IRAK4 degradation agent as well as pharmaceutical composition and pharmaceutical application thereof

Abstract

The invention provides an IRAK4 degradation agent as shown in a formula I as well as preparation and application thereof, and particularly provides a compound as shown in the formula I as well as a deuterated substance, a stereoisomer, a geometric isomer, a tautomer, a solvate, a hydrate, a prodrug, pharmaceutically acceptable salt or eutectic and a pharmaceutical composition thereof. The invention further discloses a preparation method of the compound and application of the compound in IRAK4 related diseases such as autoimmune diseases, inflammatory diseases and cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically, to a compound of general formula I or its deuterated product, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, pharmaceutical composition, and a preparation method thereof, as well as use in IRAK4-related diseases such as tumors, inflammation or autoimmune system diseases. Background Art

[0002] The protein degradation targeting chimera (PROTAC) technology is a targeted protein degradation technology proposed by Craig Crews et al. in 2001. This type of molecule can bind to the target protein and E3 ubiquitin ligase at the same time, thereby inducing the target protein to be degraded by the ubiquitin-proteasome system (UPS) in the human body. At present, many PROTAC molecules have shown significant therapeutic effects on related diseases in preclinical and clinical studies, so this technology has received widespread attention in recent years.

[0003] IRAK4 is a serine / threonine protein kinase. As the first kinase in the TLR-MYD88 signaling pathway in innate immunity, it plays both phosphorylation and scaffolding roles, and is crucial in the signal transduction of innate immune activation. IRAK4 has been reported to play an important role in the occurrence and development of inflammatory diseases, autoimmune diseases and various malignant tumors, and is a highly potential therapeutic target. Traditional IRAK4 small molecule inhibitors can only inhibit its phosphorylation effect, and cannot completely block the activation of IRAK4-related pathways. PROTAC molecules can degrade IRAK4, thereby blocking both the scaffolding effect and the phosphorylation effect, and completely blocking the activation of IRAK4-related pathways. Therefore, PROTAC molecules targeting IRAK4 have great potential in the treatment of IRAK4-related inflammation, autoimmune diseases, tumors and other diseases. Summary of the invention

[0004] The present invention aims to provide a compound of general formula I having IRAK4 degradation activity or its deuterated product, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, pharmaceutical composition, as well as a preparation method and use thereof in IRAK4-related diseases such as autoimmune diseases, inflammatory diseases or cancer.

[0005] In the first aspect of the present invention, there is provided a compound of formula I or a deuterated substance, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal thereof:

[0006]

[0007] in:

[0008] Ring T is selected from a 5-9 membered heteroaromatic ring;

[0009] L' is -CONH- or -NHCO-, wherein the left side is connected to the ring T and the right side is connected to the parent core;

[0010] E is CH or N;

[0011] R x is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -O-L1-R a 、-NR b R c 、-C(O)NR b R c ; The substitution refers to one or more R j replace;

[0012] R b , R c Each is independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution refers to a halogen, a hydroxyl, an amino, a carbonyl, a cyano, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy, or one or more of the following: b and R c Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R j replace;

[0013] L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C6 alkyl chain; and one or more hydrogen atoms on L1 are optionally replaced by halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0014] Each R aEach is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to the substitution of one or more R j replace;

[0015] Each R j Each is independently selected from halogen, carbonyl, -L2-CN, -L2-OR k 、-L2-COOR k 、-L2-NR k R m 、-L2-CONR k R m 、-L2-S(O) 2 NR k R m , substituted or unsubstituted C1-C6 alkyl, -L2-substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, -L2-substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, -L2-substituted or unsubstituted 6-10 membered aryl, -L2-substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to substitution by one or more of the following groups: halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy, -C(O)(halogenated or unhalogenated C1-C3 alkyl);

[0016] L2 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogens on L2 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0017] R k , R m are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 acyl; the substitution refers to one or more halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 replace;

[0018] Every R yEach is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to halogen, hydroxyl, amino, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy, or one or more thereof;

[0019] m is selected from 1 or 2;

[0020] Every R z Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carbonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substitution refers to substitution by one or more of halogen, hydroxyl, amino, cyano;

[0021] n is selected from 1, 2, 3, 4;

[0022] L is a covalent bond or a divalent saturated or unsaturated straight or branched C1-C30 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by one or more of the following structures: -Cy-, -O-, -C(O)-, -C(S)-, -NH-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -OC(O)NH-, -NHC(O)O-, -S-, -S(O) 2 -、-NHS(O) 2 -、-S(O) 2 NH-、-P(O)(OR n )-、-P(O)(NR n 2 )-、-P(O)(R n )-、-N=CH-、

[0023] in:

[0024] Each Cy is independently selected from the following rings: a saturated or partially saturated C3-C12 carbocyclic ring (including a monocyclic ring, a bridged ring, a condensed ring, or a spirocyclic ring), a saturated or partially saturated 4-12 membered heterocyclic ring (including a monocyclic ring, a bridged ring, a condensed ring, or a spirocyclic ring), a 6-14 membered aromatic ring, or a 5-14 membered heteroaromatic ring;

[0025] r is 0, 1, 2, 3, 4, or 5;

[0026] Every R nEach is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkoxy;

[0027] Any one or more hydrogen atoms on L are optionally replaced by R 1 Replace; each R 1 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -L3-substituted or unsubstituted saturated or partially saturated C3-C12 carbocyclic ring (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclic ring (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted 6-14 membered aromatic ring, -L3-substituted or unsubstituted 5-14 membered heteroaromatic ring, -L3-substituted or unsubstituted -NR d R e , -L3-substituted or unsubstituted-COOR d , -L3-substituted or unsubstituted-CONR d R e , -L3-substituted or unsubstituted-S(O) 2 NR d R e , where R d , R e Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 acyl, C1-C6 sulfonyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , C1-C6 alkyl which may be substituted or unsubstituted by halogen, hydroxy or amino, C1-C6 alkoxy which may be substituted or unsubstituted by halogen, hydroxy or amino;

[0028] L3 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C6 alkyl chain; and one or more hydrogen atoms on L3 are optionally replaced by halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0029] Or: two R on the same atom 1 The group optionally forms a saturated or partially saturated C3-C12 carbocyclic ring, a saturated or partially saturated 4-12 membered heterocyclic ring together with its middle atom; the heterocyclic ring is optionally substituted by one or more R p replace;

[0030] Each R p Each is independently selected from halogen, hydroxyl, amino, cyano, carbonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl.

[0031] LBM is the E3 ubiquitin ligase binding part.

[0032] In another preferred embodiment, ring T is a 5-9 membered nitrogen-containing heteroaromatic ring.

[0033] In another preferred embodiment, ring T is a 5-membered heteroaromatic ring or a 9-membered condensed heteroaromatic ring.

[0034] In another preferred embodiment, the 9-membered fused heteroaromatic ring is a 6-membered aromatic ring or a heteroaromatic ring fused with a 5-membered heteroaromatic ring.

[0035] In another preferred embodiment, ring T is a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a pyridine ring, or a pyrazolo[1,5-a]pyrimidine.

[0036] In another preferred embodiment, ring T is selected from the following structures:

[0037] in, Indicates the site of attachment to L'.

[0038] In another preferred embodiment, each R y Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to substitution by one or more of halogen, hydroxyl, amino, halogenated or unhalogenated C1-C6 alkyl.

[0039] In another preferred embodiment, each R y Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more of halogen, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, trichloromethyl.

[0040] In another preferred embodiment, each R y Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more of halogen, hydroxyl, amino, and methyl.

[0041] In another preferred embodiment, each R yEach is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more of hydroxyl, halogenated C1-C3 alkyl, amino, and methyl.

[0042] In another preferred embodiment, Selected from the following structures:

[0043]

[0044] In another preferred embodiment, L' is selected from in, indicates the site of attachment to loop T, Indicates the site of connection with the mother nucleus, preferably

[0045] In another preferred embodiment, R x is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -O-L1-R a 、-NR b R c 、-C(O)NR b R c ; The substitution refers to one or more R j replace;

[0046] R b , R c Each is independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution refers to substitution by one or more of halogen, hydroxyl, amino, carbonyl, and cyano; or R b and R c Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R j replace;

[0047] L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C6 alkyl chain; and one or more hydrogen atoms on L1 are optionally replaced by halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0048] Each R aEach is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to the substitution of one or more R j replace;

[0049] Each R j Each is independently selected from halogen, carbonyl, -L2-CN, -L2-OR k 、-L2-COOR k 、-L2-NR k R m 、-L2-CONR k R m 、-L2-S(O) 2 NR k R m , substituted or unsubstituted C1-C6 alkyl, -L2-substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, -L2-substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, -L2-substituted or unsubstituted 6-10 membered aryl, -L2-substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to substitution by one or more of the following groups: halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy, -C(O)(halogenated or unhalogenated C1-C3 alkyl);

[0050] L2 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogens on L2 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0051] R k , R m are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 acyl; the substitution refers to halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 One or more substitutions in .

[0052] In another preferred embodiment, R xis selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-8 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, -O-L1-R a 、-NR b R c ; The substitution refers to one or more R j replace.

[0053] In another preferred embodiment, R b , R c Each is independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution refers to halogen, hydroxyl, amino, cyano, -CONH 2 One or more substitutions in R b and R c Optionally, together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic ring, which is optionally replaced by one or more R j replace.

[0054] In another preferred embodiment, R b , R c Each is independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, and the substitution refers to substitution by one or more of halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, and halogenated or unhalogenated C1-C6 alkoxy.

[0055] In another preferred embodiment, L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L1 are optionally replaced by halogen, hydroxyl, amino, cyano, -CONH 2 replace.

[0056] In another preferred embodiment, L1 is selected from a chemical bond or a divalent saturated or unsaturated straight or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L1 are optionally substituted by halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, or halogenated or unhalogenated C1-C6 alkoxy.

[0057] In another preferred embodiment, each R aEach is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-8 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to the substitution of one or more R j replace.

[0058] In another preferred embodiment, each R a Each is independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted saturated or partially saturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-8 membered heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to the substitution of one or more R j replace.

[0059] In another preferred embodiment, each R j Each is independently selected from halogen, carbonyl, -L2-CN, -L2-OR k 、-L2-COOR k 、-L2-NR k R m 、-L2-CONR k R m 、-L2-S(O) 2 NR k R m , substituted or unsubstituted C1-C4 alkyl; the substitution refers to substitution by one or more of the following groups: halogen, hydroxyl, amino, cyano.

[0060] In another preferred embodiment, each R j Each is independently selected from halogen, carbonyl, -L2-CN, -L2-OR k , substituted or unsubstituted C1-C4 alkyl; the substitution refers to substitution by one or more of the following groups: halogen, hydroxyl, amino, cyano.

[0061] In another preferred embodiment, L2 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L2 are optionally substituted by halogen, hydroxyl, amino or cyano.

[0062] In another preferred embodiment, R k , R m Each of the following is independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.

[0063] In another preferred embodiment, R xis selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-6 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, -O-L1-R a 、-NR b R c ; The substitution refers to one or more R j replace;

[0064] R b , R c are each independently selected from a hydrogen atom, a C1-C4 alkyl group, or R b and R c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic ring, which is optionally substituted by one or more R j replace;

[0065] L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L1 are optionally substituted by halogen;

[0066] Each R a Each is independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to the substitution of one or more R j replace;

[0067] Each R j Each is independently selected from halogen, -L2-CN, -L2-OR k 、-L2-COOR k 、-L2-NR k R m 、-L2-CONR k R m 、-L2-S(O) 2 NR k R m , halogenated or unhalogenated C1-C4 alkyl;

[0068] R k , R m Each of the following is independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.

[0069] In another preferred embodiment, R xis halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkoxy, -NR b R c ; The substitution refers to one or more R j replace.

[0070] In another preferred embodiment, R b , R c are each independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution refers to substitution by halogen; or R b and R c Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R j replace.

[0071] In another preferred embodiment, each R j Each is independently selected from halogen, carbonyl, substituted or unsubstituted C1-C6 alkyl, -(C0-C3 alkyl)-CN, -(C0-C3 alkyl)-OR k 、-(C0-C3 alkyl)-COOR k 、-(C0-C3 alkyl)-NR k R m 、-(C0-C3 alkyl)-CONR k R m , -(C0-C3 alkyl)-substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, -(C0-C3 alkyl)-substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, -(C0-C3 alkyl)-substituted or unsubstituted 6-10 membered aryl, -(C0-C3 alkyl)-substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to substitution by one or more of the following groups: halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

[0072] In another preferred embodiment, R xis selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-6 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C1-C6 alkoxy, -NR b R c ; The substitution refers to one or more R j replace;

[0073] R b , R c are each independently selected from a hydrogen atom, a C1-C4 alkyl group, or R b and R c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic ring, which is optionally substituted by one or more R j replace;

[0074] L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;

[0075] Each R a Each is independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to the substitution of one or more R j replace;

[0076] Each R j Each is independently selected from halogen, -(C0-C3 alkyl)-CN, -(C0-C3 alkyl)-OR k 、-(C0-C3 alkyl)-COOR k 、-(C0-C3 alkyl)-NR k R m 、-(C0-C3 alkyl)-CONR k R m , halogenated or unhalogenated C1-C4 alkyl;

[0077] R k , R m Each of the following is independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.

[0078] In another preferred embodiment, R xis selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O-L1-R a 、-NH 2 、-N(C1-C4 alkyl) 2 , C3-C6 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to the substitution of one or more R j replace;

[0079] Wherein, L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;

[0080] Each R a Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclyl substituted by alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted by alkyl;

[0081] Each R j Each is independently selected from halogen, hydroxy, C1-C6 alkylhydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0082] In another preferred embodiment, R x Selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, and the following structures:

[0083]

[0084] In another preferred embodiment, R x Preferred is halogen, such as fluorine, chlorine, bromine.

[0085] In another preferred embodiment, R z Preferred are hydrogen, halogen, C1-C6 alkyl, more preferred are hydrogen, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and more preferred is hydrogen.

[0086] In another preferred embodiment, L is a covalent bond or a divalent saturated or unsaturated straight or branched C1-C20 hydrocarbon chain, wherein 1-6 methylene units of L are independently replaced by one or more of the following structures: -Cy-, -O-, -C(O)-, -C(S)-, -NH-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -OC(O)NH-, -NHC(O)O-, -N=CH-,

[0087] In another preferred embodiment, L is a divalent saturated or unsaturated straight or branched C1-C10 hydrocarbon chain, wherein 1-6 methylene units of L are independently replaced by one or more of the following structures: -Cy-, -O-, -C(O)-, -C(S)-, -NH-, -NHC(O)-, -C(O)NH-,

[0088] In another preferred embodiment, each Cy is independently selected from the following rings: a saturated C3-C10 carbocyclic ring (including a monocyclic ring, a bridged ring, a condensed ring, and a spirocyclic ring), a saturated 4-10 membered heterocyclic ring (including a monocyclic ring, a bridged ring, a condensed ring, and a spirocyclic ring), a C6-C10 aromatic ring, and a 5-10 membered heteroaromatic ring.

[0089] In another preferred embodiment, each Cy is independently selected from the following rings: cyclobutane, cyclopentane, cyclohexane, a 4-membered nitrogen-containing heterocycle, a 5-membered nitrogen-containing heterocycle, a 6-membered nitrogen-containing heterocycle, an 8-membered nitrogen-containing spiro heterocycle, a 9-membered nitrogen-containing spiro heterocycle, a C6 aromatic ring, a 5-membered nitrogen-containing heteroaromatic ring, and a 6-membered nitrogen-containing heteroaromatic ring.

[0090] In another preferred embodiment, each Cy is independently selected from the following rings: cyclobutane, cyclopentane, cyclohexane, Benzene ring, naphthalene ring,

[0091] In another preferred embodiment, each R 1 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -L3-substituted or unsubstituted saturated or partially saturated C3-C8 carbocyclic ring (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted saturated or partially saturated 4-8 membered heterocyclic ring (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted 5-8 membered heteroaromatic ring, -L3-substituted or unsubstituted -NR d R e , -L3-substituted or unsubstituted-COOR d , -L3-substituted or unsubstituted-CONR d Re , -L3-substituted or unsubstituted-S(O) 2 NR d R e , where R d , R e Each is independently selected from hydrogen, C1-C4 alkyl, C2-C4 acyl, C1-C4 sulfonyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , C1-C6 alkyl which may be substituted or unsubstituted by halogen, hydroxy or amino, C1-C6 alkoxy which may be substituted or unsubstituted by halogen, hydroxy or amino;

[0092] L3 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L3 are optionally replaced by halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

[0093] In another preferred embodiment, each R 1 Each is independently selected from halogen, hydroxy, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, NR d R e , where R d , R e Each is independently selected from C1-C3 alkyl.

[0094] In another preferred embodiment, L is a divalent saturated or unsaturated C1-C20 hydrocarbon chain, wherein 1-5 methylene units of L are independently replaced by: -Cy-, -O-, -C(O)-, -NH-,

[0095] Wherein, each Cy is independently selected from the following rings: a 4-membered nitrogen-containing heterocycle, a 5-membered nitrogen-containing heterocycle, and a 6-membered nitrogen-containing heterocycle.

[0096] In another preferred embodiment, the compound has a structure shown in Formula II:

[0097]

[0098] Among them, R x , L as described herein;

[0099] R y1 Selected from halogen, hydroxyl, amino, -CONH2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0100] Preferably, R y1 Selected from hydrogen, NH 2 ;

[0101] R x is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O-L1-R a 、-NH 2 、-N(C1-C4 alkyl) 2 , C3-C6 cycloalkyl, substituted or unsubstituted 5-8 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more halogen or C1-C3 alkyl;

[0102] L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;

[0103] Each R a Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered heterocyclyl substituted by alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted by alkyl;

[0104] More preferably, L is selected from the following structures:

[0105]

[0106]

[0107] In another preferred embodiment, LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-aa:

[0108]

[0109] in:

[0110] Q 1 , Q 2 , Q 3 , Q 4 Each independently selected from C (when linked to L), CR 21 or N;

[0111] Each R 21Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 ;

[0112] R 3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , C2-C6 acyl;

[0113] Each R f Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0114] n1 is selected from 0, 1 or 2.

[0115] In another preferred embodiment, Q 1 , Q 2 , Q 3 , Q 4 One of them is C (when connected to L), and the others are CH.

[0116] In another preferred embodiment, Q 1 , Q 2 , Q 3 , Q 4 One of them is C (when connected to L), and one of them is CR 21 , the others are CH, among which R 21 Selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy.

[0117] In another preferred embodiment, R 3 Selected from hydrogen, halogenated or unhalogenated C1-C3 alkyl.

[0118] In another preferred embodiment, R f For hydrogen.

[0119] In another preferred embodiment, LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-aa-1:

[0120]

[0121] Among them, R 21It is selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen.

[0122] In another preferred embodiment, LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-bb:

[0123]

[0124] in:

[0125] X is selected from CH or N;

[0126] V is selected from C or N;

[0127] U selected from CR 4 NR 5 or O;

[0128] P 1 , P 2 , P 3 , P 4 Each independently selected from C (when linked to L), CR 22 or N;

[0129] R 22 , R 4 , R 5 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkoxy;

[0130] Each R g Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0131] n2 is selected from 0, 1 or 2.

[0132] In another preferred embodiment, P 1 , P 2 , P 3 , P 4 One of them is C (when connected to L), and the others are CH.

[0133] In another preferred embodiment, R 22 , R g All are hydrogen, R 4 , R 5Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy.

[0134] In another preferred embodiment, LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-bb-1, Formula I-bb-2 or Formula I-bb-3:

[0135]

[0136] in,

[0137] Every R 22 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

[0138] In another preferred embodiment, LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of formula I-cc:

[0139]

[0140] in:

[0141] W is CH or N;

[0142] Y is a covalent bond, -N(R 6 )-、-C(O)-N(R 6 )-、-N(R 6 )-C(O)-, wherein the left side of the above divalent group is connected to ring B;

[0143] Ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring;

[0144] Each R 23 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 ;

[0145] R 6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkoxy, C2-C6 acyl;

[0146] Each R h Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0147] n3 is selected from 0, 1 or 2;

[0148] s is selected from 0, 1 or 2.

[0149] In another preferred embodiment, ring B is selected from a benzene ring and a pyridine ring.

[0150] In another preferred embodiment, each R 23 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, halogenated or unhalogenated C1-C3 alkoxy.

[0151] In another preferred embodiment, R 6 Selected from hydrogen, C1-C3 alkyl.

[0152] In another preferred embodiment, R h For hydrogen.

[0153] In another preferred embodiment, LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of Formula I-cc-1 or Formula I-cc-2:

[0154]

[0155] Y is a covalent bond, -N(R 6 )-、-C(O)-N(R 6 )-, wherein the left side of the above divalent group is connected to ring B;

[0156] W is CH or N;

[0157] Every R 23 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

[0158] In another preferred embodiment, LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of formula I-dd:

[0159]

[0160] in:

[0161] D is selected from -CH 2 -, -C(O)-; and the H atom is optionally replaced by a substituent selected from the group consisting of halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0162] A 1 , A 2 , A 3 , A 4 Each independently selected from C (when linked to L), CR 24, N;

[0163] Each R 24 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 、-SO 2 NH 2 ;

[0164] Each R i Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0165] n4 is selected from 0, 1 or 2.

