hz,1H),4.37(dt,J=12.9,7.8Hz,1H),4.05(d, J=19.2Hz,1H),3.35–3.18(m,3H),2.82(q,J=12.2Hz,4H),2.65–2.46(m,2H),2.30–2.18(m,2H),2.15(dd,J=11.2 ,5.7Hz,1H),2.04(dt,J=13.6,7.1Hz,2H),1.89(s,2H),1.60(d,J=2.4Hz,3H),1.04(s,2H),0.85(d,J=5.3Hz,2H).

[0212]

[0213] Example 24: The method was the same as in Example 1, yielding yellow target product 24 in 59% yield. LC-MS (ESI) + )m / z 798.3(M+H) + . 1 H NMR(400MHz,)δ9.28(s,2H),9.07(s,1H),7.94(s,1H),7.90(d,J=8.8Hz,1H),7.81–7.61(m,2H),7.45(d,J=8.3Hz,1H),6. 84(d,J=2.1Hz,1H),6.65(dd,J=8.4,2.2Hz,1H),4.80(dd,J=11.5,5.4Hz,1H),4.59(d,J=13.4Hz,1H),4.22(t,J=11.6Hz, 1H),3.91(d,J=14.0Hz,1H),3.54(dd,J=13.2,6.2Hz,1H),3.13(q,J=8.3,6.4Hz,3H),2.73–2.58(m,3H),2.30(dd,J=15.2 ,7.4Hz,2H),2.11(d,J=13.6Hz,2H),2.01–1.96(m,1H),1.81(s,2H),1.61(s,4H),1.47(s,3H),0.91(s,2H),0.72(s,2H).

[0214]

[0215] Example 25: The method described in Example 1 was the same, yielding yellow target product 25 in 67% yield. LC-MS (ESI) + )m / z 812.3(M+H) + .

[0216]

[0217] Example 26: Following the same method as in Example 1, yellow target product 26 was obtained in 77% yield. LC-MS (ESI) + )m / z 826.3(M+H) + .

[0218]

[0219] Example 27: The method was the same as in Example 1, yielding yellow target product 27 in 71% yield. LC-MS (ESI) + )m / z 840.4(M+H) + . 1 H NMR(400MHz,)δ9.27(s,2H),9.06(s,1H),7.93(s,1H),7.88(d,J=8.8Hz,1H),7.73(d,J=8.8Hz,1H),7.42(d,J=8.3Hz,1H),6.81(d,J=2. 1Hz,1H),6.61(dd,J=8.4,2.2Hz,1H),4.81–4.74(m,1H),4.58(d,J=13.5Hz,1H),4.21(ddt,J=11.5,8.2,4.1Hz,1H),3.90(d,J=14.0Hz, 1H),3.17–3.08(m,1H),3.05(t,J=7.0Hz,2H),2.66(ddt,J=19.4,15.9,6.8Hz,4H),2.26(t,J=7.6Hz,2H),2.15–2.03(m,2H),1.97(td,J =7.4,6.3,2.9Hz,1H),1.88–1.73(m,2H),1.56–1.48(m,4H),1.47(s,3H),1.27(p,J=6.4,4.9Hz,7H),0.90(s,2H),0.73(d,J=6.0Hz,2H).

[0220]

[0221] Example 28: Following the same method as in Example 1, yellow target product 28 was obtained in 64% yield. LC-MS (ESI)+ )m / z 809.3(M+H) + .

[0222]

[0223] Example 29: Following the same method as in Example 1, yellow target product 29 was obtained in 73% yield. LC-MS (ESI) + )m / z 810.3(M+H) + . 1 H NMR(400MHz,)δ9.63(d,J=4.1Hz,2H),9.42(d,J=2.4Hz,1H),8.33(s,1H),8.24(t,J=8.1Hz,1H),8.13(d,J=25.9Hz,2H),7.85(t,J =7.8Hz,1H),7.63(d,J=9.8Hz,2H),7.49(dt,J=9.5,4.5Hz,1H),5.16(t,J=14.3Hz,1H),5.04–4.84(m,1H),4.57(d,J=32.5Hz,1H) ,4.11–3.74(m,2H),3.60–3.36(m,3H),3.14(t,J=13.8Hz,2H),2.98(ddt,J=40.5,23.8,10.4Hz,4H),2.51(dd,J=36.8,14.2Hz,2H ),2.40–2.25(m,1H),2.17(d,J=11.7Hz,4H),2.03(t,J=9.9Hz,2H),1.88–1.74(m,3H),1.26(d,J=18.0Hz,2H),1.14–0.97(m,2H).

[0224]

[0225] Example 30: Following the same method as in Example 1, yellow target product 30 was obtained in a yield of 62%. LC-MS (ESI) + )m / z 796.3(M+H) + . 1H NMR(400MHz,)δ9.43(s,2H),9.23(s,1H),8.24(s,1H),8.07(d,J=12.3Hz,2H),7.77(s,1H),7.68(d,J=8. 4Hz,1H),6.99(s,1H),6.76(t,J=6.6Hz,1H),4.97(d,J=9.2Hz,1H),4.76(d,J=13.5Hz,1H),4.44(s,1H), 4.04(d,J=28.9Hz,1H),3.81–3.48(m,5H),3.42(d,J=13.3Hz,1H),2.84(dt,J=34.8,13.0Hz,4H),2.45–2 .21(m,4H),2.15(dd,J=12.8,8.3Hz,1H),2.11–1.93(m,2H),1.85(s,3H),1.29–1.22(m,2H),0.91(s,2H).

[0226]

[0227] Example 31: Following the same method as in Example 1, the yellow target product 31 was obtained in a yield of 68%. LC-MS (ESI) + )m / z 824.3(M+H) + .

[0228]

[0229] Example 32: The method was the same as in Example 1, yielding the yellow target product 32 in 70% yield. LC-MS (ESI) + )m / z 832.3(M+H) + .

[0230]

[0231] Example 33: The method was the same as in Example 1, yielding the yellow target product 33 in 61% yield. LC-MS (ESI) + )m / z 889.3(M+H) + . 1H NMR(400MHz,)δ9.33(s,2H),9.14(s,1H),8.02(s,1H),7.94(d,J=8.8Hz,1H),7.78(d,J=8.2Hz,2H),7.72(s,1H),7.37( dd,J=8.4,6.9Hz,3H),7.05(d,J=7.2Hz,1H),6.72(d,J=8.5Hz,1H),4.93–4.83(m,1H),4.63(d,J=13.8Hz,1H),4.53(s, 2H),4.38–4.29(m,1H),4.29–4.17(m,2H),3.95(d,J=14.2Hz,1H),3.27–3.17(m,1H),2.87(t,J=12.9Hz,1H),2.82–2.6 6(m,3H),2.21(t,J=17.1Hz,2H),2.12–2.04(m,1H),2.02–1.87(m,2H),1.54(s,3H),0.97(s,2H),0.81(d,J=6.1Hz,2H).