[0166] In another preferred embodiment, A 1 , A 2 , A 3 , A 4 One of them is C (when connected to L), and the others are CH.

[0167] In another preferred embodiment, A 1 , A 2 , A 3 , A 4 One of them is C (when connected to L), and one of them is CR 24 , the others are CH, among which R 24 Selected from halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy.

[0168] In another preferred embodiment, R i For hydrogen.

[0169] In another preferred embodiment, LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of Formula I-dd-1 or Formula I-dd-2:

[0170]

[0171] in,

[0172] Every R 24 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

[0173] In another preferred embodiment, LBM is a VHL E3 ubiquitin ligase binding part and has a structure of formula I-ee:

[0174]

[0175] in:

[0176] G is selected from S, O;

[0177] H 1 , H 2 , H 3 , H 4 Each is independently selected from CH or N; and the H atom is optionally replaced by a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, halogenated or unhalogenated C1-C3 alkyl, halogenated or unhalogenated C1-C3 alkoxy;

[0178] Z 1 , Z 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0179] I 1 , I 2 , I 3 , I 4 , I 5 Each is independently selected from H, halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;

[0180] R 7 is selected from H, C1-C6 alkyl which is optionally substituted or unsubstituted by halogen or hydroxy or amino;

[0181] R 8 , R 9 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl; the substitution refers to halogen, hydroxyl, amino, mercapto, cyano, -CONH 2 、-SO 2 NH 2 ;

[0182] R 10 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, -CO-(substituted or unsubstituted C1-C6 alkyl), -CO-(substituted or unsubstituted C3-C10 cycloalkyl), -SO 2 -(substituted or unsubstituted C1-C6 alkyl), -SO 2 -(substituted or unsubstituted C3-C10 cycloalkyl); the substitution refers to halogen, hydroxyl, amino, mercapto, cyano, -CONH 2 、-SO 2 NH 2 One or more substitutions in .

[0183] In another preferred embodiment, H 1 , H 2 , H 3 , H 4 All are CH.

[0184] In another preferred embodiment, Z 1 , Z 2 Each is independently selected from H, C1-C3 alkyl.

[0185] In another preferred embodiment, I 1 , I 2 , I 3 , I 4 , I 5 Both are H.

[0186] In another preferred embodiment, R 7 is selected from substituted or unsubstituted C1-C6 alkyl groups.

[0187] In another preferred embodiment, R 8 , R 9 Each is independently selected from substituted or unsubstituted C1-C6 alkyl, wherein the substitution refers to substitution by halogen, hydroxyl, amino, and mercapto.

[0188] In another preferred embodiment, the LBM is formed by -NH-, R 8 , R 9 , R 10 Connect with L.

[0189] In another preferred embodiment, the LBM is substituted by -NH-, R 8 , R 9 , R 10 One of the hydrogen atoms in is connected to L.

[0190] In another preferred embodiment, Z 1 is C1-C3 alkyl, Z 2 is hydrogen, R 7 It is a C1-C3 alkyl group.

[0191] In another preferred embodiment, the compound is selected from the structure shown in the following formula:

[0192]

[0193]

[0194]

[0195] or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal; wherein R x , Ry , T, E, L, L' are as defined above; R 2 Selected from hydrogen, halogen, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

[0196] In another preferred embodiment, the compound is selected from the structure shown in the following formula:

[0197]

[0198]

[0199]

[0200] or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal; wherein R x , R y , T, L are as defined above; R 2 is selected from hydrogen, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy;

[0201] Preferably, Selected from the following structures:

[0202] R x is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O-L1-R a 、-NH 2 、-N(C1-C4 alkyl) 2 , C3-C6 cycloalkyl, substituted or unsubstituted 5-8 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more halogen or C1-C3 alkyl;

[0203] L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;

[0204] Each R a Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered heterocyclyl substituted by alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted by alkyl;

[0205] L is selected from the following structures:

[0206]

[0207]

[0208] In another preferred embodiment, R x , R y , R z , E, L, L', m, n, and LBM parts are each independently the corresponding groups of compounds 1-102.

[0209] The second aspect of the present invention provides a pharmaceutical composition, which comprises the following components:

[0210] 1) a therapeutically effective amount of one or more compounds as described in the first aspect of the present invention or deuterated derivatives, stereoisomers, geometric isomers, tautomers, solvates, hydrates, prodrugs, pharmaceutically acceptable salts or cocrystals thereof; and

[0211] 2) Pharmaceutically acceptable carriers or excipients.

[0212] In another preferred embodiment, the pharmaceutical composition further comprises one or more active substances selected from the following: immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, vinca alkaloids, paclitaxel, DNA damaging agents, Bcl-2 inhibitors, BTK inhibitors, JAK inhibitors, Hsp90 inhibitors, ALK inhibitors, FLT3 inhibitors, PI3K inhibitors and SYK inhibitors.

[0213] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention or its deuterated product, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition described in the second aspect of the present invention, which is used for a use selected from the group consisting of:

[0214] 1) Preparation of drugs for preventing and / or treating IRAK4-mediated diseases;

[0215] 2) Prepare drugs for degrading IRAK4.

[0216] In another preferred embodiment, the drug is also used to inhibit a protein kinase selected from the following group: RET, VEGFR, ErbB2, FLT3, FLT3-ITD or other FLT3 mutations, or a combination thereof.

[0217] In another preferred embodiment, the disease is selected from the following group: cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic diseases, endometriosis, sepsis, atherosclerosis, diseases related to organ transplantation, immunodeficiency disorders, bone-destructive diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver disease, pathological immune diseases involving T cell activation, cardiovascular diseases and central nervous system diseases.

[0218] In another preferred embodiment, the cancer or proliferative disease is selected from the group consisting of benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, colorectal adenoma, head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, epithelial cell cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, pancreatic Adenoductal carcinoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma, melanoma and hematological malignancies; the hematological malignancies are selected from Hodgkin's or non-Hodgkin's lymphoma, myelodysplastic syndrome, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, primary effusion lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia, B-prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, mantle cell lymphoma, small lymphocytic lymphoma, intravascular large B-cell lymphoma or cutaneous T-cell lymphoma.

[0219] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, diabetic neuropathy, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes, metabolic syndrome, obesity, and organ transplantation.

[0220] In another preferred embodiment, the autoimmune disease and inflammatory disorder are selected from the following groups: eye diseases (such as eye allergies, conjunctivitis, dry eyes or spring conjunctivitis), diseases affecting the nose (such as allergic rhinitis); autoimmune blood disorders (such as hemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, arthritis, polychondritis, scleroderma, dermatomyositis, polymyositis, chronic hepatitis, myasthenia gravis, Stephen's disease. - Johnson syndrome, idiopathic sprue, inflammatory bowel disease, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, toxic diffuse goiter, interstitial pulmonary fibrosis, psoriasis arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, glomerulonephritis (with or without nephrotic syndrome,Optionally include idiopathic nephrotic syndrome or minimal change disease), chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disease, obesity, hypercholesterolemia, heart disease, chronic heart failure, Behcet's disease, incontinence pigmenti, Paget's disease, pancreatitis, asthma (allergic, non-allergic, mild, moderate, severe, bronchitis or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, chronic obstructive pulmonary disease, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease (Addison's disease), lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura purpura), hepatitis, suppurative hidradenitis, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, liver fibrosis, renal fibrosis, alcoholic fatty liver disease, non-alcoholic fatty liver disease, cardiac fibrosis, psoriasis, psoriatic arthritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, local pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, fallopian tube Inflammation, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, cryopyrin-associated periodic syndromes (CAPS), osteoarthritis, juvenile arthritis, systemic lupus erythematosus.

[0221] In a fourth aspect of the present invention, a method for preventing and / or treating an IRAK4-mediated disease is provided, the method comprising the steps of:

[0222] The compound or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal as described in the first aspect of the present invention, or the pharmaceutical composition as described in the second aspect of the present invention is administered to a subject in need thereof.

[0223] In another preferred embodiment, the subject is a human or non-human mammal.

[0224] In the fifth aspect of the present invention, a method for degrading IRAK4 protein is provided, the method comprising: incubating the compound or its deuterated product, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal as described in the first aspect of the present invention, or the pharmaceutical composition as described in the second aspect of the present invention with cells in need thereof.

[0225] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0226] After long-term and in-depth research, the inventors have provided a novel IRAK4 degrader compound, which is different from the IRAK4 inhibitors in the prior art and can directly degrade IRAK4 protein instead of just inhibiting it, so its activity is significantly improved, and it has excellent selectivity for tumor cells and normal cells, so it can be used to prepare a compound for preventing and / or treating IRAK4-mediated related diseases such as cancer, inflammatory diseases and autoimmune diseases. Based on the above findings, the inventors have completed the present invention.

[0227] the term

[0228] In this document, when the listed linking group does not specify its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B from left to right to form You can also connect ring A and ring B from right to left to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0229] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond (-), a straight dotted bond (-----), or a wavy bond (-). For example, -OCH 3 The straight solid bond in the group indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy lines in the phenyl group indicate that the bond is connected to other groups through the 1st and 4th carbon atoms in the phenyl group; when the bond is on the ring without a clear point of attachment, such as Indicates that the bond can be connected to any connectable site on the ring, including at least These 4 types of connections; when the bond is connected to the molecule in the square brackets, such as It means that the bond can be attached to any connectable site on the molecule.

[0230] It means that this bond can be a single bond or a double bond, as long as the structure of the formed compound is stable.

[0231] In this article, the term "spirocycle" or "spirocyclic group" refers to a polycyclic group in which the single rings share a carbon atom (called a spiro atom). They may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Spirocyclic groups are divided into single spirocyclic groups, double spirocyclic groups, or polyspirocyclic groups according to the number of spiro atoms shared between the rings. The rings may be different or the same. Each ring of the spirocyclic ring may contain 0-5 heteroatoms or groups containing heteroatoms (including but not limited to N, S (O) n or O, wherein n is 0, 1, 2). "Spiro" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent. Non-limiting examples of spiro include:

[0232]

[0233] In this article, the term "fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Each ring of the fused ring may contain 0-5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(O) nor O, wherein n is 0, 1, 2). According to the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl. "Condensed ring" or "condensed ring group" can be monovalent, divalent, trivalent or tetravalent. Non-limiting examples of condensed rings include:

[0234]

[0235] In this article, "bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S (O) n or O, wherein n is 0, 1, 2). A "bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent. Non-limiting examples of bridged rings include:

[0236]

[0237] The term "alkyl" refers to a substituted or unsubstituted straight or branched saturated aliphatic hydrocarbon group. "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups. In particular, the "C0 alkyl" mentioned in the claims of the present invention refers to the case where the group is a chemical bond.

[0238] In addition, in the present invention, the term "alkyl" includes saturated or unsaturated, straight chain, branched, cyclic 1-10 carbon atoms of the whole carbon alkyl or alkyl 1-3 carbon atoms of which are substituted by heteroatoms such as oxygen, nitrogen, sulfur, and aralkyl connected by 1 or more carbon atoms. In addition, the alkyl is unsubstituted or substituted.

[0239] The term "C2-C6 alkenyl" refers to a group formed by an olefin having 2 to 6 carbon atoms losing one or two hydrogen atoms, wherein the olefin may be a monoolefin, a diolefin or a triolefin, such as -CH=CH 2 、-CH 2 CH=CH 2 、-CH=CHCH 3 , -CH=CH-, or a similar group.

[0240] The term "C2-C6 alkynyl" refers to a group formed by an alkyne having 2-6 carbon atoms losing one or two hydrogen atoms. The alkyne can be a monoalkyne, a dialkyne or a trialkyne, such as ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0241] The term "alkoxy" refers to a substituted or unsubstituted straight or branched "-O-alkyl". The term "C1-C6 alkoxy" includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0242] The term "alkylamino" refers to a substituted or unsubstituted straight or branched chain "-NH-alkyl" or "-N(alkyl) 2 For example, "C1-C6 alkylamino" refers to a substituted or unsubstituted straight or branched chain "-NH-(C1-C6 alkyl)" or "-N(C1-C6 alkyl) 2 ”, which includes but is not limited to methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, dimethylamino and di-tert-butylamino.

[0243] "C2-C6 acyl" refers to a substituted or unsubstituted straight or branched "-C(=O)-(C1-C5 alkyl)". The term "C2-C6 acyl" includes, but is not limited to, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, sec-butyryl, tert-butyryl, and n-hexanoyl.

[0244] "C1-C6sulfonyl" refers to a substituted or unsubstituted straight or branched chain "-S(=O) 2 -(C1-C6 alkyl)".

[0245] The term "halogen" refers to F, Cl, Br or I.

[0246] The term "halo" means that one or more hydrogens are replaced by F, Cl, Br or I.

[0247] The term "haloalkyl" means that one or more hydrogens of an alkyl group are replaced by halogen, including monohaloalkyl, dihaloalkyl and polyhaloalkyl. For example, "C1-C3 haloalkyl" means a monohaloalkyl, dihaloalkyl and polyhaloalkyl group comprising 1 to 3 carbon atoms. Examples of C1-C3 haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, difluoropropyl, dichloroethyl and dichloropropyl etc.

[0248] Unless otherwise specified, the term "haloalkoxy" means that one or more hydrogens of an alkoxy group are replaced by halogen, specifically including monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy. For example, "C1-C3 haloalkoxy" means monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy containing 1 to 3 carbon atoms. Examples of C1-C3 haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, 3-bromopropoxy, etc.

[0249] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon and the quaternary ammonium form of any basic nitrogen).

[0250] As used herein, the terms "unsaturated" and "partially saturated" both refer to rings containing at least one double bond or triple bond. Both encompass rings with multiple unsaturated sites, but do not include aryl or heteroaryl moieties as defined herein.

[0251] As used herein, the term "divalent saturated or unsaturated hydrocarbon chain" refers to a straight or branched divalent alkylene chain, a divalent alkenylene chain and a divalent alkynylene chain as defined below.

[0252] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by an optional substituent.

[0253] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a structure in which at least one single bond in a polymethylene chain is replaced with a double bond, wherein one or more hydrogen atoms are replaced by an optional substituent.

[0254] The term "alkynylene" refers to a divalent alkynyl group. A substituted alkynylene chain is a structure in which at least one single bond in a polymethylene chain is replaced with a triple bond, wherein one or more hydrogen atoms are replaced with an optional substituent.

[0255] The term "aryl" or "aromatic ring" refers to a 6-14-membered monocyclic, bicyclic or polycyclic aromatic hydrocarbon group, wherein at least one ring is aromatic. In this article, the term "aryl" also includes groups in which an aromatic ring is fused to one or more carbocyclic or heterocyclic rings, wherein the connecting group or point of connection is located on the aromatic ring. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, indanyl, phthalimide, naphthimide, phenanthridinyl, tetrahydronaphthyl, etc.

[0256] The term "heteroaryl" or "heteroaromatic ring" refers to a 5-14 membered monocyclic, bicyclic or polycyclic aromatic hydrocarbon group, wherein at least one ring is aromatic and has one to five heteroatoms. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the term "heteroaryl" also includes groups in which a heteroaryl ring is fused to one or more aromatic, carbocyclic or heterocyclic rings, wherein the radical or point of attachment is on the heteroaryl ring, non-limiting examples of which include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenathiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.

[0257] In this article, "cycloalkyl" and "carbocycle" are used interchangeably and refer to 3 to 12-membered saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbons. Carbocycles can be further divided into three categories: spirocyclic, condensed ring, and bridged ring. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, decahydronaphthalene, spiro[5.5]undecane, bicyclo[2.2.1]heptane, etc.

[0258] In this article, the term "heterocycle", "heterocyclyl" refers to a 3-14-membered monocyclic, bicyclic or polycyclic hydrocarbon, which is saturated or partially unsaturated and has one or more heteroatoms as defined above except for carbon atoms. Heterocycles can be further divided into three categories: spirocycles, condensed rings and bridged rings. Heterocycles can be connected to other structures of the molecule at any heteroatom or carbon atom to produce a stable structure. Embodiments of heterocyclyl include but are not limited to azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrophenylthio, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, oxazolidinyl, piperazinyl, dioxane-based, dioxolane-based, morpholinyl and quinuclidine. The terms "heterocycle" and "heterocyclyl" also include groups in which a heterocycle is fused to one or more aromatic, heteroaromatic or carbocyclic rings, wherein the radical or point of attachment is on the heterocycle, such as indolinyl, 3H-indolyl, chromanyl or tetrahydroquinolinyl.

[0259] The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on the basis of what is chemically feasible. The terms "substituted", "substituted" and "substituted" all mean that one or more hydrogens of the specified part are replaced by suitable substituents. Unless otherwise specified, "substituted", "substituted", "substituted" and "optionally substituted" groups may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituents may be the same or different at each position. The combination of substituents contemplated by the present invention is preferably a combination of substituents that form stable or chemically feasible compounds.

[0260] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0261] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid; another preferred class of salts is this Salts formed by the compounds of the invention with bases, such as alkali metal salts (e.g. sodium salts or potassium salts), alkaline earth metal salts (e.g. magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0262] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0263] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug includes but is not limited to carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0264] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) all fall within the scope of the present invention.

[0265] Additionally, unless otherwise stated, structures depicted herein also include compounds that differ only in the presence of one or more isotopes of atoms. For example, structures having a structure including replacement of hydrogen by deuterium or tritium or by 13 C or 14 Compounds in which carbon is replaced by C. Within the scope of the present invention, such compounds are suitable as analytical tools (eg as probes in biological assays) or as therapeutic agents according to the present invention.

[0266] The term "tautomer" means that structural isomers of different energies can interconvert over a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, and valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0267] As used herein, the term "inhibitor" is defined as a compound that binds to and inhibits the function of IRAK kinase.

[0268] As used herein, the term "degrader" is defined as a compound that can bind to IRAK kinase and E3 ligase and cause the ubiquitination and degradation of IRAK kinase.

[0269] As used herein, the term "optionally" means with or without, for example "optionally substituted" means substituted or unsubstituted.

[0270] Herein, the pharmaceutically acceptable solvates of the compound represented by the general formula I are not particularly limited, and preferably include: solvates of the compound represented by the general formula I with water, ethanol, isopropanol, diethyl ether, acetone, and the like.

[0271] Compound

[0272] The present invention provides a compound of general formula I or its deuterated product, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal:

[0273]

[0274] Each of the variables is as defined and described above.

[0275] In another preferred embodiment, the compound is selected from the structure shown in the following formula:

[0276]

[0277]

[0278] or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal; wherein R x , R y , T, L as defined in claim 1; R 2 Selected from hydrogen, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy.

[0279] In another preferred embodiment, L is selected from the following table:

[0280]

[0281]

[0282]

[0283] In another preferred embodiment, the right side of L in the above table is connected to the LBM part, and the left side is connected to the mother core part. In another preferred embodiment, LBM is selected from the following table:

[0284]

[0285]

[0286] In another preferred embodiment, the compound is selected from the compounds listed in the following table:

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] Salt type

[0307] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0308] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0309] The term "prodrug" includes a class of compounds, or salts or solutions of compounds, which may be biologically active or inactive, and which undergo metabolism or chemical reactions in the human body after being taken by appropriate methods. The prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compounds.

[0310] Preparation of the compounds of the present invention

[0311] The following reaction schemes exemplify methods for preparing the compounds of the present invention.

[0312] Reaction Scheme Ⅰ

[0313]

[0314] The general synthesis method of the IRAK binding part of the present invention is shown in Reaction Scheme I. It comprises the following steps:

[0315] 1. Compound 1a is reduced under palladium carbon / hydrogen or iron powder / ammonium chloride conditions to obtain compound 1b;

[0316] 2. Compound 1b is reacted with N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate condensation agent to obtain compound 1c;

[0317] 3. Compound 1c was deprotected by removing the Boc protecting group under trifluoroacetic acid to obtain compound 1d.

[0318] Reaction route II

[0319]

[0320] The general synthesis method of a class of compounds of the present invention is shown in Reaction Scheme II. It comprises the following steps:

[0321] 1. Compounds 2a and 2b undergo substitution reaction under the action of an organic base to obtain compound 2c;

[0322] 2. Compound 2c reacts with p-toluenesulfonyl chloride in the presence of sodium iodide and silver oxide to obtain compound 2d;

[0323] 3. Compound 2d undergoes substitution reaction with compound 1d in the presence of an organic base to give compound 2e.

[0324] Reaction Scheme III

[0325]

[0326] The general synthesis method of a class of compounds of the present invention is shown in Reaction Scheme III. It comprises the following steps:

[0327] 1. Compounds 3a and 3b underwent Mitsunobu reaction in the presence of triphenylphosphine and diisopropyl azodicarboxylate to give compound 3c;

[0328] 2. Compound 3c undergoes substitution reaction with compound 1d in the presence of an organic base to obtain compound 3d.

[0329] Reaction Scheme IV

[0330]

[0331] The general synthesis method of a class of compounds of the present invention is shown in Reaction Scheme IV. It comprises the following steps:

[0332] 1. Compound 4a and 1d undergo substitution reaction under the action of an organic base to obtain compound 4b;

[0333] 2. Compound 4b reacts under trifluoroacetic acid to obtain compound 4c;

[0334] 3. Compound 4c reacts with 4d in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole condensation agent to obtain compound 4e.