[0232]

[0233] Example 34: The method was the same as in Example 1, yielding the yellow target product 34 in 63% yield. LC-MS (ESI) + )m / z 838.3(M+H) + .

[0234]

[0235] Example 35: Intermediate I1 (20 mg, 0.042 mmol) and 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylindololin-5-yl)piperidin-4-carboxaldehyde (16 mg, 0.042 mmol) were added to a 10 mL round-bottom flask and dissolved in 1,2-dichloroethane. The mixture was stirred at room temperature for 30 min, and then sodium triacetoxyborohydride (18 mg, 0.084 mmol) was added. The mixture was stirred at room temperature for another 5 h. After the reaction was complete, the reaction solution was evaporated to dryness and purified using a 200-300 mesh silica gel column (DCM:MeOH = 20:1) to obtain the yellow target product 35 in 68% yield. LC-MS (ESI) was used for further analysis. + )m / z 796.3(M+H) + . 1H NMR(400MHz,Chloroform-d)δ10.06(s,1H),9.37(s,2H),9.26(s,1H),8.39–7.82(m,4H),7.71(d,J=8.5Hz,2H),7.49 (s,1H),7.32(d,J=2.3Hz,1H),7.08(dd,J=8.6,2.3Hz,1H),5.00(dd,J=12.1,5.2Hz,1H),4.22–4.07(m,1H),4.01(d, J=13.0Hz,2H),3.01(q,J=13.7,13.3Hz,4H),2.93–2.71(m,3H),2.31(d,J=6.0Hz,2H),2.27–2.11(m,5H),2.10–1.95 (m,2H),1.95–1.68(m,5H),1.37(d,J=12.5Hz,2H),1.27(d,J=2.4Hz,1H),1.02(s,2H),0.86(p,J=10.6,10.1Hz,2H).

[0236]

[0237] Example 36: The method described in Example 35 was the same, yielding yellow target product 36 in 73% yield. LC-MS (ESI) + )m / z 782.3(M+H) + .

[0238]

[0239] Example 37: I1 (20 mg, 0.042 mmol) and 5-(3-chloropropyn-1-yl)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione (0.042 mmol) were dissolved in 6 mL of DMF. N,N-diisopropylethylamine (0.126 mmol) was added, and the mixture was heated to 80°C with stirring and reacted overnight. The reaction solution was diluted with 30 mL of ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography (DCM:MeOH = 30:1) to obtain the yellow target product 37, with a yield of 43%. LC-MS (ESI) + )m / z 737.3(M+H) + .

[0240]

[0241] Example 38: The method described in Example 37 was the same, yielding the yellow target product 38 in 51% yield. LC-MS (ESI)+ )m / z 751.3(M+H) + .

[0242]

[0243] Example 39: The method described in Example 37 was the same, yielding yellow target product 39 in 48% yield. LC-MS (ESI) + )m / z 765.3(M+H) + .

[0244]

[0245] Example 40: The method described in Example 37 was the same, yielding a yellow target product 40 in 50% yield. LC-MS (ESI) + )m / z 779.3(M+H) + .

[0246]

[0247] Example 41: The method described in the same manner as in Example 37 yielded the yellow target product 41 in a yield of 43%. LC-MS (ESI) + )m / z 793.3(M+H) + .

[0248]

[0249] Example 42: The method was the same as in Example 37, yielding the yellow target product 42 in 46% yield. LC-MS (ESI) + )m / z 807.3(M+H) + .

[0250]

[0251] Example 43: The method described in the same manner as in Example 37 yielded the yellow target product 43 in a yield of 49%. LC-MS (ESI) + )m / z 821.3(M+H) + .

[0252]

[0253] Example 44: Following the same method as in Example 1, yellow target product 44 was obtained in 69% yield. LC-MS (ESI) + )m / z 827.3(M+H) + . 1H NMR(400MHz,)δ9.50(s,2H),9.30(s,1H),8.21(s,1H),8.11(d,J=8.0Hz,2H),8.04–7. 97(m,2H),7.89(s,1H),7.75(d,J=7.9Hz,2H),7.57(d,J=7.9Hz,2H),5.18–5.06(m,1H) ,4.90(s,1H),4.50(t,J=11.7Hz,1H),4.00(s,1H),3.39(s,1H),3.17(s,1H),3.00–2.9 4(m,1H),2.94–2.85(m,2H),2.41–2.07(m,5H),1.72(s,3H),1.16(s,2H),0.98(s,2H).

[0254]

[0255] Example 45: Following the same method as in Example 1, the yellow target product 45 was obtained in 65% yield. LC-MS (ESI) + )m / z 884.3(M+H) + .

[0256]

[0257] Example 46: Following the same method as in Example 1, the yellow target product 46 was obtained in 71% yield. LC-MS (ESI) + )m / z 831.3(M+H) + . 1 H NMR(400MHz,)δ9.70(s,2H),9.49(s,1H),8.42(s,1H),8.30(d,J=8.7Hz,1H),8.17(s,1H),8.06(d,J=7 .6Hz,2H),7.96–7.76(m,2H),7.64(d,J=7.6Hz,2H),7.49(d,J=7.7Hz,2H),5.30(d,J=9.9Hz,1H),5.09 (s,1H),4.71(d,J=11.8Hz,1H),4.20(s,1H),3.66(d,J=15.2Hz,1H),3.60–3.46(m,1H),3.38(d,J=34. 7Hz, 4H), 3.09 (q, J=12.3, 10.8Hz, 3H), 2.43 (t, J=54.4Hz, 5H), 1.92 (s, 3H), 1.35 (s, 2H), 1.16 (s, 2H).

[0258]

[0259] Example 47: The method was the same as in Example 1, yielding yellow target product 47 in 67% yield. LC-MS (ESI) + )m / z 888.3(M+H) + .