[0335] Reaction Scheme V

[0336]

[0337] The general synthesis method of a class of compounds of the present invention is shown in Reaction Scheme V. It comprises the following steps:

[0338] 1. Compound 5-1a / 5-1b and secondary amine 5c undergo substitution reaction under the action of an organic base to obtain compound 5-2a / 5-2b;

[0339] 2. Compound 5-2a / 5-2b is treated with a Dess-Martin oxidant to give aldehyde 5-3a / 5-3b;

[0340] 3. Compound 5d reacts with 5e in the presence of an organic base to give compound 5f;

[0341] 4. Compound 5f was treated with trifluoroacetic acid to give secondary amine 5g;

[0342] 5. Secondary amine 5g reacts with aldehyde 5-3a / 5-3b in the presence of acetic acid and sodium triacetoxyborohydride to undergo reductive amination to give compound 5h.

[0343] Pharmaceutical compositions containing compounds of formula I

[0344] The present invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of one or more of the compound of formula I, its pharmaceutical salt, its prodrug, and its hydrate and solvate, and optionally, a pharmaceutically acceptable carrier, which can be used to treat diseases related to IRAK4 activity or expression. The pharmaceutical composition can be prepared in various forms according to different administration routes.

[0345] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0346] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween 80), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0347] The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

[0348] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0349] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0350] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0351] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0352] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0353] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0354] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0355] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0356] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0357] use

[0358] Since the compounds of the present invention have excellent degradation activity against IRAK4, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredients can be used to treat, prevent and alleviate diseases related to the activity or expression of IRAK4, such as preventing and / or treating diseases related to abnormal expression of the IRAK4 signaling pathway. According to the prior art, the compounds of the present invention can be used to treat the following diseases: cancer, autoimmune diseases, inflammatory diseases and thromboembolic diseases. Preferably, the compounds can be used to treat the following diseases: diffuse large B-cell lymphoma, multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, pancreatic ductal carcinoma, rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and irritable bowel syndrome.

[0359] Treatment

[0360] The present invention also provides a method for treating IRAK4-related diseases, comprising administering an inhibitory effective amount of the compound or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, or the pharmaceutical composition to a patient in need thereof.

[0361] The present invention also provides a non-diagnostic, non-therapeutic method for inhibiting IRAK4 activity, which comprises administering an inhibitory effective amount of the compound or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, or the pharmaceutical composition to a patient in need thereof.

[0362] Compared with the prior art, the present invention has the following main advantages:

[0363] (1) The degrading agent prepared by using the compound has a significant inhibitory effect on IRAK4 enzyme activity.

[0364] (2) The compound can achieve significant degradation of IRAK4 enzyme at the nM level.

[0365] (3) The compound also has a significant inhibitory effect on the proliferation of various cancer cells mediated by IRAK4 at the cellular level.

[0366] (4) The compound has excellent inhibitory selectivity for normal cells / tumor cells.

[0367] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0368] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Shanghai Bid Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biopharmaceutical Technology Co., Ltd., Titan Technology, Anaiji Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0369] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using Bruker Avance III 400M, 500M, and 600M NMR.

[0370] Example 1

[0371]

[0372] Step 1: Preparation of intermediate I-1-1

[0373] A mixture of 2.5 g of 2-amino-4-bromopyridine, 4.1 g of ethyl 4-oxazolecarboxylate, 338 mg of palladium acetate, 1.0 g of 2-(dicyclohexylphosphino)biphenyl, 9.4 g of cesium carbonate and 51 ml of diethyl carbonate was stirred at 120°C for 20 hours under argon protection. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 4:1 to obtain 452 mg of intermediate I-1-1 as a yellow solid, with a yield of 13%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.99(s,1H),8.08(d,J=5.3Hz,1H),7.05(s,1H),6.99(d,J=5.3Hz,1H),6. 32(s,2H),4.32(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).LCMS(ESI)m / z[M+H] + 234.1.

[0374] Step 2: Preparation of intermediate I-1-2

[0375] A mixture of 919 mg of intermediate I-1-1, 500 mg of lithium hydroxide monohydrate, 14 ml of tetrahydrofuran, 7 ml of methanol, and 3.5 ml of water was stirred at room temperature for 1 hour. The reaction solution was first concentrated to dryness, then diluted with 10 ml of water, and then adjusted to pH = 5 with 1 mol / L hydrochloric acid, filtered, and the filter cake was collected to obtain 769 mg of intermediate I-1-2 as a yellow solid with a yield of 95%. LCMS (ESI) m / z [M+H] + 206.2.

[0376] Step 3: Preparation of intermediate I-1-3

[0377] A mixture of 25.0 g of 1-(bromomethyl)-4-chloro-2-fluorobenzene, 6.9 g of magnesium chips, 650 mg of iodine and 150 ml of anhydrous ether was stirred at 40°C for 30 minutes under argon protection, and then the reaction solution was dropped into a mixture of 18.8 g of N-tert-butyloxycarbonyl-4-piperidone and 400 ml of anhydrous ether at -78°C, and stirred at room temperature for 2 hours. The reaction solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was subjected to column chromatography with ethyl acetate: petroleum ether = 15:85 to obtain 22.3 g of crude compound I-1-3 as a white solid, which was directly used in the next step. LCMS (ESI) m / z [M+Na] + 366.1.

[0378] Step 4: Preparation of intermediate I-1-4

[0379] A mixture of 3.5 g of intermediate I-1-3, 3.5 g of potassium tert-butoxide and 95 ml of tetrahydrofuran was stirred at 65° C. for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated to dryness and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 1:9 to obtain 2.0 g of intermediate I-1-4 as a white solid with a yield of 61%. 1 H NMR(400MHz,Chloroform-d)δ7.03(d,J=7.9Hz,1H),6.80(dd,J=7.9,1.8Hz,1H),6.75(d,J=1.8Hz,1H) ,3.88-3.64(m,2H),3.52-3.31(m,2H),2.94(s,2H),1.95-1.84(m,2H),1.73-1.64(m,2H),1.47(s,9H).

[0380] Step 5: Preparation of intermediate I-1-5

[0381] A mixture of 300 mg of intermediate I-1-4, 10 ml of dichloromethane and 3 ml of trifluoroacetic acid was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to dryness, slurried with ether, filtered, and the filter cake was collected to obtain 280 mg of intermediate I-1-5 as a white solid, with a yield of 89%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.70(s,2H),7.18(d,J=7.8Hz,1H),6.88-6.83(m,2H),3.23-3.08(m,4H),3.05(s,2H),2.02-1.84(m,4H).LCMS(ESI)m / z[M+H] + 224.1.

[0382] Step 6: Preparation of intermediate I-1-6

[0383] A mixture of 200 mg of intermediate I-1-5, 294 μl of N,N-diisopropylethylamine, 107 μl of trifluoroacetic anhydride and 8 ml of dichloromethane was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with dichloromethane, and the organic phase was concentrated to dryness to obtain 200 mg of crude intermediate I-1-6 as a yellow oil, which was directly used in the next step without further purification. 1H NMR(400MHz,Chloroform-d)δ7.05(d,J=7.8Hz,1H),6.84(d,J=7.8Hz,1H),6.78(s,1H),4.39-4.30(m,1H),3.93-3.80 (m,1H),3.72-3.58(m,1H),3.39-3.31(m,1H),2.98(s,2H),2.10-2.01(m,2H),1.84-1.70(m,2H).LCMS(ESI)m / z[M+H] + 320.1.

[0384] Step 7: Preparation of intermediate I-1-7

[0385] A mixture of 100 mg of intermediate I-1-6, 1.7 ml of concentrated nitric acid and 4 ml of dichloromethane was stirred at room temperature overnight. Water was added to the reaction solution, extracted with dichloromethane, and the organic phase was concentrated to dryness. The residue was subjected to column chromatography with ethyl acetate: petroleum ether = 3:1 to obtain 68 mg of intermediate I-1-7 as a yellow oil with a yield of 60%. 1 H NMR(400MHz,Chloroform-d)δ7.86(s,1H),6.92(s,1H),4.43-4.35(m,1H),3.96-3.87(m,1H) ),3.69-3.58(m,1H),3.40-3.30(m,1H),3.08(s,2H),2.13-2.04(m,2H),1.89-1.78(m,2H).

[0386] Step 8: Preparation of intermediate I-1-8

[0387] A mixture of 34 mg of intermediate I-1-7, 48 mg of potassium carbonate, 2 ml of methanol and 0.7 ml of water was stirred at room temperature for 40 minutes, water was added to the reaction solution, extracted with dichloromethane, and the organic phase was concentrated to dryness to obtain 26 mg of intermediate I-1-8 as a yellow oil, which was directly used in the next step without further purification. LCMS (ESI) m / z [M+H] + 269.1.

[0388] Step 9: Preparation of intermediate I-1-9

[0389] A mixture of 716 mg of intermediate I-1-8, 700 mg of di-tert-butyl dicarbonate and 8 ml of 1,4-dioxane was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 1:3 to obtain 563 mg of intermediate I-1-9 as a yellow solid with a yield of 45%. 1H NMR(400MHz,Chloroform-d)δ7.83(s,1H),6.87(s,1H),3.84-3.71(m,2H),3.4 1-3.30(m,2H),3.03(s,2H),1.95-1.88(m,2H),1.78-1.70(m,2H),1.46(s,9H).

[0390] Step 10: Preparation of intermediate I-1-10

[0391] A mixture of 1.5 g of intermediate I-1-9, 2.3 g of iron powder, 2.2 g of ammonium chloride, 20 ml of ethanol and 7 ml of water was stirred at 50°C for 2 hours. The reaction solution was filtered through diatomaceous earth and concentrated to dryness. The residue was chromatographed with ethyl acetate: petroleum ether = 1:3 to obtain 1.16 g of intermediate I-1-10 as a yellow solid with a yield of 84%. 1 H NMR (400 MHz, Methanol-d 4 )δ6.71(s,1H),6.60(s,1H),3.74-3.66(m,2H),3.42-3.29(m,2H),2.90(s,2H),1.85-1.76(m,2H),1.71-1.61(m,2H),1.44(s,9H).

[0392] Step 11: Preparation of intermediate I-1-11

[0393] A mixture of 124 mg of intermediate I-1-10, 151 mg of intermediate I-1-2, 278 mg of HATU, 270 μl of N,N-diisopropylethylamine and 7 ml of DMF was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol = 15:1 to obtain 95 mg of intermediate I-1-11 as a yellow solid, with a yield of 49%. 1 H NMR(400MHz,Chloroform-d)δ9.21(s,1H),8.36(s,1H),8.24(s,1H),8.22(d,J=5.2Hz,1H),7.28(d,J=5.2Hz,1H),7.15(s,1H), 6.85(s,1H),4.71(s,2H),3.82-3.69(m,2H),3.44-3.33(m,2H),3.01(s,2H),1.94-1.85(m,2H),1.72-1.67(m,2H),1.47(s,9H).

[0394] Step 12: Preparation of intermediate I-1-12

[0395] A mixture of 95 mg of intermediate I-1-11, 3 ml of dichloromethane and 1 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, re-dissolved in 7 ml of methanol, and ammonia water was added dropwise until the pH was about 7, followed by extraction with dichloromethane and water. The organic phase was concentrated to dryness to obtain 60 mg of intermediate I-1-12 as a yellow solid with a yield of 78%. 1 H NMR (600MHz, Methanol-d4) δ8.63 (s, 1H), 8.07 (d, J = 5.4Hz, 1H), 7.92 (s, 1H), 7.26-7.22 (m, 2H), 6.9 7(s,1H),3.40-3.36(m,4H),3.18(s,2H),2.21-2.17(m,2H),2.09-2.02(m,2H).LCMS(ESI)m / z[M+H] + 426.2. Step 13: Preparation of Intermediate I-1-13

[0396] A mixture of 500 mg of 2-(2,6-dicarbonyl-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione, 405 mg of 2-[2-(2-aminoethoxy)ethoxy]ethanol, 820 μL of DIPEA and 10 mL of DMSO was stirred at 90°C for 12 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with methanol: dichloromethane = 5:95 to obtain 481 mg of intermediate I-1-13 as a yellow oil with a yield of 66%. 1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.48(t,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.55(t,J=5.6Hz,1H),4.95-4. 86(m,1H),3.74-3.69(m,4H),3.67(s,4H),3.62-3.58(m,2H),3.46(q,J =5.4Hz,2H),2.91-2.67(m,4H),2.14-2.07(m,1H).LCMS(ESI)m / z[M+H] + 406.1.

[0397] Step 14: Preparation of intermediate I-1-14

[0398] A mixture of 10 mg of intermediate I-1-13, 6 mg of silver oxide, 6 mg of sodium iodide, 5 mg of p-toluenesulfonyl chloride and 2 ml of DCM was stirred at room temperature for 8 hours. The reaction solution was filtered and then thinly layered with dichloromethane / methanol = 20:1 to obtain 2 mg of intermediate I-1-14 as a yellow oil, yield: 14%. LCMS (ESI) m / z [M+Na]+ 582.3.

[0399] Step 15: Preparation of Example 1

[0400] A mixture of 22 mg of I-1-12, 29 mg of I-1-14, 30 μl of N,N-diisopropylethylamine and 0.5 ml of DMSO was stirred at 80°C overnight. Water was added to the reaction solution and extracted with dichloromethane. The organic phase was concentrated to dryness, and the residue was prepared with dichloromethane:methanol = 15:1 to prepare a thin layer to obtain 26 mg of compound 1 as a light yellow solid, with a yield of 62%. 1 H NMR(400MHz,Chloroform-d)δ9.52(brs,1H),9.17(s,1H),8.35(s,1H),8.23(d,J=5.4Hz,1H),8.21(s,1H),7.50 (t,J=8.0Hz,1H),7.28-7.27(m,1H),7.13(s,1H),7.11(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.81(s,1H),6.51 (t,J=5.5Hz,1H),5.00-4.93(m,1H),4.78(s,2H),3.96(s,2H),3.74(t,J=5.2Hz,3H),3.70(s,4H),3.49-3.43(m, 2H),3.20-3.04(m,4H),3.02(s,2H),2.92-2.70(m,4H),2.54-2.22(m,2H),2.16-2.08(m,1H),2.06-1.97(m,2H).

[0401] Example 2

[0402]

[0403] Example 2 can be prepared by the same method as Example 1. 1H NMR(400MHz,Chloroform-d)δ9.20(s,1H),8.39(s,1H),8.28-8.23(m,2H),7.51(t,J=8.0Hz,1 H),7.32-7.29(m,2H),7.17(s,1H),7.12(d,J=8.0Hz,1H),6.92(d,J=8.0Hz,1H),6.84(s,1H), 6.52(t,J=5.5Hz,1H),4.98-4.92(m,1H),4.76(s,2H),4.06-3.83(m,2H),3.78-3.64(m,12H), 3.51-3.44(m,2H),3.21-2.95(m,6H),2.93-2.75(m,4H),2.18-2.12(m,1H),2.11-1.98(m,3H).

[0404] Example 3

[0405]

[0406] Example 3 can be prepared by the same method as Example 1. 1 H NMR(600MHz,Chloroform-d)δ9.18(s,1H),8.37(s,1H),8.25-8.21(m,2H),7.49(t,J=7.8Hz,1H),7.30-7.27 (m,2H),7.15(s,1H),7.10(d,J=7.8Hz,1H),6.90(d,J=7.8Hz,1H),6.82(s,1H),6.49(t,J=4.8Hz,1H),4.93-4 .90(m,1H),4.73(s,2H),4.08-3.84(m,2H),3.69(t,J=5.4Hz,3H),3.67-3.64(m,15H),3.44(q,J=5.5Hz,2H) ,3.22-3.08(m,3H),3.06(s,2H),2.90-2.85(m,1H),2.82-2.70(m,3H),2.15-2.10(m,1H),2.09-2.03(m,2H).

[0407] Example 4

[0408]

[0409] Step 1: Preparation of intermediate I-4-1

[0410] A mixture of 206 mg of 3-(5-hydroxy-1-carbonylisoindol-2-yl)piperidine-2,6-dione, 250 mg of triethylene glycol mono-p-toluenesulfonate, 394 mg of triphenylphosphine and 5 ml of tetrahydrofuran was stirred under ice bath for 1 hour, followed by addition of 303 mg of diisopropyl azodicarboxylate and stirring at room temperature overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 86 mg of crude I-4-1, a colorless oil, which was directly used in the next step without further purification. LCMS (ESI) m / z [M+H] + 561.2.

[0411] Step 2: Preparation of Example 4

[0412] A mixture of 43 mg of I-4-1, 30 mg of I-1-12, 40 μl of DIPEA and 1 ml of DMSO was stirred at 80°C overnight. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol = 8:1 to prepare a thin layer to obtain 24 mg of compound 5 as a white solid, with a yield of 42%. 1 H NMR(600MHz,Chloroform-d)δ9.19(s,1H),8.70(s,1H),8.37(s,1H),8.27(s,1H),8.21(d,J=5.2Hz,1H),7.76(d,J=8 .3Hz,1H),7.37(d,J=2.3Hz,1H),7.27(d,J=5.2Hz,1H),7.24(dd,J=8.3,2.3Hz,1H),7.15(s,1H),6.82(s,1H),4.98-4 .93(m,1H),4.89(s,2H),4.29(q,J=4.0Hz,2H),4.13-4.05(m,2H),3.90(t,J=4.5Hz,2H),3.75-3.70(m,4H),3.67-3.5 7(m,2H),3.24-3.19(m,3H),3.06(s,2H),2.92-2.70(m,3H),2.67-2.53(m,2H),2.19-2.11(m,1H),2.08-1.99(m,3H).

[0413] Example 5

[0414]

[0415] Example 5 can be prepared by the same method as Example 6. 1H NMR(600MHz,Chloroform-d)δ9.17(s,1H),8.60(s,1H),8.39(s,1H),8.26(s,1H),8.18(d,J=5.5Hz,1H),7.7 7(d,J=8.3Hz,1H),7.37(d,J=2.2Hz,1H),7.29(d,J=5.5Hz,1H),7.23(dd,J=8.3,2.2Hz,1H),7.21(s,1H),6. 83(s,1H),5.20(s,2H),4.98-4.93(m,1H),4.27(t,J=4.6Hz,2H),4.09-4.03(m,2H),3.88(t,J=4.6Hz,2H),3 .75-3.63(m,10H),3.26-3.20(m,3H),3.08(s,2H),2.92-2.71(m,4H),2.66-2.60(m,2H),2.16-2.07(m,3H).

[0416] Example 6

[0417]

[0418] Step 1: Preparation of intermediate I-6-1

[0419] 806 mg of intermediate I-1-9, 1.08 g of pyridine-4-boronic acid, 319 mg of Pd(dppf)Cl 2 A mixture of 1.43 g cesium carbonate, 1.2 ml water and 12 ml 1,4-dioxane was stirred at 100°C overnight under argon protection. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 824 mg of I-6-1 as a light yellow solid, with a yield of 91%. 1 HNMR(400MHz,Chloroform-d)δ8.65(d,J=5.1Hz,2H),7.94(s,1H),7.19(d,J=5.1Hz,2H),6.67(s,1H),3.88-3.7 4(m,2H),3.43-3.34(m,2H),3.11(s,2H),2.00-1.92(m,2H),1.83-1.72(m,2H),1.48(s,9H).LCMS(ESI)m / z[M+H] + 412.1.

[0420] Step 2: Preparation of intermediate I-6-2

[0421] The preparation of intermediate I-6-2 is the same as intermediate I-1-10. 1H NMR(400MHz,Chloroform-d)δ8.71-8.60(m,2H),7.46-7.35(m,2H),6.64(s,1H),6.57(s,1H),3.8 5-3.65(m,2H),3.64-3.26(m,4H),2.97(s,2H),1.97-1.82(m,2H),1.73-1.66(m,2H),1.47(s,9H).

[0422] Step 3: Preparation of intermediate I-6-3

[0423] The preparation of intermediate I-6-3 is the same as intermediate I-1-11. 1 H NMR (400MHz, Chloroform-d) δ8.81(s,1H),8.76(d,J=4.8Hz,2H),8.28(s,1H),8.21(s,1H),8.17(d,J=5.3Hz,1H),7.41(d,J=4.8Hz,2H),7.05(d,J=5. 3Hz,1H),6.87(s,1H),6.74(s,1H),4.96(s,2H),3.84-3.69(m,2H),3.48-3 .36(m,2H),3.10(s,2H),1.99-1.91(m,2H),1.80-1.69(m,2H),1.48(s,9H).

[0424] Step 4: Preparation of intermediate I-6-4

[0425] The preparation of intermediate I-6-4 is the same as intermediate I-1-12. LCMS (ESI) m / z [M+H] + 469.2.

[0426] Step 5: Preparation of intermediate I-6-5

[0427] The preparation of intermediate I-6-5 is the same as intermediate I-1-13. LCMS (ESI) m / z [M+H] + 450.1.