[0260]

[0261] Example 48: Following the same method as in Example 1, yellow target product 48 was obtained in 64% yield. LC-MS (ESI) + )m / z 895.3(M+H) + . 1 H NMR(400MHz,)δ9.45(s,2H),9.25(s,1H),8.41–7.81(m,4H),7.59(dd,J=8.4,3.2Hz,1H),6.99(s,1H),6.81(d,J=8.4Hz,1H),4.94( t,J=8.3Hz,1H),4.72(d,J=13.5Hz,1H),4.47(d,J=13.6Hz,1H),4.42–4.32(m,1H),3.98(d,J=14.0Hz,1H),3.65(tt,J=10.3,5.2Hz ,1H),3.27(t,J=12.8Hz,2H),2.93(d,J=12.5Hz,1H),2.89–2.69(m,4H),2.50(q,J=9.0,8.2Hz,4H),2.25(dd,J=22.7,13.0Hz,2H), 2.12(td,J=17.6,16.0,9.8Hz,3H),1.97(p,J=7.6,7.0Hz,4H),1.64(s,3H),1.43(dd,J=13.2,7.3Hz,3H),1.09(s,2H),0.93(s,2H).

[0262]

[0263] Example 49: Following the same method as in Example 1, yellow target product 49 was obtained in a yield of 67%. LC-MS (ESI) + )m / z 921.3(M+H) + . 1H NMR(400MHz,)δ9.44(d,J=2.6Hz,2H),9.22(s,1H),8.10(s,1H),8.06(d,J=8.8Hz,1H),7.91(s,1H),7.82(s,1H),7.70(dd,J=8.5,3.3Hz,1 H),7.31(d,J=8.6Hz,1H),7.11(t,J=8.9Hz,1H),4.96(dd,J=10.1,6.8Hz,1H),4.75(s,1H),4.39(d,J=12.5Hz,1H),4.05(dd,J=26.5,13.6H z,3H),3.67(p,J=6.7Hz,1H),3.35(h,J=6.9,4.2Hz,3H),3.17(q,J=7.5Hz,1H),3.09(t,J=12.5Hz,1H),2.94–2.71(m,5H),2.27(d,J=22.5 Hz,2H),2.20–2.11(m,1H),2.08–1.86(m,4H),1.77(dt,J=25.1,12.2Hz,2H),1.63(s,3H),1.40(d,J=6.9Hz,6H),1.07(s,2H),0.89(s,2H).

[0264]

[0265] Example 50: Following the same method as in Example 1, the yellow target product 50 was obtained in a yield of 74%. LC-MS (ESI) + )m / z 800.3(M+H) + .

[0266]

[0267] Example 51: The method was the same as in Example 1, yielding the yellow target product 51 in 57% yield. LC-MS (ESI) + )m / z 844.3(M+H) + .

[0268]

[0269] Example 52: The method was the same as in Example 1, yielding the yellow target product 52 in 61% yield. LC-MS (ESI) + )m / z 888.3(M+H) + .

[0270]

[0271] Example 53: The method was the same as in Example 1, yielding the yellow target product 53 in 77% yield. LC-MS (ESI) + )m / z 932.4(M+H) + .

[0272]

[0273] Example 54: The method was the same as in Example 1, yielding yellow target product 54 in 72% yield. LC-MS (ESI) + )m / z 946.4(M+H) + . 1 H NMR(400MHz,)δ9.43(s,2H),9.22(s,1H),8.08(s,1H),8.05(d,J=8.7Hz,1H),7.89(d,J=8.7Hz,1H),7.83(s,1H),7.50(t,J=7 .9Hz,1H),7.07(d,J=7.1Hz,1H),6.96(d,J=8.6Hz,1H),5.03–4.89(m,1H),4.71(d,J=13.4Hz,1H),4.40(s,1H),4.12(d,J=13. 8Hz,1H),3.80(t,J=6.6Hz,2H),3.72(t,J=5.4Hz,3H),3.66(d,J=9.5Hz,10H),3.48(t,J=5.4Hz,2H),3.36(s,1H),3.27(t,J= 12.9Hz,1H),2.97–2.59(m,6H),2.19(dt,J=34.3,11.0Hz,3H),1.99(d,J=15.2Hz,2H),1.63(s,3H),1.06(s,2H),0.89(s,2H).

[0274]

[0275] Example 55: The method was the same as in Example 1, yielding the yellow target product 55 in 81% yield. LC-MS (ESI) + )m / z 752.3(M+H) + . 1H NMR(400MHz,)δ8.07(s,1H),7.70(dd,J=14.5,8.2Hz,3H),7.48(d,J=8.8Hz,1H),6.99(s,1H),6.75(d,J =8.4Hz,1H),4.99–4.91(m,1H),4.74(d,J=13.6Hz,1H),4.45–4.33(m,1H),4.24–4.14(m,1H),3.71(dd,J =15.3,7.2Hz,2H),3.59(ddd,J=21.0,16.4,9.3Hz,3H),3.40(s,1H),2.96–2.71(m,4H),2.44–2.29(m,3 H),2.29–2.20(m,1H),2.18–2.11(m,1H),2.03(d,J=13.1Hz,2H),1.58(s,3H),1.01(s,2H),0.84(s,2H).

[0276]

[0277] Example 56: Following the same method as in Example 1, the yellow target product 56 was obtained in 86% yield. LC-MS (ESI) + )m / z 743.3(M+H) + .

[0278]

[0279] Example 57: The method was the same as in Example 1, yielding the yellow target product 57 in 78% yield. LC-MS (ESI) + )m / z 797.3(M+H) + . 1H NMR(400MHz,)δ9.43(s,2H),9.23(s,1H),8.24(s,1H),8.07(d,J=12.3Hz,2H),7.77(s,1H),7.68(d,J=8. 4Hz,1H),6.99(s,1H),6.76(t,J=6.6Hz,1H),4.97(d,J=9.2Hz,1H),4.76(d,J=13.5Hz,1H),4.44(s,1H), 4.04(d,J=28.9Hz,1H),3.81–3.48(m,5H),3.42(d,J=13.3Hz,1H),2.84(dt,J=34.8,13.0Hz,4H),2.45–2 .21(m,4H),2.15(dd,J=12.8,8.3Hz,1H),2.11–1.93(m,2H),1.85(s,3H),1.29–1.22(m,2H),0.91(s,2H).

[0280]

[0281] Example 58: The method described in Example 35 was the same, yielding the yellow target product 58 in 64% yield. LC-MS (ESI) + )m / z 732.3(M+H) + .