[0428] Step 6: Preparation of intermediate I-6-6

[0429] The preparation of intermediate I-6-6 is the same as intermediate I-1-14. 1H NMR(400MHz,Chloroform-d)δ8.25(brs,1H),7.78(d,J=8.1Hz,2H),7.48(dd,J=8.5, 7.1Hz,1H),7.32(d,J=8.1Hz,2H),7.09(d,J=7.1Hz,1H),6.92(d,J=8.5Hz,1H),6.48( t,J=5.7Hz,1H),4.96-4.88(m,1H),4.18-4.11(m,2H),3.73-3.66(m,4H),3.64(s,4H ),3.59(s,4H),3.50-3.44(m,2H),2.90-2.69(m,3H),2.43(s,3H),2.15-2.09(m,1H).

[0430] Step 7: Preparation of Example 6

[0431] The preparation method of Example 6 is the same as step 15 in Example 1. 1 H NMR(600MHz,Chloroform-d)δ9.26(s,1H),8.79(s,1H),8.76(d,J=6.0Hz,2H),8.28(s,1H),8.19(s,1H),8.17(d,J=5.3Hz, 1H),7.48(t,J=7.2Hz,1H),7.38(d,J=6.0Hz,2H),7.09(d,J=7.2Hz,1H),7.04(d,J=5.3Hz,1H),6.89(d,J=7.2Hz,1H),6.87 (s,1H),6.70(s,1H),6.48(t,J=5.7Hz,1H),4.97(s,2H),4.95-4.91(m,1H),4.09-4.01(m,2H),3.73-3.64(m,12H),3.45(q ,J=5.4Hz,2H),3.31-3.18(m,4H),3.15(s,2H),2.91-2.82(m,1H),2.81-2.73(m,2H),2.70-2.56(m,2H),2.15-2.09(m,3H).

[0432] Example 7

[0433]

[0434] Example 7 can be prepared by the same method as Example 8. 1H NMR(600MHz,Chloroform-d)δ9.18(s,1H),8.67(s,1H),8.35(s,1H),8.24-8.21(m,2H),7.56(s,1H),7.38(q,J=8.1Hz,4H),7. 28(d,J=4.0Hz,1H),7.15(s,1H),7.08(d,J=8.3Hz,1H),6.83(s,1H),5.08(t,J=7.2Hz,1H),4.76(t,J=8.0Hz,1H),4.69(s,2H), 4.52(d,J=8.2Hz,1H),4.49(s,1H),4.15(d,J=11.5Hz,1H),3.77-3.70(m,3H),3.69-3.59(m,11H),3.56(dd,J=11.5,3.5Hz,1H ),3.02(s,2H),2.88-2.57(m,4H),2.57-2.41(m,8H),2.14-2.08(m,1H),2.03-1.94(m,3H),1.47(d,J=6.9Hz,3H),1.05(s,9H).

[0435] Example 8

[0436]

[0437] Step 1: Preparation of intermediate I-8-1

[0438] A mixture of 50 mg of tert-butyl bromo-ethylene glycol propionate, 73 mg of I-1-10, 60 μL of DIPEA, and 1 mL of DMSO was stirred at 60°C overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was subjected to column chromatography with methanol: dichloromethane = 8:92 to obtain 34 mg of I-8-1 as a yellow solid, with a yield of 31%. 1 H NMR(400MHz,Chloroform-d)δ9.18(s,1H),8.35(s,1H),8.25-8.18(m,2H),7.29-7.26(m,1H),7.14(s,1H),6.83(s,1H),4.72( s,2H),3.75-3.64(m,4H),3.61(s,4H),3.00(s,2H),2.81-2.63(m,6H),2.50(t,J=6.6Hz,2H),2.01-1.90(m,4H),1.44(s,9H).

[0439] Step 2: Preparation of Example 8

[0440] A mixture of 34 mg of I-8-1, 3 ml of dichloromethane and 0.6 ml of trifluoroacetic acid was stirred at room temperature for 1 hour, and the reaction solution was concentrated to dryness to obtain crude I-8-2. A mixture of the crude I-8-2, 74 μl of DIPEA, 21 mg of EDCI, 15 mg of HOBT, 38 mg of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride and 3 ml of dichloromethane was reacted at room temperature overnight. The reaction solution was directly prepared with dichloromethane: methanol: ammonia water = 10:1:0.1 to obtain 31 mg of compound 8 as a light yellow solid with a yield of 49%. 1 H NMR(600MHz,Chloroform-d)δ9.17(s,1H),8.66(s,1H),8.37(s,1H),8.23(s,1H),8.17(d,J=5.5Hz,1H),7.82(d,J=7.9Hz,1H),7.42-7.37(m,4H ),7.29(d,J=5.5Hz,1H),7.21(s,1H),7.11(d,J=7.9Hz,1H),6.82(s,1H ),5.21(s,2H),5.11(t,J=7.3Hz,1H),4.83(t,J=8.3Hz,1H),4.62(d,J=8 .8Hz,1H),4.50(s,1H),4.07-4.00(m,3H),3.86-3.81(m,1H),3.78-3.7 2(m,1H),3.70-3.62(m,6H),3.61-3.58(m,1H),3.57-3.53(m,1H),3.36- 3.32(m,1H),3.30-3.20(m,3H),3.13-3.05(m,3H),2.56-2.48(m,6H),2 .32-2.27(m,2H),2.11-2.04(m,2H),1.51(d,J=7.0Hz,3H),1.04(s,9H).

[0441] Example 9

[0442]

[0443] Example 9 can be prepared by the same method as Example 8. 1H NMR(600MHz,Chloroform-d)δ9.18(s,1H),8.65(s,1H),8.36(s,1H),8.26(s,1H),8.22(d,J=5.4Hz,1H),7.57(d,J=7.5Hz,1H),7.39-7.33(m,4H),7 .29(d,J=5.4Hz,1H),7.16(s,1H),6.83(s,1H),6.79(d,J=7.5Hz,1H),5.0 8(t,J=7.2Hz,1H),4.85-4.80(m,2H),4.64(d,J=8.8Hz,1H),4.47(s,1H),4 .36(t,J=6.5Hz,1H),4.10(d,J=11.5Hz,1H),3.99-3.94(m,1H),3.87-3.8 2(m,2H),3.78-3.74(m,1H),3.59-3.52(m,3H),3.29-3.18(m,4H),3.09(s, 2H),2.66-2.57(m,3H),2.52(s,3H),2.49-2.43(m,2H),2.42-2.37(m,1H) ,2.27-2.23(m,1H),2.13-2.07(m,2H),1.48(d,J=7.0Hz,3H),1.05(s,9H).

[0444] Example 10

[0445]

[0446] Embodiment 11

[0447]

[0448] Example 12

[0449]

[0450] Example 12 can be prepared by the same method as Example 4. 1 H NMR (600 MHz, DMSO-d 6)δ11.10(s,1H),9.72(s,1H),9.01(s,1H),8.83(d,J=4.5Hz,2H),7.98(d,J=4.5Hz,2H ),7.83(d,J=8.3Hz,1H),7.62(s,1H),7.46(s,1H),7.37(d,J=8.3Hz,1H),6.98(s,1H), 5.13-5.09(m,1H),4.32(t,J=4.4Hz,2H),3.80(t,J=4.3Hz,2H),3.64-3.49(m,8H),3. 03(s,2H),2.94-2.84(m,2H),2.62-2.53(m,4H),2.08-1.99(m,2H),1.89-1.72(m,4H).

[0451] Embodiment 13

[0452]

[0453] Example 13 can be prepared by the same method as Example 4. 1 H NMR (600 MHz, DMSO-d 6 )δ11.10(s,1H),10.25(s,1H),8.44-8.37(m,2H),8.22(d,J=7.5Hz,1H),8.01( s,1H),7.82(d,J=8.3Hz,1H),7.45(s,1H),7.36(dd,J=8.3,2.3Hz,1H),7.00(s, 1H),5.13-5.08(m,1H),4.32(t,J=4.3Hz,2H),3.80(t,J=4.4Hz,2H),3.74-3.4 2(m,8H),3.06(s,2H),2.93-2.83(m,2H),2.63-2.51(m,4H),2.10-1.60(m,6H).

[0454] Embodiment 14

[0455]

[0456] Example 14 can be prepared by the same method as Example 4. 1 H NMR (600 MHz, DMSO-d 6)δ11.10(s,1H),10.13(s,1H),8.15-8.11(m,2H),7.87(s,1H),7.85-7 .81(m,2H),7.46(s,1H),7.37(d,J=8.4Hz,1H),6.99(s,1H),5.13-5.09 (m,1H),4.32(s,2H),3.80(s,2H),3.64-3.49(m,8H),3.02(s,2H),2.92 -2.84(m,2H),2.62-2.52(m,4H),2.06-2.01(m,1H),1.90-1.66(m,5H).

[0457] Embodiment 15

[0458]

[0459] Example 15 can be prepared by the same method as Example 4. 1 H NMR (600 MHz, DMSO-d 6 )δ11.10(s,1H),10.38(s,1H),8.74(d,J=4.7Hz,1H),8.16(d,J=7.7Hz,1H),8.09(t,J=7.7Hz ,1H),8.04(s,1H),7.83(d,J=8.3Hz,1H),7.72-7.68(m,1H),7.45(s,1H),7.37(d,J=8.3Hz,1H ),6.99(s,1H),5.13-5.08(m,1H),4.32(t,J=4.4Hz,2H),3.80(t,J=4.4Hz,2H),3.63-3.50(m, 7H),3.03(s,2H),2.93-2.82(m,2H),2.67-2.52(m,5H),2.06-2.01(m,1H),1.90-1.67(m,5H).

[0460] Example 16

[0461]

[0462] Embodiment 17

[0463]

[0464] Embodiment 18

[0465]

[0466] Embodiment 19

[0467]

[0468] Embodiment 20

[0469]

[0470] Embodiment 21

[0471]

[0472] Embodiment 22

[0473]

[0474] Embodiment 23

[0475]

[0476] Embodiment 24

[0477]

[0478] Embodiment 25

[0479]

[0480] Embodiment 26

[0481]

[0482] Embodiment 27

[0483]

[0484] Embodiment 28

[0485]

[0486] Embodiment 29

[0487]

[0488] Embodiment 30

[0489]

[0490] Embodiment 31

[0491]

[0492] Embodiment 32

[0493]

[0494] Embodiment 33

[0495]

[0496] Embodiment 34

[0497]

[0498] Embodiment 35

[0499]

[0500] Embodiment 36

[0501]

[0502] Embodiment 37

[0503]

[0504] Embodiment 38

[0505]

[0506] Embodiment 39

[0507]

[0508] Embodiment 40

[0509]

[0510] Embodiment 41

[0511]

[0512] Embodiment 42

[0513]

[0514] Embodiment 43

[0515]

[0516] Embodiment 44

[0517]

[0518] Embodiment 45

[0519]

[0520] Embodiment 46

[0521]

[0522] Embodiment 47

[0523]

[0524] Embodiment 48

[0525]

[0526] Embodiment 49

[0527]

[0528] Embodiment 50

[0529]

[0530] Embodiment 51

[0531]

[0532] Embodiment 52

[0533]

[0534] Example 52 can be prepared by the same method as Example 55. 1 H NMR(600MHz,Chloroform-d)δ9.15(s,1H),8.42(s,1H),8.35(s,1H),8.26(s,1H),8.23(d,J=5.3Hz,1H),7.76(d,J=8 .3Hz,1H),7.38(d,J=2.3Hz,1H),7.29(dd,J=5.3,1.4Hz,1H),7.23(dd,J=8.3,2.3Hz,1H),7.15(s,1H),6.42(s,1H),4 .97-4.92(m,1H),4.72(s,2H),4.28(t,J=4.6Hz,2H),4.13-4.00(m,2H),3.92(s,3H),3.90(t,J=4.6Hz,2H),3.75-3.6 9(m,5H),3.66-3.59(m,2H),3.26-3.13(m,4H),3.02(s,2H),2.92-2.70(m,4H),2.17-2.12(m,1H),2.07-2.00(m,2H).

[0535] Embodiment 53

[0536]

[0537] Example 53 can be prepared by the same method as Example 55. 1H NMR(600MHz,Chloroform-d)δ9.40(s,1H),8.39(brs,1H),8.33(s,1H),8.29(s,1H),8.23(d,J=5.3Hz,1H),7 .77(d,J=8.3Hz,1H),7.38(d,J=1.8Hz,1H),7.27(s,1H),7.25-7.22(m,1H),7.11(s,1H),6.44(s,1H),4.97- 4.92(m,1H),4.69(s,2H),4.53-4.48(m,1H),4.27(t,J=4.7Hz,2H),3.98-3.83(m,4H),3.78-3.60(m,7H),3. 18-3.03(m,2H),3.00(s,2H),2.96-2.70(m,5H),2.17-2.11(m,1H),2.08-1.97(m,3H),1.44(d,J=6.0Hz,6H).

[0538] Embodiment 54

[0539]

[0540] Embodiment 55

[0541]

[0542] Step 1: Preparation of intermediate I-55-1

[0543] Intermediate I-55-1 is prepared from 2,4-difluorobenzyl bromide as a starting material by the same method as steps 3 to 9 in the synthesis of Example 1. 1 H NMR(400MHz,Chloroform-d)δ7.94(d,J=7.7Hz,1H),6.61(d,J=11.5Hz,1H),3.84-3.73(m ,2H),3.43-3.32(m,2H),3.03(s,2H),1.97-1.88(m,2H),1.80-1.70(m,2H),1.48(s,9H).

[0544] Step 2: Preparation of intermediate I-55-2

[0545] A mixture of 1.49 ml of 2,2-difluoroethanol, 1.41 g of sodium hydride (60% dispersed in mineral oil) and 30 ml of tetrahydrofuran was stirred at 0°C for half an hour, followed by the addition of 4.14 g of compound I-55-1, and stirred at room temperature for 2.5 hours. Saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 4:1 to obtain 3.67 g of compound I-55-2 as a yellow solid, with a yield of 75%. 1 H NMR(400MHz,Chloroform-d)δ7.84(s,1H),6.45(s,1H),6.16(tt,J=55.0,4.2Hz,1H),4.25(td,J=12.6,4.2H z,2H),3.84-3.70(m,2H),3.43-3.32(m,2H),2.99(s,2H),1.95-1.87(m,2H),1.80-1.69(m,2H),1.47(s,9H).

[0546] Step 3: Preparation of intermediate I-55-3

[0547] The preparation method of intermediate I-55-3 is the same as I-1-10. 1 H NMR (400 MHz, Methanol-d 4 )δ6.69(s,1H),6.43(s,1H),6.18(tt,J=55.1,3.8Hz,1H),4.18(td,J=13.8,3.8Hz,2H),3.75-3.70(m,2H ),3.42-3.33(m,2H),2.91(s,2H),1.86-1.80(m,2H),1.72-1.64(m,2H),1.47(s,9H).LCMS(ESI)m / z[M+H] + 385.1.

[0548] Step 4: Preparation of intermediate I-55-4

[0549] The preparation method of intermediate I-55-4 is the same as I-1-11. 1H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.32(s,1H),8.27(s,1H),8.23(d ,J=5.3Hz,1H),7.28(m,1H),7.14(s,1H),6.44(s,1H),6.20(tt,J=54.8,3.9 Hz,1H),4.67(s,2H),4.27(td,J=13.1,3.9Hz,2H),3.75-3.69(m,2H),3.44- 3.36(m,2H),3.00(s,2H),1.93-1.87(m,2H),1.75-1.70(m,2H),1.48(s,9H).

[0550] Step 5: Preparation of intermediate I-55-5

[0551] The preparation method of intermediate I-55-5 is the same as I-1-12. LCMS (ESI) m / z [M+H] + 472.2.

[0552] Step 6: Preparation of Example 55

[0553] This step is the same as step 2 in Example 4. 1 H NMR(600MHz,Chloroform-d)δ9.30(s,1H),8.64(s,1H),8.33(s,1H),8.28(s,1H),8.21(d,J=5.4Hz,1H),7.76 (d,J=8.3Hz,1H),7.37(s,1H),7.24(dd,J=8.3,5.4Hz,2H),7.12(s,1H),6.42(s,1H),6.21(t,J=54.8Hz,1H), 4.98-4.92(m,1H),4.79(s,2H),4.32-4.23(m,4H),4.11-4.01(m,2H),3.90(t,J=4.5Hz,2H),3.75-3.58(m,7H ),3.23-3.10(m,3H),3.04(s,2H),2.92-2.71(m,3H),2.37-2.32(m,1H),2.18-2.12(m,1H),2.09-1.98(m,3H).

[0554] Embodiment 56

[0555]

[0556] Embodiment 57

[0557]

[0558] Embodiment 58

[0559]

[0560] Embodiment 59

[0561]

[0562] Embodiment 60

[0563]

[0564] Embodiment 61

[0565]

[0566] Step 1: Preparation of intermediate I-61-1

[0567] Intermediate I-61-1 is prepared from 2,4-difluorobenzyl bromide as a starting material by the same method as steps 3 to 7 in the synthesis of Example 1. 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=7.6Hz,1H),6.68(d,J=11.3Hz,1H),4.45-4.37(m,1H),3.98- 3.90(m,1H),3.71-3.62(m,1H),3.43-3.34(m,1H),3.10(s,2H),2.14-2.08(m,2H),1.92-1.83(m,2H).

[0568] Step 2: Preparation of intermediate I-61-2

[0569] A mixture of 100 mg of intermediate I-61-1 and 2 ml of 2 mol / L dimethylamine tetrahydrofuran solution was stirred at 45°C for 1.5 hours. The reaction solution was concentrated to dryness, and the residue was chromatographed with ethyl acetate: petroleum ether = 15:95 to obtain 114 mg of compound I-61-2 as a yellow oil with a yield of 100%. 1 H NMR(400MHz,Chloroform-d)δ7.77(s,1H),6.39(s,1H),4.36-4.28(m,1H),3.91-3.83(m,1H),3.67-3.59(m, 1H),3.41-3.32(m,1H),2.97(s,2H),2.86(s,6H),2.07-2.00(m,2H),1.86-1.75(m,2H).LCMS(ESI)m / z[M+H] + 374.1.

[0570] Step 3: Preparation of intermediate I-61-3

[0571] The preparation method of intermediate I-61-3 is the same as I-1-10. 1 H NMR (400 MHz, Methanol-d 4 )δ6.66(s,1H),6.54(s,1H),4.22-4.15(m,1H),3.88-3.80(m,1H),3.72-3.63(m,1H),3.48-3. 38(m,1H),2.93(s,2H),2.59(s,6H),2.00-1.91(m,2H),1.83-1.72(m,2H).LCMS(ESI)m / z[M+H] + 344.3.

[0572] Step 4: Preparation of intermediate I-61-4

[0573] The preparation method of intermediate I-61-4 is the same as I-1-11. 1 H NMR(400MHz,Chloroform-d)δ9.70(s,1H),8.35(s,1H),8.28(s,1H),8.24(d,J=5.3Hz,1H),7.30(d,J=5.3Hz,1H),7.14(s,1H),6.69(s,1H),4.67( s,2H),4.38-4.29(m,1H),3.91-3.83(m,1H),3.72-3.62(m,1H),3.44-3.3 5(m,1H),3.03(s,2H),2.72(s,6H),2.10-2.03(m,2H),1.84-1.75(m,2H).

[0574] Step 5: Preparation of intermediate I-61-5

[0575] The preparation method of intermediate I-61-5 is the same as I-1-8. LCMS (ESI) m / z [M+H] + 435.2.

[0576] Step 6: Preparation of Example 61

[0577] This step is the same as step 2 in Example 4. 1H NMR(400MHz,Chloroform-d)δ9.68(s,1H),8.45(s,1H),8.36(s,1H),8.27(s,1H),8.23(d,J=5.3Hz,1H),7 .77(d,J=8.3Hz,1H),7.38(d,J=2.4Hz,1H),7.29(dd,J=5.3,1.4Hz,1H),7.24(dd,J=8.3,2.4Hz,1H),7.13 (s,1H),6.64(s,1H),4.98-4.92(m,1H),4.72(s,2H),4.30-4.26(m,2H),3.99-3.88(m,4H),3.77-3.67(m, 6H),3.16-3.05(m,3H),3.02(s,2H),2.93-2.73(m,5H),2.71(s,6H),2.17-2.12(m,1H),2.08-1.98(m,3H).

[0578] Embodiment 62

[0579]

[0580] Embodiment 63

[0581]

[0582] Step 1: Preparation of intermediate I-63-1

[0583] Intermediate I-63-1 is prepared from 4-bromo-2-fluorobenzyl bromide as the starting material by the same method as steps 3 to 9 in the synthesis of Example 1. 1 H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.09(s,1H),3.84-3.73(m,2H),3.4 1-3.31(m,2H),3.01(s,2H),1.96-1.87(m,2H),1.79-1.68(m,2H),1.47(s,9H).

[0584] Step 2: Preparation of intermediate I-63-2

[0585] 90 mg of compound I-63-1, 83 mg of cyclopropylboronic acid, 17 mg of Pd(dppf)Cl 2 , 100 mg potassium carbonate, 1 ml water and 5 ml 1,4-dioxane were stirred at 90°C for 3 hours under argon protection. The reaction solution was concentrated to dryness, and the residue was chromatographed with ethyl acetate: petroleum ether = 1:9 to obtain 66 mg of compound I-63-2 as a yellow oil with a yield of 76%. 1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),6.49(s,1H),3.83-3.71(m,2H),3.42-3.33(m,2H),3.00(s,2H), 2.55-2.47(m,1H),1.92-1.86(m,2H),1.74-1.70(m,2H),1.47(s,9H),1.06-1.01(m,2H),0.69-0.62(m,2H).

[0586] Step 3: Preparation of intermediate I-63-3

[0587] The preparation method of intermediate I-63-3 is the same as I-1-10. LCMS (ESI) m / z [M+H] + 345.2.

[0588] Step 4: Preparation of intermediate I-63-4

[0589] The preparation method of intermediate I-63-4 is the same as I-1-11. 1 H NMR(400MHz,Chloroform-d)δ9.38(s,1H),8.35(s,1H),8.22(d,J=5.3Hz,1H),8.08(s,1H),7.28-7.26(m,1H),7.11(s,1H),6.63(s,1H),4.71(s, 2H),3.77-3.68(m,2H),3.45-3.35(m,2H),3.00(s,2H),1.91-1.86(m,3H ),1.71-1.65(m,2H),1.47(s,9H),1.12-1.07(m,2H),0.75-0.70(m,2H).

[0590] Step 5: Preparation of intermediate I-63-5

[0591] The preparation method of intermediate I-63-5 is the same as I-1-12. LCMS (ESI) m / z [M+H] + 432.3.

[0592] Step 6: Preparation of Example 63

[0593] This step is the same as step 2 in Example 4. 1H NMR(600MHz,Chloroform-d)δ9.37(s,1H),8.40-8.34(m,2H),8.23(d,J=5.3Hz,1H),8.08(s,1H),7.76(d,J= 8.3Hz,1H),7.37(d,J=2.3Hz,1H),7.27-7.26(m,1H),7.23(dd,J=8.3,2.3Hz,1H),7.10(s,1H),6.60(s,1H),4 .98-4.92(m,1H),4.69(s,2H),4.27(t,J=4.6Hz,2H),3.92-3.89(m,2H),3.88-3.57(m,8H),3.01(s,2H),2.99 -2.69(m,8H),2.16-2.12(m,1H),2.03-1.94(m,3H),1.91-1.87(m,1H),1.10-1.07(m,2H),0.72-0.70(m,2H).

[0594] Embodiment 64

[0595]

[0596] Step 1: Preparation of intermediate I-64-1

[0597] 140 mg of compound I-63-1, 119 mg of zinc cyanide, 39 mg of Pd(PPh 3 ) 4 The mixture was stirred at 100°C for 11 hours under argon protection. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with ethyl acetate: petroleum ether = 1:3 to obtain 59 mg of compound I-64-1 as a yellow solid, with a yield of 48%. 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.17(s,1H),3.88-3.77(m,2H),3.4 2-3.32(m,2H),3.14(s,2H),1.99-1.91(m,2H),1.82-1.74(m,2H),1.48(s,9H).

[0598] Step 2: Preparation of intermediate I-64-2

[0599] A mixture of 90 mg of compound I-64-1, 90 mg of 10% Pd / C and 4 ml of tetrahydrofuran was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated to dryness to obtain 90 mg of crude compound I-64-2 as a yellow solid, which was directly used in the next reaction without further purification. 1H NMR(400MHz,Chloroform-d)δ6.72(s,1H),6.59(s,1H),4.07(s,2H),3.80-3.70(m,2H ),3.39-3.31(m,2H),2.93(s,2H),1.88-1.82(m,2H),1.70-1.66(m,2H),1.47(s,9H).

[0600] Step 3: Preparation of intermediate I-64-3

[0601] The preparation method of intermediate I-64-3 is the same as I-1-11. 1 H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.38(s,1H),8.30(s,1H),8.21(d,J=5.3Hz,1H),7.28-7.27(m,1H),7.17(s,1H),6. 97(s,1H),4.78(s,2H),3.83-3.73(m,2H),3.42-3.33(m,2H),3.09(s,2H),1.95-1.88(m,2H),1.77-1.74(m,2H),1.48(s,9H).

[0602] Step 4: Preparation of intermediate I-64-4

[0603] The preparation method of intermediate I-64-4 is the same as I-1-12. LCMS (ESI) m / z [M+H] + 417.1.

[0604] Step 5: Preparation of Example 64

[0605] The experimental method of this step is the same as step 2 of Example 4. 1 H NMR(600MHz,Chloroform-d)δ9.29(s,1H),8.51(s,1H),8.38(s,1H),8.30(s,1H),8.22(d,J= 5.3Hz,1H),7.77(d,J=8.3Hz,1H),7.36(d,J=2.3Hz,1H),7.27-7.26(m,1H),7.25-7.22(m,1H) ,7.16(s,1H),6.95(s,1H),4.99-4.95(m,1H),4.75(s,2H),4.31-4.23(m,3H),3.93-3.89(m, 3H),3.75-3.63(m,7H),3.09(s,2H),2.97-2.68(m,7H),2.17-2.11(m,1H),2.02-1.94(m,3H).

[0606] Embodiment 65

[0607]

[0608] Embodiment 66

[0609]

[0610] Embodiment 67

[0611]

[0612] Example 67 can be prepared by the same method as Example 61. 1 H NMR (400 MHz, DMSO-d 6 )δ10.41(brs,2H),9.07(s,1H),8.79(s,1H),8.64(d,J=5.2Hz,1H),8.22(d,J=8. 2Hz,1H),7.87(s,1H),7.84(d,J=8.2Hz,1H),7.70-7.65(m,2H),7.18(s,1H),6.2 7(s,2H),5.58-5.52(m,1H),4.88-4.83(m,2H),4.44-4.34(m,9H),4.21-4.17(m, 2H),4.15-4.11(m,2H),4.07-4.03(m,1H),3.64-3.51(m,13H),2.79-2.61(m,5H).

[0613] Embodiment 68

[0614]

[0615] Embodiment 69

[0616]

[0617] Embodiment 70

[0618]

[0619] Embodiment 71

[0620]

[0621] Embodiment 72

[0622]

[0623] Embodiment 73

[0624]

[0625] Embodiment 74

[0626]

[0627] Embodiment 75

[0628]

[0629] Embodiment 76

[0630]

[0631] Embodiment 77

[0632]

[0633] Embodiment 78

[0634]

[0635] Embodiment 79

[0636]

[0637] Embodiment 80

[0638]

[0639] Embodiment 81

[0640]

[0641] Embodiment 82

[0642]

[0643] Embodiment 83

[0644]

[0645] Embodiment 84

[0646]

[0647] Embodiment 85

[0648]

[0649] Embodiment 86

[0650]

[0651] Embodiment 87

[0652]

[0653] Step 1: Preparation of intermediate I-87-1

[0654] A mixture of 2 g of 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione, 1.25 g of 4-hydroxymethylpiperidine, 5 ml of DIPEA and 8 ml of DMSO was stirred at 110°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was concentrated to dryness to obtain 3.3 g of crude compound I-87-1 as a yellow solid, which was directly used in the next step without further purification. 1 HNMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),7.64(d,J=8.5Hz,1H),7.30(d,J=2.3Hz,1H),7.22(dd,J=8.5,2.3Hz,1H),5.09-5.03(m,1H),4.49(t,J=5.3Hz,1H),4. 09-4.03(m,3H),3.27(t,J=5.7Hz,2H),3.00-2.82(m,4H),2.62-2.53(m,2H),2.05-2.00(m,1H),1.77-1.62(m,3H).LCMS(ESI)m / z[M+H] + 372.2.

[0655] Step 2: Preparation of intermediate I-87-2

[0656] A mixture of 3.2 g of compound I-87-1, 6.6 g of Dess-Martin periodinane, and 30 ml of DCM was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to dryness. The residue was chromatographed with petroleum ether: ethyl acetate = 3:7 to obtain 1.4 g of compound I-87-2 as a yellow solid with a yield of 37%. LCMS (ESI) m / z [M+H] + 370.2.

[0657] Step 3: Preparation of intermediate I-87-3

[0658] A mixture of 90 mg of compound I-55-5, 186 mg of 1-tert-butyloxycarbonyl-4-iodomethylpiperidine, 100 μL of DIPEA and 4 mL of DMSO was stirred at 55°C overnight. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=96:4 to obtain 124 mg of compound I-87-3 as a yellow oil with a yield of 97%. 1HNMR(400MHz,Chloroform-d)δ9.29(s,1H),8.32(s,1H),8.28(s,1H),8.21(d,J=5.0Hz,1H ),7.25(d,J=5.0Hz,1H),7.14(s,1H),6.41(s,1H),6.20(tt,J=54.9,3.8Hz,1H),4.77(s,2 H),4.26(td,J=13.0,3.9Hz,2H),4.20-4.10(m,2H),3.41-3.32(m,1H),3.14-3.01(m,4H), 2.84-2.68(m,5H),2.14-1.99(m,5H),1.44(s,9H),1.32-1.21(m,4H).LCMS(ESI)m / z[M+H] + 669.4.

[0659] Step 4: Preparation of intermediate I-87-4

[0660] A mixture of 39 mg of compound I-87-3, 0.75 ml of trifluoroacetic acid and 3 ml of DCM was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, diluted with methanol, and saturated sodium hydroxide solution was added to adjust the pH to 7, then concentrated to dryness, and the residue was prepared with dichloromethane: methanol: ammonia water = 8: 1: 0.1 to obtain 21 mg of intermediate I-87-4 as a yellow solid with a yield of 64%. 1 HNMR (400MHz, Methanol-d 4 )δ8.65(s,1H),8.10-8.06(m,2H),7.35-7.30(m,2H),6.70(s,1H),6.31(tt,J=54.6,3.4Hz,1H),4.38(td,J=13.9,3.6Hz,2H),3 .51-3.43(m,5H),3.37(s,2H),3.13-3.05(m,3H),2.31-2.21(m,5H),2.20-2.10(m,3H),1.65-1.52(m,3H).LCMS(ESI)m / z[M+H] + 569.3.

[0661] Step 5: Preparation of Example 87

[0662] A mixture of 20 mg of compound I-87-4, 14 mg of compound I-87-2, 5 μL of glacial acetic acid and 1 mL of 1,2-dichloroethane was stirred at room temperature for 2 hours, followed by the addition of 140 mg of sodium triacetoxyborohydride and stirring at room temperature overnight. The reaction solution was concentrated to dryness, and the residue was prepared with dichloromethane: methanol: ammonia water = 8:1:0.1 to obtain 5 mg of compound 87 as a yellow solid, with a yield of 8%. 1 H NMR (400 MHz, Methanol-d 4 )δ8.59(s,1H),8.09-8.04(m,2H),7.68(d,J=8.5Hz,1H),7.37(d,J=2.3Hz,1H),7.28-7.22 (m,3H),6.66(s,1H),6.29(tt,J=54.8,3.6Hz,1H),5.11-5.04(m,1H),4.36(td,J=13.9,3.6 Hz,2H),4.14-4.07(m,2H),3.65-3.54(m,2H),3.16-2.95(m,11H),2.92-2.65(m,6H),2.19 -2.04(m,9H),1.98-1.91(m,2H),1.69-1.56(m,2H),1.49-1.38(m,2H).LCMS(ESI)m / z[M+H] + 922.5.

[0663] Embodiment 88

[0664]

[0665] Step 1: Preparation of intermediate I-88-1

[0666] The preparation of intermediate I-88-1 is the same as that of intermediate I-87-1. LCMS (ESI) m / z [M+H] + 344.1.

[0667] Step 2: Preparation of intermediate I-88-2

[0668] The preparation of intermediate I-88-2 is the same as intermediate I-87-2. 1 H NMR (400 MHz, Methanol-d 4)δ7.62(d,J=8.3Hz,1H),6.79(d,J=2.1Hz,1H),6.63(dd,J=8.3,2.1Hz,1H),5.08-5.01(m,1H),4.74(d,J=6.2H z,1H),4.07(td,J=8.3,2.0Hz,2H),3.95-3.88(m,2H),2.97-2.89(m,1H),2.87-2.80(m,1H),2.77-2.65(m,2H).

[0669] Step 3: Preparation of Example 88

[0670] This step is the same as step 5 in the preparation method of Example 87. 1 H NMR (600 MHz, Methanol-d 4 )δ8.64(s,1H),8.08(s,1H),8.06(d,J=5.9Hz,1H),7.67(d,J=7.6Hz,1H),7.34(s,1H),7.33(d,J= 5.9Hz,1H),6.86(s,1H),6.70(d,J=7.6Hz,1H),6.69(s,1H),6.29(t,J=54.8Hz,1H),5.09-5.04(m, 1H),4.39-4.30(m,4H),3.92-3.87(m,2H),3.64-3.49(m,6H),3.40-3.34(m,2H),3.20-2.99(m,6H ),2.90-2.81(m,1H),2.77-2.67(m,2H),2.32-2.07(m,9H),1.76-1.60(m,2H).LCMS(ESI)m / z[M+H] + 894.5.

[0671] Embodiment 89

[0672]

[0673] Step 1: Preparation of intermediate I-89-1

[0674] The preparation of intermediate I-89-1 is the same as intermediate I-87-3. LCMS (ESI) m / z [M+H] + 641.4.

[0675] Step 2: Preparation of intermediate I-89-2

[0676] The preparation of intermediate I-89-2 is the same as intermediate I-87-4. LCMS (ESI) m / z [M+H] + 541.3.

[0677] Step 3: Preparation of Example 89

[0678] This step is the same as step 5 in the preparation method of Example 87. 1 H NMR (600 MHz, Methanol-d 4 )δ8.67(s,1H),8.08-8.03(m,2H),7.68(d,J=8.5Hz,1H),7.43(s,1H),7.38(d,J=6.1Hz,1H),7.36(s,1H),7.24(d,J=6. 1Hz,1H),6.68(s,1H),6.28(t,J=54.7Hz,1H),5.10-5.05(m,1H),4.42(s,2H),4.39-4.33(m,2H),4.19-4.12(m,2H),4.1 1-4.07(m,2H),3.65-3.37(m,6H),3.27-3.17(m,3H),3.13(s,2H),3.06-3.01(m,2H),2.89-2.82(m,1H),2.78-2.69(m, 2H),2.23-2.14(m,4H),2.14-2.08(m,1H),2.04-1.96(m,1H),1.90-1.84(m,2H),1.45-1.37(m,2H).LCMS(ESI)m / z[M+H] + 894.5.

[0679] Embodiment 90

[0680]

[0681] Step 1: Preparation of intermediate I-90-1

[0682] The preparation of intermediate I-90-1 is the same as that of intermediate I-87-1. LCMS (ESI) m / z [M+H] + 390.1.

[0683] Step 2: Preparation of intermediate I-90-2

[0684] The preparation of intermediate I-90-2 is the same as intermediate I-87-2. 1H NMR(400MHz,Chloroform-d)δ9.73(s,1H),8.02(s,1H),7.48(d,J=10.9Hz,1H),7.39(d,J=7.3Hz,1H),4.96-4.90(m,1 H),3.63-3.55(m,2H),3.06-2.97(m,2H),2.94-2.68(m,3H),2.54-2.45(m,1H),2.17-2.05(m,3H),1.93-1.81(m,2H).

[0685] Step 3: Preparation of intermediate I-90-3

[0686] The preparation of intermediate I-90-3 is the same as intermediate I-87-3. 1 H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.34(s,1H),8.28(s,1H),8.25(d,J=4.5Hz,1H),7 .30(d,J=4.5Hz,1H),7.16(s,1H),6.46(s,1H),6.22(tt,J=54.9,3.9Hz,1H),4.70(s,2H),4.2 9(td,J=13.1,3.9Hz,2H),4.00-3.94(m,2H),3.89-3.83(m,2H),3.21-3.12(m,1H),3.02(s,2 H),2.55-2.42(m,4H),2.07-1.99(m,2H),1.91-1.82(m,2H),1.46(s,9H).LCMS(ESI)m / z[M+H] + 627.3.

[0687] Step 4: Preparation of intermediate I-90-4

[0688] The preparation of intermediate I-90-4 is the same as intermediate I-87-4. LCMS (ESI) m / z [M+H] + 527.2.

[0689] Step 5: Preparation of Example 90

[0690] A mixture of 47 mg of compound I-90-4, 42 mg of compound I-90-2, 13 μL of glacial acetic acid, 3.5 mL of tetrahydrofuran and 3.5 mL of 1,2-dichloroethane was stirred at room temperature for 2 hours, and then 269 mg of sodium triacetoxyborohydride was added and stirred at room temperature overnight. The reaction solution was concentrated to dryness, and the residue was prepared with dichloromethane: methanol: ammonia water = 10: 1: 0.1 to obtain 20 mg of compound 90 as a yellow solid, with a yield of 24%. 1H NMR (400 MHz, DMSO-d 6 )δ11.11(s,1H),9.33(s,1H),8.91(s,1H),8.10(d,J=5.3Hz,1H),8.00(s,1H),7.71(d,J=11.4Hz, 1H),7.45(d,J=7.3Hz,1H),7.08-7.00(m,2H),6.77(s,1H),6.61-6.30(m,3H),5.14-5.06(m,1H), 4.41(td,J=14.7,3.5Hz,2H),3.64-3.56(m,2H),3.00(s,2H),2.93-2.82(m,4H),2.68-2.52(m,4H ),2.48-2.26(m,5H),2.07-1.99(m,1H),1.92-1.63(m,8H),1.41-1.15(m,4H).LCMS(ESI)m / z[M+H] + 898.4.

[0691] Embodiment 91

[0692]

[0693] Step 1: Preparation of intermediate I-91-1

[0694] The preparation of intermediate I-91-1 is the same as intermediate I-87-1. LCMS (ESI) m / z [M+H] + 362.1.

[0695] Step 2: Preparation of intermediate I-91-2

[0696] The preparation of intermediate I-91-2 is the same as intermediate I-87-2. 1 H NMR(400MHz,Chloroform-d)δ9.95(s,1H),8.03(s,1H),7.40(d,J=10.7Hz,1H),6.87(d,J=7.4Hz,1 H),4.94-4.88(m,1H),4.41-4.32(m,4H),2.92-2.86(m,1H),2.84-2.67(m,3H),2.15-2.11(m,1H).

[0697] Step 3: Preparation of intermediate I-91-3

[0698] The preparation of intermediate I-91-3 is the same as intermediate I-87-3. 1H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.32(s,1H),8.26(s,1H),8.22(d,J=5.3Hz ,1H),7.27-7.26(m,1H),7.13(s,1H),6.43(s,1H),6.20(tt,J=54.9,3.9Hz,1H),4.70( s,2H),4.34-4.13(m,4H),3.90-3.80(m,2H),3.06-2.96(m,4H),2.95-2.83(m,3H),2.7 9-2.65(m,3H),2.07-2.00(m,3H),1.88-1.81(m,2H),1.46(s,9H).LCMS(ESI)m / z[M+H] + 655.3.

[0699] Step 4: Preparation of intermediate I-91-4

[0700] The preparation of intermediate I-91-4 is the same as intermediate I-87-4. LCMS (ESI) m / z [M+H] + 555.2.

[0701] Step 5: Preparation of Example 91

[0702] A mixture of 6 mg of compound I-91-4, 5 mg of compound I-91-2, 1.2 μL of glacial acetic acid and 0.5 mL of DMSO was stirred at room temperature for 2 hours, followed by the addition of 35 mg of sodium triacetoxyborohydride and stirring at room temperature overnight. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol = 8:1 to obtain 5.5 mg of compound 91 as a yellow solid, with a yield of 55%. 1 H NMR (400 MHz, DMSO-d 6)δ11.08(s,1H),9.35(s,1H),8.91(s,1H),8.10(d,J=5.2Hz,1H),8.03(s,1H),7.61(d,J=11. 1Hz,1H),7.07-7.01(m,2H),6.91(d,J=7.6Hz,1H),6.79(s,1H),6.63-6.28(m,3H),5.09-5.0 3(m,1H),4.43(td,J=14.7,3.4Hz,2H),4.33-4.26(m,2H),3.89(s,2H),3.19-2.96(m,8H),2. 94-2.82(m,3H),2.63-2.52(m,4H),2.18-1.82(m,9H),1.80-1.63(m,2H).LCMS(ESI)m / z[M+H] + 898.5.

[0703] Embodiment 92

[0704]

[0705] Step 1: Preparation of intermediate I-92-1

[0706] The preparation of intermediate I-92-1 is the same as that of intermediate I-87-1. LCMS (ESI) m / z [M+H] + 376.1.

[0707] Step 2: Preparation of intermediate I-92-2

[0708] The preparation of intermediate I-92-2 is the same as intermediate I-87-2. 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.53(d,J=10.9Hz,1H),7.44(d,J=7.3Hz,1H),4.99- 4.90(m,1H),3.61(t,J=6.1Hz,4H),2.94-2.72(m,3H),2.66(t,J=6.0Hz,4H),2.19-2.10(m,1H).

[0709] Step 3: Preparation of Example 92

[0710] The preparation method of Example 92 is the same as step 5 in the preparation method of Example 91. 1 H NMR (400 MHz, DMSO-d 6)δ11.12(s,1H),9.38(s,1H),9.00(s,1H),8.13(d,J=5.8Hz,1H),8.04(s,1H),7.77(d,J=11.2Hz,1H),7.23 -7.17(m,2H),7.14(d,J=5.7Hz,1H),7.06(s,1H),6.81(s,2H),6.61-6.34(m,1H),5.16-5.09(m,1H),4.44( td,J=14.9,3.4Hz,2H),3.83-3.65(m,4H),3.52-3.46(m,2H),3.21-3.04(m,6H),2.99-2.86(m,3H),2.69-2 .56(m,2H),2.45-2.38(m,2H),2.33-2.13(m,8H),2.09-1.99(m,2H),1.96-1.81(m,3H).LCMS(ESI)m / z[M+H] + 912.5.