[0282]

[0283] Example 59: The method described in Example 35 was the same, yielding the yellow target product 59 in 57% yield. LC-MS (ESI) + )m / z 743.3(M+H) + .

[0284]

[0285] Example 60: The method was the same as in Example 35, yielding a yellow target product 60 in 61% yield. LC-MS (ESI) + )m / z 797.3(M+H) + . 1H NMR(400MHz,)δ9.49(d,J=4.0Hz,2H),9.30(d,J=4.1Hz,1H),8.14(d,J=8.7Hz,2H),7.81(s,1H ),7.75(d,J=8.5Hz,1H),7.42(s,1H),7.38(s,1H),7.16(d,J=8.6Hz,1H),5.06–4.96(m,1H),4 .22(s,1H),4.06(d,J=12.8Hz,2H),3.20–3.01(m,4H),2.97–2.76(m,3H),2.38(s,2H),2.22(d ,J=23.3Hz,7H),2.00(d,J=13.1Hz,2H),1.95–1.83(m,4H),1.44(d,J=3.9Hz,2H),0.96(s,4H).

[0286]

[0287] Example 61: The method was the same as in Example 35, yielding a yellow target product 61 in 54% yield. LC-MS (ESI) + )m / z 814.3(M+H) + .

[0288]

[0289] Example 62: The method described in Example 35 was the same, yielding the yellow target product 62 in 48% yield. LC-MS (ESI) + )m / z 814.3(M+H) + .

[0290]

[0291] Example 63: The method described in Example 35 was the same, yielding a yellow target product 63 in 52% yield. LC-MS (ESI) + )m / z 832.3(M+H) + .

[0292]

[0293] Example 64: The method was the same as in Example 35, yielding the yellow target product 64 in 47% yield. LC-MS (ESI) + )m / z 794.3(M+H) + . 1H NMR(400MHz,)δ9.33–9.15(m,3H),8.34(d,J=20.7Hz,1H),8.24(d,J=24.4Hz,1H),8.05–7.87(m,2H),7.87–7 .75(m,1H),7.75–7.62(m,1H),7.43(d,J=24.2Hz,1H),7.30–7.16(m,1H),5.17–5.01(m,1H),4.14(t,J=12.0H z,2H),3.58–3.43(m,3H),3.16(q,J=11.7,10.4Hz,4H),3.06–2.85(m,3H),2.51–2.38(m,2H),2.27(tt,J=23. 7,11.0Hz,7H),2.13–1.89(m,3H),1.85–1.67(m,3H),1.53(s,1H),1.15(d,J=23.4Hz,2H),1.06–1.00(m,2H).

[0294]

[0295] Example 65: The method was the same as in Example 35, yielding the yellow target product 65 in 51% yield. LC-MS (ESI) + )m / z 782.4(M+H) + .

[0296]

[0297] Example 66: The method was the same as in Example 1, yielding the yellow target product 66 in 81% yield. LC-MS (ESI) + )m / z 834.3(M+H) + .

[0298]

[0299] Example 67: The method was the same as in Example 1, yielding the yellow target product 67 in 74% yield. LC-MS (ESI) + )m / z 848.3(M+H) + .

[0300]

[0301] Example 68: The method was the same as in Example 1, yielding the yellow target product 68 in 77% yield. LC-MS (ESI) + )m / z 848.3(M+H) + .

[0302]

[0303] Example 69: The method described in Example 1 was the same, yielding a yellow target product 69 in 67% yield. LC-MS (ESI) + )m / z 863.3(M+H) + .

[0304]

[0305] Example 70: The method described in Example 35 was the same, yielding the yellow target product 70 in 67% yield. LC-MS (ESI) + )m / z 893.4(M+H) + .

[0306]

[0307] Example 71: The method described in the same manner as in Example 35 yielded the yellow target product 72 in 52% yield. LC-MS (ESI) + )m / z 879.4(M+H) + .

[0308]

[0309] Example 72: The method was the same as in Example 35, yielding the yellow target product 72 in 46% yield. LC-MS (ESI) + )m / z 851.4(M+H) + .

[0310]

[0311] Example 73: The method described in Example 35 was the same, yielding the yellow target product 73 in 48% yield. LC-MS (ESI) + )m / z 879.4(M+H) + .

[0312]

[0313] Example 74: The method described in Example 35 was the same, yielding the yellow target product 74 in 49% yield. LC-MS (ESI) + )m / z 836.4(M+H) + .

[0314]

[0315] Example 75: The method was the same as in Example 35, yielding the yellow target product 75 in 41% yield. LC-MS (ESI) + )m / z 814.4(M+H) + .

[0316]

[0317] Example 76: The method was the same as in Example 1, yielding a white target product 76 with a yield of 73%. LC-MS (ESI) + )m / z 941.4(M+H) + .

[0318]

[0319] Example 77: The method described in the same manner as in Example 1 yielded a white target product 77 in 68% yield. LC-MS (ESI) + )m / z 969.4(M+H) + .

[0320]

[0321] Example 78: Following the same method as in Example 1, a white target product 78 was obtained with a yield of 69%. LC-MS (ESI) + )m / z 997.5(M+H) + .

[0322]

[0323] Example 79: Following the same method as in Example 1, a white target product 79 was obtained with a yield of 82%. LC-MS (ESI) + )m / z 1025.5(M+H) + .

[0324]

[0325] Example 80: Following the same method as in Example 1, the yellow target product 80 was obtained in a yield of 76%. LC-MS (ESI) + )m / z 774.2(M+H) + .

[0326]

[0327] Example 81: The method was the same as in Example 1, yielding the yellow target product 81 in 79% yield. LC-MS (ESI) + )m / z 788.3(M+H) + .

[0328]

[0329] Example 82: The method was the same as in Example 1, yielding the yellow target product 82 in 83% yield. LC-MS (ESI) + )m / z 802.3(M+H) + .

[0330]

[0331] Example 83: The method was the same as in Example 1, yielding the yellow target product 83 in 78% yield. LC-MS (ESI) + )m / z 816.3(M+H) + .

[0332]

[0333] Example 84: The method described in Example 1 was the same, yielding the yellow target product 85 in 74% yield. LC-MS (ESI) + )m / z 830.3(M+H) + .

[0334]

[0335] Example 85: The method was the same as in Example 1, yielding the yellow target product 85 in 76% yield. LC-MS (ESI) + )m / z 844.3(M+H) + .

[0336]

[0337] Example 86: The method was the same as in Example 1, yielding the yellow target product 86 in 77% yield. LC-MS (ESI) + )m / z 858.3(M+H) + .

[0338]

[0339] Example 87: The method was the same as in Example 1, yielding the yellow target product 87 in 72% yield. LC-MS (ESI) + )m / z 802.3(M+H) + .

[0340]

[0341] Example 88: The method was the same as in Example 1, yielding the yellow target product 88 in 80% yield. LC-MS (ESI) + )m / z 816.3(M+H) + .

[0342]

[0343] Example 89: Following the same method as in Example 1, the yellow target product 89 was obtained in 78% yield. LC-MS (ESI) + )m / z 830.3(M+H) + .

[0344]

[0345] Example 90: The method was the same as in Example 1, yielding the yellow target product 90 in 83% yield. LC-MS (ESI) + )m / z 844.3(M+H) + .

[0346]

[0347] Example 91: The method was the same as in Example 1, yielding the yellow target product 91 in 83% yield. LC-MS (ESI) + )m / z 828.3(M+H) + .

[0348]

[0349] Example 92: The method was the same as in Example 1, yielding the yellow target product 92 in 76% yield. LC-MS (ESI) + )m / z 836.3(M+H) + .

[0350]

[0351] Example 93: The method was the same as in Example 1, yielding the yellow target product 93 in 77% yield. LC-MS (ESI) + )m / z 842.3(M+H) + .

[0352]

[0353] Example 94: The method was the same as in Example 1, yielding the yellow target product 94 in 87% yield. LC-MS (ESI) + )m / z 814.3(M+H) + .

[0354]

[0355] Example 95: The method was the same as in Example 1, yielding the yellow target product 95 in 78% yield. LC-MS (ESI) + )m / z 828.3(M+H) + .

[0356]

[0357] Example 96: The method was the same as in Example 1, yielding the yellow target product 96 in 73% yield. LC-MS (ESI) + )m / z 800.3(M+H) + .

[0358]

[0359] Example 97: The method was the same as in Example 1, yielding the yellow target product 97 in 75% yield. LC-MS (ESI) + )m / z 836.3(M+H) + .

[0360]

[0361] Example 98: The method was the same as in Example 1, yielding the yellow target product 98 in 79% yield. LC-MS (ESI) + )m / z 842.3(M+H) + .

[0362]

[0363] Example 99: The method described in Example 35 was the same, yielding the yellow target product 99 in 74% yield. LC-MS (ESI) + )m / z 786.3(M+H) + .

[0364]

[0365] Example 100: The method was the same as in Example 35, yielding a yellow target product 100 with a yield of 48%. LC-MS (ESI) + )m / z 800.3(M+H) + .

[0366]

[0367] Example 101: The method was the same as in Example 1, yielding a yellow target product 101 in 81% yield. LC-MS (ESI) + )m / z 831.3(M+H) + .

[0368]

[0369] Example 102: The method was the same as in Example 1, yielding the yellow target product 102 in 76% yield. LC-MS (ESI) + )m / z 835.3(M+H) + .

[0370]

[0371] Example 103: The method was the same as in Example 35, yielding the yellow target product 103 in 49% yield. LC-MS (ESI) + )m / z 855.3(M+H) + .

[0372]

[0373] Example 104: The method was the same as in Example 35, yielding the yellow target product 104 in 52% yield. LC-MS (ESI) + )m / z 869.3(M+H) + .

[0374]

[0375] Example 105: The method was the same as in Example 35, yielding the yellow target product 105 in 47% yield. LC-MS (ESI) + )m / z 883.4(M+H) + .

[0376]

[0377] Example 106: Following the same method as in Example 1, the yellow target product 106 was obtained in 73% yield. LC-MS (ESI) + )m / z 733.3(M+H) + .

[0378]

[0379] Example 107: The method was the same as in Example 1, yielding the yellow target product 107 in 71% yield. LC-MS (ESI) +)m / z 747.3(M+H) + .

[0380]

[0381] Example 108: The method was the same as in Example 1, yielding the yellow target product 108 in 87% yield. LC-MS (ESI) + )m / z 761.3(M+H) + .

[0382]

[0383] Example 109: The method was the same as in Example 1, yielding the yellow target product 109 in 75% yield. LC-MS (ESI) + )m / z 789.3(M+H) + .

[0384]

[0385] Example 110: Following the same method as in Example 1, the yellow target product 110 was obtained in 77% yield. LC-MS (ESI) + )m / z 747.3(M+H) + .

[0386]

[0387] Example 111: The method was the same as in Example 1, yielding the yellow target product 111 in 72% yield. LC-MS (ESI) + )m / z 761.3(M+H) + .

[0388]

[0389] Example 112: The method was the same as in Example 1, yielding the yellow target product 112 in 71% yield. LC-MS (ESI) + )m / z 775.4(M+H) + .

[0390]

[0391] Example 113: The method was the same as in Example 1, yielding the yellow target product 113 in 79% yield. LC-MS (ESI) + )m / z 789.3(M+H) + .

[0392]

[0393] Example 114: The method was the same as in Example 1, yielding the yellow target product 114 in 85% yield. LC-MS (ESI) + )m / z 773.3(M+H) + .

[0394]

[0395] Example 115: Following the same method as in Example 1, the yellow target product 115 was obtained in 82% yield. LC-MS (ESI) + )m / z 781.3(M+H) + .

[0396]

[0397] Example 116: Following the same method as in Example 1, the yellow target product 116 was obtained in 76% yield. LC-MS (ESI) + )m / z 787.3(M+H) + .

[0398]

[0399] Example 117: The method was the same as in Example 35, yielding the yellow target product 117 in 50% yield. LC-MS (ESI) + )m / z 745.3(M+H) + .

[0400]

[0401] Example 118: Following the same method as in Example 1, the yellow target product 118 was obtained in 73% yield. LC-MS (ESI) + )m / z 759.3(M+H) + .

[0402]

[0403] Example 119: The method described in the same manner as in Example 35 yielded the yellow target product 119, with a yield of 59%. LC-MS (ESI) + )m / z 731.3(M+H) + .

[0404]

[0405] Example 120: Following the same method as in Example 1, the yellow target product 120 was obtained in 69% yield. LC-MS (ESI)+ )m / z 745.3(M+H) + .

[0406]

[0407] Example 121: Following the same method as in Example 1, the yellow target product 121 was obtained in 74% yield. LC-MS (ESI) + )m / z 773.3(M+H) + .