[0711] Embodiment 93

[0712]

[0713] Step 1: Preparation of intermediate I-93-1

[0714] The preparation of intermediate I-93-1 is the same as intermediate I-87-1. 1 H NMR (400MHz, Chloroform-d) δ8.20 (s, 1H), 7.46 (d, J = 11.1Hz, 1H), 7.38 (d, J = 7.3Hz, 1H), 4.96-4. 88(m,1H),3.33(t,J=4.9Hz,4H),3.20(s,2H),2.94-2.68(m,7H),2.17-2.09(m,1H),1.48(s,9H).

[0715] Step 2: Preparation of intermediate I-93-2

[0716] A mixture of 50 mg of compound I-93-1, 3 ml of 4 mol / L hydrochloric acid dioxane solution, 1.5 ml of dioxane, and 0.5 ml of water was stirred at room temperature for 4 hours. The reaction solution was concentrated to dryness to obtain the crude intermediate I-93-2 as a yellow solid, which was directly used in the next reaction. LCMS (ESI) m / z [M+H] + 419.0.

[0717] Step 3: Preparation of Example 93

[0718] A mixture of 38 mg of compound I-55-5, 182 mg of crude compound I-93-2, 53 mg of HATU, 70 μl of DIPEA and 3 ml of DMSO was stirred at room temperature overnight. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol: ammonia water = 10: 1: 0.1 to obtain 7 mg of compound 93 as a yellow solid, with a yield of 10%. 1 HNMR(400MHz,Chloroform-d)δ9.33(s,1H),8.32(s,1H),8.29(s,1H),8.27-8.21(m,2H),7.48(d,J=10.9Hz,1H),7.39(d ,J=7.2Hz,1H),7.28(d,J=5.4Hz,1H),7.14(s,1H),6.46(s,1H),6.19(tt,J=54.8,3.6Hz,1H),4.98-4.89(m,1H),4.70(s ,2H),4.28(td,J=13.0,3.8Hz,2H),4.22-4.15(m,1H),3.87-3.78(m,1H),3.67-3.58(m,1H),3.42-3.26(m,7H),3.03(s, 2H),2.94-2.77(m,3H),2.77-2.71(m,4H),2.18-2.11(m,1H),2.06-1.92(m,2H),1.81-1.69(m,2H).LCMS(ESI)m / z[M+H] + 872.3.

[0719] Embodiment 94

[0720]

[0721] Step 1: Preparation of intermediate I-94-1

[0722] A mixture of 15 mg of compound I-55-5, 10 mg of 1-Boc-4-piperidinic acid, 18 mg of HATU, 17 μL of N,N-diisopropylethylamine and 1 mL of N,N-dimethylformamide was stirred at room temperature overnight. Water was added to the reaction solution, filtered, and the filter cake was prepared with dichloromethane:methanol = 15:1 to obtain 17 mg of intermediate I-94-1 as a white solid with a yield of 78%. 1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.32(s,1H),8.27(s,1H),8.21(d,J=5.3Hz,1H),7.2 5(d,J=5.3Hz,1H),7.13(s,1H),6.44(s,1H),6.20(tt,J=54.9,3.9Hz,1H),4.79(s,2H),4.32-4 .08(m,5H),3.73-3.66(m,1H),3.64-3.54(m,1H),3.37-3.27(m,1H),3.01(s,2H),2.82-2.72(m ,2H),2.70-2.61(m,1H),2.03-1.92(m,2H),1.79-1.61(m,6H),1.45(s,9H).LCMS(ESI)m / z[M+H] + 683.4.

[0723] Step 2: Preparation of intermediate I-94-2

[0724] The preparation of intermediate I-94-2 is the same as intermediate I-87-4. LCMS (ESI) m / z [M+H] + 583.2.

[0725] Step 3: Preparation of Example 94

[0726] The preparation of Example 94 is the same as step 5 in the preparation of Example 91. 1 H NMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),9.35(s,1H),8.92(s,1H),8.11(d,J=5.2Hz,1H),8.04(s,1H),7.64(d,J=11.1Hz,1H),7.06(d,J=5 .2Hz,1H),7.03(s,1H),6.94(d,J=7.5Hz,1H),6.80(s,1H),6.61-6.32(m,3H),5.11-5.04(m,1H),4.44(td,J=14.8, 3.4Hz,2H),4.35(s,2H),4.07-3.94(m,2H),3.86-3.79(m,1H),3.73-3.65(m,1H),3.62-3.41(m,6H),3.06(s,2H), 3.04-2.94(m,2H),2.94-2.83(m,2H),2.69-2.56(m,3H),2.06-1.98(m,1H),1.96-1.66(m,8H).LCMS(ESI)m / z[M+H] +926.3.

[0727] Embodiment 95

[0728]

[0729] Step 1: Preparation of intermediate I-95-1

[0730] A mixture of 500 mg of ethyl 2,4-difluorobenzoate, 513 mg of 4-(dimethoxymethyl)-piperidine, 1.4 ml of DIPEA and 5 ml of DMSO was stirred at 100°C for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate = 9:1 to obtain 488 mg of compound I-95-1 as a white solid, with a yield of 56%. 1 HNMR(400MHz,Chloroform-d)δ7.79(t,J=8.9Hz,1H),6.61(dd,J=8.9,2.5Hz,1H),6.49(dd,J=15.0,2.5Hz,1H),4.33(q,J=7.1Hz,2H) ,4.05(d,J=6.7Hz,1H),3.89-3.80(m,2H),3.37(s,6H),2.88-2.79(m,2H),1.88-1.80(m,3H),1.44-1.33(m,5H).LCMS(ESI)m / z[M+H] + 326.1.

[0731] Step 2: Preparation of intermediate I-95-2

[0732] A mixture of 300 mg of intermediate I-95-1, 231 mg of lithium hydroxide monohydrate, 4 ml of tetrahydrofuran, 2 ml of methanol, and 2 ml of water was stirred at room temperature for 7 hours. The reaction solution was first concentrated to dryness, then diluted with 2 ml of water, and then adjusted to pH = 5 with 1 mol / L hydrochloric acid, filtered, and the filter cake was collected to obtain 118 mg of intermediate I-95-2 as a white solid, with a yield of 43%. LCMS (ESI) m / z [M+H] + 298.1.

[0733] Step 3: Preparation of intermediate I-95-3

[0734] A mixture of 100 mg of intermediate I-95-2, 52 mg of 3-amino-2,6-piperidindione, 192 mg of HATU, 176 μL of N,N-diisopropylethylamine and 3 mL of N,N-dimethylformamide was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol = 97:3 to obtain 132 mg of compound I-95-3 as a white solid, with a yield of 96%.1 H NMR(400MHz,Chloroform-d)δ8.00-7.90(m,2H),7.39(dd,J=14.2,5.7Hz,1H),6.71(dd,J=9.1,2.5Hz,1H),6.51(dd,J=16.5,2.5Hz,1H),4.82-4.74(m,1H ),4.06(d,J=6.6Hz,1H),3.88-3.82(m,2H),3.37(s,6H),2.89-2.75(m,5H), 2.74-2.66(m,1H),1.88-1.80(m,3H),1.46-1.35(m,2H).LCMS(ESI)m / z[M+H] + 408.2.

[0735] Step 4: Preparation of intermediate I-95-4

[0736] A mixture of 60 mg of intermediate I-95-3, 0.35 ml of 2 mol / L sulfuric acid and 0.7 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Saturated sodium carbonate solution was added to the reaction solution, extracted with dichloromethane, and the organic phase was concentrated to dryness. The residue was prepared with dichloromethane: methanol = 20:1 to prepare a thin layer to obtain 36 mg of compound I-95-3 as a white solid, with a yield of 68%. 1 H NMR(400MHz,Chloroform-d)δ9.69(s,1H),8.31(s,1H),7.94(t,J=9.0Hz,1H),7.41( dd,J=13.9,5.7Hz,1H),6.71(dd,J=9.0,2.5Hz,1H),6.51(dd,J=16.3,2.5Hz,1H),4. 82-4.74(m,1H),3.78-3.71(m,2H),3.10-3.01(m,2H),2.83-2.76(m,2H),2.72-2.63 (m,1H),2.55-2.46(m,1H),2.03-1.87(m,3H),1.76-1.69(m,2H).LCMS(ESI)m / z[M+H] + 362.1.

[0737] Step 5: Preparation of Example 95

[0738] The preparation of Example 95 is the same as step 5 in the preparation of Example 91. 1 H NMR (600 MHz, DMSO-d 6)δ10.83(s,1H),9.35(s,1H),8.95(s,1H),8.12(d,J=5.7Hz,1H),8.03-7.99(m,2H),7.62(t,J=9.0Hz,1H),7.18(s, 1H),7.11(d,J=5.7Hz,1H),6.89-6.71(m,5H),6.45(tt,J=54.3,3.5Hz,1H),4.74-4.69(m,1H),4.42(td,J=14.7,3.5 Hz,2H),4.37-4.02(m,3H),3.93-3.87(m,2H),3.23-3.08(m,8H),3.04(s,2H),2.85-2.79(m,3H),2.79-2.73(m,2H) ,2.54-2.51(m,2H),2.03-1.98(m,2H),1.97-1.91(m,2H),1.90-1.84(m,2H),1.80-1.76(m,2H).LCMS(ESI)m / z[M+H] + 872.3.

[0739] Embodiment 96

[0740]

[0741] Step 1: Preparation of intermediate I-96-1

[0742] A mixture of 500 mg of 3,4-difluoronitrobenzene, 550 mg of 4-(dimethoxymethyl)-piperidine, 868 mg of potassium carbonate and 5 ml of acetonitrile was stirred at 80°C for 3 hours. The reaction solution was filtered and concentrated to dryness, and then column chromatography was performed with petroleum ether:ethyl acetate = 85:15 to obtain 834 mg of compound I-96-1 as a yellow solid, with a yield of 89%. 1 H NMR (400MHz, Chloroform-d) δ7.94 (dd, J=9.5, 2.6Hz, 1H), 7.86 (dd, J=8.8, 2.6Hz, 1H), 6.89 (t, J=8.8Hz, 1H), 4.08 (d, J=6. 6Hz,1H),3.72(d,J=12.5Hz,2H),3.37(s,6H),2.89-2.78(m,2H),1.89-1.78(m,3H),1.54-1.43(m,2H).LCMS(ESI)m / z[M+H] + 299.1.

[0743] Step 2: Preparation of intermediate I-96-2

[0744] A mixture of 420 mg of intermediate I-96-1, 710 mg of iron powder, 678 mg of ammonium chloride, 3 ml of tetrahydrofuran, 4 ml of methanol and 3 ml of water was stirred at 60°C for 4 hours. The reaction solution was filtered and concentrated to dryness, and the residue was chromatographed with petroleum ether: ethyl acetate = 3:1 to obtain 330 mg of compound I-96-2 as a brown solid with a yield of 87%. 1 H NMR(400MHz,Chloroform-d)δ6.81(t,J=8.9Hz,1H),6.44-6.36(m,2H),4.09(d,J=7.4Hz,1H),3.52(brs,2H),3.36(s,6 H),3.32-3.26(m,2H),2.60-2.51(m,2H),1.85-1.78(m,2H),1.74-1.65(m,1H),1.58-1.46(m,2H).LCMS(ESI)m / z[M+H] + 269.1.

[0745] Step 3: Preparation of intermediate I-96-3

[0746] A mixture of 163 mg of intermediate I-96-2, 103 μL of 3-bromopiperidine-2,6-dione, 127 mg of sodium bicarbonate and 4 mL of N,N-dimethylformamide was stirred overnight at 80°C. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was chromatographed with petroleum ether:ethyl acetate = 1:2 to obtain 128 mg of compound I-96-3 as a white solid, with a yield of 56%. 1 H NMR (400MHz, Chloroform-d) δ7.95 (s, 1H), 6.88 (t, J = 9.2Hz, 1H), 6.44-6.37 (m, 2 H),4.58(d,J=3.7Hz,1H),4.10(d,J=7.3Hz,1H),3.99(dt,J=12.4,4.3Hz,1H),3.3 7(s,6H),3.34-3.28(m,2H),2.91-2.83(m,1H),2.79-2.69(m,1H),2.62-2.49(m, 3H),1.95-1.79(m,3H),1.75-1.66(m,1H),1.57-1.47(m,2H).LCMS(ESI)m / z[M+H] + 380.2.

[0747] Step 4: Preparation of intermediate I-96-4

[0748] A mixture of 107 mg of intermediate I-96-3, 1.4 ml of 4 mol / L hydrochloric acid dioxane solution, 0.7 ml of water and 1 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The reaction solution was added with saturated sodium carbonate solution and extracted with dichloromethane. The organic phase was concentrated to dryness and the residue was prepared with dichloromethane: methanol = 20:1 to obtain 15 mg of compound I-96-4 as a brown oil with a yield of 16%. LCMS (ESI) m / z [M+H] + 334.1.

[0749] Step 5: Preparation of Example 96

[0750] The preparation of Example 96 is the same as step 5 in the preparation of Example 91. 1 H NMR (600 MHz, DMSO-d 6 )δ10.77(s,1H),9.33(s,1H),8.90(s,1H),8.11(d,J=5.2Hz,1H),8.01(s,1H),7.0 5(d,J=5.2Hz,1H),7.02(s,1H),6.83(t,J=9.3Hz,1H),6.76(s,1H),6.54-6.33(m, 5H),5.81(d,J=7.7Hz,1H),4.44-4.39(m,2H),4.31-3.81(m,5H),3.24-2.92(m,11 H),2.75-2.68(m,1H),2.44-2.36(m,4H),1.88-1.70(m,10H).LCMS(ESI)m / z[M+H] + 844.5.

[0751] Embodiment 97

[0752]

[0753] Step 1: Preparation of intermediate I-97-1

[0754] A mixture of 20 mg of N-4-bromophenyl barbituric acid, 19 mg of 4-methoxybenzyl chloride, 40 mg of cesium carbonate and 1 ml of DMF was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the residue was thinly layered with dichloromethane to obtain 50 mg of compound I-97-1 as a white solid with a yield of 100%. 1 H NMR (400 MHz, DMSO-d 6)δ7.61-7.56(m,2H),7.33-7.28(m,2H),7.24-7.20(m,2H),6.88-6.83(m,2H),4.79 (s,2H),3.80(t,J=6.7Hz,2H),3.72(s,3H),2.90-2.88(m,2H).LCMS(ESI)m / z[M+H] + 389.0.

[0755] Step 2: Preparation of intermediate I-97-2

[0756] A mixture of 15 mg of intermediate I-97-1, 9 mg of 4-hydroxymethylpiperidine, 2.6 mg of palladium acetate, 10 mg of tBuXPhos, 38 mg of cesium carbonate and 1 ml of 1,4-dioxane was stirred at 90°C for 6 hours under argon protection. The reaction solution was concentrated to dryness, and the residue was developed once with dichloromethane:methanol=20:1 to obtain 5 mg of intermediate I-97-2 as a colorless oil with a yield of 30%. LCMS(ESI)m / z[M+H] + 424.2.

[0757] Step 3: Preparation of intermediate I-97-3

[0758] A mixture of 285 mg of intermediate I-97-2, 0.26 ml of trifluoromethanesulfonic acid and 4 ml of trifluoroacetic acid was stirred at room temperature for 3 hours. The reaction solution was neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was concentrated to dryness and the residue was chromatographed with dichloromethane:methanol = 96:4 to obtain 82 mg of compound I-97-3 as a red solid with a yield of 40%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.25(s,1H),7.12(d,J=8.8Hz,2H),6.92(d,J=8.6Hz,2H),4.47(s,1H),3.74-3.64(m,4H),3.28(d,J=6 .3Hz,2H),2.71-2.58(m,4H),1.78-1.70(m,2H),1.57-1.45(m,1H),1.29-1.16(m,2H).LCMS(ESI)m / z[M+H] + 304.1.

[0759] Step 4: Preparation of intermediate I-97-4

[0760] A mixture of 10.5 mg of intermediate I-97-3, 39 mg of IBX and 1 ml of DMSO was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, and the organic phase was concentrated to dryness. The residue was prepared with dichloromethane: methanol = 13:1 to prepare a thin layer to obtain 6 mg of compound I-97-4 as a white solid with a yield of 57%. LCMS (ESI) m / z [M+H] + 302.2.

[0761] Step 5: Preparation of Example 97

[0762] The preparation of Example 97 is the same as step 5 in the preparation of Example 91. 1 H NMR (400 MHz, DMSO-d 6 )δ10.25(s,1H),9.33(s,1H),8.91(s,1H),8.10(d,J=5.2Hz,1H),8.00(s,1H),7.13(d,J=8.5Hz,2H), 7.04(d,J=5.2Hz,1H),7.03(s,1H),6.92(d,J=8.5Hz,2H),6.77(s,1H),6.59-6.30(m,3H),4.41(td,J= 14.6,3.0Hz,2H),3.94-3.73(m,3H),3.73-3.64(m,5H),3.21-3.08(m,2H),2.99(s,2H),2.85-2.71(m ,2H),2.71-2.59(m,5H),2.46-2.31(m,4H),1.88-1.73(m,6H),1.66-1.58(m,1H).LCMS(ESI)m / z[M+H] + 812.3.

[0763] Embodiment 98

[0764]

[0765] Step 1: Preparation of intermediate II-98-1

[0766] A mixture of 44 mg of compound I-55-5, 144 μL of 1,2-dibromoethane, 48 μL of N,N-diisopropylethylamine and 2 mL of DMSO was stirred at room temperature overnight. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol: ammonia water = 10: 1: 0.1 to obtain 10 mg of compound II-98-1 as a white solid with a yield of 18%. 1 HNMR (400 MHz, DMSO-d 6)δ9.33(s,1H),8.91(s,1H),8.11(d,J=5.3Hz,1H),8.00(s,1H),7.05(d,J=5.3Hz,1H),7.03(s,1H),6.79(s,1H),6.60-6.31(m,3 H),4.42(td,J=14.7,3.4Hz,2H),3.71(t,J=6.7Hz,2H),2.99(s,2H),2.70(t,J=6.7Hz,2H),2.66-2.55(m,4H),1.88-1.72(m,4H).

[0767] Step 2: Preparation of intermediate II-98-2

[0768] 15 mg of 3-bromo-1-methyl-7-nitro-1H-indazole, 37 mg of 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 6.5 mg of Pd(dppf)Cl 2 , 58 mg of cesium carbonate, 0.5 ml of water and 2.5 ml of 1,4-dioxane were stirred at 90°C overnight under argon protection. The reaction solution was concentrated to dryness, and the residue was prepared with petroleum ether: ethyl acetate = 6:1 to obtain 12 mg of compound II-98-2 as a yellow solid with a yield of 44%. LCMS (ESI) m / z [M+H] + 467.2.

[0769] Step 3: Preparation of intermediate II-98-3

[0770] 1.2 g of intermediate II-98-2, 1.3 g of 20% Pd(OH) 2 / C and 55 ml of 1,4-dioxane were stirred at 40°C for 24 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth and concentrated to dryness to obtain 600 mg of crude compound II-98-3 as a black oil, which was used directly in the next step. LCMS (ESI) m / z [M+H] + 259.0.

[0771] Step 4: Preparation of intermediate II-98-4

[0772] A mixture of 500 mg of intermediate II-98-3, 334 mg of p-toluenesulfonic acid, 804 mg of KI, 576 μL of tert-butyl nitrite and 25 mL of acetonitrile was stirred at 40°C overnight under argon protection. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was chromatographed with petroleum ether: ethyl acetate = 3:2 to obtain 218 mg of compound II-98-4 as a yellow solid, with a yield of 30%. 1H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.87(d,J=7.7Hz,1H),7.66(d,J=7.7Hz,1H),6.85(t,J=7.7Hz,1H),4.38(s, 3H),4.31-4.23(m,1H),3.06-2.96(m,1H),2.73-2.65(m,1H),2.56-2.46(m,1H),2.41-2.33(m,1H).LCMS(ESI)m / z[M+H] + 370.2.

[0773] Step 5: Preparation of intermediate II-98-5

[0774] 218 mg of intermediate II-98-4, 184 mg of tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate, 187 mg of Pd(PPh 3 ) 2 Cl 2 , 68 mg of cuprous iodide, 410 μl of triethylamine and 10 ml of DMF were stirred at room temperature overnight under argon protection. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was chromatographed with petroleum ether: ethyl acetate = 1:1 to obtain 253 mg of compound II-98-5 as a yellow solid, with a yield of 89%. 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.67(d,J=7.7Hz,1H),7.50(d,J=7.7 Hz,1H),7.09(t,J=7.7Hz,1H),4.50(s,2H),4.35(s,3H),4.30-4.26(m,1H),3.83 -3.74(m,3H),3.17-3.09(m,2H),3.06-2.95(m,1H),2.73-2.64(m,1H),2.56-2. 47(m,1H),2.42-2.33(m,1H),1.93-1.84(m,2H),1.64-1.58(m,2H),1.46(s,9H).