[0408]

[0409] Example 122: The method was the same as in Example 1, yielding the yellow target product 122 in 79% yield. LC-MS (ESI) + )m / z 781.3(M+H) + .

[0410]

[0411] Example 123: The method was the same as in Example 1, yielding the yellow target product 123 in 73% yield. LC-MS (ESI) + )m / z 787.3(M+H) + .

[0412]

[0413] Example 124: Following the same method as in Example 1, yellow target product 124 was obtained in 67% yield. LC-MS (ESI) + )m / z 776.3(M+H) + .

[0414]

[0415] Example 125: The method was the same as in Example 1, yielding the yellow target product 125 in 66% yield. LC-MS (ESI) + )m / z 800.3(M+H) + .

[0416]

[0417] Example 126: Following the same method as in Example 1, yellow target product 126 was obtained in 78% yield. LC-MS (ESI) + )m / z 746.3(M+H) + .

[0418]

[0419] Example 127: The method was the same as in Example 1, yielding yellow target product 127 in 55% yield. LC-MS (ESI) + )m / z 760.3(M+H) + . 1 H NMR (400MHz, Chloroform-d) δ11.11(s,1H),10.19(s,1H),8.43(d,J=1.6Hz,1H),8.42(d,J=1.7Hz,1H),8.02(s,1H),7.85(s,1H),7.81(s,1H),7.61(d ,J=2.1Hz,1H),7.60(d,J=1.5Hz,1H),7.53(d,J=8.3Hz,1H),7.19(s,1H),7 .03(td,J=5.0,3.3Hz,1H),6.90(d,J=2.3Hz,1H),6.67(d,J=8.4Hz,1H),4.8 8(dd,J=12.0,5.3Hz,1H),4.78–4.58(m,2H),4.25(td,J=11.4,9.5,5.9Hz, 1H),3.91(d,J=14.0Hz,1H),3.25–3.04(m,3H),2.79(td,J=15.6,14.7,3.7H z,2H),2.74–2.60(m,2H),2.36–2.21(m,2H),2.21–2.01(m,3H),1.94–1.72 (m,4H),1.58(q,J=7.9Hz,5H),0.85(d,J=2.4Hz,2H),0.71(q,J=4.4Hz,2H).

[0420]

[0421] Example 128: Following the same method as in Example 1, yellow target product 128 was obtained in 53% yield. LC-MS (ESI) + )m / z 774.3(M+H) + .

[0422]

[0423] Example 129: Following the same method as in Example 1, yellow target product 129 was obtained in 71% yield. LC-MS (ESI) + )m / z 746.3(M+H) + .

[0424]

[0425] Example 130: Following the same method as in Example 1, the yellow target product 130 was obtained in a yield of 62%. LC-MS (ESI) + )m / z 774.3(M+H) + .

[0426]

[0427] Example 131: The method was the same as in Example 1, yielding a yellow target product 131 in 76% yield. LC-MS (ESI) + )m / z 788.3(M+H) + . 1 H NMR(400MHz,Chloroform-d)δ10.64(s,1H),10.25(s,1H),8.52(dt,J=5.1,1.5Hz,1H),8.48(s,1H),7.99(d,J=2.0Hz,2H),7.82(s,1H),7.73–7.6 3(m,2H),7.52(dd,J=8.6,7.1Hz,1H),7.12(dd,J=7.1,3.7Hz,2H),6.92( d,J=8.5Hz,1H),6.27(t,J=5.7Hz,1H),4.99–4.88(m,1H),4.75(d,J=13. 6Hz,1H),4.34(q,J=4.4Hz,1H),3.99(d,J=13.9Hz,1H),3.32(q,J=6.5Hz ,2H),3.20(t,J=12.9Hz,1H),2.95–2.68(m,4H),2.41(t,J=7.3Hz,2H),2 .31–2.09(m,3H),2.01–1.82(m,4H),1.72(h,J=7.3Hz,4H),1.50(p,J=7. 8Hz,2H),1.34–1.20(m,4H),0.93(d,J=5.1Hz,2H),0.79(q,J=4.5Hz,2H).

[0428]

[0429] Example 132: The method was the same as in Example 1, yielding the yellow target product 132 in 62% yield. LC-MS (ESI) + )m / z 772.3(M+H) + .

[0430]

[0431] Example 133: The method was the same as in Example 1, yielding the yellow target product 133 in 82% yield. LC-MS (ESI) + )m / z 786.3(M+H) + .

[0432]

[0433] Example 134: The method was the same as in Example 35, yielding the yellow target product 134 in 52% yield. LC-MS (ESI) + )m / z 744.3(M+H) + .

[0434]

[0435] Example 135: The method was the same as in Example 1, yielding the yellow target product 135 in 72% yield. LC-MS (ESI) + )m / z 758.3(M+H) + .

[0436]

[0437] Example 136: The method described in the same manner as in Example 35 yielded the yellow target product 136, with a yield of 42%. LC-MS (ESI) + )m / z 730.3(M+H) + .

[0438]

[0439] Example 137: Following the same method as in Example 1, yellow target product 137 was obtained in 69% yield. LC-MS (ESI) + )m / z 744.3(M+H) + .

[0440]

[0441] Example 138: Following the same method as in Example 1, the yellow target product 138 was obtained in 74% yield. LC-MS (ESI) + )m / z 772.3(M+H) + .

[0442]

[0443] Example 139: Following the same method as in Example 1, yellow target product 139 was obtained in 78% yield. LC-MS (ESI) + )m / z 786.3(M+H)+ .

[0444]

[0445] Example 140: Following the same method as in Example 1, the yellow target product 140 was obtained in 83% yield. LC-MS (ESI) + )m / z 779.3(M+H) + .

[0446]

[0447] Example 141: The method was the same as in Example 1, yielding a yellow target product 141 in 72% yield. LC-MS (ESI) + )m / z 811.3(M+H) + .

[0448]

[0449] Example 142: The method was the same as in Example 1, yielding the yellow target product 142 in 87% yield. LC-MS (ESI) + )m / z 783.3(M+H) + .

[0450]

[0451] Example 143: Following the same method as in Example 1, the yellow target product 143 was obtained in 76% yield. LC-MS (ESI) + )m / z 769.3(M+H) + .

[0452]

[0453] Example 144: Following the same method as in Example 1, yellow target product 144 was obtained with a yield of 71%. LC-MS (ESI) + )m / z 797.3(M+H) + .

[0454]

[0455] Example 145: Following the same method as in Example 1, the yellow target product 145 was obtained in 83% yield. LC-MS (ESI) + )m / z 811.3(M+H) + .

[0456]

[0457] Example 146: Following the same method as in Example 1, yellow target product 146 was obtained in 65% yield. LC-MS (ESI) + )m / z 804.3(M+H) + .

[0458]

[0459] Example 147: The method was the same as in Example 35, yielding yellow target product 147 in 42% yield. LC-MS (ESI) + )m / z 769.3(M+H) + .

[0460]

[0461] Example 148: The method described in the same manner as in Example 35 yielded the yellow target product 148, with a yield of 46%. LC-MS (ESI) + )m / z 755.3(M+H) + .

[0462]

[0463] Example 149: The method was the same as in Example 35, yielding yellow target product 149 in 44% yield. LC-MS (ESI) + )m / z 801.3(M+H) + .

[0464]

[0465] Example 150: The method was the same as in Example 35, yielding the yellow target product 150 in 41% yield. LC-MS (ESI) + )m / z 787.3(M+H) + .

[0466]

[0467] Example 151: The method was the same as in Example 1, yielding a yellow target product 151 in 83% yield. LC-MS (ESI) + )m / z 822.3(M+H) + .

[0468]

[0469] Example 152: The method was the same as in Example 1, yielding the yellow target product 152 in 81% yield. LC-MS (ESI) +)m / z 836.4(M+H) + .

[0470]

[0471] Example 153: The method was the same as in Example 1, yielding the yellow target product 153 in 74% yield. LC-MS (ESI) + )m / z 808.3(M+H) + .

[0472]

[0473] Example 154: Following the same method as in Example 1, the yellow target product 154 was obtained in 72% yield. LC-MS (ESI) + )m / z 836.3(M+H) + .

[0474]

[0475] Example 155: The method was the same as in Example 1, yielding the yellow target product 155 in 75% yield. LC-MS (ESI) + )m / z 829.3(M+H) + .

[0476]

[0477] Example 156: The method was the same as in Example 35, yielding yellow target product 156 in 32% yield. LC-MS (ESI) + )m / z 794.3(M+H) + .

[0478]

[0479] Example 157: The method was the same as in Example 35, yielding yellow target product 157 in 42% yield. LC-MS (ESI) + )m / z 780.2(M+H) + .

[0480]

[0481] Example 158: The method described in Example 35 was the same, yielding the yellow target product 158 ​​in 45% yield. LC-MS (ESI) + )m / z 835.2(M+H) + .

[0482]

[0483] Example 159: The method described in Example 35 was the same, yielding yellow target product 159 in 43% yield. LC-MS (ESI) + )m / z 875.4(M+H) + .

[0484]

[0485] Example 160: The method was the same as in Example 35, yielding the yellow target product 160 in 47% yield. LC-MS (ESI) + )m / z 890.4(M+H) + .

[0486]

[0487] Example 161: The method was the same as in Example 35, yielding the yellow target product 161 in 51% yield. LC-MS (ESI) + )m / z 849.3(M+H) + .

[0488]

[0489] Example 162: The method was the same as in Example 35, yielding the yellow target product 162 in 52% yield. LC-MS (ESI) + )m / z 783.3(M+H) + .

[0490]

[0491] Example 163: The method was the same as in Example 35, yielding the yellow target product 163 in 47% yield. LC-MS (ESI) + )m / z 838.4(M+H) + .

[0492]

[0493] Example 164: The method was the same as in Example 35, yielding the yellow target product 164 in 43% yield. LC-MS (ESI) + )m / z 822.4(M+H) + .

[0494]

[0495] Example 165: The method was the same as in Example 35, yielding the yellow target product 165 in 39% yield. LC-MS (ESI) + )m / z 801.4(M+H) + .

[0496]

[0497] Example 166: The method was the same as in Example 35, yielding yellow target product 166 in 42% yield. LC-MS (ESI) + )m / z 856.4(M+H) + .

[0498]

[0499] Example 167: The method was the same as in Example 35, yielding yellow target product 167 in 38% yield. LC-MS (ESI) + )m / z 841.3(M+H) + .

[0500]

[0501] Example 168: The method was the same as in Example 35, yielding the yellow target product 168 in 44% yield. LC-MS (ESI) + )m / z 756.3(M+H) + .

[0502]

[0503] Example 169: The method was the same as in Example 35, yielding yellow target product 169 in 41% yield. LC-MS (ESI) + )m / z 811.4(M+H) + .

[0504]

[0505] Example 170: The method was the same as in Example 35, yielding the yellow target product 170 in 47% yield. LC-MS (ESI) + )m / z 796.4(M+H) + .

[0506] Biological test example 1

[0507] 1. Bioactivity assay of compounds at the Western blot level

[0508] 1.1 Experimental Materials:

[0509] THP-1 human acute single cells (purchased from ATCC, catalog number TIB-202) were cultured in a 37°C, 5% CO2 incubator. The culture medium consisted of RPMI 1640 (purchased from Gibco, catalog number 22400-105), supplemented with 10% FBS (Gibco, catalog number 10091148); 1% PenStrep (purchased from Gibco, catalog number 15140); and 0.05 mM 2-mercaptoethanol (purchased from Sigma, catalog number M6250).

[0510] 1.2 Experimental Methods:

[0511] THP-1 cells were suspended in 1 mL of culture medium and placed in 12-well cell culture plates (3 × 10⁵ to 5 × 10⁵ cells / well). Different concentrations of the compounds of this invention were used for treatment. After incubation for 24 h, cells were collected, centrifuged to remove the supernatant, and then washed once with PBS, which was then discarded. 100 μL of 2× Loading Buffer (the 5× Loading Buffer formulation is: 250 mM Tris-HCl (pH 6.8), 10% (w / v) SDS, 0.5% (w / v) bromophenol blue, 50% (v / v) glycerol, and 5% (w / v) β-mercaptoethanol (2-ME)) was added to each sample. The mixture was thoroughly vortexed and denatured at 95 °C for 15 min. After rehydration, the mixture was stored at -20 °C or used directly for Western blotting. Then, 10 μL of protein sample was taken and treated with 10%... SDS-PAGE gel electrophoresis was used to separate protein samples. The voltage was 80 volts in the stacking gel. Once the protein samples entered the separating gel, the voltage was adjusted to 120 volts, and electrophoresis was continued until bromophenol blue had almost completely escaped the PAGE gel. After electrophoresis, the samples were wet-transferred to a PVDF membrane at 4°C (100V, 1.5h). After transfer, the membrane was blocked with 5% milk for one hour. After blocking, the membrane was washed three times with PBST for 5 minutes each time, and then coated with primary antibody IRAK4 (purchased from Abcam, catalog number ab119942) and β-Act... Incubate overnight at 4°C with the antibody (purchased from Beyotime, catalog number AF0003) and GAPDH (purchased from Diagbio, catalog number Db106). After incubation, recover the antibody and wash three times with PBST for 5 minutes each time. Then incubate with the corresponding rabbit (CST:#7074) / mouse (CST:#7076) secondary antibody at room temperature for 1 hour. Recover the secondary antibody and wash the membrane three times with PBST for 10 minutes each time. Develop the membrane using chemiluminescent buffer (purchased from Vazyme, catalog number E412-01) on a Tianneng developing instrument. The development results are analyzed for grayscale using ImageJ, and the degradation ratio is obtained by normalization. The results are shown in Table 1 and [Table data missing]. Figure 1As shown.