[0775] Step 6: Preparation of intermediate II-98-6

[0776] A mixture of 25 mg of intermediate II-98-5, 0.4 ml of trifluoroacetic acid and 2 ml of dichloromethane was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, the residue was redissolved in methanol, and saturated sodium hydroxide was added to adjust the pH to 7; then it was concentrated to dryness again, and the residue was prepared with dichloromethane: methanol: ammonia water = 7: 1: 0.1 to prepare a thin layer to obtain 15 mg of compound II-98-6 as a yellow solid, with a yield of 76%. LCMS (ESI) m / z [M+H] + 381.1.

[0777] Step 7: Preparation of Example 98

[0778] A mixture of 10 mg of intermediate II-98-1, 7.5 mg of intermediate II-98-6, 9 μl of DIPEA and 1 ml of DMSO was stirred at 70°C overnight. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol: ammonia water = 150: 17: 2 to obtain 4 mg of compound 98 as a white solid, with a yield of 27%. 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.33(s,1H),8.27(s,1H),8.24-8.20(m,2H),7.69(d,J=8.1Hz,1H), 7.49(d,J=7.1Hz,1H),7.28-7.26(m,1H),7.15-7.07(m,2H),6.42(s,1H),6.20(tt,J=54.8,4.3Hz,1H),4.76(s, 2H),4.49(s,2H),4.34(s,3H),4.31-4.22(m,3H),3.06-2.94(m,11H),2.90-2.81(m,4H),2.73-2.65(m,2H),2. 55-2.48(m,1H),2.41-2.35(m,1H),2.33-2.25(m,2H),2.14-2.04(m,2H),2.03-1.96(m,2H),1.95-1.86(m,2H).

[0779] Embodiment 99

[0780]

[0781] Step 1: Preparation of intermediate II-99-1

[0782] A mixture of 30 mg of compound I-55-5, 6.5 μL of chloroacetyl chloride, 27 μL of triethylamine, 2 mL of tetrahydrofuran and 1 mL of DMSO was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol = 10:1 to prepare a thin layer to obtain 13 mg of compound II-99-1 as a yellow-white solid, with a yield of 25%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.34(s,1H),8.91(s,1H),8.10(d,J=5.2Hz,1H),8.02(s,1H),7.04(d,J=5.2Hz,1H),7.02(s,1H),6.81(s,1H),6.61-6.30(m,3H),4.48-4 .37(m,4H),3.85-3.77(m,1H),3.67-3.57(m,1H),3.56-3.47(m,1H),3.44-3.36(m,1H),3.05(s,2H),1.93-1.68(m,4H).LCMS(ESI)m / z[M+H] + 548.2.

[0783] Step 2: Preparation of Example 99

[0784] A mixture of 11 mg of intermediate II-99-1, 8.5 mg of intermediate II-98-6, 11 μL of DIPEA and 1 mL of DMSO was stirred at 40°C for 4 hours. Water was added to the reaction solution, extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was prepared with dichloromethane: methanol = 10:1 to prepare a thin layer to obtain 6 mg of compound 99 as a white solid, with a yield of 33%. 1 H NMR (400 MHz, DMSO-d 6)δ10.92(s,1H),9.35(s,1H),8.91(s,1H),8.10(d,J=5.2Hz,1H),8.03(s,1H),7.79(d,J=7.7Hz,1H),7.52(d,J =7.7Hz,1H),7.13(t,J=7.7Hz,1H),7.04(d,J=5.2Hz,1H),7.03(s,1H),6.80(s,1H),6.61-6.30(m,3H),4.57(s, 2H),4.47-4.38(m,3H),4.30(s,3H),3.88-3.70(m,2H),3.69-3.34(m,7H),3.06(s,2H),2.71-2.59(m,2H),2.4 3-2.31(m,2H),2.23-2.12(m,2H),2.10-1.95(m,2H),1.94-1.77(m,4H),1.76-1.64(m,2H).LCMS(ESI)m / z[M+H] + 892.4.

[0785] Embodiment 100

[0786]

[0787] Step 1: Preparation of intermediate II-100-1

[0788] The preparation of intermediate II-100-1 is the same as intermediate I-55-2. 1 H NMR(400MHz,Chloroform-d)δ7.77(s,1H),6.44(s,1H),4.62-4.54(m,1H),3.76(s,2H),3.43-3. 33(m,2H),2.96(s,2H),1.95-1.86(m,2H),1.77-1.69(m,2H),1.47(s,9H),1.39(d,J=6.0Hz,6H).

[0789] Step 2: Preparation of intermediate II-100-2

[0790] The preparation of intermediate II-100-2 is the same as intermediate I-55-3. 1 H NMR (400 MHz, Methanol-d 4)δ6.66(s,1H),6.37(s,1H),4.53-4.41(m,1H),3.79-3.66(m,2H),3.47-3.34(m,2H),2.89(s, 2H),1.87-1.75(m,2H),1.73-1.61(m,2H),1.47(s,9H),1.34-1.28(m,6H).LCMS(ESI)m / z[M+H] + 363.2.

[0791] Step 3: Preparation of intermediate II-100-3

[0792] The preparation of intermediate II-100-3 is the same as intermediate I-55-4. 1 H NMR(400MHz,Chloroform-d)δ10.25(s,1H),8.80(d,J=7.0Hz,1H),8.74(s,1H), 8.66(d,J=4.0Hz,1H),8.42(s,1H),7.02(dd,J=7.0,4.0Hz,1H),6.46(s,1H),4.6 1-4.53(m,1H),3.77-3.66(m,2H),3.48-3.37(m,2H),2.99(s,2H),1.96-1.86(m, 2H),1.76-1.67(m,2H),1.47(s,9H),1.44(d,J=6.0Hz,6H).LCMS(ESI)m / z[M+Na] + 530.4.

[0793] Step 4: Preparation of intermediate II-100-4

[0794] The preparation of intermediate II-100-4 is the same as that of intermediate I-55-5. LCMS (ESI) m / z [M+H] + 408.2.

[0795] Step 5: Preparation of Example 100

[0796] This step is the same as step 7 in the preparation method of Example 98. 1H NMR(400MHz,Chloroform-d)δ10.27(s,1H),8.83(dd,J=7.1,1.7Hz,1H),8.78(s,1H),8.69(dd,J=4.0,1.7Hz,1H),8.44(s,1H ),8.03(s,1H),7.71(d,J=7.1Hz,1H),7.52(d,J=7.1Hz,1H),7.15-7.10(m,1H),7.05(dd,J=7.1,4.0Hz,1H),6.46(s,1H),4.61 -4.50(m,2H),4.37(d,J=1.4Hz,3H),4.33-4.29(m,1H),3.08-2.94(m,8H),2.93-2.77(m,4H),2.76-2.66(m,2H),2.58-2.50( m,1H),2.43-2.37(m,1H),2.19-2.13(m,6H),2.08-2.00(m,4H),1.93-1.84(m,2H),1.47(d,J=6.0Hz,6H).LCMS(ESI)m / z[M+H] + 814.4.

[0797] Embodiment 101

[0798]

[0799] Step 1: Preparation of intermediate II-101-1

[0800] The preparation of intermediate II-101-1 is the same as intermediate II-98-5. 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.17(d,J=7.9Hz,1H),6.99(t,J=7.9Hz,1H),6.76(d,J=7.9Hz,1H),5.23-5.17(m,1H),4.45 (s,2H),3.79-3.73(m,5H),3.16-3.08(m,2H),2.98-2.66(m,4H),2.26-2.19(m,1H),1.91-1.86(m,2H),1.61-1.56(m,2H),1.46(s,9H).

[0801] Step 2: Preparation of intermediate II-101-2

[0802] The preparation of intermediate II-101-2 is the same as that of intermediate II-98-6. LCMS (ESI) m / z [M+H] + 397.2.

[0803] Step 3: Preparation of Example 101

[0804] The preparation method of Example 101 is the same as step 2 in the preparation method of Example 99. 1 H NMR (600 MHz, DMSO-d 6 )δ11.12(s,1H),9.34(s,1H),8.91(s,1H),8.11(d,J=5.1Hz,1H),8.02(s,1H),7.18(d,J=7.7Hz,1H),7.12( d,J=5.1Hz,1H),7.06-7.02(m,3H),6.80(s,1H),6.56-6.30(m,3H),5.43-5.38(m,1H),4.50(s,2H),4.42(t d,J=14.5,3.3Hz,2H),3.82-3.72(m,1H),3.68-3.60(m,5H),3.58-3.34(m,7H),3.10-3.01(m,3H),2.93-2. 85(m,1H),2.75-2.68(m,1H),2.65-2.60(m,1H),2.05-1.76(m,8H),1.73-1.67(m,1H).LCMS(ESI)m / z[M+H] + 908.3.

[0805] Embodiment 102

[0806]

[0807] Step 1: Preparation of intermediate II-102-1

[0808] A mixture of 407 mg of 2-difluoromethyl-4-bromopyridine, 230 mg of ethyl 4-oxazolecarboxylate, 37 mg of palladium acetate, 98 mg of tri(o-methylphenyl)phosphine, 1 g of cesium carbonate and 8 ml of DMF was stirred at 70°C for 3 hours under argon protection. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 15:85 to obtain 305 mg of intermediate II-102-1 as a yellow oil with a yield of 70%. 1 H NMR(400MHz,Chloroform-d)δ8.81(d,J=5.1Hz,1H),8.37(s,1H),8.32(s,1H),8.08(d,J=5.1Hz ,1H),6.70(t,J=55.2Hz,1H),4.45(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H).LCMS(ESI)m / z[M+H] + 269.0.

[0809] Step 2: Preparation of intermediate II-102-2

[0810] The preparation of intermediate II-102-2 is the same as intermediate I-1-2. LCMS (ESI) m / z [M+H] + 241.1.

[0811] Step 3: Preparation of intermediate II-102-3

[0812] The preparation of intermediate II-102-3 is the same as intermediate I-55-4. 1 H NMR (400 MHz, DMSO-d 6 )δ9.46(s,1H),9.06(s,1H),8.94(d,J=5.1Hz,1H),8.21(s,1H),8.11(d,J=5.1Hz,1H),8.02(s,1H),7.10(t,J=54.7Hz,1H),6.80(s,1H ),6.47(tt,J=54.3,3.3Hz,1H),4.47-4.38(m,2H),3.59-3.50(m,2H),3.41-3.36(m,2H),3.02(s,2H),1.83-1.67(m,4H),1.42(s,9H).

[0813] Step 4: Preparation of intermediate II-102-4

[0814] The preparation of intermediate II-102-4 is the same as intermediate I-55-5. LCMS (ESI) m / z [M+H] + 507.1.

[0815] Step 5: Preparation of Example 102

[0816] The preparation of Example 102 is the same as step 2 in the preparation of Example 4. 1H NMR(400MHz,Chloroform-d)δ9.34(s,1H),8.83(d,J=5.1Hz,1H),8.56(s,1H),8.42(s,1H),8.27(s,2H),8.01(d,J=5.1Hz,1H), 7.76(d,J=8.3Hz,1H),7.37(d,J=2.3Hz,1H),7.23(dd,J=8.3,2.3Hz,1H),6.72(t,J=55.3Hz,1H),6.43(s,1H),6.21(tt,J=54.7 ,3.8Hz,1H),4.97-4.90(m,1H),4.31-4.22(m,4H),3.96-3.92(m,2H),3.92-3.88(m,2H),3.75-3.66(m,4H),3.41-3.23(m,2H), 3.11-3.02(m,4H),3.01(s,2H),2.90-2.72(m,3H),2.36-2.26(m,2H),2.16-2.11(m,1H),2.06-1.99(m,2H).LCMS(ESI)m / z[M+H] + 895.3.

[0817] Test Example 1

[0818] IRAK4 protein degradation activity test of compounds

[0819] 1. Test methods

[0820] Preparation of cell protein samples: OCI-LY10 cells in the logarithmic growth phase were inoculated at an appropriate density in a 12-well plate. After the cells were stable, each compound was added for 24 hours, the culture medium was discarded by centrifugation, and the cell pellet was washed three times with pre-cooled PBS. After the supernatant was aspirated, 1× SDS gel loading buffer was added to lyse the cells. The cell lysate was heated in a 100°C metal bath for 30 minutes and then stored at -20°C.

[0821] Take an appropriate amount of protein sample for SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). After the electrophoresis, transfer the protein on the gel to a nitrocellulose membrane using a semi-dry electrotransfer system. Then place the nitrocellulose membrane in a 5% skim milk blocking solution prepared with TBS (TBS-T) containing 1% Tween 20. After blocking at room temperature for 1 h, place the membrane in the corresponding primary antibody and incubate overnight at 4 °C. Wash the membrane three times with TBS-T, 10 min each time. Place the membrane in the corresponding rabbit or mouse secondary antibody dilution and incubate at room temperature for 1 h. After washing the membrane 3 times as above with TBS-T, develop the color with a chromogenic reagent. Quantify the protein bands using Image J software and calculate the degradation rate D (%).

[0822] The calculation formula for D (%) is as follows:

[0823] D (%) = [Control group (relative gray scale 目的蛋白 / relative gray scale 内参蛋白 ) - Compound group (relative gray scale 目的蛋白 / relative gray scale 内参蛋白 )] / Control group (relative gray scale 目的蛋白 / relative gray scale 内参蛋白 ) × 100%

[0824] 2. Experimental results

[0825] Table 1. Degradation effect of the compound on IRAK4 in OCI-LY10 cells at a concentration of 10 nM

[0826]

[0827] Note: D (%) refers to the degradation rate of the compound of the present invention on IRAK4 protein in OCI-LY10 cells detected by the Western Blot method at 10 nM. A represents D (%) > 75%; B represents 50% < D (%) < 75%; C represents 35% < D (%) < 50%; D represents D (%) < 35%. The experimental results are the average values of two independent repeated experiments.

[0828] KT-474: It is Example I-417 in Patent WO2020113233.

[0829] 3. Experimental conclusions

[0830] The compounds of the present invention can effectively degrade IRAK4 kinase protein in cells. At a concentration of 10 nM, compared with KT-474, Examples 52, 53, 55, 61, 63, 64, 67, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, and 101 significantly improve the degradation effect of IRAK4; when the drug concentration is increased to 25 nM, the degradation rates of IRAK4 by Examples 4 and 8 (Example 4: 46.3%; Example 8: 41.5%) are better than the degradation rate of IRAK4 by KT-474 (35.2%).

[0831] Test Example 2

[0832] Inhibition of IRAK4 kinase activity by compounds

[0833] 1. Test methods

[0834] Using Z′-LYTE TM Kinase kit was used to detect the kinase inhibitory activity of the compound. The main steps are as follows: 2.5 μL / well of compound solution or solvent control of different concentrations was added to a 384-well plate, and two replicate wells were set for each concentration. The solvent control group was set as follows: 0% phosphorylation control group, 0% inhibition control group, and 100% phosphorylation control group. The enzyme and substrate were diluted into a mixture of 1.5 ng / well and 2 μM / well with kinase buffer, and 5 μL / well was added to the test compound group, 0% phosphorylation control group, and 0% inhibition control group; accordingly, the phosphorylation substrate solution was added to the 100% phosphorylation group at 5 μL / well. 2.5 μL of ATP (final concentration of 400 μM) was added to the test compound group and 0% inhibition control group to start the reaction, and the 384-well plate was placed in a 27°C oven for 1 hour. The secondary reaction reagent was added at 5 μL / well and reacted in an oven at 27°C for 1 h. Finally, 5 μL of the stop reagent was added to terminate the reaction. The fluorescence value was detected at 445 nm and 520 nm using a fluorescence detection microplate reader (Synergy 2, BIOTEK), and the inhibition rate was calculated using the following formula:

[0835] Calculate the transmit signal ratio:

[0836] Transmitted signal ratio = Transmitted signal 香豆素(445nm) / Transmit signal 荧光素(520nm)

[0837] Calculation of phosphorylation rate

[0838] Phosphorylation rate % = [(emission signal ratio × F 100％ )–C 100％ ] / [(C 0％ –C 100％ )+[transmitted signal ratio×(F 100％ –F0％ )]]×100%

[0839] C 100％ : Average coumarin emission signal of 100% phosphorylation control wells

[0840] C 0％ : Average coumarin emission signal of 0% phosphorylation control wells

[0841] F 100％ : Average fluorescence emission signal of 100% phosphorylation control wells

[0842] F 0％ : Average fluorescence emission signal of 0% phosphorylation control wells

[0843] Inhibition rate % = [1-(sample phosphorylation rate / 0% phosphorylation control well phosphorylation rate)] × 100%

[0844] IC 50 The nonlinear four-parameter method in Graphpad Prism 8.0 software was used to fit the inhibition curve at each concentration and calculate it.

[0845] 2. Experimental results

[0846] Table 2. Inhibitory activity of compounds on IRAK4 kinase

[0847]

[0848] Note: The experiment was repeated twice or more independently. 50 Values ​​are expressed as Mean±SD.

[0849] 3. Experimental conclusion

[0850] The results are shown in Table 2. The compounds of the present invention have good kinase inhibitory effects on IRAK4 and are significantly better than KT-474.

[0851] Test Example 3

[0852] Proliferation inhibition experiment of the compound on tumor cell line OCI-LY10 and human skin fibroblast cell line GM00637

[0853] The OCI-LY10 tumor cell line is a diffuse large B-cell lymphoma cell line, which is the most common subtype of non-Hodgkin's lymphoma.

[0854] 1. Test methods

[0855] The CCK-8 (Cell Counting Kit-8) method was used to detect the inhibitory effect of the compound on cell proliferation. The steps of the CCK-8 detection method are as follows: According to the cell growth rate, OCI-LY10 and GM00637 cells in the logarithmic growth phase are inoculated in a 96-well culture plate at different concentrations at 90 μL / well. After the cells are stable, different concentrations of the compound are added at 10 μL / well. Three replicate wells are set for each concentration, and corresponding solvent controls and cell-free blank control wells are set. After the cells are placed in an incubator for 72 hours, 10 μL / well of CCK-8 reagent is added and reacted for 2-4 hours, and then the OD value at a wavelength of 450nm is measured using an enzyme reader. The formula for calculating the inhibition rate of the compound on cell growth is: Inhibition rate % = (OD value of the control group - OD value of the drug group) / OD value of the control group × 100%. Half inhibition dose IC 50 The values ​​were obtained by fitting the inhibition curve using the four-parameter method using the software attached to the microplate reader. The experimental results are shown in Table 3.

[0856] 2. Experimental results

[0857] Table 3. Proliferation inhibitory activity of compounds on OCI-LY10 tumor cells and GM00637 normal cells

[0858]

[0859] Note: IC 50 The values ​​are represented by Mean±SD of three independent repeated experiments.

[0860] Compound A: Compound B: Compound C: They are respectively Examples I-28, I-29, and I-30 in Patent CN 112480101;

[0861] 3. Experimental conclusion

[0862] Compared with compounds A, B, C and KT-474, the compounds of the present invention have significantly improved inhibitory effects on the proliferation of OCI-LY10 lymphoma cells, and at the same time, significantly improved selectivity for normal cells GM00637 (selectivity greater than 10 times), indicating that the compounds of the present invention have excellent therapeutic effects on lymphoma.

[0863] Test Example 4

[0864] The compound was tested for the inhibition of proliferation of tumor cell lines such as melanoma B16-F10, human colorectal cancer SW620, human pancreatic cancer PANC-1 and hematological tumor MV4-11.

[0865] 1. Test methods

[0866] The CCK-8 (Cell Counting Kit-8) method was used to detect the inhibitory effect of the compound on cell proliferation. The steps of the CCK-8 detection method are as follows: According to the cell growth rate, B16-F10, SW620, PANC-1 and MV4-11 cells in the logarithmic growth phase are inoculated in a 96-well culture plate at different concentrations at 90 μL / well. After the cells are stable, different concentrations of the compound are added at 10 μL / well. Three replicate wells are set for each concentration, and corresponding solvent controls and cell-free blank control wells are set. After the cells are placed in an incubator for 72 hours, 10 μL / well of CCK-8 reagent is added to react for 2-4 hours, and the OD value at a wavelength of 450nm is measured using an enzyme reader. The formula for calculating the inhibition rate of the compound on cell growth is: Inhibition rate % = (OD value of the control group - OD value of the drug group) / OD value of the control group × 100%. Half inhibition dose IC 50 The values ​​were obtained by fitting the inhibition curve using the four-parameter method using the software attached to the microplate reader.

[0867] 2. Experimental conclusion

[0868] Compared with compounds A, B, C and KT-474, the compounds of the present invention significantly improve the proliferation inhibition effect on various tumor cell lines such as melanoma B16-F10, human colorectal cancer SW620, human pancreatic cancer PANC-1 and hematological tumor MV4-11, and have broad-spectrum anti-tumor activity.