[0512] Table 1 Results of IRAK4 protein degradation activity

[0513]

[0514]

[0515] Note: A: Half-maximal degradation concentration <30 nM; >90% degradation (24-hour treatment);

[0516] B: 30 nM < half-maximum degradation concentration < 100 nM; > 50% degradation but < 90% (24-hour treatment);

[0517] C: 100 nM < half-maximum degradation concentration < 1000 nM; > 10% degradation but < 50% (24-hour treatment);

[0518] D: No significant degradation, half-maximal degradation concentration >1000nM.

[0519] From Table 1 and Figure 1 The results show that most of the compounds in this invention exhibit high IRAK4 protein degradation activity. Biological Test Example 2: In vitro THP-1 cell activity evaluation

[0520] THP-1 cellular TNFα ELISA assay

[0521] 2.1 Experimental Methods:

[0522] The TNF-a content in cell culture supernatant samples was detected using a TNF-a ELISA kit. TNF-a was produced by THP-1 cells stimulated with 150 ng / mL LPS (sigma, Cat#L6529).

[0523] THP-1 cells in normal logarithmic growth phase were cultured at a certain concentration (1×10⁻⁶). 5 100 nL of the sample was seeded in a 96-well plate (Coming #3599) and incubated in a cell culture incubator. After two hours, 16.9 nL of different concentrations of the test compound (8 × final concentration) was added and incubated in the incubator. After one hour, 16.7 μL of 1200 ng / mL LPS was added and incubated in the incubator. After 18 hours, the culture supernatant was collected and the TNF-α content was detected using a TNF-α ELISA kit. Finally, the OD signal (OD450-OD570) was read on an Envision plate reader.

[0524] 2.2 Data Analysis:

[0525] Convert the OD450-OD570 signal values ​​to percentage suppression rates.

[0526] Inhibition rate % = (ZPE-sample) / (ZPE-HPE)×100.

[0527] HPE represents the OD450-OD570 signal values ​​of control wells without lipopolysaccharide (LPS)-stimulated cells, and ZPE represents the OD450-OD570 signal values ​​of control wells with LPS-stimulated cells. The IC50 of the compounds was calculated using the XLFit add-in in Excel. 50 value.

[0528] The test results are summarized in Table 2.

[0529] As shown in Table 2, the compounds of this invention exhibited good inhibitory activity against TNF-α production in THP-1 cells during the cell viability assay.

[0530] Table 2 Results of in vitro screening tests of the compounds of this invention

[0531] compound <![CDATA[THP-1 / IC 50 (nM)]]> Example 3 26.1 Example 35 6.5 Example 36 18.3 Example 60 16.8 Example 64 5.2

[0532] Biological Test Example 3: Pharmacokinetic Study in Mice

[0533] 3.1 Experimental Objective:

[0534] This study aimed to investigate the pharmacokinetics of the test compound in the plasma of male CD-1 mice after intravenous and oral administration.

[0535] 3.2 Experimental Procedure:

[0536] Intravenous injection group: An appropriate amount of the test compound (the compound prepared in Example 35 of this invention) was weighed, dissolved in 5% DMSO / 10% Solutol / 85% H2O, and the pH was adjusted to 4-5 with 6M hydrochloric acid. A clear solution of 1.0 mg / mL was prepared by vortexing, filtered through a 0.22 μM microporous membrane, and then used for later use. Six- to ten-week-old male CD-1 mice were selected and intravenously injected with the test compound solution at a dose of 2 mg / kg. Sample collection times were: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0537] Oral administration group: An appropriate amount of the test compound was weighed, dissolved in 5% DMSO / 10% Solutol / 85% H2O, and the pH was adjusted to 4-5 with 6M hydrochloric acid. A clear solution of 2.0 mg / mL was prepared by vortexing and filtered through a 0.22 μM microporous membrane for later use. Six- to ten-week-old male CD-1 mice were selected and orally administered the test compound solution at a dose of 10 mg / kg. Samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0538] Approximately 50 μL of whole blood was collected via the jugular vein at each time point to prepare plasma for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were euthanized under CO2 anesthesia after the last time point PK sample was collected. WinNonlin was used. TM The non-compartmental model of the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA) was used to process plasma concentrations, and the pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The experimental results are shown in Table 3.

[0539] As shown in Table 3, the compounds of this invention exhibit good bioavailability in CD-1 mouse pharmacokinetic studies.

[0540] Table 3 Pharmacokinetic results of the test compounds (Example 35)

[0541]

[0542]

Claims

1. A compound, characterized in that: It is the compound shown in Formula I. In Formula I, T is selected from the following groups: ； L is selected from the following groups: E is selected from the following groups: 。 2. The following compounds: 。 3. A drug, characterized in that: The active ingredient of the drug is the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. The drug according to claim 3, characterized in that: The excipients of the drug are pharmaceutically acceptable carriers.

5. The drug according to claim 3, characterized in that: The excipients of the drug are excipients.

6. The drug according to claim 5, characterized in that: The excipient is a diluent and / or a medium.

7. The use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the drug of any one of claims 3-6, in the preparation of any of the functional pharmaceutical products described in 1)-2): 1) Used to degrade or inhibit IRAK4; 2) Treatment or prevention of IRAK4-related diseases.

8. The application according to claim 7, characterized in that: The IRAK4-related diseases are non-Hodgkin's lymphoma or autoimmune diseases. The autoimmune disease mentioned is at least one of the following: rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, multiple sclerosis, asthma, and chronic arthritis.

Images