[0869] Test Example 5

[0870] In vivo pharmacodynamic study of the compound in a human B-cell lymphoma OCI-LY10 cell SCID mouse xenograft tumor model

[0871] 1. Test methods

[0872] OCI-LY10 cells in the logarithmic growth phase were collected, resuspended by centrifugation and washed three times with PBS. OCI-LY10 cells were inoculated subcutaneously in the right axilla of SCID mice at a concentration of 5 million cells / 100 μL / mouse. When the average tumor volume reached 100 mm 3 Around 200 μg / kg, mice were randomly divided into groups, 6 in each group, and the grouping day was designated as Day 0. The test compound groups were given a dose between 0-100 mg / kg. During the experiment, the animal body weight and tumor volume (TV) were measured twice a week, and clinical symptoms were observed and recorded daily.

[0873] The tumor volume was calculated as follows:

[0874] TV=1 / 2×a×b 2 , where a and b are the length and width of the tumor, respectively.

[0875] The calculation formula of tumor inhibition rate TGI (%) is as follows:

[0876] TGI (%) = [1-(average tumor volume at the end of treatment group administration-average tumor volume at the beginning of treatment group administration) / (average tumor volume at the end of vehicle group administration-average tumor volume at the beginning of vehicle group administration)] × 100%

[0877] The relative tumor volume (RTV) was calculated from the measurement results using the following formula:

[0878] RTV=Vt / V 0 , where V 0 Vt is the tumor volume measured at the time of group administration (Day 0), and Vt is the tumor volume at a certain measurement.

[0879] In this study, experimental data were expressed as Mean ± SEM.

[0880] Statistical analysis The RTV data at the end of the experiment were analyzed using Graphpad Prism 8.0 software. The comparison between two groups was analyzed using t-test, and the comparison between three or more groups was analyzed using one-way ANOVA. If the variance was equal (F value was not significantly different), Tukey's method was used for analysis. If the variance was not equal (F value was significantly different), Games-Howell method was used for testing. p<0.05 was considered to be significantly different.

[0881] 2. Experimental conclusion

[0882] The compound of the present invention has a tumor-inhibiting effect in a human large B-cell lymphoma OCI-LY10 cell SCID mouse xenograft tumor model.

[0883] Test Example 6

[0884] Effects of compounds on the secretion of inflammatory factors TNF-α and IL-6 in RAW 264.7 and THP-1 cells stimulated by LPS

[0885] 1. Test methods

[0886] RAW 264.7 and THP-1 cells in the logarithmic growth phase were seeded in 12-well plates at an appropriate density. After stabilization, gradiently diluted compounds and positive drugs were added for treatment for 2 hours, and then stimulated with 5 μg / mL LPS for 24 hours. The cell supernatant was collected and the TNF-α and IL-6 secretion levels were detected by ELISA.

[0887] Note: Experimental data are expressed as Mean ± SD; data were analyzed using Graphpad Prism 8.0 software Statistical analysis was performed using the ANOVA method, and data between the two groups were considered to be significantly different when p < 0.05.

[0888] 2. Experimental conclusion

[0889] In the LPS-stimulated RAW264.7 and THP-1 cell models, the compounds of the present invention can significantly inhibit the secretion of TNF-α and IL-6, and the inhibitory activity is positively correlated with the dose.

[0890] Test Example 7

[0891] Evaluation of the effectiveness of compounds in the mouse model of acute peritoneal inflammation

[0892] 1. Test methods

[0893] Fifty female Balb / c mice were used. After the mice were adapted to the environment, they were randomly divided into five groups (n=10) according to their body weight: a normal control group (G1), a vehicle (model, G2) group, and a test compound group (G3-G5). The test compound groups were administered at a dose between 0 and 100 mg / kg.

[0894] Model induction: The acute peritonitis model in mice was established by intraperitoneal injection of LPS. One hour after administration, each group of mice was stimulated by intraperitoneal injection of 5 mg / kg LPS for 2 hours. Blood was collected from the mouse orbits and serum was separated for ELISA to detect the levels of inflammatory factors.

[0895] Note: Experimental data are expressed as Mean ± SEM; data were analyzed using Graphpad Prism 8.0 software Statistical analysis was performed using the ANOVA method, and data between the two groups were considered to be significantly different when p < 0.05.

[0896] 2. Experimental conclusion

[0897] The compound of the present invention has a therapeutic effect on a mouse acute peritonitis model.

[0898] Test Example 8

[0899] Evaluation of the effectiveness of compounds on the mouse acute enteritis model

[0900] 1. Test methods

[0901] Fifty female Balb / c mice were used. After the mice were adapted to the environment, they were randomly divided into five groups (n=10) according to their body weight: a normal control group (G1), a vehicle (model, G2) group, and a test compound group (G3-G5). The test compound groups were administered at a dose between 0 and 100 mg / kg.

[0902] Model induction: On day 0 before the start of the experiment, DSS at a concentration of 2.5% was added to the drinking water of mice to induce enteritis. After 7 days of DSS drinking, the drinking water of mice was replaced with sterile pure water. Mice were treated with the test compound from day 0 until the end of the experiment. During the experiment, the disease activity index (DAI) of mice was recorded every day, including the degree of weight loss, the softness and hardness of stool, and the degree of fecal occult blood. Each score ranged from 0 to 4 points, with a total of 0 to 12 points. The difference in DAI between the normal group, the modeling group and the drug-treated group was counted daily. The mice were euthanized on the tenth day of the experiment to terminate the experiment.

[0903] Note: Experimental data are expressed as Mean ± SEM; data were analyzed using Graphpad Prism 8.0 software Statistical analysis was performed using the ANOVA method, and data between the two groups were considered to be significantly different when p < 0.05.

[0904] 2. Experimental conclusion

[0905] The compound of the invention has a therapeutic effect on a mouse acute enteritis model.

[0906] Test Example 9

[0907] Evaluation of the effectiveness of compounds in atopic dermatitis models in mice

[0908] 1. Test methods

[0909] Fifty female Balb / c mice were used. After the mice were adapted to the environment, they were randomly divided into five groups (n=10) according to their body weight: a normal control group (G1), a vehicle (model, G2) group, and a test compound group (G3-G5). The test compound groups were administered at a dose between 0 and 100 mg / kg.

[0910] Model induction: MC903 was diluted with anhydrous ethanol to a concentration of 45 μM. From the first day to the fifth day and the eighth day to the twelfth day of the experiment, 25 μL of MC903 was applied to both ears of the mice to induce atopic dermatitis mouse model, and the control group was applied with an equal volume of anhydrous ethanol. The mice were given the test compound treatment from the beginning of modeling until the end of the experiment.

[0911] During the experiment, the thickness of the mouse ears was recorded, and the skin lesions of the mice were observed, including erythema, scaling, epidermal exfoliation or scratches, edema and papules, and scored. The scoring standard is 0 to 12 points, divided into four levels: none, mild, moderate and severe, recorded as 0, 1, 2, and 3 points respectively.

[0912] (1) Erythema: 0 to 3, respectively: none; pink; dark red; deep red;

[0913] (2) Scale: 0 to 3, respectively, none; thin, bran-like desquamation; flaky, thin scales; and abundant, thick scales.

[0914] (3) Epidermal exfoliation or scratches: 0 to 3, respectively, none; a few shallow exfoliations; an increased number of epidermal exfoliations but mostly superficial exfoliations, with deep exfoliations rarely seen; a large number of diffuse superficial exfoliations and deep exfoliations;

[0915] (4) Edema and papules: 0 to 3 represent none; barely perceptible; clearly visible and slightly raised above the skin surface; and clearly raised above the skin surface.

[0916] Note: Experimental data are expressed as Mean ± SEM; data were analyzed using Graphpad Prism 8.0 software Statistical analysis was performed using the ANOVA method, and data between the two groups were considered to be significantly different when p < 0.05.

[0917] 2. Experimental conclusion

[0918] The compound of the invention has a therapeutic effect on atopic dermatitis model in mice.

[0919] Test Example 10

[0920] Evaluation of the effectiveness of compounds on the mouse psoriasis model

[0921] 1. Test methods

[0922] Fifty female Balb / c mice were used. After the mice were adapted to the environment, they were randomly divided into five groups (n=10) according to their body weight: a normal control group (G1), a vehicle (model, G2) group, and a test compound group (G3-G5). The test compound groups were administered at a dose between 0 and 100 mg / kg.

[0923] Model induction: The back skin of mice was shaved one day in advance (the shaved surface area was 2×3 cm). For the next 7 days, 62.5 mg of imiquimod was applied to the shaved area of ​​the model group and the test compound group, and 62.5 mg of vaseline was applied to the normal control group as a control, and the test compound was given for treatment at the same time. During the experiment, the thickness of the mouse model skin was measured every day, and the changes in the mouse skin disease were observed. The scores were based on the three indicators of dermatitis, erythema, scaling and infiltration, and were divided into five levels: none, mild, moderate, severe and extremely severe, which were recorded as 0, 1, 2, 3, and 4 points respectively.

[0924] (1) Erythema: 0 to 4, respectively, no erythema; light red; red; dark red; very dark red;

[0925] (2) Scaling: 0 to 4, respectively, no scaling; slight scaling on some lesions; scaling on most lesions, mainly in the form of flaky scales; lesions are almost completely covered with thick scales; lesions are completely covered with scales, with very thick scales in layers;

[0926] (3) Infiltration degree: 0 to 4 means the lesion is flush with normal skin; the lesion is slightly raised; the lesion is raised; the lesion is thickened and obviously raised; and the lesion is extremely raised.

[0927] Note: Experimental data are expressed as Mean ± SEM; data were analyzed using Graphpad Prism 8.0 software Statistical analysis was performed using the ANOVA method, and data between the two groups were considered to be significantly different when p < 0.05.

[0928] 2. Experimental conclusion

[0929] The compound of the present invention has a therapeutic effect on a mouse psoriasis model.

[0930] Test Example 11

[0931] Study on the preventive and therapeutic effects of compounds on rheumatoid arthritis in mice

[0932] 1. Test methods

[0933] Fifty male DBA / 1J mice were used. After the mice were adapted to the environment, the basal hind paw volume, arthritis index score and bilateral hind paw pain threshold of all animals were measured. According to body weight, hind paw volume, arthritis index and bilateral hind paw pain threshold, the mice were divided into 5 groups (n=10): normal control group (G1), solvent (model, G2) group, test compound group (G3-G5) group, and the test compound group was administered at a dose of 0-100 mg / kg.

[0934] Model induction: 1 mg / mL bovine type II collagen was mixed and emulsified with complete Freund's adjuvant (CFA) in equal volumes to prepare type II collagen emulsion. 0.1-0.2 mL of the emulsion was injected into the skin at the base of the mouse tail to induce inflammation in the mice. On the 21st day, the mice were boosted with incomplete Freund's adjuvant CII. The mice were given the test compound from the 21st day until the end of the experiment.

[0935] After the first immunization, the arthritis score was assessed and the progression of arthritis was continuously monitored. The arthritis score of each limb was assessed based on the severity of swelling. 0: normal; 1: mild but definite redness and swelling of the ankle or wrist joint; 2: moderate redness and swelling of the ankle or wrist joint; 3: severe redness and swelling of the entire paw including the fingers; 4: severe inflammation of the limb with involvement of multiple joints. The arthritis score of each mouse was defined as the sum of the scores of all four paws.

[0936] The experimental data were expressed as Mean ± SEM. Graphpad Prism 8.0 was used for statistical analysis. The data between the two groups were considered to be significantly different when p < 0.05.

[0937] 2. Experimental conclusion

[0938] The compound of the invention has a therapeutic effect on a mouse rheumatoid arthritis model.

[0939] Experimental Conclusion

[0940] Based on the above-mentioned biological activity test experimental data, it can be found that the compounds of the present invention can be used as IRAK4 degraders to treat various IRAK4-induced diseases or conditions such as tumors, peritonitis, acute enteritis, atopic dermatitis, psoriasis, rheumatoid arthritis, etc.

[0941] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula I or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal: in: Ring T is selected from a 5-9 membered heteroaromatic ring; L' is -CONH- or -NHCO-, wherein the left side is connected to the ring T and the right side is connected to the parent core; E is CH or N; R x is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -O-L1-R a 、-NR b R c 、-C(O)NR b R c ; The substitution refers to one or more R j replace; R b , R c Each is independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution refers to substitution by halogen, hydroxyl, amino, carbonyl, cyano, -CONH2, -SO2NH2, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; or R b and R c Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R j replace; L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C6 alkyl chain; and one or more hydrogens on L1 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; Each R a Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to the substitution of one or more R j replace; Each R j Each is independently selected from halogen, carbonyl, -L2-CN, -L2-OR k 、-L2-COOR k 、-L2-NR k R m 、-L2-CONR k R m 、-L2-S(O)2NR k R m , substituted or unsubstituted C1-C6 alkyl, -L2-substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, -L2-substituted or unsubstituted saturated or partially saturated 3-12-membered heterocyclyl, -L2-substituted or unsubstituted 6-10-membered aryl, -L2-substituted or unsubstituted 5-10-membered heteroaryl; the substitution refers to substitution by the following groups: halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy, -C(O)(halogenated or unhalogenated C1-C3 alkyl); L2 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogens on L2 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; R k , R m Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 acyl; the substitution refers to substitution by one or more halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2; Every R y Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted saturated or partially saturated C3-C10 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to substitution by halogen, hydroxyl, amino, -CONH2, -SO2NH2, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; m is selected from 1 or 2; Every R z Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carbonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substitution refers to substitution by halogen, hydroxyl, amino, cyano; n is selected from 1, 2, 3, 4; L is a covalent bond or a divalent saturated or unsaturated linear or branched C1-C30 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by one or more of the following structures: -Cy-, -O-, -C(O)-, -C(S)-, -NH-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -OC(O)NH-, -NHC(O)O-, -S-, -S(O)2-, -NHS(O)2-, -S(O)2NH-, -P(O)(OR n )-、-P(O)(NR n 2)-、-P(O)(R n )-、-N=CH-、 in: Each Cy is independently selected from the following rings: a saturated or partially saturated C3-C12 carbocyclic ring (including a monocyclic ring, a bridged ring, a condensed ring, or a spirocyclic ring), a saturated or partially saturated 4-12 membered heterocyclic ring (including a monocyclic ring, a bridged ring, a condensed ring, or a spirocyclic ring), a 6-14 membered aromatic ring, or a 5-14 membered heteroaromatic ring; r is 0, 1, 2, 3, 4, or 5; Every R n Each is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkoxy; Any one or more hydrogen atoms on L are optionally replaced by R 1 Replace; each R 1 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -L3-substituted or unsubstituted saturated or partially saturated C3-C12 carbocyclic ring (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted saturated or partially saturated 4-12 membered heterocyclic ring (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted 6-14 membered aromatic ring, -L3-substituted or unsubstituted 5-14 membered heteroaromatic ring, -L3-substituted or unsubstituted -NR d R e , -L3-substituted or unsubstituted-COOR d , -L3-substituted or unsubstituted-CONR d R e , -L3-substituted or unsubstituted-S(O)2NR d R e , where R d , R e Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 acyl, C1-C6 sulfonyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2, C1-C6 alkyl optionally substituted or unsubstituted by halogen or hydroxyl or amino, C1-C6 alkoxy optionally substituted or unsubstituted by halogen or hydroxyl or amino; L3 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C6 alkyl chain; and one or more hydrogens on L3 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; Or: two R on the same atom 1 The group optionally forms a saturated or partially saturated C3-C12 carbocyclic ring, a saturated or partially saturated 4-12 membered heterocyclic ring together with its middle atom; the heterocyclic ring is optionally substituted by one or more R p replace; Each R p Each is independently selected from halogen, hydroxyl, amino, cyano, carbonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl; LBM is the E3 ubiquitin ligase binding part.

2. The compound according to claim 1 or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, characterized in that: Formula I has the following structure: This part has the following structure:

3. The compound according to claim 1 or 2, or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, characterized in that: R x is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or partially saturated 3-8 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, -O-L1-R a 、-NR b R c ; The substitution refers to one or more R j replace; R b , R c Each is independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution refers to halogen, hydroxyl, amino, cyano, -CONH2; or R b and R c Optionally, together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic ring, which is optionally replaced by one or more R j replace; L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L1 are optionally substituted by halogen, hydroxyl, amino, cyano, -CONH2; Each R a Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially saturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or partially saturated 4-8 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to the substitution of one or more R j replace; Each R j Each is independently selected from halogen, carbonyl, -L2-CN, -L2-OR k 、-L2-COOR k 、-L2-NR k R m 、-L2-CONR k R m 、-L2-S(O)2NR k R m , substituted or unsubstituted C1-C4 alkyl; the substitution refers to substitution by the following groups: halogen, hydroxyl, amino, cyano; L2 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; and one or more hydrogen atoms on L2 are optionally substituted by halogen, hydroxyl, amino, or cyano; R k , R m Each of the following is independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.

4. The compound according to claim 1 or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, characterized in that: LBM is the cereblon E3 ubiquitin ligase binding moiety and has the structure shown in Formula I-aa: in: Q 1 , Q 2 , Q 3 , Q 4 Each independently selected from C (when linked to L), CR 21 or N; Each R 21 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2; R 3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2, C2-C6 acyl; Each R f Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; n1 is selected from 0, 1 or 2, or LBM is the cereblon E3 ubiquitin ligase binding moiety and has the structure shown in Formula I-bb: in: X is selected from CH or N; V is selected from C or N; U selected from CR 4 NR 5 or O; P 1 , P 2 , P 3 , P 4 Each independently selected from C (when linked to L), CR 22 or N; R 22 , R 4 , R 5 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2, halogenated or unhalogenated C1-C6 alkoxy; Each R g Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; n2 is selected from 0, 1 or 2, Alternatively, LBM is a celeblon E3 ubiquitin ligase binding moiety and has the structure of Formula I-cc: in: W is CH or N; Y is a covalent bond, -N(R 6 )-、-C(O)-N(R 6 )-、-N(R 6 )-C(O)-, wherein the left side of the above divalent group is connected to ring B; Ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring; Each R 23 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2; R 6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkoxy, C2-C6 acyl; Each R h Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; n3 is selected from 0, 1 or 2; s is selected from 0, 1 or 2, Alternatively, LBM is a celeblon E3 ubiquitin ligase binding moiety and has the structure of Formula I-dd: in: D is selected from -CH2-, -C(O)-; and the H atom is optionally replaced by a substituent selected from the group consisting of halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; A 1 , A 2 , A 3 , A 4 Each independently selected from C (when linked to L), CR 24 , N; Each R 24 Each is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, carbonyl, -CONH2, -SO2NH2; Each R i Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; n4 is selected from 0, 1 or 2, or LBM is the VHL E3 ubiquitin ligase binding moiety and has the structure of Formula I-ee: in: G is selected from S, O; H 1 , H 2 , H 3 , H 4 Each is independently selected from CH or N; and the H atom is optionally replaced by a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, halogenated or unhalogenated C1-C3 alkyl, halogenated or unhalogenated C1-C3 alkoxy; Z 1 , Z 2 Each is independently selected from H, halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; I 1 , I 2 , I 3 , I 4 , I 5 Each is independently selected from H, halogen, hydroxyl, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy; R 7 is selected from H, C1-C6 alkyl which is optionally substituted or unsubstituted by halogen or hydroxy or amino; R 8 , R 9 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl; the substitution refers to substitution by halogen, hydroxyl, amino, mercapto, cyano, -CONH2, -SO2NH2; R 10 Selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, -CO-(substituted or unsubstituted C1-C6 alkyl), -CO-(substituted or unsubstituted C3-C10 cycloalkyl), -SO2-(substituted or unsubstituted C1-C6 alkyl), -SO2-(substituted or unsubstituted C3-C10 cycloalkyl); the substitution refers to substitution by halogen, hydroxyl, amino, mercapto, cyano, -CONH2, -SO2NH2.

5. The compound according to claim 1 or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, characterized in that: The compound is selected from the structure shown in the following formula: Where R x , R y , T, E, L', L as defined in claim 1; R 2 Selected from hydrogen, halogen, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.

6. The compound according to claim 1 or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, wherein: The compound is selected from the structure shown in the following formula: or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal; wherein R x , R y , T, L are as defined above; R 2 is selected from hydrogen, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy; Preferably, Selected from the following structures: R x is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O-L1-R a , -NH2, -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl; the substitution refers to substitution by one or more halogen or C1-C3 alkyl; L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain; Each R a Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclyl substituted by alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted by alkyl; L is selected from the following structures:

7. The compound according to claim 1 or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, characterized in that: L is selected from the following structures:

8. The compound according to claim 1 or its deuterated form, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, wherein: The LBM is selected from the following structures:

9. The compound according to any one of claims 1 to 8, or a deuterated substance, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal thereof, characterized in that: The compound is selected from the following structures:

10. A pharmaceutical composition, characterized in that Includes the following components: 1) A compound according to any one of claims 1 to 9, or a deuterated substance, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal thereof; and 2) Pharmaceutically acceptable carriers or excipients.

11. Use of the compound of claims 1 to 9 or its deuterated product, stereoisomer, geometric isomer, tautomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of claim 10, characterized in that: Used for preparing drugs for preventing and treating IRAK4-mediated diseases; and / or used for preparing drugs for degrading IRAK4.

12. The use according to claim 11, characterized in that The disease is selected from the group consisting of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic diseases, endometriosis, sepsis, atherosclerosis, diseases associated with organ transplantation, immunodeficiency disorders, bone-destructive diseases, proliferative diseases, infectious diseases, diseases associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune diseases involving T cell activation, cardiovascular diseases, and central nervous system diseases.

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